Method for preparing phthalazinone derivatives and intermediates thereof

Abstract

The present application provides a method for preparing 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one or a pharmaceutically acceptable salt thereof, an intermediate in its preparation, a method for preparing the intermediate, and a composition and product comprising the compound obtained by the method producing high purity and high yield.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Serial No. 63 / 013,310, 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 methods for preparing phthalazinone derivatives as poly (ADP-ribose) polymerase (PARP) inhibitors, intermediates used in these preparation methods, methods for preparing said intermediates, and compositions and products including said derivatives prepared by methods that produce high purity and high yield. Background Art

[0004] Patent Document 1 (US Pat. No. 9,682,973) discloses phthalazinone derivatives having anticancer activity as poly(ADP-ribose) polymerase (PARP) inhibitors, racemates, enantiomers or diastereomers thereof, or pharmaceutically acceptable salts thereof.

[0005] The patent document discloses a method for preparing phthalazinone derivatives, and specifically in Examples 143 and 171, discloses a method for preparing 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharmaceutically acceptable salt thereof, as shown in Reaction Scheme 1 below.

[0006] [Reaction Scheme 1]

[0007]

[0008] When 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharmaceutically acceptable salt thereof is prepared according to the above-mentioned preparation method, the reaction is not completely carried out in each step, resulting in a very low total yield of the final product relative to the starting material. In addition, due to the generation of various impurities, purification by column chromatography is required. In addition, since most of the prepared intermediates exist in the liquid phase, it is difficult to achieve quantitative reaction in each step, and due to poor quality reproducibility, it is difficult to apply to large-scale (e.g., large-scale and commercial) production.

[0009] Specifically, in the synthesis of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Example 143, Step 2), the reaction was not completed even when the reaction was carried out for 24 hours or longer. Further, due to the generation of multiple related materials, an additional purification step, including column chromatography, was required to obtain a substantially pure sample, which reduced the final yield.

[0010]

Prior art documents

[0011] [Patent Documents]

[0012] (Patent Document 0001) US 9,682,973 Summary of the invention

[0013]

Technical issues

[0014] One aspect of the present invention provides a method for preparing 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharmaceutically acceptable salt thereof, wherein one or more intermediates are obtained in a solid phase and wherein reduced impurity formation avoids the need for additional purification steps, thereby increasing the overall yield in a manner suitable for large-scale (e.g., large-scale and commercial) production.

[0015] Another aspect provides one or more novel intermediates that can be used in the preparation methods described above.

[0016] Another aspect provides a process for preparing the one or more intermediates.

[0017] Also provided are compositions and products prepared by the method of the present invention, said compositions and products containing the compound of formula 1 or a pharmaceutically acceptable salt thereof.

[0018] Other objects and advantages of the present invention will become apparent from the following detailed description taken together with the accompanying drawings. 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.

[0019]

Technical solution

[0020] According to one aspect of the present invention, there is provided a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof:

[0021] [Formula 1]

[0022]

[0023] The method comprises the step (a2) of deprotecting the compound of formula 4 to prepare the compound of formula 1:

[0024] [Formula 4]

[0025]

[0026] Where X 1 It is an amine protecting group.

[0027] According to another aspect of the present invention, there is provided a method for preparing a compound of formula 4, the method comprising the step (a1) of reacting a compound of formula 2 with a compound of formula 3:

[0028] [Formula 2]

[0029]

[0030] Among them, X 1 is an amine protecting group, and HA is an acid that forms an acid addition salt; and

[0031] [Formula 3]

[0032]

[0033] According to another aspect of the present invention, there is provided a method for preparing a compound of formula 2,

[0034] [Formula 2]

[0035]

[0036] The method comprises:

[0037] The amine protecting group X 1 Introducing into the compound of formula 6 to prepare the compound of formula 7 step (b1); and

[0038] Removal of the azetidine nitrogen protecting group X from the compound of formula 7 2 In step (b2) of preparing the compound of formula 2:

[0039] [Formula 6]

[0040]

[0041] [Formula 7]

[0042]

[0043] Among them, X 1 is an amine protecting group,

[0044] X 2 is an azetidine nitrogen protecting group, and

[0045] HA is an acid that forms an acid addition salt.

[0046] According to another aspect of the present invention, there is provided a compound of formula 2:

[0047] [Formula 2]

[0048]

[0049] Among them, X 1 is an amine protecting group,

[0050] HA is an acid that forms an acid addition salt.

[0051] According to another aspect of the present invention, there is provided a compound of formula 4:

[0052] [Formula 4]

[0053]

[0054] Where X 1 It is an amine protecting group.

[0055] According to another aspect of the present invention, there is provided a compound of formula 7:

[0056] [Formula 7]

[0057]

[0058] Among them, X 1 is an amine protecting group, and

[0059] X 2 It is an azetidine nitrogen protecting group.

[0060] [Effects of the present invention]

[0061] According to one aspect of the present invention, one or more intermediates produced according to the inventive method can be obtained in solid phase, thus resulting in a more convenient separation of the intermediate. In each process, the reaction for producing the intermediate can be completed with minimal side reactions and low levels of impurities, and therefore does not need to be subjected to column chromatography, which is previously separated and purified to obtain substantially pure compounds. Due to the reduction in impurity production and the easy separation of the intermediate, the final product can be obtained with high purity and high yield. Therefore, the preparation method according to one aspect of the present invention can be prepared with higher purity and higher yield and more economically 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one or its pharmaceutically acceptable salt, and is therefore suitable for a large amount of (e.g., large-scale and commercial) production. DETAILED DESCRIPTION

[0062] Hereinafter, the present invention will be described in more detail.

[0063] Unless otherwise defined, all technical terms used in the present invention have the same meanings as those generally understood by those skilled in the art of the present invention. In addition, although preferred methods or examples are described in the specification, methods or examples similar to or equivalent thereto also fall within the scope of the present invention. In addition, the term "comprising" is intended to have the meaning of inclusion, and allows inclusion of other elements except the listed elements.

[0064] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (eg, molecular weight, reaction conditions), and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about."

[0065] As used herein, the term "compound of formula" is not intended to be limited to the formula Unless otherwise indicated, when a structure is illustrated, it is understood to encompass all possible stereoisomers and tautomers thereof.

[0066] The term "protecting group" refers to a functional group that is bonded to a functional group such as an amino group or an alcohol group by a covalent bond to protect it from unintended reactions and allows regeneration of the functional group (ie, deprotection) after treating the protecting group with an appropriate reagent.

[0067] As used herein, the term "the intermediate produced according to the method of the present invention is obtained in a solid phase" means that the intermediate is obtained in a solid form by, for example, filtration and drying or similar steps known in the art.

[0068] The term "ambient temperature" refers to a room environment temperature in the range of about 1°C to about 30°C.

[0069] The contents of all publications cited herein as references are hereby incorporated by reference into this specification in their entirety.

[0070] The explanation and embodiment disclosed in the present invention can be applied to other explanations and embodiments respectively. 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 by the specific description described herein.

[0071] One aspect of the present invention provides a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof,

[0072] [Formula 1]

[0073]

[0074] The method comprises

[0075] Step (a2) of deprotecting the compound of formula 4 to prepare the compound of formula 1:

[0076] [Formula 4]

[0077]

[0078] Where X 1 It is an amine protecting group.

[0079] The compound of formula 4 can be prepared by reacting a compound of formula 2 with a compound of formula 3 in step (a1):

[0080] [Formula 2]

[0081]

[0082] Where X 1 is an amine protecting group, and HA is an acid that forms an acid addition salt;

[0083] [Formula 3]

[0084]

[0085] Another aspect of the present invention provides a method for preparing a compound of formula 4, the method comprising the step (a1) of reacting a compound of formula 2 with a compound of formula 3:

[0086] [Formula 2]

[0087]

[0088] [Formula 3]

[0089]

[0090] in

[0091] X 1 is an amine protecting group, and

[0092] HA is an acid that forms an acid addition salt.

[0093] As indicated above, HA may be any acid that forms an acid addition salt. For example, the acid addition salt may be a hydrohalide. The hydrohalide acid may comprise hydrochloric acid (HCl), hydrobromic acid (HBr) or hydroiodic acid (HI), preferably hydrochloric acid (HCl).

[0094] In step (a1), the compound of formula 4 can be obtained through the amide bond between the compound of formula 2 and the compound of formula 3. In step (a2), the compound of formula 1 can be obtained by removing X, which is a protective group of the amine group of the compound of formula 4. 1 get.

[0095] In one embodiment, the method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be represented by Reaction Scheme 2 below.

[0096] [Reaction Scheme 2]

[0097]

[0098] The compound of formula 3 used in step (a1) can be prepared according to any method known in the art, for example, the method disclosed in WO2004 / 080976 (see part b in "Synthesis of key intermediates").

[0099] In one embodiment, the compound of formula 2 may be in the form of a hydrochloride salt, wherein HA is hydrochloric acid. 1 It may be possible to protect X in the reaction of step (a1). 1 Any amine protecting group of the amine group to which it is bonded. This amine protecting group may include, but is not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) or p-methoxybenzyl (PMB).

[0100] The step (a1) of preparing the compound of formula 4 can be carried out under any conditions that allow the formation of an amide bond between the azetidine amine of the compound of formula 2 and the carboxyl group of the compound of formula 3.

[0101] In one embodiment, step (a1) can be carried out in the presence of an amide coupling reagent. An amide coupling reagent refers to a reagent that activates the carboxyl group of a reactant during reaction with an amine to form an amide group. The amide coupling reagent may include, but is not limited to, trimethylacetyl chloride, 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), or any combination thereof.

[0102] Step (a1) may be performed in the presence of a base, for example, in the presence of at least one base selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

[0103] In one embodiment, step (a1) can be performed in the presence of both at least one amide coupling reagent and at least one base.

[0104] In one embodiment, step (a1) can be carried out in the presence of both at least one amide coupling reagent and at least one base, wherein the at least one amide coupling reagent is selected from the group consisting of pivaloyl chloride, 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and any combination thereof, and the at least one base is selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

[0105] For the reaction in step (a1), a solvent that does not inhibit the reaction can be used. For example, the solvent can be selected from acetonitrile, acetone, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide and any combination thereof. In one embodiment, the solvent can be toluene.

[0106] The reaction in step (a1) can be carried out at a temperature of about -20°C to reflux temperature, and in some embodiments, about -20°C to about 120°C, and in other embodiments, about -10°C to about 40°C.

[0107] In step (a1), the compound of formula 4 as a product of the reaction can be obtained in a solid phase. Therefore, by filtering and drying, the compound of formula 4 can be obtained in a solid form.

[0108] Step (a2) of preparing the compound of formula 1 is to remove the amine protecting group X from the compound of formula 4 1 and is used to remove the amine protecting group X 1 The reaction conditions can be varied according to the amine protecting group X 1 varies depending on the type.

[0109] In one embodiment, when X 1 When fluorenylmethoxycarbonyl (Fmoc), step (a2) of preparing the compound of formula 1 may comprise reacting the compound of formula 4 with a non-nucleophilic base. The non-nucleophilic base is not limited to a specific type and may be a base that can effectively remove the amine protecting group X. 1 Any non-nucleophilic base. For example, the non-nucleophilic base can be selected from piperidine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene and any combination thereof. In this case, the solvent used for the reaction in step (a2) can be acetonitrile, tetrahydrofuran, N,N-dimethylformamide or any combination thereof. For example, when X 1 When it is fluorenylmethoxycarbonyl (Fmoc), the non-nucleophilic base and solvent can be piperidine and acetonitrile, diisopropylethylamine and tetrahydrofuran, or 8-diazabicyclo[5,4,0]undec-7-ene and N,N-dimethylformamide, respectively.

[0110] In another embodiment, in step (a2), when X 1 When trifluoroacetyl (Tfa) is present, the compound of formula 4 may be reacted with a basic base. The basic base is not limited to a specific type and may be a base that can effectively separate the amine protecting group X. 1For example, the alkaline base may be potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate, or any combination thereof. In this case, the solvent used for the reaction in step (a2) may be a solvent in which water is added to a C1-C4 straight-chain alcohol, a C1-C4 branched-chain alcohol, or any combination thereof. For example, when X 1 In the case of trifluoroacetyl (Tfa), the alkaline base and the solvent may be potassium hydroxide and isopropanol / water, potassium carbonate and methanol / water, sodium hydroxide and methanol / water or sodium carbonate and ethanol / water, respectively.

[0111] In yet another embodiment, in step (a2), when X 1 When X is p-methoxybenzyl (PMB), the compound of formula 4 can react with an acid. The acid is not limited to a particular type and can be any acid that can effectively remove the amine protecting group. For example, trifluoroacetic acid can be used as a reagent and solvent. In this case, in the reaction of step (2), the ratio (w / v) of the weight of the compound of formula 4 to the volume of trifluoroacetic acid can be about 1:5 to about 1:40. For example, when X 1 When it is p-methoxybenzyl (PMB), the ratio (w / v) of the compound of formula 4 to trifluoroacetic acid used in the reaction of step (a2) may be about 1:10.

[0112] In step (a2), the compound of formula 1 as a product of the reaction can be obtained in a solid phase. Therefore, by filtering and drying, the compound of formula 1 can be obtained in a solid form.

[0113] The step (a3) ​​of preparing the acid addition salt of the compound of formula 1 by reacting the compound of formula 1 with an acid can be further performed to prepare a pharmaceutically acceptable salt of the compound of formula 1. Those skilled in the art can use a suitable method to prepare the acid addition salt of the compound of formula 1 based on the common sense in the field of organic chemistry. The acid addition salt of the compound of formula 1 can be any pharmaceutically acceptable acid addition salt, such as an acid addition salt formed by a free acid. The free acid can be an inorganic acid or an organic acid. The inorganic acid can be hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. The organic acid can be, but is not limited to, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, adipic acid, L- or D- tartaric acid, DL- tartaric acid, citric acid, lactic acid, benzoic acid, mandelic acid, salicylic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glycolic acid, pyruvic acid, glucuronic acid, glutamic acid, aspartic acid or any combination thereof.

[0114] In one embodiment, the acid addition salt can be an inorganic acid addition salt, and in one embodiment, a hydrochloric acid addition salt. The reaction in step (a) of preparing the acid addition salt of the compound of Formula 1 can be carried out in any solvent that does not inhibit the formation of the acid addition salt. For example, the solvent can be selected from alcohols, ketones, ethers, acetates, dichloromethane, chloroform, and any combination thereof, and in some embodiments, can be C1-C5 alcohols, C3-C 10 Ketone, C2-C 10 ether, C2-C4 alkyl acetate, dichloromethane, chloroform or any combination thereof.

[0115] The reaction in step (a3) ​​can be carried out at a temperature ranging from about -20°C to reflux temperature, and in some embodiments, at a temperature ranging from about -20°C to about 50°C, and in other embodiments, at a temperature ranging from about -10°C to about 30°C.

[0116] In one embodiment, the hydrochloride of the compound of Formula 1 can be prepared by adding anhydrous hydrochloric acid or concentrated hydrochloric acid to the compound represented by Formula 1 at a temperature in the range of about -20°C to reflux temperature, using an alcohol, a mixture of an alcohol and a ketone, a mixture of an alcohol and dichloromethane, a mixture of an alcohol and chloroform, a mixture of an alcohol and an ether, or a mixture of an alcohol and an acetate as a solvent. For example, the alcohol, the ketone, the ether, and the acetate can be C1-C5 alcohol, C3-C 10 Ketone, C2-C 10 Ethers and C2-C4 alkyl acetates.

[0117] In one embodiment, the hydrochloride of the compound of Formula 1 can be prepared by adding anhydrous hydrochloric acid or concentrated hydrochloric acid to the compound represented by Formula 1 at a temperature in the range of about -20°C to the reflux temperature or lower, using an alcohol, a mixture of an alcohol and a ketone, a mixture of an alcohol and dichloromethane, a mixture of an alcohol and chloroform, or a mixture of an alcohol and an ether as a solvent, and then filtering and drying the solid thus formed. For example, the alcohol, the ketone, and the ether can be C1-C5 alcohol, C3-C 10 Ketones and C2-C 10 ether.

[0118] In step (a3), the acid addition salt of the compound of formula 1 as a product of the reaction can be obtained in a solid phase. Therefore, by filtering and drying, the acid addition salt of the compound of formula 1 can be obtained in a solid form.

[0119] In another aspect, there is provided a method for preparing a compound of formula 2 as represented above,

[0120] The method comprises:

[0121] By adding the amine protecting group X 1Introducing into the compound of formula 6 to prepare the compound of formula 7 step (b1); and

[0122] By removing the azetidine nitrogen protecting group X from the compound of formula 7 2 To prepare the step (b2) of the compound of formula 2:

[0123] [Formula 6]

[0124]

[0125] [Formula 7]

[0126]

[0127] Among them, in the above formula, X 1 is an amine protecting group, and X 2 It is an azetidine nitrogen protecting group.

[0128] In one embodiment, the compound of Formula 2 may be an acid addition salt, wherein HA in Formula 2 is hydrochloric acid.

[0129] In the presence of an amine protecting group X 1 Introduced into the compound of formula 6 to prepare the compound of formula 7 in the reaction of step (b1), when the compound of formula 2 is prepared from the compound of formula 7, that is, in the reaction of step (b2), the amine protecting group X 1 The secondary amine groups that are not part of the nitrogen of the azetidine ring of the compound of formula 7 can be protected. 2 In the acid addition salt compound of formula 2, the amine protecting group X 1 It can be any protecting group capable of protecting a secondary amine group not contained in the azetidine ring. For example, an amine protecting group X 1 It may be fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) or p-methoxybenzyl (PMB).

[0130] In the reaction of step (b1), the amine protecting group X 1 The reagent introduced into the compound of formula 6 can be selected according to the amine protecting group X 1 For example, the reaction of step (b1) can be carried out by reacting the compound of formula 6 with a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic anhydride, 4-methoxybenzyl chloride and any combination thereof.

[0131] The reaction of step (b1) can be carried out in the presence of a base. The base can be any base as long as it does not inhibit the amine protecting group X 1The reaction is introduced into the compound of formula 6. For example, the base can be a tertiary amine. For example, the tertiary amine can be selected from diisopropylethylamine, triethylamine, N-methylmorpholine and any combination thereof.

[0132] In one embodiment, the reaction of step (b) can be carried out in the presence of an amine protecting group X 1 For example, the reaction of step (b) can be carried out in the presence of both a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic anhydride, 4-methoxybenzyl chloride and any combination thereof, and a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine and any combination thereof.

[0133] The solvent used in the reaction of step (b) is not limited to a specific type as long as it does not inhibit the reaction. For example, the solvent may be selected from acetonitrile, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, and any combination thereof.

[0134] The reaction of step (b1) can be carried out at a temperature ranging from about -20°C to reflux temperature or lower, and in some embodiments, at a temperature ranging from about -20°C to about 120°C, and in other embodiments, at a temperature ranging from about -10°C to about 80°C.

[0135] The reaction of step (b2) for preparing the compound of formula 2 carried out after the reaction of step (b1) may comprise removing the azetidine nitrogen protecting group X from the compound of formula 7. 2 The process of replacing the protecting group with hydrogen instead. Azetidine nitrogen protecting group X 2 can be any protecting group that can be removed, leaving behind the amine protecting group X 1 is not removed and replaced by hydrogen. For example, the azetidine nitrogen protecting group X 2 Can be selected from the group consisting of: butoxycarbonyl (Boc), triphenylmethyl (Trt) and tetrahydropyranyl (THP). In one embodiment, the azetidine nitrogen protecting group X 2 It is butoxycarbonyl (Boc).

[0136] The process of replacing with hydrogen in step (b2) may be performed at a temperature of about -20°C to reflux temperature, and in some embodiments, at a temperature ranging from about 0°C to about 90°C.

[0137] For example, the substitution with hydrogen in the reaction of step (b2) can be carried out by reacting the compound of formula 7 with an acid, thereby removing the azetidine nitrogen protecting group X from the compound of formula 7. 2 , and replace the protecting group with hydrogen. The acid is not limited to a specific type, and can be an acid that can effectively remove the azetidine nitrogen protecting group X2 Any acid that forms an acid addition salt of Formula 2. For example, the acid can be a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid. In one embodiment, the acid can be anhydrous hydrochloric acid or concentrated hydrochloric acid.

[0138] The solvent used in the process of replacing with hydrogen in the reaction of step (b2) can be any solvent that does not inhibit the corresponding reaction. 2 When it is butoxycarbonyl (Boc), the solvent may be selected from acetone, ethyl acetate, C1-C4 straight or branched alcohol and any combination thereof.

[0139] In one embodiment, when X 2 In the case of butoxycarbonyl (Boc), the acid and solvent used in the reaction of step (b2) may be hydrochloric acid and acetone, or hydrochloric acid and ethyl acetate, or hydrochloric acid and isopropanol, or hydrochloric acid and ethanol, or hydrochloric acid and methanol, respectively.

[0140] In the reaction of step (b2), X is removed from the compound of formula 7 by adding an acid to a solvent and replacing it with hydrogen. 2 Afterwards, the acid addition salt of Formula 2 can be prepared by evaporation without post-treatment or by precipitation by adding a suitable solvent. The suitable solvent added to precipitate the acid addition salt can be selected from ethyl acetate, acetone, n-hexane, isopropanol and any combination thereof, but is not limited thereto. Taking into account the conditions required for the solvent in the corresponding reaction, those of ordinary skill in the art can select any suitable solvent.

[0141] In one embodiment, the hydrochloride salt of the acid addition salt of the compound of Formula 2 can be prepared by adding concentrated hydrochloric acid to the compound of Formula 7 in methanol and allowing the reaction to occur, concentrating the reaction product under reduced pressure, and then reflux by adding ethyl acetate, stirring at ambient temperature, and then filtering and drying.

[0142] The compound of formula 6 can be prepared by step (b0) of the reductive amination reaction of the compound represented by formula 5:

[0143] [Formula 5]

[0144]

[0145] Among them, in formula 5, X 2 It is an azetidine nitrogen protecting group.

[0146] In the reaction of step (b0), the reductive amination reaction of the compound of formula 5 can be carried out by those of ordinary skill in the art based on common sense known in the art. In one embodiment, in the reaction of step (b0), by using trifluoroethanol as a solvent and sodium borohydride to carry out reductive amination in the absence of a catalyst or additive, a compound of formula 6 can be prepared in high yield (see Synthesis 2011, Issue 3, Pages 490-496).

[0147] In one embodiment, the method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof can be represented by Reaction Scheme 3 below.

[0148] [Reaction Scheme 3]

[0149]

[0150] According to an exemplary preparation method of the present invention, for example, as represented by Reaction Scheme 3, 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharmaceutically acceptable salt thereof can be prepared with higher purity and higher yield. In one embodiment, the yield can be about 3 to 10 times, preferably 5 to 8 times, higher than the yield obtained in the known method disclosed, for example, in US 9,682,973. In another embodiment, the final product obtained in the method of the present invention can have a purity of at least 90%, preferably at least 95%, more preferably at least 97%, and most preferably at least 99% (including 99.5% or 99.9%) when identified by percentage area of ​​HPLC.

[0151] In the method for preparing formula 1 compound or its pharmaceutically acceptable salt, according to one aspect of the present invention, one or more intermediates (for example, formula 2 or 4 compounds) produced according to the inventive method can be obtained with solid phase, thus resulting in a more convenient separation of the intermediate. In each process, the reaction for producing the intermediate is completed, and the production of related materials is seldom, and therefore it is not necessary to carry out column chromatography, which was previously required for separation and purification. Due to the reduction produced by related materials and the easy separation of intermediates, the final product can be obtained in high yield. In addition, since it is possible to avoid the column chromatography as a method that is not suitable for a large amount of (for example, large-scale and commercial) production, and quality reproducibility can be improved, and therefore the method can be advantageously applied to mass production.

[0152] In another aspect, a compound of formula 2 is provided:

[0153] [Formula 2]

[0154]

[0155] Among them, in formula 2, X 1 is an amine protecting group, and HA is an acid that forms an acid addition salt.

[0156] The amine protecting group X 1 The group may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.

[0157] HA may be any acid that forms an acid addition salt. For example, HA may be a hydrohalic acid. The hydrohalic acid may be hydrochloric acid, hydrobromic acid or hydroiodic acid, and may be, for example, hydrochloric acid.

[0158] As described above, the compound of formula 2 is a novel intermediate compound in a solid phase, which is not used in the existing method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof. When the compound of formula 2 is used as an intermediate, all products of subsequent steps, including the intermediate, can be obtained in a solid phase. The purification step can then be minimized, which results in a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof with high yield and high purity. Therefore, the compound of formula 1 or a pharmaceutically acceptable salt thereof can be produced in large quantities (e.g., large-scale and commercial) with high yield and high purity.

[0159] In one embodiment, the compound of formula 2 can be selected from the group consisting of the following compounds:

[0160] (9H-fluoren-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride of formula 2a,

[0161] [Formula 2a]

[0162]

[0163] N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride of formula 2b,

[0164] [Formula 2b]

[0165] as well as

[0166] N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropylamine hydrochloride of formula 2c,

[0167] [Formula 2c]

[0168]

[0169] In another aspect, a compound of formula 4 is provided:

[0170] [Formula 4]

[0171]

[0172] Where X 1 It is an amine protecting group.

[0173] The amine protecting group X 1 The group may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.

[0174] As described above, the compound of formula 4 is a novel intermediate compound in a solid phase, which is not used in the existing method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof. When the compound of formula 4 is used as an intermediate, the compound of formula 1 can be obtained in a solid phase. The purification step can then be minimized, which results in a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof in high yield and high purity. Therefore, the compound of formula 1 or a pharmaceutically acceptable salt thereof can be produced based on a large amount (e.g., large-scale and commercial) production with high yield and high purity.

[0175] In one embodiment, the compound of formula 4 can be selected from the group consisting of the following compounds:

[0176] (9H-fluoren-9-yl)methyl cyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate of formula 4a,

[0177] [Formula 4a]

[0178]

[0179] N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide of formula 4b,

[0180] [Formula 4b]

[0181] as well as

[0182] 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carbonyl]-4-fluorobenzyl)phthalazin-1(2H)-one of formula 4c,

[0183] [Formula 4c]

[0184]

[0185] In another aspect, a compound of formula 7 is provided:

[0186] [Formula 7]

[0187]

[0188] Where X 1 is an amine protecting group, and

[0189] X 2 It is an azetidine nitrogen protecting group.

[0190] The amine protecting group X 1 The group may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.

[0191] Azetidine Nitrogen Protecting Group X 2 Can be selected from the group consisting of: butoxycarbonyl (Boc), triphenylmethyl (Trt) and tetrahydropyranyl (THP). In one embodiment, the azetidine nitrogen protecting group X 2 It may be butoxycarbonyl (Boc).

[0192] As described above, the compound of Formula 7 is a novel intermediate compound that is not used in the existing method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0193] In one embodiment, the compound of formula 7 can be selected from the group consisting of the following compounds:

[0194] tert-butyl 3-([([(9H-fluoren-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate of formula 7a,

[0195] [Formula 7a]

[0196]

[0197] tert-butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate of formula 7b,

[0198] [Formula 7b]

[0199] as well as

[0200] tert-butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carboxylate of formula 7c,

[0201] [Formula 7c]

[0202]

[0203] In another aspect of the invention, the method of the invention is used to prepare a drug substance, a pharmaceutical composition or a medicament comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof. When the compound of formula 1 or a pharmaceutically acceptable salt thereof is used as a drug substance, the intermediate compound described herein may be present as an impurity. When present as an impurity, the amount of each of the compounds of formulae 2 to 7 may be controlled to be present in trace amounts, for example, not more than about 1.0% or less, about 0.5% or less, about 0.2% or less, about 0.1% or less of the drug substance, or not present at all.

[0204] Therefore, on the one hand, the substantially pure form of the compound of formula 1 prepared by the method of the present invention is provided as a drug substance in the preparation of a pharmaceutical composition or a drug. In one embodiment, the present invention encompasses a pharmaceutical composition comprising a substantially pure drug substance, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof is present in the drug substance in an amount greater than about 90%, about 95%, about 97%, about 99%, about 99.5% or about 99.9%. The purity percentage can be determined using methods well known in the art. For example, under suitable chromatography (e.g., HPLC) detection conditions, the purity percentage can be determined by reference to the percentage of the peak area measured to the sum of the peak areas of all peaks.

[0205] Therefore, in one aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the compound is prepared by the method of the present invention (e.g., one or more intermediates described herein and Reaction Scheme 1 and Reaction Scheme 2). The pharmaceutical composition of the present invention can be administered to a patient to treat cancer, including cancers that are sensitive to PARP inhibitors. Such formulations may include binders, fillers, disintegrants, lubricants, colorants and preservatives, as well as other pharmaceutically acceptable excipients.

[0206] In another non-limiting embodiment, the present invention provides a product comprising a compound of formula 1,

[0207] [Formula 1]

[0208]

[0209] or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 or the pharmaceutically acceptable salt thereof is produced by the method of the present invention as described above, such as shown in Reaction Scheme 2 and Reaction Scheme 3.

[0210] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are for illustrative purposes only, and the present invention is not intended to be limited to these examples.

[0211] Example 1:

[0212] Preparation of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate (Formula 6a)

[0213]

[0214] 1.0kg 3-formylazetidine-1-carboxylic acid tert-butyl ester is added to the reactor, and 6.5kg trifluoroethanol is added thereto. 0.3kg cyclopropylamine is added at 0°C, stirred at ambient temperature for 1 hour, and the reactor is then cooled to 0°C. 0.2kg sodium borohydride is slowly added, and stirred at ambient temperature for 1 hour, and the reactor is then cooled to 0°C. After 10.0kg water is slowly added thereto, the reaction mixture is extracted with 6.7kg dichloromethane, and the water layer thus obtained is further extracted with 6.7kg dichloromethane. The organic layer is washed with 15% sodium chloride aqueous solution, treated with 0.5kg anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to produce 0.98kg of compound 6a (yield: 80.1%) in the form of yellow oil. In the absence of a separate purification process, compound 6a is used in subsequent processes.

[0215] 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)

[0216] Example 2:

[0217] tert-Butyl 3-([([(9H-fluoren-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate (Formula 7a: X 1 =Fmoc)

[0218]

[0219] 4.0kg of dichloromethane is added to the reactor, to which 300.0g of 3-[(cyclopropylamino)methyl]azetidine-1-carboxylic acid tert-butyl ester prepared in Example 1 and 188.4g of diisopropylethylamine are sequentially added, 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 compound 7a in the form of yellow oil. In the absence of a separate purification process, compound 7a is used in subsequent processes.

[0220] 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)

[0221] Example 3:

[0222] 3-[(Cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylic acid tert-butyl ester (Formula 7b: X 1 Preparation of =Tfa)

[0223]

[0224] 2.7kg of dichloromethane is added to the reactor, and 200.0g of 3-[(cyclopropylamino)methyl]azetidine-1-carboxylic acid tert-butyl ester prepared in Example 1 is added thereto. 107.3g of triethylamine is added thereto, and the reactor is then cooled to 0°C. 222.7g of trifluoroacetic anhydride 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. 2.0kg of water is added thereto to wash the organic layer, and the organic layer is further washed with 2.0kg of 1N hydrochloric acid aqueous solution. The organic layer is further washed with 7% sodium chloride aqueous solution, treated with 100.0g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to thereby quantitatively produce 284.8g of compound 7b in the form of white solid and yellow oil. In the absence of a separate purification process, compound 7b is used in subsequent processes.

[0225] 1 H NMR(CDCl3,400MHz)δ3.99(t,2H),3.60-3.57(m,2H),2.90(d,2H),2.68-2.60 (m,1H),2.10-2.06(m,1H),1.44(s,9H),0.46-0.41(m,2H),0.32-0.28(m,2H)

[0226] Example 4:

[0227] tert-Butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carboxylate (Formula 7c: X 1 Preparation of =PMB

[0228]

[0229] 1.4 kg of acetonitrile was added to the reactor, to which 226.3 g of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate prepared in Example 1 and 111.3 g of triethylamine were added in sequence, and the reactor was then cooled to 0 ° C. 156.6 g of 4-methoxybenzyl chloride was slowly added thereto and stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure, and 2.0 kg of water and 1.8 kg of ethyl acetate (EA) were added thereto to separate the organic layer. The organic layer was further washed with 2.0 kg of 0.5 N aqueous hydrochloric acid.

[0230] The organic layer was further washed with a 7% sodium chloride aqueous solution, treated with 100.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to thereby obtain 285.8 g of Compound 7c as a yellow oil (yield: 82.5%). Compound 7c was used in the subsequent process without a separate purification process.

[0231] 1 H NMR(CDCl3,400MHz)δ7.17-7.13(m,2H),6.85-6.82(m,2H),3.88(t,2H),3.80(s,3H),3.65(s,2H),3.47-3.43 (m,2H),2.78-2.72(m,1H),2.66(d,2H),1.72-1.67(m,1H),1.41(s,9H),0.51-0.47(m,2H),0.37-0.34(m,2H)

[0232] Example 5:

[0233] (9H-fluoren-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride (Formula 2a: X 1 =Fmoc, HA = HCl)

[0234]

[0235] 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 Example 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 compound 2a (yield: 91.2%).

[0236] 1 H 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)

[0237] Example 6:

[0238] N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride (Formula 2b: X 1 =Tfa, HA=HCl)

[0239]

[0240] 650 mL of methanol was added to the reactor, to which 64.5 g of tert-butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate prepared in Example 3 and 22.0 mL of concentrated hydrochloric acid were added in sequence, and the resulting mixture was then heated. The reaction was carried out at reflux temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. 50 mL of isopropanol and 600 mL of ethyl acetate were added to the residue, stirred overnight at ambient temperature, filtered, and then dried at 40 ° C to thereby produce 44.7 g of compound 2b (yield: 86.3%).

[0241] 1 H NMR(DMSO-d6,400MHz)δ9.39(br,2H),3.98-3.93(m,2H),3.77-3.72(m,2H),3.67(d,2H),3.09-3.01(m,1H),2.96-2.90(m,1H),0.88-0.86(m,4H)

[0242] Example 7:

[0243] N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropylamine hydrochloride (Formula 2c: X 1 =PMB, HA = HCl)

[0244]

[0245] 520 mL of isopropanol was added to the reactor, to which 52.0 g of tert-butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carboxylate prepared in Example 4 and 19.0 mL of concentrated hydrochloric acid were added in sequence, and the resulting mixture was then heated. The reaction was carried out at reflux temperature for 6 hours, and then the reaction mixture was concentrated under reduced pressure. 85 mL of isopropanol and 210 mL of n-hexane were added to the residue, stirred overnight at ambient temperature, filtered, and then dried under vacuum to thereby produce 34.0 g of compound 2c (yield: 80.1%).

[0246] 1 H NMR(CDCl3,400MHz)δ9.29-9.18(m,2H),7.54(m,2H),6.89-6.88(m,2H),4.41(m,3H),4.24(m,2H),3.92 (m,2H),3.77(m,3H),3.68(m,2H),2.58(m,1H),1.40-1.36(m,1H),1.00(m,1H),0.91(m,1H),0.71(m,1H)

[0247] Example 8:

[0248] Cyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate (9H-fluoren-9-yl)methyl

[0249] (Formula 4a: X 1 =Fmoc)

[0250]

[0251] 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)carbamate hydrochloride prepared in Example 5 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. 70 mL of ethyl acetate and 350 mL of n-hexane were added to the residue, stirred overnight at ambient temperature, filtered, and then dried at 50° C., to thereby produce 63.2 g of Compound 4a (yield: 91.3%).

[0252] 1 H 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)

[0253] Example 9:

[0254] N-Cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide

[0255] (Formula 4b: X 1 Preparation of =Tfa)

[0256]

[0257] 300mL of dichloromethane was added to the reactor, and 29.8g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid and then 17.9g of 1,1'-carbonyldiimidazole were added thereto in sequence. The reaction was carried out at ambient temperature for 1 hour, the reactor was cooled to 15°C, and then 28.5g of N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride prepared in Example 6 was slowly added thereto, and then 19.4g of triethylamine was added. Afterwards, the reaction mixture was stirred at ambient temperature for 1 hour, 300mL of water was added 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 washed with 5% aqueous sodium chloride solution, treated with 10.0g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 400 mL of methanol was added to the residue, stirred at 0°C for 2 hours, filtered, and then dried at 50°C, to thereby produce 44.7 g of Compound 4b (yield: 89.1%).

[0258] 1 H NMR(DMSO-d6,400MHz)δ12.62(s,1H),8.27-8.25(m,1H),7.97(d,1H),7.90-7.86(m,1H),7.83-7.79(m,1H),7.48-7.46(m,2H) ,7.24-7.19(m,1H),4.33(s,2H),4.14-4.02(m,2H),3.79-3.62(m,4H),3.01-2.91(m,1H),2.88-2.85(m,1H),0.87-0.68(m,4H)

[0259] Example 10:

[0260] 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carbonyl]-4-fluorobenzyl)phthalazin-1(2H)-one (Formula 4c: X 1 Preparation of =PMB

[0261]

[0262] 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. 31.1g of N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropylamine hydrochloride prepared in Example 7 was then added thereto, and 19.4g of triethylamine was then 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 the organic layer was then washed with 1N aqueous hydrochloric acid solution and 1N aqueous sodium carbonate solution. The organic layer was washed with 5% aqueous sodium chloride solution, treated with 10.0g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 300 mL of toluene was added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 50° C., to thereby produce 47.0 g of Compound 4c (yield: 81.2%).

[0263] 1 H NMR(DMSO-d6,400MHz)δ12.61(s,1H),8.26(d,1H),7.98(d,1H),7.92-7.87(m,1H),7.84-7. 80(m,1H),7.52-7.48(m,2H),7.43-7.42(m,1H),7.26-7.12(m,2H),6.97(d,2H),4.32(m,2H) ,4.26(m,2H),4.18-4.09(m,2H),3.90-3.82(m,2H),3.77(s,3H),3.36(m,1H),3.32(m,2H),2 .55-2.50(m,1H),1.19-1.13(m,1H),0.86-0.85(m,1H),0.80-0.75(m,1H),0.69-0.68(m,1H)

[0264] Example 11:

[0265] Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1) (1)

[0266]

[0267] 150 mL of acetonitrile was added to the reactor, and 30.0 g of cyclopropyl ([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamic acid (9H-fluorene-9-yl)methyl ester and 34.5 g of piperidine prepared in Example 8 were added 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. The filtrate was then 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. 80 mL of methanol and 40 mL of dichloromethane were added to the residue, 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 produce 17.5 g of Compound 1 (yield: 90.1%).

[0268] 1 H 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)

[0269] Example 12:

[0270] Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1) (2)

[0271]

[0272] To the reactor were added 300 mL of methanol, 30.0 g of N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide prepared in Example 9, and then the reactor was cooled to 0°C. 60 mL of a 20% aqueous potassium carbonate solution was slowly added to the reactor so that the internal temperature of the reactor did not exceed 20°C, and the reaction mixture was stirred overnight at ambient temperature. 240 mL of water and 300 mL of dichloromethane were added thereto 300 mL to extract the aqueous layer, and then the aqueous layer was further extracted with 300 mL of dichloromethane. Then, the organic layer was mixed therewith, washed with a 5% aqueous sodium chloride solution, and then concentrated. 100 mL of methanol and 50 mL of dichloromethane were added to the residue, and then 200 mL of acetone was slowly added thereto. The obtained solid was stirred at ambient temperature overnight, filtered, and dried at 40°C to thereby produce 22.4 g of Compound 1 (yield: 92.1%).

[0273] 1 H NMR(DMSO-d6,400MHz)δ12.59(s,1H),8.27-8.25(m,1H),7.97(d,1H),7.91–7.87(m,1H),7.84-7.80(m,1H),7.46–7.42(m,2 H),7.22–7.18(m,1H),4.32(s,2H),4.04–3.55(m,4H),2.74–2.63(m,3H),2.30(br,1H),2.02–1.97(m,1H),0.34–0.14(m,4H)

[0274] Example 13:

[0275] Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1) (3)

[0276]

[0277] 100 mL of trifluoroacetic acid was added to the reactor, and 10.0 g of 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carbonyl]-4-fluorobenzyl)phthalazin-1(2H)-one prepared in Example 10 was added thereto, and stirred at 60° C. for 1 hour. The reactor was then cooled to 0° C., 100 mL of dichloromethane 100 mL was added thereto, and then 100 mL of water was slowly added thereto. The aqueous layer was further washed with 100 mL of dichloromethane, adjusted to pH 9 or higher with a 1N sodium hydroxide aqueous solution, and then extracted with 100 mL of dichloromethane. The aqueous layer was further extracted with 100 mL of dichloromethane, and the organic layer was mixed therewith, washed with a 5% sodium chloride aqueous solution, and then concentrated. 60 mL of methanol and 30 mL of dichloromethane were added to the residue, and 120 mL of acetone was slowly added thereto. The obtained solid was stirred at ambient temperature overnight, filtered, and dried at 40°C to thereby produce 13.4 g of Compound 1 (yield: 86.9%).

[0278] 1 H NMR(DMSO-d6,400MHz)δ12.59(s,1H),8.27-8.25(m,1H),7.98(d,1H),7.91–7.87(m,1H),7.85-7.80(m,1H),7.46–7.42(m,2 H),7.23–7.18(m,1H),4.32(s,2H),4.04–3.55(m,4H),2.74–2.63(m,3H),2.30(br,1H),2.02–1.97(m,1H),0.34–0.14(m,4H)

[0279] Example 14:

[0280] Preparation of the hydrochloride salt of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1a) (1)

[0281]

[0282] 40 mL of methanol and 100 mL of acetone were added to the reactor, 10.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one prepared in Example 11 was added thereto, and then the reactor was cooled to 0° C. 2.4 g of concentrated hydrochloric acid was slowly added thereto over 30 minutes, stirred overnight at ambient temperature, filtered, and dried at 40° C. to thereby produce 10.4 g of Compound 1a (yield: 95.7% and HPLC purity: 99.86% [area %]).

[0283] 1 H NMR(DMSO-d6,400MHz)δ12.61(s,1H),9.37(br,2H),8.27-8.25(m,1H),7.98(d1H),7.93-7.88(m,1H),7.85-7.81(m,1H),7.49-7.45( m,2H),7.25-7.20(m,1H),4.33(s,2H),4.13-3.82(m,4H),3.31–3.22(m,2H),3.07–3.00(m,1H),2.65–2.60(m,1H),0.91-0.67(m,4H)

[0284] Example 15:

[0285] Preparation of the hydrochloride salt of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1a) (2)

[0286]

[0287] 40 mL of ethanol and 60 mL of ethyl acetate were added to the reactor, 10.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one prepared in Example 12 was added thereto, and then the reactor was cooled to 0° C. 2.4 g of concentrated hydrochloric acid was slowly added thereto over 30 minutes, stirred overnight at ambient temperature, filtered, and dried at 40° C. to give 10.4 g of Compound 1a (yield: 92.1% and HPLC purity: 99.86% [area %]).

[0288] 1H NMR(DMSO-d6,400MHz)δ12.60(s,1H),9.19(br,2H),8.27-8.25(m,1H),7.98(d,1H),7.93 -7.89(m,1H),7.85-7.81(m,1H),7.50-7.44(m,2H),7.25-7.20(m,1H),4.33(s,2H),4.13 -3.81(m,4H),3.30-3.22(m,2H),3.05-2.98(m,1H),2.65-2.61(m,1H),0.88-0.68(m,4H)

[0289] Example 16:

[0290] Preparation of the hydrochloride salt of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1a) (3)

[0291]

[0292] 50 mL of ethanol and 100 mL of tert-butyl methyl ether were added to the reactor, 10.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one prepared in Example 13 was added thereto, and then the reactor was cooled to 0° C. 2.4 g of concentrated hydrochloric acid was slowly added thereto over 30 minutes, stirred overnight at ambient temperature, filtered, and dried at 40° C. to give 10.6 g of Compound 1a (yield: 97.2% and HPLC purity: 99.80% [area %]).

[0293] 1 H NMR(DMSO-d6,400MHz)δ12.60(s,1H),9.23(br,2H),8.27-8.25(m,1H),7.98(d,1H),7.93 -7.89(m,1H),7.85-7.81(m,1H),7.50-7.44(m,2H),7.25-7.20(m,1H),4.33(s,2H),4.13 -3.81(m,4H),3.28-3.22(m,2H),3.08-2.97(m,1H),2.66-2.62(m,1H),0.89-0.68(m,4H)

[0294] The described embodiments are considered to be merely illustrative and non-restrictive in all respects. Those of ordinary skill in the art will recognize that the present invention may be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention. Therefore, the scope of the present invention is indicated by the appended claims rather than by the foregoing description. All changes falling within the equivalent meaning and scope of the claims should be included within the scope of the present invention.

Claims

1. A method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, [Formula 1] The method comprises: Prepare the compound of formula 4, [Formula 4] Where X 1 is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB), Wherein the compound of formula 4 is prepared by reacting the compound of formula 2 with the compound of formula 3 [Formula 2] Where X 1 is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB), and HA is an acid forming an acid addition salt [Formula 3] wherein the preparation of the compound of formula 4 is carried out in the presence of at least one amide coupling reagent and at least one base, wherein the at least one amide coupling reagent is selected from the group consisting of: 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and any combination thereof, and wherein the at least one base is triethylamine; and The compound of formula 4 is deprotected.

2. The method according to claim 1, wherein HA is hydrochloric acid, hydrobromic acid or hydroiodic acid.

3. The method according to any one of claims 1 to 2, wherein X 1 is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyl (PMB).

4. The method according to any one of claims 1 to 2, comprising reacting the compound of formula 4 with a non-nucleophilic base, wherein X in formula 4 1 It is fluorenylmethoxycarbonyl (Fmoc).

5. The method according to any one of claims 1 to 2, comprising reacting the compound of formula 4 with a basic base, wherein X in formula 4 1 It is trifluoroacetyl (Tfa).

6. The method according to any one of claims 1 to 2, comprising reacting the compound of formula 4 with an acid, wherein X in formula 4 1 It is p-methoxybenzyl (PMB).

7. The method according to any one of claims 1 to 2, further comprising reacting the compound of Formula 1 with an acid to prepare a pharmaceutically acceptable acid addition salt of the compound of Formula 1.

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