HK40089418B - Process for preparing a phthalazinone derivative and intermediates thereof - Google Patents

Description

Methods for preparing phthalazinone derivatives and their intermediates

Cross-references to related applications

This application claims priority to U.S. Serial No. 63/013,310, filed April 21, 2020, the contents of which are incorporated herein by reference in their entirety.

Technical Field

This 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 comprising said derivatives prepared by methods producing high purity and high yield.

Background Technology

Patent document 1 (US 9,682,973) discloses phthalazinone derivatives with anticancer activity as poly(ADP-ribose) polymerase (PARP) inhibitors, their racemic, enantiomers or diastereomers or pharmaceutically acceptable salts thereof.

The patent documents disclose methods for preparing phthalazinone derivatives, and specifically in Examples 143 and 171, methods for preparing 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharmaceutically acceptable salt thereof are disclosed, as shown in reaction scheme 1 below.

[Reaction Scheme 1]

When preparing 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one or a pharmaceutically acceptable salt thereof according to the above preparation method, the reaction is not completed in each step, resulting in a very low overall yield of the final product relative to the starting material. Furthermore, purification by column chromatography is required due to the generation of various impurities. Additionally, quantitative reaction is difficult to achieve in each step because most of the prepared intermediates are present in the liquid phase, and the poor quality reproducibility makes it difficult to apply to large-scale (e.g., large-scale and commercial) production.

Specifically, in the synthesis of 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one (Example 143, step 2), the reaction did not complete even when it proceeded for 24 hours or longer. Furthermore, due to the generation of various related materials, additional purification steps, including column chromatography, were required to obtain a substantially pure sample, which reduced the final yield.

[Existing Technical Documents]

[Patent Documents]

(Patent Document 0001) US 9,682,973

Summary of the Invention

[Technical Issues]

One aspect of the invention provides a method for preparing 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one or a pharmaceutically acceptable salt thereof, wherein one or more intermediates are obtained in a solid phase, and wherein the reduction in 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.

On the other hand, one or more novel intermediates are provided that can be used in the preparation methods described above.

On the other hand, a method for preparing the one or more intermediates is provided.

Compositions and products prepared by the method of the present invention are also provided, the compositions and products containing a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Other objects and advantages of the invention will become apparent from the following detailed description, together with the accompanying drawings. Contents not described herein can be fully recognized and inferred by those skilled in the art or similar art, and therefore their description is omitted.

[Technical Solution]

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

[Formula 1]

The method includes step (a2) of deprotecting the compound of formula 4 to prepare the compound of formula 1:

[Formula 4]

^X1 is an amine protecting group.

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

[Equation 2]

Where ^X1 is an amine protecting group, and HA is an acid that forms an acid addition salt; and

[Formula 3]

According to another aspect of the present invention, a method for preparing compound of formula 2 is provided.

[Equation 2]

The method includes:

Step (b1) of introducing an amine protecting group ^X1 into the compound of formula 6 to prepare the compound of formula 7; and

Step (b2) to prepare compound 2 by removing the nitrogen protecting group ^X2 of the nitrogen heterocyclic butane from compound 7:

[Formula 6]

[Formula 7]

Where ^X1 is an amine protecting group,

^X2 is a nitrogen-protecting group of azahexacyclic butane, and

HA is an acid that forms an acid addition salt.

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

[Equation 2]

Where ^X1 is an amine protecting group,

HA is an acid that forms an acid addition salt.

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

[Formula 4]

^X1 is an amine protecting group.

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

[Formula 7]

Where ^X1 is an amine protecting group, and

X ² is a nitrogen protecting group of a nitrogen heterocyclic butane.

【Effects of the Invention】

According to one aspect of the invention, one or more intermediates produced by the method according to the invention can be obtained in a solid phase, thus leading to more convenient separation of the intermediates. In each process, the reaction for producing the intermediate can be carried out with minimal side reactions and low levels of impurities, and therefore column chromatography, which is required for prior separation and purification to obtain substantially pure compounds, is not necessary. Due to the reduction in impurity generation and the ease of separation of the intermediates, the final product can be obtained with high purity and high yield. Therefore, the preparation method according to one aspect of the invention can prepare 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one or a pharmaceutically acceptable salt thereof with higher purity, higher yield, and more economically, and is therefore suitable for large-scale (e.g., large-scale and commercial) production.

Detailed Implementation

The invention will be described in more detail below.

Unless otherwise defined, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art related to this invention. Furthermore, although preferred methods or examples are described in the specification, similar or equivalent methods or examples also fall within the scope of this invention. Additionally, the term "comprising" is intended to have the meaning of inclusion and allows for the inclusion of additional elements besides those listed.

Unless otherwise specified, all figures representing the amount, properties (such as molecular weight, reaction conditions, etc.) of an ingredient as used in this specification and claims shall be understood to be modified by the term “about” in all cases.

As used herein, the term "compound of formula" is not intended to be limited to formula. Unless otherwise stated, when describing a structure, it should be understood to include all its possible stereoisomers and tautomers.

The term "protecting group" refers to a functional group that is covalently bonded to a functional group such as an amino or alcohol group to protect it from unintentional reactions, and that allows the functional group to regenerate (i.e., deprotect) after treatment with a suitable reagent.

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

The term "ambient temperature" refers to indoor ambient temperature in the range of about 1°C to about 30°C.

All publications cited in this document as references are incorporated herein in their entirety.

The explanations and embodiments disclosed in this invention can be applied to other explanations and embodiments. That is, all combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention should not be limited to the specific descriptions herein.

One aspect of the present invention provides a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[Formula 1]

The method includes

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

[Formula 4]

^X1 is an amine protecting group.

The compound of formula 4 can be prepared by step (a1) of reacting the compound of formula 2 with the compound of formula 3:

[Equation 2]

Where ^X1 is an amine protecting group, and HA is an acid that forms an acid addition salt;

[Formula 3]

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:

[Equation 2]

[Formula 3]

in

^X1 is an amine protecting group, and

HA is an acid that forms an acid addition salt.

As shown above, HA can be any acid that forms an acid addition salt. For example, the acid addition salt can be a hydrohalic acid. Hydrohalic acids can include hydrochloric acid (HCl), hydrobromic acid (HBr), or hydroiodic acid (HI), preferably hydrochloric acid (HCl).

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 the protecting group ^X1, which is the amine group of the compound of formula 4.

In one embodiment, the method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be represented by reaction scheme 2 below.

[Reaction Scheme 2]

The compound of formula 3 used in step (a1) can be prepared according to any method known in the art, such as the method disclosed in WO2004/080976 (see part b in “Synthesis of key intermediates”).

In one embodiment, the compound of formula 2 may be in the form of a hydrochloride salt, wherein HA is hydrochloric acid. ^X1 may be any amine protecting group capable of protecting the amine group bonded to ^X1 in the reaction of step (a1). This amine protecting group may include, but is not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxybenzyl (PMB).

The step (a1) for preparing the compound of formula 4 can be carried out under any conditions that allow the formation of an amide bond between the azacyclic butaneamine of formula 2 and the carboxyl group of formula 3.

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

Step (a1) can be carried out 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.

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

In one embodiment, step (a1) may be performed in the presence of at least one amide coupling agent and at least one base, wherein the at least one amide coupling agent is selected from the group consisting of: trimethylacetyl 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.

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.

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

In step (a1), the compound of formula 4, which is a product of the reaction, can be obtained in a solid phase. Therefore, by filtration and drying, the compound of formula 4 can be obtained in solid form.

Step (a2) for preparing compound 1 is a reaction that removes the amine protecting group ^X1 from compound 4, and the reaction conditions for removing the amine protecting group ^X1 can vary depending on the type of amine protecting group ^X1 .

In one embodiment, when ^X1 is fluorenylmethoxycarbonyl (Fmoc), step (a2) of preparing the compound of formula 1 may comprise reacting the compound of formula 4 with a nonnucleophilic base. The nonnucleophilic base is not limited to a specific type and may be any nonnucleophilic base capable of effectively removing the amine protecting group ^X1 . For example, the nonnucleophilic base may 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) may be acetonitrile, tetrahydrofuran, N,N-dimethylformamide, or any combination thereof. For example, when ^X1 is fluorenylmethoxycarbonyl (Fmoc), the nonnucleophilic base and solvent may be piperidine and acetonitrile, diisopropylethylamine and tetrahydrofuran, or 8-diazabicyclo[5,4,0]undec-7-ene and N,N-dimethylformamide, respectively.

In another embodiment, in step (a2), when ^X1 is trifluoroacetyl (Tfa), the compound of formula 4 can react with a basic base. The basic base is not limited to a specific type and can be any basic base capable of effectively separating the amine protecting group ^X1 . For example, the basic base can 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) can 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 ^X1 is trifluoroacetyl (Tfa), the basic base and solvent can be potassium hydroxide and isopropanol/water, potassium carbonate and methanol/water, sodium hydroxide and methanol/water, or sodium carbonate and ethanol/water, respectively.

In another embodiment, in step (a2), when ^X1 is p-methoxybenzyl (PMB), the compound of formula 4 can react with an acid. The acid is not limited to a specific type and can be any acid capable of effectively removing the amine protecting group. For example, trifluoroacetic acid can be used as both a reagent and a solvent. In this case, the weight ratio (w/v) of the compound of formula 4 to the volume of trifluoroacetic acid in the reaction of step (a2) can be from about 1:5 to about 1:40. For example, when ^X1 is p-methoxybenzyl (PMB), the ratio (w/v) of the compound of formula 4 to trifluoroacetic acid in the reaction of step (a2) can be from about 1:10.

In step (a2), the compound of formula 1, which is a product of the reaction, can be obtained in a solid phase. Therefore, by filtration and drying, the compound of formula 1 can be obtained in solid form.

The preparation of an acid addition salt of Formula 1 can be further carried out by reacting the compound with an acid (a3), thereby preparing a pharmaceutically acceptable salt of Formula 1. Those skilled in the art, based on common knowledge in the field of organic chemistry, can use suitable methods to prepare the acid addition salt of Formula 1. The acid addition salt of Formula 1 can be any pharmaceutically acceptable acid addition salt, such as an acid addition salt formed from a free acid. The free acid can be an inorganic acid or an organic acid. Inorganic acids can be hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Organic acids can be, but are 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.

In one embodiment, the acid addition salt may be an inorganic acid addition salt, and in one embodiment, it is a hydrochloric acid addition salt. The reaction in step (a) of preparing the acid addition salt of compound 1 may be carried out in any solvent that does not inhibit the formation of the acid addition salt. For example, the solvent may be selected from alcohols, ketones, ethers, acetates, dichloromethane, chloroform, and any combination thereof, and in some embodiments, may be _C1 - _C5 alcohols, _C3 - _C10 ketones, _C2 - _C10 ethers, _C2 - _C4 alkyl acetates, dichloromethane, chloroform, or any combination thereof.

The reaction in step (a3) can be carried out at a temperature from about -20°C to the reflux temperature, and in some embodiments at a temperature in the range of about -20°C to about 50°C, and in other embodiments at a temperature in the range of about -10°C to about 30°C.

In one embodiment, the hydrochloride salt 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 ranging from about -20°C to reflux temperature, using an alcohol, a mixture of alcohols and ketones, a mixture of alcohols and dichloromethane, a mixture of alcohols and chloroform, a mixture of alcohols and ethers, or a mixture of alcohols and acetates as solvents. For example, the alcohol, ketone, ether, and acetate can be _C1 - _C5 alcohols, _C3 - _C10 ketones, _C2 - _C10 ethers, and _C2 - _C4 alkyl acetates, respectively.

In one embodiment, the hydrochloride salt 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 ranging from about -20°C to reflux temperature or lower, using an alcohol, a mixture of alcohols and ketones, a mixture of alcohols and dichloromethane, a mixture of alcohols and chloroform, or a mixture of alcohols and ethers as solvents, and then filtering and drying the solid thus formed. For example, the alcohol, ketone, and ether can be _C1 - _C5 alcohols, _C3 - _C10 ketones, and _C2 - _C10 ethers, respectively.

In step (a3), the acid addition salt of compound 1, which is a product of the reaction, can be obtained in a solid phase. Therefore, by filtration and drying, the acid addition salt of compound 1 in solid form can be obtained.

On the other hand, a method for preparing the compound of formula 2 as shown above is provided.

The method includes:

Step (b1) for preparing compound 7 by introducing an amine protecting group ^X1 into compound 6; and

Step (b2) for preparing compound 2 by removing the nitrogen protecting group ^X2 of nitrogen heterocyclic butane from compound 7:

[Formula 6]

[Formula 7]

In the above formula, ^X1 is an amine protecting group, and ^X2 is a nitrogen protecting group of azacyclobutane.

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

In step (b1) of the reaction to prepare compound 7 by introducing amine protecting group ^X1 into compound 6, when compound 2 is prepared from compound 7, i.e., in step (b2), amine protecting group ^X1 can protect the secondary amine group of nitrogen in the aza-butane ring of compound 7 that is not part of the nitrogen. Therefore, in the preparation of the acid addition salt compound of formula 2 by the deprotection reaction of the aza-butane nitrogen protecting group ^X2 of compound 7, amine protecting group ^X1 can be any protecting group capable of protecting the secondary amine group not contained in the aza-butane ring. For example, amine protecting group ^X1 can be fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxybenzyl (PMB).

In the reaction of step (b1), the reagent capable of introducing the amine protecting group ^X1 into the compound of formula 6 can vary depending on the specific type of the amine protecting group ^X1 . 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.

The reaction in 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 reaction that introduces the amine protecting group ^X1 into the compound of formula 6. For example, the base can be a tertiary amine. For example, a tertiary amine can be selected from diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

In one embodiment, the reaction in step (b) can be carried out in the presence of both a reagent capable of introducing an amine protecting group ^X1 and a base. For example, the reaction in 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 the base selected from diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

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

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

The reaction in step (b2), which follows the reaction in step (b1) to prepare compound 2, may comprise the removal of the aziridine nitrogen protecting group ^X2 from the compound of formula 7 and, conversely, the substitution of said protecting group with hydrogen. The aziridine nitrogen protecting group ^X2 may be any protecting group that can be removed, leaving the amine protecting group ^X1 unremoved and substituted with hydrogen. For example, the aziridine nitrogen protecting group ^X2 may be selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt), and tetrahydropyranyl (THP). In one embodiment, the aziridine nitrogen protecting group ^X2 is butoxycarbonyl (Boc).

The hydrogen substitution process in step (b2) can be carried out at a temperature from about -20°C to the reflux temperature, and in some embodiments, at a temperature in the range of about 0°C to about 90°C.

For example, the hydrogen substitution process in step (b2) can be carried out by reacting the compound of formula 7 with an acid, thereby removing the nitrogen-protecting group ^X2 of the azahexabutane from the compound of formula 7, and then substituting the protecting group with hydrogen. The acid is not limited to a specific type and can be any acid capable of effectively removing the nitrogen-protecting group ^X2 of the azahexabutane and forming 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.

The solvent used in the hydrogen substitution process in step (b2) can be any solvent that does not inhibit the corresponding reaction. For example, when the nitrogen protecting group ^X2 of the azahexacyclic butane is a butoxycarbonyl (Boc), the solvent can be selected from acetone, ethyl acetate, _C1 - _C4 straight-chain or branched alcohols, and any combination thereof.

In one embodiment, when ^X2 is butoxycarbonyl (Boc), the acid and solvent used in step (b2) can 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.

In the reaction of step (b2), after removing ^X2 from the compound of formula 7 by adding an acid to the solvent and replacing it with hydrogen, the acid addition salt of formula 2 can be prepared by evaporation without post-treatment or by precipitation with the addition of a suitable solvent. A suitable solvent for precipitating the acid addition salt can be selected from, but is not limited to, ethyl acetate, acetone, n-hexane, isopropanol, and any combination thereof. Any suitable solvent can be selected by those skilled in the art, taking into account the conditions required for the solvent in the corresponding reaction.

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

The compound of Formula 6 can be prepared by step (b0) of the reductive amination reaction of the compound represented by Formula 5:

[Formula 5]

In Formula 5, ^X2 is a nitrogen protecting group of aza-butane.

In the reaction of step (b0), the reductive amination of the compound of formula 5 can be carried out by a person skilled in the art based on common knowledge known in the art. In one embodiment, in the reaction of step (b0), the compound of formula 6 can be prepared in high yield by reductive amination using trifluoroethanol as a solvent and sodium borohydride without a catalyst or additive (see Synthesis, 2011, Vol. 3, pp. 490-496).

In one embodiment, the method for preparing the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be represented by reaction scheme 3 below.

[Reaction Scheme 3]

According to the exemplary preparation method of the present invention, for example as represented by reaction scheme 3, 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-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 higher, preferably 5 to 8 times higher, than that obtained by known methods disclosed, for example, in US 9,682,973. In another embodiment, the final product obtained by 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% (containing 99.5% or 99.9%) when identified by percentage area by HPLC.

In the method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, according to one aspect of the invention, one or more intermediates (e.g., compounds of formula 2 or 4) generated by the method according to the invention can be obtained in a solid phase, thus leading to more convenient separation of the intermediates. In each process, the reaction for generating the intermediate is completed, and the production of related materials is minimal, and therefore column chromatography, which is previously required for separation and purification, is not necessary. Due to the reduction in the production of related materials and the ease of separation of the intermediates, the final product can be obtained in high yield. Furthermore, since column chromatography, which is unsuitable for large-scale (e.g., large-scale and commercial) production, can be avoided, and quality reproducibility can be improved, the method can therefore be advantageously applied to large-scale production.

On the other hand, a compound of formula 2 is provided:

[Equation 2]

In Equation 2, ^X1 is an amine protecting group, and HA is an acid that forms an acid addition salt.

The amine protecting group ^X1 can be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.

HA can be any acid that forms an acid addition salt. For example, HA can be a hydrohalic acid. Hydrohalic acids can be hydrochloric acid, hydrobromic acid, or hydroiodic acid, and can be hydrochloric acid, for example.

As described above, the compound of Formula 2 is a novel solid-phase intermediate compound that has not been used in existing methods for preparing the compound of Formula 1 or its pharmaceutically acceptable salts. 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. Purification steps can then be minimized, leading to a method for preparing the compound of Formula 1 or its pharmaceutically acceptable salts in high yield and high purity. Therefore, the compound of Formula 1 or its pharmaceutically acceptable salts can be produced in large quantities (e.g., on a large scale and commercially) with high yield and high purity.

In one embodiment, the compound of formula 2 may be selected from the group consisting of the following compounds:

Formula 2a (9H-fluorene-9-yl)methyl(azacyclobutane-3-ylmethyl)(cyclopropyl)carbamate hydrochloride,

[Equation 2a]

N-(azacyclobutane-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride of formula 2b

[Equation 2b]

as well as

N-(azacyclobutane-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropylamine hydrochloride of formula 2c

[Equation 2c]

On the other hand, a compound of formula 4 is provided:

[Formula 4]

^X1 is an amine protecting group.

The amine protecting group ^X1 can be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.

As described above, the compound of Formula 4 is a novel solid-phase intermediate compound that has not been used in existing methods for preparing the compound of Formula 1 or its pharmaceutically acceptable salts. When the compound of Formula 4 is used as an intermediate, the compound of Formula 1 can be obtained in a solid phase. Purification steps can then be minimized, resulting in a method for preparing the compound of Formula 1 or its pharmaceutically acceptable salts in high yield and high purity. Therefore, the compound of Formula 1 or its pharmaceutically acceptable salts can be produced in large quantities (e.g., on a large scale and commercially) with high yield and high purity.

In one embodiment, the compound of formula 4 may be selected from the group consisting of the following compounds:

Cyclopropyl ([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azacyclobutane-3-yl]methyl)carbamate (9H-fluorene-9-yl)methyl ester of formula 4a,

[Equation 4a]

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

[Formula 4b]

as well as

Formula 4c contains 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azacyclobutane-1-carbonyl]-4-fluorobenzyl)phthalazine-1(2H)-one.

[Formula 4c]

On the other hand, a compound of formula 7 is provided:

[Formula 7]

Where ^X1 is an amine protecting group, and

X ² is a nitrogen protecting group of a nitrogen heterocyclic butane.

The amine protecting group ^X1 can be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.

The nitrogen protecting group ^X2 of the azahexacyclic butane can be selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt), and tetrahydropyranyl (THP). In one embodiment, the nitrogen protecting group ^X2 of the azahexacyclic butane can be butoxycarbonyl (Boc).

As described above, the compound of Formula 7 is a novel intermediate compound that has not been used in existing methods for preparing the compound of Formula 1 or its pharmaceutically acceptable salts.

In one embodiment, the compound of formula 7 may be selected from the group consisting of:

3-([([(9H-fluorene-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azacyclobutane-1-carboxylic acid tert-butyl ester of formula 7a

[Formula 7a]

3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azacyclobutane-1-carboxylic acid tert-butyl ester of formula 7b

[Formula 7b]

as well as

3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azacyclobutane-1-carboxylic acid tert-butyl ester of formula 7c

[Formula 7c]

In another aspect of the invention, the method of the invention is used to prepare a pharmaceutical substance, pharmaceutical composition, or pharmaceutical product comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof. When a compound of Formula 1 or a pharmaceutically acceptable salt thereof is used as a pharmaceutical substance, the intermediate compounds described herein may be present as impurities. When present as impurities, the amount of each compound of Formulas 2 to 7 may be controlled to be present in trace amounts, for example, not exceeding about 1.0% or less, about 0.5% or less, about 0.2% or less, about 0.1% or less of the pharmaceutical substance, or not present at all.

Therefore, in one aspect, the substantially pure form of Formula 1 compound prepared by the method of the present invention is provided as a pharmaceutical substance for use in the preparation of a pharmaceutical composition or a medicament. In one embodiment, the present invention covers pharmaceutical compositions comprising substantially pure pharmaceutical substances, wherein the Formula 1 compound or a pharmaceutically acceptable salt thereof is present in the pharmaceutical 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 chromatographic (e.g., HPLC) detection conditions, the purity percentage can be determined by referring to the percentage of the measured peak area relative to the sum of the peak areas of all peaks.

Therefore, in one aspect, the present invention provides pharmaceutical compositions 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 methods of the present invention (e.g., one or more intermediates described herein, and reaction schemes 1 and 2). The pharmaceutical compositions of the present invention can be administered to patients to treat cancer, including cancers sensitive to PARP inhibitors. Such formulations may contain binders, fillers, disintegrants, lubricants, colorants, and preservatives, as well as other pharmaceutically acceptable excipients.

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

[Formula 1]

Or a pharmaceutically acceptable salt thereof, wherein the compound of formula 1 or the pharmaceutically acceptable salt thereof is produced by the methods of the present invention as described above, such as those shown in reaction schemes 2 and 3.

The invention will be described in more detail below with reference to the following examples. However, these examples are for illustrative purposes only, and the invention is not intended to be limited to these examples.

Example 1:

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

1.0 kg of tert-butyl 3-formylazetane-1-carboxylate was added to the reactor, along with 6.5 kg of trifluoroethanol. 0.3 kg of cyclopropylamine was added at 0°C, and the mixture was stirred at ambient temperature for 1 hour, after which the reactor was cooled to 0°C. 0.2 kg of sodium borohydride was slowly added, and the mixture was stirred at ambient temperature for 1 hour, after which the reactor was cooled to 0°C. After the slow addition of 10.0 kg of water, the reaction mixture was extracted with 6.7 kg of dichloromethane, and the resulting aqueous layer was further extracted with 6.7 kg of dichloromethane. The organic layer was washed with a 15% sodium chloride aqueous solution, treated with 0.5 kg of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to yield 0.98 kg of compound 6a as a yellow oil (yield: 80.1%). Compound 6a was used in subsequent processes without a separate purification process.

¹ H NMR (CDCl ₃ ,400MHz)δ3.99(t,2H),3.60-3.57(m,2H),2.90(d,2H),2.66-2.62(m,1H),2.1 1-2.06(m,1H),1.59(br,1H),1.44(s,9H),0.46-0.42(m,2H),0.32-0.28(m,2H)

Example 2:

Preparation of 3-([([(9H-fluorene-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (Formula 7a: X ¹ = Fmoc)

4.0 kg of dichloromethane was added to a reactor, followed by the sequential addition of 300.0 g of tert-butyl 3-[(cyclopropylamino)methyl]azacyclobutane-1-carboxylate prepared in Example 1 and 188.4 g of diisopropylethylamine. The reactor was then cooled to 0 °C. 377.2 g of 9-fluorenylmethoxycarbonyl chloride was slowly added to the reactor, ensuring the internal temperature did not exceed 20 °C, and the reaction mixture was stirred for 1 hour. 5.0 kg of water was added to wash the organic layer, followed by further washing with 5.0 kg of 1N hydrochloric acid aqueous solution. The organic layer was further washed with 15% sodium chloride aqueous solution and treated with 250.0 g of anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to quantitatively produce 576.7 g of compound 7a as a yellow oil. Compound 7a was used in subsequent processes without a separate purification process.

¹ H NMR (CDCl ₃ ,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)

Example 3:

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

2.7 kg of dichloromethane was added to the reactor, along with 200.0 g of tert-butyl 3-[(cyclopropylamino)methyl]azacyclobutane-1-carboxylate prepared in Example 1. 107.3 g of triethylamine was added, and the reactor was then cooled to 0°C. 222.7 g of trifluoroacetic anhydride was slowly added to the reactor, ensuring the internal temperature did not exceed 20°C, and the reaction mixture was stirred for 1 hour. 2.0 kg of water was added to wash the organic layer, followed by further washing with 2.0 kg of 1N hydrochloric acid aqueous solution. The organic layer was further washed with 7% sodium chloride aqueous solution, treated with 100.0 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to quantitatively produce 284.8 g of compound 7b as a white solid and yellow oil. Compound 7b was used in subsequent processes without a separate purification process.

¹ H NMR (CDCl ₃ ,400MHz)δ3.99(t,2H),3.60-3.57(m,2H),2.90(d,2H),2.68-2.60(m,1 H),2.10-2.06(m,1H),1.44(s,9H),0.46-0.41(m,2H),0.32-0.28(m,2H)

Example 4:

Preparation of 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (Formula 7c: X ¹ = PMB)

1.4 kg of acetonitrile was added to the reactor, followed by the sequential addition of 226.3 g of tert-butyl 3-[(cyclopropylamino)methyl]azacyclobutane-1-carboxylate prepared in Example 1 and 111.3 g of triethylamine. The reactor was then cooled to 0 °C. 156.6 g of 4-methoxybenzyl chloride was slowly added, and the mixture was 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 to separate the organic layer. The organic layer was further washed with 2.0 kg of 0.5 N hydrochloric acid aqueous solution.

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 obtain 285.8 g of compound 7c as a yellow oil (yield: 82.5%). Compound 7c was used in subsequent processes without a separate purification process.

¹ H NMR (CDCl ₃ ,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,2 H),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)

Example 5:

Preparation of (9H-fluorene-9-yl)methyl(azacyclobutane-3-ylmethyl)(cyclopropyl)carbamate hydrochloride (Formula 2a: X ¹ = Fmoc, HA = HCl)

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

¹ H NMR (CDCl ₃ ,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),4.52(d,2 H),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)

Example 6:

Preparation of N-(azacyclobutane-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride (Formula 2b: X ¹ = Tfa, HA = HCl)

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

¹ H NMR (DMSO-d ₆ ,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)

Example 7:

Preparation of N-(azacyclobutane-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropylamine hydrochloride (Formula 2c: X ¹ = PMB, HA = HCl)

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

¹ H NMR (CDCl ₃ ,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)

Example 8:

Cyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azacyclobutane-3-yl]methyl)carbamate (9H-fluorene-9-yl)methyl ester)

Preparation of (Equation 4a: X ¹ = Fmoc)

300 mL of dichloromethane was added to the reactor, followed by the sequential addition of 29.8 g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid and 17.9 g of 1,1'-carbonyldiimidazole. The reaction was carried out at ambient temperature for 1 hour, and then the reactor was cooled to 15°C. Then, 42.3 g of (9H-fluorene-9-yl)methyl(azacyclobutane-3-ylmethyl)(cyclopropyl)carbamate hydrochloride prepared in Example 5 was added, and 19.4 g of diisopropylamine was slowly added. The reaction mixture was stirred at ambient temperature for 1 hour, and 300 mL of water was added to wash the organic layer, followed by further washing with 1 N hydrochloric acid and 1 N sodium carbonate aqueous solution. The organic layer was further washed with 5% sodium chloride aqueous solution, treated with 10.0 g 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 yield 63.2 g of compound 4a (yield: 91.3%).

¹ H NMR (DMSO-d ₆ ,400MHz)δ12.60(s,1H),8.26-8.24(m,1H),7.97(d,1H),7.90-7.78(m, 4H),7.65-7.62(m,2H),7.48-7.28(m,7H),4.51-4.48(m,2H),4.32(s,2 H),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)

Example 9:

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

Preparation of (Equation 4b: X ¹ = Tfa)

300 mL of dichloromethane was added to the reactor, followed by the sequential addition of 29.8 g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid and then 17.9 g of 1,1'-carbonyldiimidazole. The reaction was carried out at ambient temperature for 1 hour. The reactor was then cooled to 15°C, and 28.5 g of N-(azacyclobutane-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride prepared in Example 6 was slowly added, followed by the addition of 19.4 g of triethylamine. The reaction mixture was then stirred at ambient temperature for 1 hour, 300 mL of water was added to wash the organic layer, and the organic layer was further washed with 1 N aqueous hydrochloric acid and 1 N aqueous sodium carbonate solution. The organic layer was washed with 5% aqueous sodium chloride solution, treated with 10.0 g 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 yield 44.7 g of compound 4b (yield: 89.1%).

¹ H NMR (DMSO-d ₆ ,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)

Example 10:

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

300 mL of dichloromethane was added to the reactor, followed by the sequential addition of 29.8 g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid and 17.9 g of 1,1'-carbonyldiimidazole. The reaction was carried out at ambient temperature for 1 hour, and then the reactor was cooled to 15°C. Then, 31.1 g of N-(azacyclobutane-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropylamine hydrochloride prepared in Example 7 was added, followed by the slow addition of 19.4 g of triethylamine. The reaction mixture was stirred at ambient temperature for 1 hour, and 300 mL of water was added to wash the organic layer, followed by washing with 1 N aqueous hydrochloric acid and 1 N aqueous sodium carbonate solution. The organic layer was washed with 5% aqueous sodium chloride solution, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 300 mL of toluene was added to the residue, stirred overnight at ambient temperature, filtered, and then dried at 50 °C to yield 47.0 g of compound 4c (yield: 81.2%).

¹ H NMR (DMSO-d ₆ ,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)

Example 11:

Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one (Formula 1) (1)

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)azacyclobutane-3-yl]methyl)carbamate (9H-fluorene-9-yl)methyl ester prepared in Example 8 and 34.5 g of piperidine were added sequentially. The mixture was stirred at ambient temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, 300 mL of 2N hydrochloric acid aqueous solution was added to the residue, the mixture was 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, and the organic layer was then mixed with it, washed with 5% sodium chloride aqueous solution, and then concentrated. 80 mL of methanol and 40 mL of dichloromethane were added to the residue, followed by the slow addition of 150 mL of acetone. The resulting solid was stirred overnight at ambient temperature, filtered, and dried at 40 °C to yield 17.5 g of compound 1 (yield: 90.1%).

¹ H NMR (DMSO-d ₆ ,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,2H),7.2 2-7.18(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)

Example 12:

Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one (Formula 1) (2)

Add 300 mL of methanol and 30.0 g of N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azacyclobutane-3-yl]methyl)acetamide prepared in Example 9 to the reactor, and then cool the reactor to 0°C. Slowly add 60 mL of 20% potassium carbonate aqueous solution to the reactor, ensuring the internal temperature does not exceed 20°C, and stir the reaction mixture overnight at ambient temperature. Add 240 mL of water and 300 mL of dichloromethane to the aqueous layer, and then further extract the aqueous layer with 300 mL of dichloromethane. Then mix with the organic layer, wash with 5% sodium chloride aqueous solution, and then concentrate. Add 100 mL of methanol and 50 mL of dichloromethane to the residue, and then slowly add 200 mL of acetone to the residue. The resulting solid was stirred overnight at ambient temperature, filtered, and dried at 40°C to yield 22.4 g of compound 1 (yield: 92.1%).

¹ H NMR (DMSO-d ₆ ,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,2H),7.2 2–7.18(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)

Example 13:

Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one (Formula 1) (3)

100 mL of trifluoroacetic acid was added to the reactor, along with 10.0 g of 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azacyclobutane-1-carbonyl]-4-fluorobenzyl)phthalazine-1(2H)-one prepared in Example 10, and the mixture was stirred at 60 °C for 1 hour. The reactor was then cooled to 0 °C, and 100 mL of dichloromethane was added, followed by the slow addition of 100 mL of water. The aqueous layer was further washed with 100 mL of dichloromethane, adjusted to pH 9 or higher with 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 with it, washed with 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. The resulting solid was stirred overnight at ambient temperature, filtered, and dried at 40°C to yield 13.4 g of compound 1 (yield: 86.9%).

¹ H NMR (DMSO-d ₆ ,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,2H),7.2 3–7.18(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)

Example 14:

Preparation of hydrochloride of 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one (Formula 1a) (1)

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

¹ H NMR (DMSO-d ₆ ,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)

Example 15:

Preparation of hydrochloride of 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one (Formula 1a) (2)

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

1H NMR (DMSO-d ₆ ,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)

Example 16:

Preparation of hydrochloride of 4-[3-(3-[(cyclopropylamino)methyl]azacyclobutane-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one (Formula 1a) (3)

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

¹ H NMR (DMSO-d ₆ ,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)

The described embodiments are to be considered merely illustrative and not restrictive in all respects. Those skilled in the art will recognize that the invention may be practiced in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the scope of the invention is indicated by the appended claims rather than by the foregoing description. All variations falling within the equivalent meaning and scope of the claims should be covered within the scope of the invention.

Claims (7)

1. A method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, [Formula 1] The method includes: Prepare compound 4, [Formula 4] Where ^X1 is an amine protecting group selected from the group consisting of: fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB). Compound of Formula 4 is prepared by reacting compound of Formula 2 with compound of Formula 3 [Formula 2]. Where ^X1 is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), and HA is an acid that forms an acid addition salt. [Formula 3] The preparation of the compound of formula 4 is carried out in the presence of at least one amide coupling agent and at least one base. The at least one amide coupling agent is selected from the group consisting of 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and any combination thereof. The at least one base is triethylamine; and Deprotect the compound of formula 4. 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 ^X1 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 nonnucleophilic base, wherein X ¹ in formula 4 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 ^X1 in formula 4 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 ¹ in formula 4 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.