WO2024025389A1 - Method for preparing intermediate of phthalazinone derivative - Google Patents

Abstract

The present invention relates to a method for preparing a phthalazinone derivative, which is an inhibitor of Poly (ADP-ribose) polymerase (PARP), and a method for preparing an intermediate used in the preparation method and an acid addition salt thereof.

Description

Method for producing intermediates of phthalazinone derivatives

The present invention relates to a method for producing a phthalazinone derivative, which is a PARP inhibitor (Poly (ADP-ribose) polymerase) inhibitor, an intermediate used in the production method, and a method for producing an acid addition salt thereof.

Patent Document 1 (US Patent Application Publication US2021/0323946 A1) discloses a phthalazinone derivative, which is a PARP inhibitor (Poly (ADP-ribose) polymerase) inhibitor, and a method for producing the same. The production method disclosed in the above document prepares the key intermediate, tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate, from tert -butyl 3-formylazetidine-1-carboxylate. , relates to a method of producing phthalazinone derivatives from the intermediate prepared in this way.

tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate disclosed in Patent Document 1 is a material in the early stage of production containing the main building blocks of phthalazinone derivatives and is described in the dictionary of phthalazinone derivatives. It is a reference material that repeatedly produces final quality results that meet established acceptance criteria and is a key intermediate in the production of phthalazinone derivatives.

In order to commercially produce tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate, a key intermediate of phthalazinone derivatives, tert -butyl 3-formylazetidine-1-carboxylate Although the supply of raw materials for boxylate must be smooth, tert -butyl 3-formylazetidine-1-carboxylate is not in sufficient supply, is expensive, and has poor quality reproducibility. Additionally, the material requires special storage and handling due to its unique properties. Specifically, it is preferable to store it at a low temperature of -20℃, it is unstable in moisture, and the aldehyde functional group can be easily oxidized by oxygen in the air and converted to carboxylic acid, so it is sensitive to air, so it should be stored separately filled with nitrogen or argon gas. It is recommended to do so.

In addition, separate equipment and procedures are required to maintain and distribute substances such as tert -butyl 3-formylazetidine-1-carboxylate, which are sensitive to storage conditions and temperature, in optimal condition, but these equipment and procedures In order to establish a distribution procedure that includes additional time and costs, the manufacturing cost of phthalazinone derivatives is bound to increase.

Therefore, compared to tert -butyl 3-formylazetidine-1-carboxylate, it can be supplied smoothly, is easy to store and manage, and has no aldehyde functional group, so raw materials that are less likely to be oxidized in the air are used, making it a key intermediate. A new production method for producing tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate is needed.

In order to devise such a manufacturing method, the Hoffmann alkylation reaction can be considered as a general method of introducing a secondary amine containing a cyclopropyl group outside the azetidine ring. The Hoffmann alkylation reaction is a direct preparation method that involves treating primary amines with halide compounds or their equivalents (e.g. dialkylsulfates or sulfonates). Although the direct N -alkylation reaction is in principle the most common and direct route to the formation of secondary amines and the conversion appears simple, when prepared in this way, the concomitant peralkylation leads to the formation of primary, secondary, as well as quaternary ammonium salts. It is well known that it is not suitable for producing secondary amines because it generates a mixture of tertiary amines and has low selectivity (Non-patent Document 1: Comprehensive Organic Synthesis, Pergamon Press, 1991, Vol. 6, 65-102).

To avoid this problem, a manufacturing method that can selectively N-alkylate amines using inexpensive γ-alumina with a wide range of alcohols (Non-patent Document 2: Tetrahedron Lett. 1999, 40, 3689-3692) Although this has been reported, this method requires very high temperature and harsh reaction conditions of 200 to 300°C, so it is not suitable for the production of secondary amines.

Meanwhile, an amide reduction reaction is a method that can form secondary amines without going through a direct N-alkylation reaction. The amide reduction reaction occurs by the nucleophilic addition of a hydride ion to the amide carbonyl group, and following the nucleophilic addition, the aluminate anion is released, releasing an oxygen atom, and the resulting iminium ion intermediate is further reduced with LiAlH ₄ to produce an amine. (Non-patent Document 3: Organic Chemistry, 9th edition, Brooks Cole, John E. McMurry, 711-713). The amide reduction reaction has the advantage of selectively producing secondary amines from secondary amides because it can selectively produce amines by converting the amide carbonyl group to a methylene group.

However, in order to proceed with the amide reduction reaction, a strong reducing agent such as LiAlH ₄ , which is a metal hydride, must be used. LiAlH ₄ is a substance that reacts violently with water, so it can be exposed to water when the handler accidentally introduces it or comes into contact with moisture in a humid environment. When this occurs, it reacts with the generated lithium hydroxide and reaches the boiling point in an instant, which can cause an explosion, making it difficult to use in large-scale processes such as pharmaceutical manufacturing for safety reasons.

Alternative reaction scheme that can selectively reduce secondary amides using triflic acid anhydride (Tf ₂ O) and metal-free Hantzsch Ester Hydride (HEH) without using metal hydrides such as LiAlH ₄ Although it has been reported (Non-patent Document 4: J. Am. Chem. Soc. 2010, 132, 12817-12819), this method also requires harsh reaction conditions at a very low temperature of -78°C for activation of the amide, so secondary amines It is not suitable for manufacturing.

As seen above, existing methods for forming secondary amines using raw materials other than tert -butyl 3-formylazetidine-1-carboxylate have harsh or hazardous reaction conditions, poor yield, or low chemical stability. Because it has problems due to selectivity, a new preparation method that can selectively prepare secondary amine compounds such as tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate under mild reaction conditions This is required.

[Prior art literature]

[Patent Document]

(Patent Document 0001) US Patent Application Publication US 2021/0323946 A1

(Patent Document 0002) U.S. Registered Patent Publication 9,844,550 B2

[Non-patent literature]

(Non-patent Document 0001) Comprehensive Organic Synthesis ; Pergamon Press, 1991, Vol. 6, 65-102

(Non-patent document 0002) Tetrahedron Lett. 1999, 40, 3689-3692

(Non-patent document 0003) Organic Chemistry, 9th edition , Brooks Cole, John E. McMurry, 711-713

(Non-patent Document 0004) J. Am. Chem. Soc . 2010, 132, 12817-12819

One aspect of the present invention is Using a relatively low cost, smooth supply and stable azetidine compound as a raw material, tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxyl, a key intermediate of phthalazinone derivatives, is produced under mild conditions. The aim is to provide a manufacturing method that can selectively manufacture the rate.

Other objects and advantages of the present invention will become clearer from the following detailed description together with the appended claims. Contents not described in this specification can be fully recognized and inferred by anyone with ordinary knowledge in the technical field of this application or a similar technical field, so description thereof is omitted.

In the present invention, the inventors designed a method for producing a key intermediate of a phthalazinone derivative using an azetidine compound as a raw material, which is easier to supply, store, and manage than the azetidine compound used conventionally. Through this manufacturing method, key intermediates of phthalazinone derivatives can be manufactured at a relatively low cost.

This manufacturing method includes the step (c1) of reacting the raw material with an amine into which a protecting group, for example, a nitrobenzenesulfonyl group, is introduced and a nitrobenzenesulfonyl group under mild conditions to selectively prepare the key intermediate of the phthalazinone derivative. It includes the step (c2) of deprotecting the group.

According to the production method of the present invention, tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-car, a key intermediate of phthalazinone derivatives, is produced using raw materials that are easy to supply, store, and manage and are inexpensive. It is possible to produce voxylate, which provides significant advantages in terms of time and cost over conventional production methods.

In addition, core intermediates of phthalazinone derivatives can be selectively synthesized using raw materials substituted with leaving groups such as hydroxy groups and halogens, and the synthesis can be carried out under mild conditions.

In addition, the core intermediate obtained in liquid form can be obtained in solid form and stored stably by producing it with an acid addition salt, and the compound obtained in solid form has the advantage of being easy to store and manage because it is easy to block contamination from the outside. . In addition, since compounds in solid form are obtained through a crystallization process, they usually have the effect of improving purity.

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

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods are also included in the scope of the present invention. Additionally, the term “comprising” is intended to be inclusive and means that additional elements may be present in addition to the listed elements.

All numbers used herein expressing amounts of components, properties such as molecular weight, reaction conditions, etc. are understood to be modified in all cases by the term “about”, unless otherwise specified. Accordingly, the numbers set forth herein are approximations that may vary depending on the desired properties to be achieved by the present invention.

As used herein, the term “compound of a formula” is not intended to be limiting to that formula and is used in the same manner as the term “comprising” is commonly used. For example, when one structure is shown, it is understood that all stereoisomeric and tautomeric forms are included, unless otherwise noted.

The term "protecting group" means that when covalently attached to a functional group, such as an amino group or an alcohol group, the functional group prevents an undesirable reaction from occurring, but the functional group prevents treatment of the protecting group by an appropriate reagent. Refers to a functional group that allows it to be regenerated (i.e., deprotected).

The contents of all publications incorporated by reference herein are hereby incorporated by reference in their entirety.

Each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. Additionally, the scope of the present application cannot be considered limited by the specific description described below.

One aspect of the present invention is a method of preparing a compound of Formula 4 or an acid addition salt thereof using a compound of Formula 1,

(c1) reacting a compound of formula 1 with a compound of formula 2 to form a compound of formula 3, and

Step (c2) of forming a compound of Formula 4 by deprotecting the compound of Formula 3

The manufacturing method includes:

[Formula 1]

,

[Formula 2]

,

[Formula 3]

,

[Formula 4]

,

In Formulas 1 to 4,

X ² is a protecting group of azetidine nitrogen,

n is 1 or 2,

Z is selected from the group consisting of hydroxyl group, tosylate, bromine, chlorine, iodine, and mesylate.

In the above formula ( ¹⁾ , It is any one protecting group selected from the group consisting of (Bn), more preferably tert -butoxycarbonyl.

In Formula 1, Z is selected from the group consisting of a hydroxy group, tosylate, bromine, chlorine, iodine, and mesylate, and is preferably a hydroxy group or a tosylate.

For example, the compound of Formula 1 is 1-Boc-azetidin-3-ylmethanol, tert -butyl 3-[(tosyloxy)methyl]azetidine-1-carboxylate, tert -butyl 3-(bro parentmethyl)azetidine-1-carboxylate, tert -butyl 3-(chloromethyl)azetidine-1-carboxylate, tert- butyl 3-(iodomethyl)azetidine-1-carboxylate, or tert -butyl 3-([methylsulfonyl)oxy]methyl)azetidine-1-carboxylate.

Unlike tert -butyl 3-formylazetidine-1-carboxylate, which was used as a raw material for phthalazinone derivatives in the prior art, the compound of Formula 1 has no aldehyde functional group and is less likely to be easily oxidized in the air. Even if it is not separately filled with nitrogen or argon gas, it can be stored in a stable state and is easy to handle.

In Formula 2, n is 1 or 2, and preferably the compound of Formula 2 is N -cyclopropyl-2-nitrobenzenesulfonamide, N -cyclopropyl-4-nitrobenzenesulfonamide, and N -cyclopropyl-2. , 4-dinitrobenzenesulfonamide, preferably selected from the group consisting of N -cyclopropyl-2-nitrobenzenesulfonamide, and N -cyclopropyl-4-nitrobenzenesulfonamide.

In Formula 3, X ² is a protecting group of azetidine nitrogen, preferably tert- butoxycarbonyl, and n is 1 or 2. Preferably the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-2-nitrophenyl)sulfonamido]methyl)azetidine-1-carboxylate, tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl)sulfonamido]methyl)azetidine-1-carboxylate, and tert -butyl 3-([( N -cyclopropyl-2,4-dinitrophenyl)sulfonamido] methyl) azetidine-1-carboxylate, more preferably tert -butyl 3-([( N -cyclopropyl-2-nitrophenyl)sulfonamido]methyl)azetidine-1- carboxylate, or tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl)sulfonamido]methyl)azetidine-1-carboxylate.

In Formula 4, X ² is a protecting group of azetidine nitrogen, and is preferably tert- butoxycarbonyl.

The acid addition salt of the compound of Formula 4 may be any pharmaceutically suitable acid addition salt, for example, an acid addition salt formed by a free acid, and the free acid may be an inorganic acid or an organic acid. The inorganic acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, boric acid, or carbonic acid. acid) or any combination thereof, and the organic acid may be acetic acid, adipic acid, ascorbic acid, aspartic acid, or benzenesulfonic acid. , benzoic acid, citric acid, (+)-camphoric acid [(+)-camphoric acid], carprylic acid, camphorsulfonic acid, (+)-camphor- 10-sulfonic acid [(+)-camphor-10-sulfonic acid], oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid (tartaric acid), lactic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, cinnamic acid, methanesulfonic acid, Ethanesulfonic acid, 4-toluenesulfonic acid, glutamic acid, trifluoroacetic acid, 1-dodecanesulfonic acid, formic acid acid), pyruvic acid, or edisilic acid, or any combination thereof, but is not limited thereto. Preferably, the acid addition salt of the compound of formula (4) is formed with at least one acid selected from the group consisting of maleic acid, fumaric acid, oxalic acid, camphorsulfonic acid, and hydrochloric acid.

In one embodiment, the production method of the present invention is one in which the compound of Formula 2 is N -cyclopropyl-2-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-2-nitrophenyl ) sulfonamido] methyl) azetidine-1-carboxylate, or the compound of formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of formula 3 is tert -butyl 3-([( N - Cyclopropyl-4-nitrophenyl) sulfonamido] methyl) azetidine-1-carboxylate, or the compound of Formula 2 is N -cyclopropyl-2,4-dinitrobenzenesulfonamide, and the compound of Formula 3 This is a method for producing tert -butyl 3-([( N -cyclopropyl-2,4-dinitrophenyl)sulfonamido]methyl)azetidine-1-carboxylate.

In another embodiment, the production method of the present invention is one in which the compound of Formula 2 is N -cyclopropyl-2-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-2-nitro phenyl)sulfonamido]methyl)azetidine-1-carboxylate; or the compound of formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl)sulfonamido]methyl)azetidine. It is -1-carboxylate.

In another embodiment, the production method of the present invention is one in which Z of the compound of Formula 1 is a hydroxy group, the compound of Formula 2 is N -cyclopropyl-2-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3- ([( N -cyclopropyl-2-nitrophenyl)sulfonamido]methyl)azetidine-1-carboxylate, or

Z of the compound of Formula 1 is a hydroxy group, the compound of Formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl ) sulfonamido] methyl) azetidine-1-carboxylate, or

In the compound of formula 1, Z is a tosylate, the compound of formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitro It is phenyl)sulfonamido]methyl)azetidine-1-carboxylate.

In one embodiment, the method for producing the compound of Formula 4 can be represented as shown in Scheme 1 below.

[Scheme 1]

In step (c1), Z, which is the leaving group of the compound of Formula 1, can be replaced with the sulfonamide group of the compound of Formula 2 to form the compound of Formula 3. In step (c1), reaction conditions may vary depending on the type of Z, which is the leaving group of the compound of Formula 1.

In one embodiment, when Z of the compound of Formula 1 is a hydroxy group, step (c1) may be performed in the presence of an azo compound. Examples of the azo compound include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1'-(azodicarbonyl ) Dipiperidine [1,1'-(Azodicarbonyl)dipiperidine (ADDP)], di- p -chlorobenzyl azodicarboxylate [Di-p-chlorobenzyl azodicarboxylate (DCAD)], di- tert -butyl azodicarboxylate Boxylate [Di- tert -butyl azodicarboxylate (DBAD)], di-2-methoxyethyl azodicarboxylate [Di-2-methoxyethyl azodicarboxylate (DMEAD)], N,N,N',N' -tetriiso Propylazodicarboxamide [ N,N,N',N' -Tetraisopropylazodicarboxamide (TIPA)], N,N,N',N' -Tetramethylazodicarboxamide [ N,N,N',N' -Tetramethylazodicarboxamide (TMAD)], N,N,N',N' -Tetraisopropylazodicarboxamide [ N,N,N',N' -Tetraisopropylazodicarboxamide (TIPA)], 1,6-dimethyl-1, 5,7-hexahydro-1,4,6,7-tetrazocin-2,5-dione [1,6-Dimethyl-1,5,7-hexahydro-1,4,6,7-tetrazocin-2, 5-dione (DHTD)], or 2,2'-, 3,3'-, or 4,4'-Azopyridines [2,2′-, 3,3′-, or 4,4′-Azopyridines ( azpy)] or any combination thereof may be used, preferably the azo compound is diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dip is selected from the group consisting of peridine, and di- p -chlorobenzyl azodicarboxylate.

Step (c1) may be performed in the presence of at least one phosphine reagent or at least one phosphorane reagent. The phosphine reagent includes, for example, triphenylphosphine, tri-n-butylphosphine, and diphenyl-2-pyridylphosphine. , Tri-n-octylphosphine, Tricyclohexylphosphine, Trihexylphosphine, 4-(dimethylamino)phenyldiphenylphosphine [4-(Dimethylamino) phenyldiphenylphosphine], dicyclohexylphenylphosphine, or tri- tert -butylphosphine, or any combination thereof may be used, preferably the phosphine reagent is triphenylphosphine. It is selected from the group consisting of triphenylphosphine, tri-n-butylphosphine, and diphenyl-2-pyridylphosphine. The phosphorane reagent includes, for example, (cyanomethylene)tributylphosphorane [(Cyanomethylene)tributylphosphorane (CMBP)], or (cyanomethylene)trimethylphosphorane [(Cyanomethylene)trimethylphosphorane (CMMP)] or these. Any combination of can be used.

Said step (c1) is preferably carried out in the presence of at least one phosphine reagent or phosphorane reagent together with at least one azo compound, more preferably in the presence of at least one azo compound and at least one phosphine reagent. It is carried out under

In one embodiment, when Z of the compound of Formula 1 is selected from the group consisting of tosylate, bromine, chlorine, iodine, and mesylate, step (c1) of forming the compound of Formula 3 includes the presence of at least one base. It is carried out under In this case, the type of base that can be used is not particularly limited as long as it does not inhibit the reaction, for example, pyridine, 4-(dimethylamino)pyridine [4-(Dimethylamino)pyridine], diisopropyl Ethylamine (diisopropylethylamine), 1,8-diazabicyclo[5.4.0]undec-7-ene (1,8-diazabicyclo[5.4.0]undec-7-ene), 1,4-diazabicyclo[2.2 .2]octane (1,4-diazabicyclo[2.2.2 ]octane), morpholine, N -methylmorpholine , piperidine, sodium carbonate, sodium hydroxide (sodium hydroxide), potassium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert -butoxide, lithium hydroxide ( Lithium hydroxide, or sodium hydride may be used, preferably sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide ( lithium hydroxide) or any combination thereof may be used.

In one embodiment, the solvent used in the reaction of step (c1) is a polar aprotic solvent (e.g., ethyl acetate, dichloromethane, acetonitrile, acetone, N , N -dimethylformamide , dimethylsulfoxide, N -methyl -2-pyrrolidone, etc.). or non-polar solvents (e.g., toluene, benzene, diethyl ether, tetrahydrofuran, chloroform, 1,4-dioxane) ), etc.) or a combination thereof may be used, and preferably dichloromethane or N,N -dimethylformamide as a polar aprotic solvent is used, or toluene or tetrahydrofuran as a nonpolar solvent.

In one embodiment, the reaction of step (c1) may be performed at a temperature of about -20°C to reflux, specifically at a temperature of about -20°C to about 210°C, and more specifically at a temperature of about -10°C to about 100°C. It can be performed within a range.

The compound of Formula 1 or Formula 2 used in step (c1) can be prepared and used according to any known method, and can also be purchased and used commercially.

The step (c2) is a step in which the nitrobenzenesulfonyl group, which is a protecting group, is deprotected from the compound of Formula 3 to form the compound of Formula 4.

The deprotection reaction in step (c2) may be carried out under mild conditions, and the mild conditions mentioned herein refer to temperature conditions in the range typically operated in pharmaceutical manufacturing facilities, specifically, from about -20° C. to about 120° C. It refers to the temperature conditions included in the ℃ range. Meanwhile, harsh conditions refer to conditions outside the above temperature range, and the further away from the temperature range of the mild conditions, the more severe the conditions become. For example, high temperature conditions above 170℃ or low temperature conditions below -70℃ are severe conditions.

In one embodiment, step (c2) is performed in the presence of at least one base or at least one thiol, preferably in the presence of a base and a thiol.

In one embodiment, the type of base used in step (c2) is not particularly limited as long as it does not inhibit the reaction, for example, pyridine, 4-(dimethylamino)pyridine [4-(Dimethylamino )pyridine], diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (1,8-diazabicyclo[5.4.0]undec-7-ene), 1, 4-diazabicyclo[2.2.2]octane (1,4-diazabicyclo[2.2.2 ]octane), morpholine, N -methylmorpholine , piperidine, sodium carbonate (sodium carbonate), sodium hydroxide, potassium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide, tert -potassium butoxide (potassium tert ) -butoxide, lithium hydroxide, or sodium hydride may be used, preferably sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide. hydroxide), or lithium hydroxide, or any combination thereof may be used.

In one embodiment, the at least one thiol used in step (c2) is Thiophenol, Thioglycolic acid, Ethanethiol, 1-Decanethiol, 1-Undecanethiol, 1-Dodecanethiol, 1-Tetradecanethiol, 1-Pentadecanethiol, 1- Hexadecanethiol (1-Hexadecanethiol), p -Hexylphenylmethanethiol , p -Heptylphenylmethanethiol , p -Octylphenylmethanethiol , or It may be p -Nonylphenylmethanethiol or any combination thereof. Preferably, it is selected from the group consisting of 1-dodecanethiol, 1-pentadecanethiol, and 1-hexadecanethiol.

Thiol often contains a bad odor, and when chemicals that cause bad odor are used, it can cause various health and psychological damage to users and can also have a negative aesthetic effect. In particular, when chemicals that cause odor are used on a large scale in industries such as pharmaceutical manufacturing, regulations and work environment improvements are needed, so it is desirable to replace thiols that cause odor with odorless reagents. In step (c2), it is preferable to use an odorless thiol, for example, a thiol selected from the group consisting of 1-dodecanethiol, 1-pentadecanethiol, and 1-hexadecanethiol. It is desirable to use

In one embodiment, the acid addition salt of the compound of Formula 4 may be prepared by reacting the compound of Formula 4 with an acid to prepare an acid addition salt of the compound of Formula 4. The method for preparing the acid addition salt of the compound of Formula 4 can be appropriately performed by a person skilled in the art based on general knowledge known in the field of organic chemistry.

The compound of Formula 4 obtained in liquid form can be obtained as a solid compound by producing it as an acid addition salt. The compound obtained in solid form has the advantage of being easy to store and manage because it is easy to block contamination from the outside. In addition, since compounds in solid form are obtained through a crystallization process, they usually have the effect of improving purity.

The compound of formula (4) of the present invention or its acid addition salt may be prepared from a phthalazinone derivative. The phthalazinone derivative is a PARP inhibitor and is a compound with anticancer activity. For example, it may be one of the phthalazinone derivatives of the following formula (I) disclosed in U.S. Patent 9,844,550 B2, and is preferably 4-[ of the formula 5 below: 3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1( 2H )-one.

[Formula 5]

[Scheme 2]

A pharmaceutically acceptable salt of the compound of Formula 5 can be prepared by additionally performing the step of reacting the compound of Formula 5 in Scheme 2 with an acid to prepare an acid addition salt of the compound of Formula 5. The method for preparing the pharmaceutically acceptable salt of Formula 5 can be appropriately performed by a person skilled in the art based on common knowledge in the field of organic chemistry. The pharmaceutically acceptable salt of the compound of Formula 5 may be any pharmaceutically suitable acid addition salt, for example, an acid addition salt formed by a free acid, and the free acid may be an inorganic acid or an organic acid. The inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, and the organic acid may be acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, adipic acid, L- or D-tartaric acid, citric acid, lactic acid, and benzoic acid. , mandelic acid, salicylic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, p -toluenesulfonic acid, glycolic acid, pyraminic acid, glucuronic acid, glutamic acid, aspartic acid, or any combination thereof, but is limited thereto. It is not possible, and preferably, the pharmaceutically acceptable salt of the compound of Formula 5 is an acid addition salt formed with hydrochloric acid.

A specific example of preparing the hydrochloride salt of the compound of Chemical Formula 5 shown in Scheme 2 is as follows.

Manufacturing Example 1

tert -Preparation of butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate maleate (maleate of formula 4)

25.7 kg of toluene was added to the reaction section, 3.53 kg of triphenylphosphine, 2.56 kg of 1-Boc-azetidin-3-ylmethanol, and 2.95 kg of N -cyclopropyl-2-nitrobenzenesulfonamide were added, and the reaction section was cooled to 0°C. Cooled. 2.35 kg of diethyl azodicarboxylate was slowly added so that the internal temperature did not exceed room temperature, and stirred at room temperature for 2 hours. After completion of the reaction, the reaction section was cooled to 0°C, 8.1 kg of methanol and 2.0 kg of potassium hydroxide were added, and then 7.4 kg of 1-dodecanethiol was slowly added and stirred at room temperature overnight. The reaction mixture was added to 20 kg of 2N hydrochloric acid aqueous solution, Extracted twice with 10 kg. The aqueous layer was washed with 25.7 kg of toluene, the pH of the aqueous layer was adjusted to above 9 with 22 kg of 9% sodium hydroxide solution, and then extracted twice with 39.3 kg and 19.6 kg of dichloromethane. The combined organic layers were washed with 35 kg of 7% aqueous sodium chloride solution, the organic layer was treated with 2.65 kg of anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. 12.4 kg of ethyl acetate and 1.41 kg of maleic acid were added to the residue, and the resulting crystals were stirred at room temperature overnight, filtered, and dried at 50°C to obtain 3.4 kg of the title compound (yield 81.6%).

^1H NMR (DMSO-d6, 400MHz) δ 6.03 (s, 2H), 3.95 - 3.65 (m, 4H), 3.28 (d, 2H), 2.86 - 2.78 (m, 1H), 2.70 - 2.65 (m, 1H) ), 1.37 (s, 9H), 0.75 - 0.71 (m, 4H)

Production example 2

tert Preparation of -butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate (Formula 6)

13.3 kg of water and 0.78 kg of sodium hydroxide were added to the reaction section, the reaction section was cooled to 0°C, 3.32 kg of tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate maleate was added, and 1N sodium hydroxide was added. 2.1 kg was slowly added to adjust the pH of the water layer to above 9. The aqueous layer was extracted with 8.8 kg of dichloromethane and further extracted with 8.8 kg of dichloromethane. The combined dichloromethane was washed with 13 kg of 7% aqueous sodium chloride solution, treated with 0.93 kg of anhydrous magnesium sulfate, and then filtered. The filtrate was transferred to the reaction section, 1.1 kg of triethylamine was added, and the reaction section was cooled to 0°C. 2.25 kg of trifluoroacetic anhydride was slowly added so that the internal temperature did not exceed room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was washed with 1N aqueous hydrochloric acid solution (15 kg x 2) and then with 17.3 kg of 7% aqueous sodium chloride solution. The organic layer was dried with 0.88 kg of anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to quantitatively obtain 3.13 kg of the title compound as a mixture of white solid and yellow oil. The title compound was used in the next process without any separate separation or purification process.

^1H NMR (CDCl3, 400MHz) δ 3.99 (t, 2H), 3.60 - 3.57 (m, 2H), 2.90 (d, 2H), 2.68 - 2.60 (m, 1H), 2.11 - 2.06 (m, 1H), 1.44 (s, 9H), 0.46 - 0.41 (m, 2H), 0.32- 0.28 (m, 2H)

Production example 3

N -(azetidin-3-ylmethyl)- N Preparation of '-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride (Formula 7)

12.4 kg of methanol was added to the reaction section, 3.13 kg of tert -butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate was added, and then 1.0% concentrated hydrochloric acid was added. kg was added and heated. The reaction was carried out at reflux temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure. 4.0 kg of ethanol was added to the residue, stirred under reflux, cooled to room temperature, 11.3 kg of ethyl acetate was added, stirred overnight, filtered, and dried at 50°C to obtain 1.9 kg of the title compound (yield 75.7%).

^1H NMR (DMSO-d6, 400MHz) δ 9.18 (br, 2H), 4.00 - 3.95 (m, 2H), 3.78 - 3.73 (m, 2H), 3.67 (d, 2H), 3.10 - 3.02 (m, 1H) ), 2.96 - 2.91 (m, 1H), 0.89 - 0.88 (m, 4H)

Production example 4

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 Preparation of (Formula 8)

21.3 kg of dichloromethane was added to the reaction section, 1.6 kg of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid was added, and 1,1' -1.17 kg of carbonyldiimidazole was added and the reaction mixture was stirred at room temperature for 2 hours, then the reaction part was cooled to 15°C, and N -(azetidin-3-ylmethyl)- N '-cyclopropyl-2,2, 1.81 kg of 2-trifluoroacetamide hydrochloride was added, and 0.82 kg of triethylamine was slowly added. The reaction mixture was stirred at room temperature for 1 hour, the reaction was terminated, and the organic layer was washed by adding 15 kg of 1N aqueous hydrochloric acid solution, followed by washing the organic layer with 16 kg of water and 16 kg of 1N aqueous sodium carbonate solution. The organic layer was washed with 16 kg of 7% aqueous sodium chloride solution, treated with 0.48 kg of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. 3.2 kg of dichloromethane and 15.9 kg of n-hexane were added to the residue, stirred overnight, filtered, and dried at 50°C to obtain 2.59 kg of the title compound (yield 95.9%).

^1H NMR (DMSO-d6, 400MHz) δ 12.60 (s, 1H), 8.27 - 8.25 (m, 1H), 7.99 - 7.97 (m, 1H), 7.91 - 7.87 (m, 1H), 7.85 - 7.81 (m) , 1H), 7.48 - 7.45 (m, 2H), 7.22 (t, 1H), 4.33 (s, 2H), 4.14 - 4.02 (m, 2H), 3.79 - 3.62 (m, 4H), 3.00 - 2.93 (m , 1H), 2.88 - 2.86 (m, 1H), 0.88 - 0.85 (m, 4H)

Production example 5

4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2 H ) Preparation of -one (Formula 5)

32.6 kg of methanol was added to the reaction section, and N -cyclopropyl-2,2,2-trifluoro- N '-([1-(2-fluoro-5-[(4-oxo-3,4-di After adding 2.57 kg of hydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide, the reaction part was cooled to 0°C, 10.6 kg of 3% aqueous sodium hydroxide solution was slowly added, and the mixture was cooled to room temperature. was stirred overnight. After completion of the reaction, 55 kg of dichloromethane and 21 kg of water were injected and separated, 35.0 kg of dichloromethane was added, the aqueous layer was further extracted, and the organic layer was concentrated. 3.3 kg of methanol, 14.0 kg of dichloromethane, and 20.0 kg of water were added to the residue, and the pH was adjusted to 2 by adding 6.7 kg of 1N aqueous hydrochloric acid. The organic layer was separated and removed, and the aqueous layer was further washed by adding 35.0 kg of dichloromethane, and the organic layer was It was separated and removed. 6.76 kg of 1N sodium hydroxide was added to adjust the pH of the aqueous layer to over 10, then 51.0 kg of dichloromethane and 31.0 kg of methanol were added for extraction, and 35.0 kg of dichloromethane was added for further extraction. The organic layer was washed with 50 kg of 7% aqueous sodium chloride solution, and the separated dichloromethane was concentrated. 12.4 kg of dichloromethane and 3.3 kg of methanol were added to the residue, and 20.4 kg of n-hexane was slowly added. The resulting crystals were stirred overnight, filtered, and dried at 40°C to obtain 1.71 kg (82.2% yield) of the title compound.

^1H NMR (DMSO-d6, 400MHz) δ 12.60 (s, 1H), 8.28 - 8.25 (m, 1H), 7.99 - 7.97 (m, 1H), 7.91 - 7.87 (m, 1H), 7.85 - 7.81 (m) , 1H), 7.47 - 7.43 (m, 2H), 7.23 - 7.18 (m, 1H), 4.33 (s, 2H), 4.04 - 3.56 (m, 4H), 2.75 - 2.64 (m, 3H), 2.31 (br , 1H), 2.02 - 1.97 (m, 1H), 0.34 - 0.13 (m, 4H)

Production example 6

4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2 H ) - Preparation of hydrochloride salt (hydrochloride of formula 5)

5.4 kg of methanol was added to the reaction section, and 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1( 2H )- After adding 1.7 kg of temperature, the reaction section was cooled to 0°C. 0.4 kg of concentrated hydrochloric acid was slowly added, and 8.0 kg of acetone was added. The resulting crystals were stirred at room temperature for 3 hours, filtered, and dried at 40°C to obtain 1.73 kg of the title compound (yield 93.6%, HPLC purity: 99.896% [area %]).

^1H NMR (DMSO-d6, 400MHz) δ 12.61 (s, 1H), 9.25 (br, 2H), 8.28 - 8.26 (m, 1H), 8.00 - 7.98 (m, 1H), 7.93 - 7.89 (m, 1H) ), 7.86 - 7.82 (m, 1H), 7.50 - 7.45 (m, 2H), 7.25 - 7.21 (m, 1H), 4.33 (s, 2H), 4.13 - 3.82 (m, 4H), 3.30 - 3.22 (m , 2H), 3.06 - 2.99 (m, 1H), 2.66 - 2.61 (m, 1H), 0.89 - 0.68 (m, 4H)

Hereinafter, the method for producing the compound of Formula 4 of the present invention will be described in detail through examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited by the following examples.

Example 1

Preparation of tert -butyl 3-[(cyclopropylamino)methyl] azetidine -1-carboxylate (Formula ⁴ :

422 g of toluene was added to the reaction section, 57.8 g of triphenylphosphine, 41.2 g of 1-Boc-azetidin-3-ylmethanol, and 48.5 g of N -cyclopropyl-2-nitrobenzenesulfonamide were added, and the reaction section was cooled to 0°C. Cooled. 38.4 g of diethyl azodicarboxylate was slowly added so that the internal temperature did not exceed room temperature, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction section was cooled to 0°C, 133.5 g of methanol and 24.0 g of sodium hydroxide were added, and then 121.6 g of 1-dodecanethiol was slowly added and stirred at room temperature overnight. The reaction mixture was added to 327 g of 2N aqueous hydrochloric acid solution, Extracted twice with 146 g. The aqueous layer was washed with 422 g of toluene, the pH of the aqueous layer was adjusted to 9 or higher with 213 g of 9% aqueous sodium hydroxide solution, and then extracted twice with 644 g and 322 g of dichloromethane. The combined organic layers were washed with 600 g of 7% aqueous sodium chloride solution, and the organic layer was treated with 22 g of anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated. 204.4 g of ethyl acetate and 22.1 g of maleic acid were added to the residue, and the resulting crystals were stirred at room temperature overnight, filtered, and dried at 50°C to obtain 59.6 g of the title compound (87.0% yield).

^1H NMR (MeOD, 400MHZ) δ 6.26 (s, 2H), 4.12 - 4.07 (m, 2H), 3.75 - 3.72 (m, 2H), 3.41 (d, 2H), 2.99 - 2.88 (m, 1H), 2.78 - 2.72 (m, 1H), 1.44 (s, 9H), 0.95 - 0.89 (m, 2H), 0.88 - 0.83 (m, 2H)

Example 2

Preparation of t ert -butyl 3-[(cyclopropylamino)methyl] azetidine -1-carboxylate (Formula ⁴ :

Add 230 g of N,N -dimethylformamide to the reaction section, 48.5 g of N -cyclopropyl-4-nitrobenzenesulfonamide and 75.2 g of tert -butyl 3-[(tosyloxy)methyl]azetidine-1-carboxylate. g, 50.6 g of potassium hydroxide was added and stirred at 90°C for 2 hours. After completion of the reaction, the reaction section was cooled to 0°C, 133 g of ethanol was added, and 122.4 g of 1-pentadecanethiol was slowly added. After stirring at room temperature overnight, 440 g of ethyl acetate was added to the reaction mixture, and 2N hydrochloric acid aqueous solution was added. Extracted twice with 400 g and 200 g. The aqueous layer was washed with 422 g of toluene, the pH of the aqueous layer was adjusted to 9 or higher with 177.1 g of 9% aqueous sodium hydroxide solution, and then extracted twice with 534 g and 267 g of dichloromethane. The combined organic layers were washed with 498 g of 7% aqueous sodium chloride solution, the organic layer was treated with 18 g of anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. After adding 355.2 g of acetone and 22.1 g of fumaric acid to the residue, the resulting crystals were stirred at room temperature overnight, filtered, and dried at 50°C to obtain 56.2 g of the title compound (82.1% yield).

^1H NMR (MeOD, 400MHZ) δ 6.69 (s, 2H), 4.11 - 4.06 (m, 2H), 3.73 (m, 2H), 3.37 (d, 2H), 2.99 - 2.88 (m, 1H), 2.72 - 2.67 (m, 1H), 1.43 (s, 9H), 0.91 - 0.81 (m, 4H)

Example 3

Preparation of tert -butyl 3 - [(cyclopropylamino)methyl]azetidine-1-carboxylate (Formula ⁴ :

422 g of toluene was added to the reaction section, 52.7 g of tri-n-butylphosphine, 41.2 g of 1-Boc-azetidin-3-ylmethanol, and 48.5 g of N -cyclopropyl-4-nitrobenzenesulfonamide were added to the reaction section. Cooled to 0°C. 65.7 g of 1,1'-(azodicarbonyl)dipiperidine was slowly added so that the internal temperature did not exceed room temperature, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtered and washed with 42 g of toluene, the reaction part was cooled to 0°C, 132.9 g of ethanol and 63.6 g of sodium carbonate were added, and then 129.4 g of 1-hexadecanethiol was slowly added and stirred at room temperature overnight. Afterwards, the reaction mixture was extracted twice with 327 g and 146 g of 2N aqueous hydrochloric acid solution. The aqueous layer was washed with 422 g of toluene, the pH of the aqueous layer was adjusted to 9 or higher with 201 g of 9% aqueous sodium hydroxide solution, and then extracted twice with 644 g and 322 g of dichloromethane. The combined organic layers were washed with 600 g of 7% aqueous sodium chloride solution, and the organic layer was treated with 22 g of anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated. After adding 35.7 g of ethanol, 204.4 g of ethyl acetate, and 18.0 g of oxalic acid to the residue, the resulting crystals were stirred at room temperature overnight, filtered, and dried at 50°C to obtain 53.9 g of the title compound (85.2% yield).

^1H NMR (MeOD, 400MHZ) δ 4.11 - 4.06 (m, 2H), 3.74 (m, 2H), 3.40 (d, 2H), 3.01 - 2.91 (m, 1H), 2.76 - 2.70 (m, 1H), 1.43 (s, 9H), 0.89 (d, 4H)

Example 4

Preparation of te rt -butyl 3-[(cyclopropylamino)methyl] azetidine -1-carboxylate (Formula ⁴ :

645 g of dichloromethane was added to the reaction section, 57.8 g of triphenylphosphine, 41.2 g of 1-Boc-azetidin-3-ylmethanol, and 48.5 g of N -cyclopropyl-2-nitrobenzenesulfonamide were added, and the reaction section was kept at 0°C. It was cooled. 44.5 g of diisopropyl azodicarboxylate was slowly added so that the internal temperature did not exceed room temperature, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtered and washed with 32 g of dichloromethane, the reaction section was cooled to 0°C, 134 g of methanol and 25.2 g of lithium hydroxide monohydrate were added, and then 121.6 g of 1-dodecanethiol was slowly added. After stirring at room temperature overnight, the reaction mixture was extracted twice with 327 g and 146 g of 2N aqueous hydrochloric acid solution. The aqueous layer was washed with 422 g of toluene, the pH of the aqueous layer was adjusted to over 9 with 213 g of 9% aqueous sodium hydroxide solution, and then extracted twice with 644 g and 322 g of dichloromethane. The combined organic layers were washed with 600 g of 7% aqueous sodium chloride solution, and the organic layer was treated with 22 g of anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated. 204.4 g of ethyl acetate was added to the residue, the reaction section was cooled to 0°C, and 46.5 g of camphorsulfonic acid was slowly added. 59.3 g of n-hexane was added to the resulting crystals, stirred at room temperature overnight, filtered, and dried at 50°C to obtain the title product. Compound 74.1 g (yield 80.7%) was obtained.

^1H NMR ( _DO , 400MHZ) δ 4.18 - 4.14 (m, 2H), 3.80 - 3.76 (m, 2H), 3.46 (d, 2H), 3.29 (d, 1H), 3.04 - 3.00 (m, 1H) ), 2.87 (d, 1H), 2.75 - 2.70 (m, 1H), 2.47 - 2.38 (m, 2H), 2.17 (t, 1H), 2.09 - 2.03 (m, 1H), 2.00 (d, 1H), 1.69 - 1.62 (m, 1H), 1.50 - 1.44 (m, 10H), 1.05 (s, 3H), 0.95 - 0.90 (m, 2H), 0.88 - 0.84 (m, 5H)

Example 5

Preparation of tert -butyl 3-[(cyclopropylamino)methyl] azetidine -1-carboxylate (Formula ⁴ :

431 g of tetrahydrofuran was added to the reaction section, 58.0 g of diphenyl-2-pyridylphosphine, 41.2 g of 1-Boc-azetidin-3-ylmethanol, and 48.5 g of N -cyclopropyl-2-nitrobenzenesulfonamide were added. After addition, the reaction part was cooled to 0°C. 80.9 g of di- p -chlorobenzyl azodicarboxylate was slowly added so that the internal temperature did not exceed room temperature, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtered, washed with 22 g of tetrahydrofuran, and the filtrate was concentrated. 436 g of ethyl acetate and 134 g of methanol were added to the residue, the reaction section was cooled to 0°C, 82.9 g of potassium carbonate was added, 121.6 g of 1-dodecanethiol was slowly added, and the reaction mixture was stirred at room temperature overnight. Extracted twice with 327 g and 146 g. The pH of the water layer was adjusted to 9 or higher with 194 g of 9% aqueous sodium hydroxide solution, and then extracted twice with 644 g and 322 g of dichloromethane. The combined organic layers were washed with 600 g of 7% aqueous sodium chloride solution, and the organic layer was treated with 22 g of anhydrous magnesium sulfate, then filtered, and the filtrate was concentrated. 179.4 g of methanol was added to the residue, the reaction section was cooled to 0°C, 20 g of concentrated hydrochloric acid was slowly added, stirred for 2 hours, and concentrated. 204.4 g of ethyl acetate was added to the residue, and the resulting crystals were stirred at room temperature overnight and then filtered. After drying at 50°C, 42.3 g (yield 80.4%) of the title compound was obtained.

^1H NMR (MeOD, 400MHZ) δ 4.12 - 4.08 (m, 2H), 3.75 (m, 2H), 3.41 (d, 2H), 3.01 - 2.91 (m, 1H), 2.79 - 2.73 (m, 1H), 1.44 (s, 9H), 0.96 - 0.85 (m, 4H)

Claims (16)

1. A method of producing a compound of Formula 4 or an acid addition salt thereof using a compound of Formula 1,

   (c1) reacting a compound of formula 1 with a compound of formula 2 to form a compound of formula 3, and

   Step (c2) of forming a compound of Formula 4 by deprotecting the compound of Formula 3

   Manufacturing method comprising:

   [Formula 1]

   

   ,

   [Formula 2]

   

   ,

   [Formula 3]

   

   ,

   [Formula 4]

   

   ,

   In Formulas 1 to 4,

   X ² is a protecting group of azetidine nitrogen,

   n is 1 or 2,

   Z is selected from the group consisting of hydroxyl group, tosylate, bromine, chlorine, iodine, and mesylate.
2. The method of claim 1, wherein X ² is any one selected from the group consisting of tert- butoxycarbonyl (Boc), triphenylmethyl (Trt), tetrahydropyranyl (THP), and benzyl (Bn).
3. The method of claim 2, wherein X ² is tert -butoxycarbonyl (Boc).
4. According to any one of claims 1 to 3,

   The compound of formula 2 is N -cyclopropyl-2-nitrobenzenesulfonamide, and the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-2-nitrophenyl)sulfonamido]methyl)azetidine- 1-carboxylate, or

   The compound of Formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl)sulfonamido]methyl)azetidine- 1-carboxylate, or

   The compound of formula 2 is N -cyclopropyl-2,4-dinitrobenzenesulfonamide, and the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-2,4-dinitrophenyl)sulfonamido ]Methyl)azetidine-1-carboxylate production method.
5. According to clause 4,

   The compound of formula 2 is N -cyclopropyl-2-nitrobenzenesulfonamide, and the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-2-nitrophenyl)sulfonamido]methyl)azetidine- 1-carboxylate, or

   The compound of Formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl)sulfonamido]methyl)azetidine- Method for producing 1-carboxylate.
6. The method according to any one of claims 1 to 3, wherein Z of the compound of formula 1 is a hydroxy group or a tosylate.
7. According to any one of claims 1 to 3,

   Z of the compound of Formula 1 is a hydroxy group, the compound of Formula 2 is N -cyclopropyl-2-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-2-nitrophenyl ) sulfonamido] methyl) azetidine-1-carboxylate, or

   Z of the compound of Formula 1 is a hydroxy group, the compound of Formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl ) sulfonamido] methyl) azetidine-1-carboxylate, or

   In the compound of formula 1, Z is a tosylate, the compound of formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide, and the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitro Method for producing phenyl) sulfonamido] methyl) azetidine-1-carboxylate.
8. The production method according to any one of claims 1 to 3, wherein the deprotection step (c2) is performed in the presence of at least one base and at least one thiol.
9. The method of claim 8, wherein the at least one thiol is selected from the group consisting of 1-dodecanethiol, 1-pentadecanethiol, and 1-hexadecanethiol.
10. The method according to any one of claims 1 to 3, wherein Z of the compound of formula 1 is a hydroxy group, and step (c1) of forming the compound of formula 3 comprises at least one azo compound and at least one phosphine reagent. A manufacturing method carried out in the presence of
11. The method of claim 10, wherein the azo compound is diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine and di- p -chlorobenzyl azodicarboxylate. A manufacturing method selected from the group consisting of levoxylate.
12. The method of claim 10, wherein the phosphine reagent is selected from the group consisting of triphenylphosphine, tri-n-butylphosphine, and diphenyl-2-pyridylphosphine.
13. The method of any one of claims 1 to 3, wherein Z of the compound of formula 1 is selected from the group consisting of tosylate, bromine, chlorine, iodine, and mesylate, and forming a compound of formula 3 ( A production method wherein c1) is carried out in the presence of at least one base.
14. The method according to any one of claims 1 to 3, wherein the acid addition salt of the compound of formula 4 is formed with at least one acid selected from the group consisting of maleic acid, fumaric acid, oxalic acid, camphorsulfonic acid, and hydrochloric acid. Phosphorus manufacturing method.
15. An acid addition salt of the compound of Formula 4 prepared according to the preparation method of any one of claims 1 to 3, wherein the acid addition salt is selected from the group consisting of maleic acid, fumaric acid, oxalic acid, camphorsulfonic acid, and hydrochloric acid. compound.
16. 16. The process of claim 15 for the preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one. Compounds that are used.