WO2024025389A1 - Procédé de préparation d'un intermédiaire de dérivé de phtalazinone - Google Patents

Procédé de préparation d'un intermédiaire de dérivé de phtalazinone Download PDF

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WO2024025389A1
WO2024025389A1 PCT/KR2023/011064 KR2023011064W WO2024025389A1 WO 2024025389 A1 WO2024025389 A1 WO 2024025389A1 KR 2023011064 W KR2023011064 W KR 2023011064W WO 2024025389 A1 WO2024025389 A1 WO 2024025389A1
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formula
compound
acid
cyclopropyl
tert
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유근철
서한나
성원제
양혜란
윤진영
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아이디언스 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

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  • 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.
  • PARP inhibitor Poly (ADP-ribose) polymerase
  • Patent Document 1 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.
  • tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate a key intermediate of phthalazinone derivatives, tert -butyl 3-formylazetidine-1-carboxylate
  • 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.
  • 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.
  • 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.
  • 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).
  • halide compounds or their equivalents e.g. dialkylsulfates or sulfonates.
  • 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
  • Non-patent Document 2 Tetrahedron Lett. 1999, 40, 3689-3692
  • 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.
  • 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.
  • LiAlH 4 which is a metal hydride
  • 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.
  • 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 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.
  • 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.
  • a protecting group for example, a nitrobenzenesulfonyl group
  • tert -butyl 3-[(cyclopropylamino)methyl]azetidine-1-car 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.
  • 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.
  • 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. .
  • compounds in solid form are obtained through a crystallization process, they usually have the effect of improving purity.
  • 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).
  • 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,
  • the manufacturing method includes:
  • X 2 is a protecting group of azetidine nitrogen
  • n 1 or 2
  • Z is selected from the group consisting of hydroxyl group, tosylate, bromine, chlorine, iodine, and mesylate.
  • 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.
  • 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.
  • 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.
  • n is 1 or 2
  • 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.
  • X 2 is a protecting group of azetidine nitrogen, preferably tert- butoxycarbonyl, and n is 1 or 2.
  • 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 -but
  • 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.
  • 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, 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.
  • 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, tartaric acid (tartaric acid), lactic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, cinnamic acid, methanesulfonic acid, Ethanesulfonic acid
  • 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-dini
  • 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.
  • 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
  • the compound of Formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitrophenyl ) sulfonamido] methyl) azetidine-1-carboxylate, or
  • Z is a tosylate
  • the compound of formula 2 is N -cyclopropyl-4-nitrobenzenesulfonamide
  • the compound of formula 3 is tert -butyl 3-([( N -cyclopropyl-4-nitro It is phenyl)sulfonamido]methyl)azetidine-1-carboxylate.
  • the method for producing the compound of Formula 4 can be represented as shown in Scheme 1 below.
  • 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.
  • reaction conditions may vary depending on the type of Z, which is the leaving group of the compound of Formula 1.
  • step (c1) may be performed in the presence of an azo compound.
  • 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' -t
  • 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
  • step (c1) of forming the compound of Formula 3 includes the presence of at least one base.
  • 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,
  • 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.).
  • a polar aprotic solvent e.g., ethyl acetate, dichloromethane, acetonitrile, acetone, N , N -dimethylformamide , dimethylsulfoxide, N -methyl -2-pyrrolidone, etc.
  • non-polar solvents e.g., toluene, benzene, diethyl ether, tetrahydrofuran, chloroform, 1,4-dioxane) ), etc.
  • dichloromethane or N,N -dimethylformamide as a polar aprotic solvent is used, or toluene or tetrahydrofuran as a nonpolar solvent.
  • 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 °C 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°C or low temperature conditions below -70°C are severe conditions.
  • 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.
  • 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 carbon
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • the pharmaceutically acceptable salt of the compound of Formula 5 is an acid addition salt formed with hydrochloric acid.
  • 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 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.
  • 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%).
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne un procédé de préparation d'un dérivé de phtalazinone, qui est un inhibiteur de poly (ADP-ribose) polymérase (PARP), et un procédé de préparation d'un intermédiaire utilisé dans le procédé de préparation et un sel d'addition d'acide de celui-ci.
PCT/KR2023/011064 2022-07-29 2023-07-28 Procédé de préparation d'un intermédiaire de dérivé de phtalazinone WO2024025389A1 (fr)

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Citations (5)

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KR20150047861A (ko) * 2013-10-25 2015-05-06 한국과학기술연구원 3-아미노메틸 아제티딘 화합물, 이를 포함하는 우울증, 정신 질환, 조루증, 또는 신경병증성 통증의 예방 또는 치료용 약학 조성물, 및 상기 약학 조성물을 포함하는 제제
US9844550B2 (en) * 2013-09-13 2017-12-19 Ildong Pharm Co., Ltd Phtalazinone derivatives and manufacturing process thereof
US20210323946A1 (en) * 2020-04-21 2021-10-21 Idience Co., Ltd. Process for preparing a phthalazinone derivative and intermediates thereof
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