Method for producing phosphodiesterase inhibitors

Abstract

The present invention belongs to the field of pharmaceutical technology, specifically relates to a process and intermediate for the preparation of compounds represented by formula (I) and (I'). The process of the present invention has lower production costs and generates less three wastes, namely exhaust gas, wastewater and solid waste. JPEG2024515043000056.jpg3976

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and more specifically, relates to a method for producing phosphodiesterase inhibitors and to a production intermediate. [Background technology]

[0002] Phosphodiesterase 9 is an important member of the PDE family with very high selectivity for cGMP, and its inhibitors are used to treat cognitive impairments caused by central nervous system disorders, such as senile dementia, schizophrenia, and neurodegenerative diseases of the brain.

[0003] 6-Ethyl-4-(4-methoxy-4-methylpiperidine-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile (i.e., compound 107 in Example 71 of WO2019062733A1) is a PDE9 inhibitor.

[0004] Example 71 of WO2019062733A1 discloses a manufacturing method that includes the following steps:

[0005] [ka]

[0006] When substituents are introduced at the 4th and 6th positions of the 1,7-naphthiridine ring, coupling and nucleophilic substitution reactions are required, resulting in a long reaction flow and low overall yield. In the production process of compound 107, it is necessary to use the intermediate 4,6-dichloro-2-oxo-1,2-dihydro-1,7-naphthiridine-3-carbonitrile (which has the following structure) as a starting point for synthesis.

[0007] [ka]

[0008] Production Example 2 of WO2019062733A1 discloses a method for producing the intermediate 4,6-dichloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile.

[0009] [ka]

[0010] To obtain approximately 0.7 equivalents of the target product, 15 mL of phosphorus oxychloride (density 1.64 g / cm³) is added. 3 It is necessary to use phosphorus oxychloride (with a molecular weight of 153.33 g / mol, i.e., 24.6 g, 0.16 mol, equivalent to 7 equivalents). In other words, to obtain 1 equivalent of 6-ethyl-4-(4-methoxy-4-methylpiperidine-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile, it is necessary to use about 30 equivalents of phosphorus oxychloride in the method disclosed in WO2019062733A1.

[0011] WO2020182076A1 discloses a method for producing the same manufacturing intermediate, 4,6-dichloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile (page 28, manufacturing example 1, step 3).

[0012] WO2020182076A1 further discloses a method for producing 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyrizine-3-carbonitride (page 29, Production Example 2, Step 3). According to this method, 5.13 equivalents of phosphorus oxychloride are required to produce 1 equivalent of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyrizine-3-carbonitride, and a chromatographic separation method is also required.

[0013] Phosphorus oxychloride is highly toxic, explosive, and prone to causing environmental pollution. Therefore, it is desirable to use as little phosphorus oxychloride as possible during the synthesis process. In actual pharmaceutical processes, it is even more desirable to shorten the process flow and avoid purification operations as much as possible in order to improve yield. Therefore, improvements to the synthesis process are still needed in subsequent research processes on synthesis and amplification, and further reductions in manufacturing costs, reductions in the generation of the three types of waste (exhaust gas, wastewater, and solid waste), and improvements in the process safety factor are desired. [Overview of the project]

[0014] The present invention aims to provide a method for producing a compound of formula (I) and a production intermediate, and further to provide a method for producing a compound of formula (I') and a production intermediate.

[0015] The present invention relates to a method for producing a compound of formula (I),

[0016] [ka]

[0017] Step (C') involves reacting (I-4) with a halogenating reagent in an organic solvent to obtain (I-5),

[0018] [ka]

[0019] It is produced by step (D') in which (I-5) is subjected to a nucleophilic substitution reaction with (I-6) and a base in an organic solvent to obtain (I'),

[0020] [ka]

[0021] Of these, X is a halogen atom and M is an alkali metal ion. X1 is CH, X2 is N, X3 is CR3, X4 is CH, R3 is selected from hydrogen, an amino group, a cyano group, a halogen, a carboxyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group, (C 1-4 alkyl)2amino group, morpholinyl group, C 2-6 alkenyl group, C 1-4 alkylcarbonyl group, C 1-4 alkylaminocarbonyl group, (C 1-6 alkyl)2aminocarbonyl group, C 1-4 alkylsulfonyl group, C 1-4 alkylthio group, aminocarbonyl group, cyclopropyl group, azetidinyl group and piperazinyl group, a) Among them, the above C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group, (C 1-4 alkyl)2amino group, C 2-6 alkenyl group, C 1-4 alkylcarbonyl group, C 1-4 alkylaminocarbonyl group, (C 1-6 alkyl)2aminocarbonyl group, C 1-4 alkylsulfonyl group, C 1-4 alkylthio group, aminocarbonyl group is unsubstituted or is independently selected from one or more (under the condition of satisfying valence balance, for example, 1, 2, 3, 4 or 5) groups selected from a hydroxy group, an amino group, a halogen, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group, (C 1-4 alkyl)2amino group, cyclopropyl group, C 1-4 alkylcarbonyloxy group, and a 4-6 membered heterocyclyl group which is unsubstituted or substituted with a C 1-4 alkyl group and is optionally substituted with one or more (under the condition of satisfying valence balance, for example, 1, 2, 3, 4 or 5) groups, b) Of these, the cyclopropyl group, azetidinyl group, morpholinyl group and piperazinyl group are either unsubstituted or have a hydroxyl group, halogen, or C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C 1-4 Alkylamino group, (C 1-4 Alkyl) 2-amino group and C 1-4 The alkylcarbonyloxy group is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5 groups, under conditions that satisfy valence equilibrium), Preferably, R3 is hydrogen, halogen, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, morpholinyl group, C 2-6 Alkenyl group, C 1-4 Alkylaminocarbonyl group, (C 1-4 Selected from alkyl)2-aminocarbonyl groups and aminocarbonyl groups, a) Of these, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 1-4 Alkylaminocarbonyl group, (C 1-4 The alkyl)2-aminocarbonyl group and the aminocarbonyl group are either unsubstituted or have a hydroxyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C 1-4 Alkylamino group, (C 1-4 Alkyl)2 amino group, and unsubstituted or C 1-4 The group is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5, under conditions that satisfy valence equilibrium) independently selected from alkyl-substituted 4-6 membered heterocyclyl groups. b) Of these, the morpholinyl group is either unsubstituted or a hydroxyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C 1-4 Alkylamino group, and (C 1-4The alkyl)2amino group is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5 groups, under conditions that satisfy valence equilibrium) independently selected from the alkyl2amino group. More conveniently, R3 uses hydrogen, halogen, and C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 1-4 Selected from alkylaminocarbonyl groups and aminocarbonyl groups, Of these, C above 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 1-4 Alkylaminocarbonyl groups and aminocarbonyl groups are either unsubstituted or contain a hydroxyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C 1-4 Alkylamino group, (C 1-4 Alkyl)2 amino group, and unsubstituted or C 1-4 The group is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5, under conditions that satisfy valence equilibrium) independently selected from 4-6 membered heterocyclyl groups substituted with alkyl groups. L is a combination, Ring A is a 4-7 member monoheterocyclyl group or a 7-12 member spiroheterocyclyl group, wherein the heteroatoms of the 4-7 member monoheterocyclyl group are selected from N, and the heteroatoms of the 7-12 member spiroheterocyclyl group are selected from one or two combinations of O and N, and the 7-12 member spiroheterocyclyl group contains at least one N, and ring A is linked to L via an N atom. Preferably, ring A is a 4-7 member monoheterocyclyl group having a heteroatom selected from N, and ring A is linked to L via the N atom. More preferably, ring A is

[0022] [ka]

[0023] Selected from, More specifically, ring A is

[0024] [ka]

[0025] And, Each R1 is a hydrogen, hydroxyl group, cyano group, halogen, or C 1-4 Alkyl alkyl group, C 1-4 A group is independently selected from an alkoxy group, a pyrazolyl group, a thiazolyl group, and a triazolyl group, and among them, the C 1-4 Alkyl alkyl group, C 1-4 Alkoxy groups, pyrazolyl groups, thiazolyl groups, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups. Preferably, each R1 is hydrogen, C 1-4 Alkyl alkyl group, C 1-4 A group is independently selected from an alkoxy group, a pyrazolyl group, a thiazolyl group, and a triazolyl group, and among them, the above C 1-4 Alkyl alkyl group, C 1-4 Alkoxy groups, pyrazolyl groups, thiazolyl groups, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups. m is 0, 1, or 2. R2 provides a method for producing a compound of formula (I) selected from hydrogen.

[0026] The present invention is a method for producing a compound of formula (I'),

[0027] [ka]

[0028] Step (C) involves reacting (I'-4) with a halogenating reagent in an organic solvent to obtain (I'-5),

[0029] [ka]

[0030] It is produced by step (D), in which (I'-5) is subjected to a nucleophilic substitution reaction with (I'-6) and a base in an organic solvent to obtain (I'),

[0031] [ka]

[0032] Of these, R1 is C 1-6 It is an alkyl group, X is a halogen atom, M provides a method for producing a compound of formula (I') in which an alkali metal ion is present.

[0033] In one embodiment of the present invention, a method for producing compound (I'), Step (C) involves reacting (I'-4) with a halogenating reagent in an organic solvent to obtain (I'-5),

[0034] [ka]

[0035] It is produced by step (D), in which (I'-5) is subjected to a nucleophilic substitution reaction with (I'-6) and a base in an organic solvent to obtain (I'),

[0036] [ka]

[0037] Of these, R1 is C 1-6 It is an alkyl group, X is a halogen atom, M is K + na + Li + , Cs + A method for producing the compound (I').

[0038] In one embodiment of the present invention, a method for producing a compound of formula (I') further comprises step (B) in which (I'-3) is condensed with a base in an organic solvent to obtain (I'-4),

[0039] [ka]

[0040] R1 is C 1-6 It is an alkyl group, preferably a methyl group or an ethyl group. R2 is C 1-6 It is an alkyl group, preferably a methyl group or an ethyl group. M is K + na + Li + , Cs + And preferably K + na + A method for producing the compound of formula (I').

[0041] In one embodiment of the present invention, a method for producing a compound of formula (I') further comprises step (A) in which formulas (I'-1) and (I'-2) are condensed with a coupling reagent in an organic solvent to obtain (I'-3),

[0042] [ka]

[0043] R1 is C 1-6 It is an alkyl group, preferably a methyl group or an ethyl group. R2 is C 1-6 A method for producing a compound of formula (I') which is an alkyl group, preferably a methyl group or an ethyl group.

[0044] In one embodiment of the present invention, The coupling reagent described in step (A) is one or more of the following: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and dicyclohexylcarbodiimide. The base described in step (B) is one or more of the following: potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium methoxide. The halogenating reagents described in steps (C') and (C) are one or more of the following: phosphorus oxychloride, thionyl chloride, sulfonyl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride. The bases described in step (D') and step (D) are one or more of the following: triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0045] In one embodiment of the present invention, The base described in step (D') and step (D) is triethylamine.

[0046] In one embodiment of the present invention, The organic solvent described in step (A) is one or more of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran, preferably dichloromethane. The organic solvent described in step (B) is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably tetrahydrofuran. The organic solvent described in step (C') and step (C) is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane, preferably acetonitrile. The organic solvent described in step (D') and step (D) is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide, and is preferably ethanol.

[0047] In one embodiment of the present invention, The coupling reagent described in step (A) is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, The base described in step (B) is one or more of potassium methoxide and sodium ethoxide. The halogenating reagent described in step (C') and step (C) is phosphorus oxychloride. The base described in step (D') and step (D) is triethylamine or N,N-diisopropylethylamine.

[0048] In one embodiment of the present invention, In step (A), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-1), preferably 5 to 12 times. In step (B), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-3), preferably 3 to 12 times. In step (C'), the amount of organic solvent used is 2 to 20 times the volume of formula (I-4), preferably 4 to 10 times. In step (C), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-4), preferably 4 to 10 times. In step (D'), the amount of organic solvent used is 2 to 20 times the volume of formula (I-5), preferably 10 to 20 times.

[0049] In step (D), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-5), preferably 10 to 20 times.

[0050] In one embodiment of the present invention, The molar ratio of (I'-1), (I'-2), and the coupling reagent in step (A) above is 1:(0.5~2):(1~2). The molar ratio of (I'-3) to the base in step (B) above is 1:(1~5), The molar ratio of (I-4) and the halogenating reagent in step (C') above is 1:(1~5). The molar ratio of (I'-4) to the halogenating reagent in step (C) above is 1:(1~5). The molar ratio of (I-5), (I-6) and the base in step (D') above is 1:(0.5~2):(1~3), The molar ratio of (I'-5), (I'-6) and the base in step (D) is 1:(0.5~2):(1~3).

[0051] In one embodiment of the present invention, The molar ratio of (I-4) and the halogenating reagent in step (C') above is 1:(1~3). The molar ratio of (I'-4) to the halogenating reagent in step (C) above is 1:(1~3).

[0052] In one embodiment of the present invention, The molar ratio of (I-4) to the halogenating agent in step (C') above is 1:1, 1:1.1, 1:1.2, 1:1.5, or 1:2.3. The molar ratio of (I'-4) to the halogenating agent in step (C) above is 1:1, 1:1.1, 1:1.2, 1:1.5, or 1:2.3.

[0053] The present invention relates to a manufacturing intermediate for a compound of formula (I'), having the following structural formula,

[0054] [ka]

[0055] R1 is C 1-6 an alkyl group, preferably a methyl group or an ethyl group, M is K + , Na + , Li + , Cs + and further provides an intermediate for the production of a compound of formula (I') which is

[0056] In one embodiment of the present invention, the above production intermediate has the following structure:

[0057]

Chemical formula

[0058] The present invention further provides an intermediate for the production of a compound of formula (I') which can be used in the synthesis of a medicament for treating or preventing PDE9-mediated related diseases.

Mode for carrying out the invention

[0059] The "C 1-6 alkyl group" described in the present invention is a linear or branched alkyl group obtained by removing one hydrogen atom from a hydrocarbon moiety having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, and 1-methyl-2-methylpropyl group, etc. The above "C 1-4 alkyl group" refers to the above examples having 1 to 4 carbon atoms.

[0060] The "C 1-4The "alkoxy group" is a group in which the "C 1-4 alkyl group" defined as above is linked to the parent molecule through an oxygen atom, that is, a " 1-4 alkyl - O -" group, for example, a methoxy group, an ethoxy group, an n - propoxy group, an isopropoxy group, an n - butoxy group, a tert - butoxy group, etc.

[0061] The "C 1-4 alkylamino group", "(C 1-4 alkyl)2amino group", "(C 1-4 alkyl)2aminocarbonyl group", "C 1-4 alkylsulfonyl group", "C 1-4 alkylthio group" described in the invention respectively refer to C 1-4 alkyl - NH -, (C 1-4 alkyl)(C 1-4 alkyl)N -, (C 1-4 alkyl)(C 1-4 alkyl)N - C(O)-, C 1-4 alkyl - S(O)2 -, C 1-4 alkyl - S -.

[0062] The "4 - to 6 - membered heterocyclyl group" described in the present invention refers to a non - aromatic cyclic group in which at least one ring carbon atom of 4 to 6 members is substituted with a heteroatom selected from O, S, and N, preferably 1 to 3 heteroatoms, and simultaneously includes that carbon atoms, nitrogen atoms, and sulfur atoms can be substituted with oxo groups.

[0063] The "halogen" described in the present invention means fluorine, chlorine, bromine, iodine, etc.

[0064] The "base" described in the present invention includes organic bases and inorganic bases. Among them, organic bases include, but are not limited to, sodium tert - butoxide, potassium tert - butoxide, LiHMDS, sodium methoxide, sodium ethoxide, potassium methoxide. Inorganic bases include, but are not limited to, potassium hydroxide, sodium hydroxide, magnesium hydroxide, rubidium hydroxide.

[0065] The term "alkali metal" as used in this invention refers to the six metallic elements of Group IA of the periodic table excluding hydrogen (H), namely lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), and francium (Fr).

[0066] In this invention, "double volume" refers to the volume (mL) of solvent required to dissolve 1 g of a substance. For example, if 10 mL of solvent is required to dissolve 1 g of compound (I'-1) of formula (I), this is referred to as 10 times volume.

[0067] In particular, the present invention provides the following technical solutions: Technical proposal 1. In a method for producing the compound of formula (I),

[0068] [ka]

[0069] Step (C') involves reacting (I-4) with a halogenating reagent in an organic solvent to obtain (I-5),

[0070] [ka]

[0071] It is produced by step (D') in which (I-5) is subjected to a nucleophilic substitution reaction with (I-6) and a base in an organic solvent to obtain (I),

[0072] [ka]

[0073] Of these, X is a halogen atom and M is an alkali metal ion. X1 is CH, X2 is N, X3 is CR3, and X4 is CH. R3 consists of hydrogen, amino group, cyano group, halogen, carboxyl group, and C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, (C 1-4 Alkyl) 2 amino group, morpholinyl group, C 2-6 Alkenyl group, C 1-4 Alkylcarbonyl group, C 1-4 Alkylaminocarbonyl group, (C 1-6 Alkyl) 2-aminocarbonyl group, C 1-4 Alkyl sulfonyl group, C 1-4 Selected from alkylthio groups, aminocarbonyl groups, cyclopropyl groups, azetidinyl groups and piperazinyl groups, a) Of these, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, (C 1-4 Alkyl) 2 amino groups, C 2-6 Alkenyl group, C 1-4 Alkylcarbonyl group, C 1-4 Alkylaminocarbonyl group, (C 1-6 Alkyl) 2-aminocarbonyl group, C 1-4 Alkyl sulfonyl group, C 1-4 Alkylthio groups and aminocarbonyl groups are either unsubstituted or are hydroxyl groups, amino groups, halogens, or C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 1-4 Alkylamino group, (C 1-4 Alkyl) 2 amino group, cyclopropyl group, C 1-4 Alkylcarbonyloxy group and unsubstituted or C 1-4 The group is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5, under conditions that satisfy valence equilibrium) independently selected from 4-6 membered heterocyclyl groups substituted with alkyl groups. b) Of these, the cyclopropyl group, azetidinyl group, morpholinyl group and piperazinyl group are either unsubstituted or have a hydroxyl group, halogen, or C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C1-4 Alkylamino group, (C 1-4 Alkyl) 2-amino group and C 1-4 The alkylcarbonyloxy group is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5 groups, under conditions that satisfy valence equilibrium), L is a combination, Ring A is a 4-7 member monoheterocyclyl group or a 7-12 member spiroheterocyclyl group, wherein the heteroatom of the 4-7 member monoheterocyclyl group is selected from N, and the heteroatom of the 7-12 member spiroheterocyclyl group is selected from one or two combinations of O and N, and the 7-12 member spiroheterocyclyl group contains at least one N, and ring A is linked to L via an N atom. Each R1 is a hydrogen, hydroxyl group, cyano group, halogen, or C 1-4 Alkyl alkyl group, C 1-4 A group is independently selected from an alkoxy group, a pyrazolyl group, a thiazolyl group, and a triazolyl group, and among them, the above C 1-4 Alkyl alkyl group, C 1-4 Alkoxy groups, pyrazolyl groups, thiazolyl groups, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups. m is 0, 1, or 2. A method for producing a compound of formula (I), characterized in that R2 is selected from hydrogen.

[0074] Technical proposal 2.R3 involves hydrogen, halogen, and C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, morpholinyl group, C 2-6 Alkenyl group, C 1-4 Alkylaminocarbonyl group, (C 1-4 Selected from alkyl)2-aminocarbonyl groups and aminocarbonyl groups, a) Of these, C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 1-4 Alkylaminocarbonyl group, (C 1-4The alkyl)2-aminocarbonyl group and the aminocarbonyl group are either unsubstituted or have a hydroxyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C 1-4 Alkylamino group, (C 1-4 Alkyl) 2 amino groups, and unsubstituted or C 1-4 The group is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5, under conditions that satisfy valence equilibrium) independently selected from 4- to 6-membered heterocyclyl groups substituted with alkyl groups. b) Of these, the morpholinyl group is either unsubstituted or a hydroxyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C 1-4 Alkylamino group and (C 1-4 A method for producing an atom according to any one of the above technical proposals, characterized in that it is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5 groups under conditions that satisfy valence equilibrium) that are independently selected from the alkyl)2-amino group.

[0075] Technical proposal 3.R3 involves hydrogen, halogen, and C 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 1-4 Selected from alkylaminocarbonyl groups and aminocarbonyl groups, Of these, C above 1-4 Alkyl alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 1-4 Alkylaminocarbonyl groups and aminocarbonyl groups are either unsubstituted or contain a hydroxyl group, C 1-4 Alkoxy group, cyclopropyl group, amino group, C 1-4 Alkylamino group, (C 1-4 Alkyl)2 amino group, and unsubstituted or C 1-4 A method for producing a product according to any one of the above technical proposals, characterized in that the product is optionally substituted with one or more groups (for example, 1, 2, 3, 4, or 5 groups under conditions that satisfy valence equilibrium) independently selected from 4- to 6-membered heterocyclyl groups substituted with alkyl groups.

[0076] Technical proposal 4. A manufacturing method according to any one of the above technical proposals, characterized in that ring A is a 4- to 7-membered monoheterocyclyl group having a heteroatom selected from N, and ring A is linked to L via an N atom.

[0077] Technical proposal 5. Ring A is,

[0078] [ka]

[0079] A manufacturing method according to any one of the above technical proposals, characterized by being selected from.

[0080] Technical proposal 6. Ring A is

[0081] [ka]

[0082] A manufacturing method according to any one of the above technical proposals, characterized in that it is the same as described above.

[0083] Technical proposal 7. Each R1 is hydrogen, C 1-4 Alkyl alkyl group, C 1-4 A group is independently selected from an alkoxy group, a pyrazolyl group, a thiazolyl group, and a triazolyl group, and among them, the above C 1-4 Alkyl alkyl group, C 1-4 The manufacturing method according to any one of the above technical proposals, characterized in that the alkoxy group, pyrazolyl group, thiazolyl group, and triazolyl group are either unsubstituted or substituted with a carbonyl group.

[0084] The manufacturing method according to any one of the above technical proposals, characterized in that in step (C') of technical proposal 8, the halogenating reagent is one or more of the following: phosphorus oxychloride, thionyl chloride, sulfonyl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride.

[0085] Technical proposal 9. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the halogenating reagent is phosphorus oxychloride.

[0086] Technical proposal 10. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the molar ratio of (I-4) to the halogenating reagent is 1:(1~5).

[0087] Technical proposal 11. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the molar ratio of (I-4) to the halogenating reagent is 1:(1-3).

[0088] Technical proposal 12. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the molar ratio of (I-4) to the halogenating reagent is 1:(1.2~2.3).

[0089] Technical proposal 13. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the molar ratio of (I-4) to the halogenating reagent is approximately 1:1.5.

[0090] Technical proposal 14. A method for producing a product according to any one of the above technical proposals, characterized in that in step (D'), the base is one or more of the following: triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0091] Technical Proposal 15. A method for producing a product according to any one of the above technical proposals, characterized in that in step (D'), the base is triethylamine or N,N-diisopropylethylamine.

[0092] Technical Proposal 16. A manufacturing method according to any one of the above technical proposals, characterized in that in step (D'), the base is triethylamine.

[0093] Technical Proposal 17. A method for producing a product according to any one of the above technical proposals, characterized in that in step (D'), the base is N,N-diisopropylethylamine.

[0094] Technical proposal 18. A manufacturing method according to any one of the above technical proposals, characterized in that in step (D'), the molar ratio of (I-5), (I-6) to the base is 1:(0.5~2):(1~3).

[0095] The method for producing a product according to any one of the above technical proposals, characterized in that in step 19.(C'), the organic solvent is one or more of the following: acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane.

[0096] Technical proposal 20. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the organic solvent is acetonitrile.

[0097] The method for producing an organic solvent according to any one of the above technical proposals, characterized in that in step 21(D'), the organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0098] Technical Proposal 22. A manufacturing method according to any one of the above technical proposals, characterized in that in step (D'), the organic solvent is ethanol.

[0099] Technical proposal 23. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-4).

[0100] Technical proposal 24. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the amount of organic solvent used is 4 to 10 times the volume of formula (I'-4).

[0101] Technical Proposal 25. In step (D'), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-5).

[0102] Technical Proposal 26. In step (D'), the amount of organic solvent used is 10 to 20 times the volume of formula (I'-5).

[0103] Technical proposal 27. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the reaction temperature is 40 to 160°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 1 to 36 hours.

[0104] Technical proposal 28. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the reaction temperature is 60 to 140°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 2 to 24 hours.

[0105] Technical proposal 29. A manufacturing method according to any one of the above technical proposals, characterized in that in step (C'), the reaction temperature is 80 to 120°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 4 to 12 hours.

[0106] Technical proposal 30. A manufacturing method according to any one of the above technical proposals, characterized in that in step (D'), the reaction temperature is 40 to 120°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 0.1 to 12 hours.

[0107] Technical proposal 31. A manufacturing method according to any one of the above technical proposals, characterized in that in step (D'), the reaction temperature is 50 to 110°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 0.5 to 6 hours.

[0108] Technical proposal 32. A manufacturing method according to any one of the above technical proposals, characterized in that in step (D'), the reaction temperature is 60 to 100°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 1 to 3 hours.

[0109] Technical proposal 33. A method for producing the compound of formula (I'),

[0110] [ka]

[0111] Step (C) involves reacting (I'-4) with a halogenating reagent in an organic solvent to obtain (I'-5),

[0112] [ka]

[0113] It is produced by step (D), in which (I'-5) is subjected to a nucleophilic substitution reaction with (I'-6) and a base in an organic solvent to obtain (I'),

[0114] [ka]

[0115] Of these, R1 is C 1-6 It is an alkyl group, X is a halogen atom, A method for producing a compound of formula (I'), characterized in that M is an alkali metal ion.

[0116] Technical Proposal 34. The manufacturing method according to Technical Proposal 33, characterized in that in step (C), the halogenating reagent is one or more of the following: phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride.

[0117] Technical Proposal 35. A manufacturing method according to any one of Technical Proposals 33 to 34, characterized in that in step (C), the halogenating reagent is phosphorus oxychloride.

[0118] Technical proposal 36. A manufacturing method according to any one of technical proposals 33 to 35, characterized in that in step (C), the molar ratio of (I'-4) to the halogenating agent is 1:(1 to 5).

[0119] Technical proposal 37. A manufacturing method according to any one of technical proposals 33 to 36, characterized in that in step (C), the molar ratio of (I'-4) to the halogenating agent is 1:(1 to 3).

[0120] Technical proposal 38. A manufacturing method according to any one of technical proposals 33 to 37, characterized in that in step (C), the molar ratio of (I'-4) to the halogenating agent is 1:(1.2~2.3).

[0121] Technical proposal 39. A manufacturing method according to any one of technical proposals 33 to 38, characterized in that in step (C), the molar ratio of (I'-4) to the halogenating agent is approximately 1:1.5.

[0122] Technical proposal 40. A manufacturing method according to any one of technical proposals 33 to 39, characterized in that in step (D), the base is one or more of the following: triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0123] Technical Proposal 41. A manufacturing method according to any one of Technical Proposals 33 to 40, characterized in that in step (D), the base is triethylamine or N,N-diisopropylethylamine.

[0124] Technical Proposal 42. A manufacturing method according to any one of Technical Proposals 33 to 41, characterized in that in step (D), the base is triethylamine.

[0125] Technical Proposal 43. A manufacturing method according to any one of Technical Proposals 33 to 42, wherein in step (D), the base is N,N-diisopropylethylamine.

[0126] Technical proposal 44. A manufacturing method according to any one of technical proposals 33 to 43, characterized in that in step (D), the molar ratio of (I'-5), (I'-6) to the base is 1:(0.5~2):(1~3).

[0127] Technical Proposal 45. A manufacturing method according to one of Technical Proposals 33 to 44, characterized in that in step (C), the organic solvent is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane.

[0128] Technical Proposal 46. A manufacturing method according to any one of Technical Proposals 33 to 45, characterized in that in step (C), the organic solvent is acetonitrile.

[0129] Technical Proposal 47. A manufacturing method according to any one of Technical Proposals 33 to 46, characterized in that in step (D), the organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0130] Technical proposal 48. The manufacturing method according to any one of claims 33 to 47, characterized in that in step (D), the organic solvent is ethanol.

[0131] Technical proposal 49. A manufacturing method according to any one of technical proposals 33 to 48, characterized in that in step (C), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-4).

[0132] Technical proposal 50. A manufacturing method according to any one of technical proposals 33 to 49, characterized in that in step (C), the amount of organic solvent used is 4 to 10 times the volume of formula (I'-4).

[0133] Technical proposal 51. A manufacturing method according to any one of technical proposals 33 to 50, characterized in that in step (D), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-5).

[0134] Technical proposal 52. A manufacturing method according to any one of technical proposals 33 to 51, characterized in that in step (D), the amount of organic solvent used is 10 to 20 times the volume of formula (I'-5).

[0135] Technical proposal 53. A manufacturing method according to any one of technical proposals 33 to 52, characterized in that in step (C), the reaction temperature is 40 to 160°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 1 to 36 hours.

[0136] Technical proposal 54. A manufacturing method according to any one of technical proposals 33 to 53, characterized in that in step (C), the reaction temperature is 60 to 140°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 2 to 24 hours.

[0137] Technical proposal 55. A manufacturing method according to any one of technical proposals 33 to 54, characterized in that in step (C), the reaction temperature is 80 to 120°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 4 to 12 hours.

[0138] Technical proposal 56. A manufacturing method according to any one of technical proposals 33 to 55, characterized in that in step (D), the reaction temperature is 40 to 120°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 0.1 to 12 hours.

[0139] Technical proposal 57. A manufacturing method according to any one of technical proposals 33 to 56, characterized in that in step (D), the reaction temperature is 50 to 110°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 0.5 to 6 hours.

[0140] Technical proposal 58. A manufacturing method according to any one of technical proposals 33 to 57, characterized in that in step (D), the reaction temperature is 60 to 100°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 1 to 3 hours.

[0141] Technical proposal 59. The proposal further comprises step (B), in which (I'-3) is condensed with a base in an organic solvent to obtain (I'-4),

[0142] [ka]

[0143] R1 is C 1-6 It is an alkyl group, R2 is C 1-6 It is an alkyl group, M is K + na + Li + , Cs + A manufacturing method according to any one of the technical proposals 1 to 58, characterized in that it is the same as described above.

[0144] Technical proposal 60. The manufacturing method according to technical proposal 59, characterized in that R1 is a methyl group or an ethyl group.

[0145] Technical proposal 61. A manufacturing method according to technical proposals 59-60, characterized in that R2 is a methyl group or an ethyl group.

[0146] Technical proposal 62.M is K + or Na + A manufacturing method according to any one of the technical proposals 59 to 61, characterized in that it is the same as described above.

[0147] Technical Proposal 63. A manufacturing method according to any one of Technical Proposals 59 to 62, characterized in that in step (B), the base is one or more of the following: potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium methoxide.

[0148] Technical Proposal 64. A manufacturing method according to any one of Technical Proposals 59 to 63, characterized in that in step (B), the base is potassium methoxide and / or sodium ethoxide.

[0149] Technical proposal 65. A manufacturing method according to any one of technical proposals 59 to 64, characterized in that in step (B), the molar ratio of (I'-3) to the base is 1:(1~5).

[0150] Technical Proposal 66. A manufacturing method according to any one of Technical Proposals 59 to 65, characterized in that in step (B), the organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0151] Technical Proposal 67. The manufacturing method according to any one of Technical Proposals 59 to 66, characterized in that in step (B), the organic solvent is tetrahydrofuran.

[0152] Technical Proposal 68. A manufacturing method according to any one of Technical Proposals 59 to 67, characterized in that in step (B), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-3).

[0153] Technical proposal 69. A manufacturing method according to any one of technical proposals 59 to 68, characterized in that in step (B), the amount of organic solvent used is 3 to 12 times the volume of formula (I'-3).

[0154] Technical Proposal 70. A manufacturing method according to any one of Technical Proposals 59 to 69, characterized in that in step (B), the reaction temperature is 40 to 120°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 0.1 to 12 hours.

[0155] Technical proposal 71. A manufacturing method according to any one of technical proposals 59 to 70, characterized in that in step (B), the reaction temperature is 50 to 120°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 0.5 to 6 hours.

[0156] Technical proposal 72. A manufacturing method according to any one of technical proposals 59 to 71, characterized in that in step (B), the reaction temperature is 60 to 100°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 1 to 3 hours.

[0157] Technical proposal 73. The proposal further comprises step (A), in which formulas (I'-1) and (I'-2) are condensed with a coupling reagent in an organic solvent to obtain (I'-3),

[0158] [ka]

[0159] R1 is C 1-6 It is an alkyl group, R2 is C 1-6 A method for manufacturing according to any one of the technical proposals 59 to 72, characterized by being an alkyl group.

[0160] Technical proposal 74. The manufacturing method according to technical proposal 73, characterized in that R1 is a methyl group or an ethyl group.

[0161] Technical proposal 75. A manufacturing method according to any one of technical proposals 73 to 74, characterized in that R2 is a methyl group or an ethyl group.

[0162] Technical proposal 76. A method for producing a product according to any one of Technical proposals 73 to 75, characterized in that in step (A), the coupling reagent is one or more of the following: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and dicyclohexylcarbodiimide.

[0163] Technical Proposal 77. A manufacturing method according to any one of Technical Proposals 73 to 76, characterized in that in step (A), the coupling reagent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0164] Technical proposal 78. A manufacturing method according to any one of technical proposals 73 to 77, characterized in that in step (A), the molar ratio of (I'-1), (I'-2) to the coupling agent is 1:(0.5~2):(1~2).

[0165] Technical proposal 79. A method for producing an organic solvent according to any one of Technical proposals 73 to 78, characterized in that in step (A), the organic solvent is one or more of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran.

[0166] Technical Proposal 80. A manufacturing method according to any one of Technical Proposals 73 to 79, characterized in that in step (A), the organic solvent is dichloromethane.

[0167] Technical proposal 81. A manufacturing method according to any one of technical proposals 73 to 80, characterized in that in step (A), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-1).

[0168] Technical proposal 82. A manufacturing method according to any one of technical proposals 73 to 81, characterized in that in step (A), the amount of organic solvent used is 5 to 12 times the volume of formula (I'-1).

[0169] Technical proposal 83. A manufacturing method according to any one of technical proposals 73 to 82, characterized in that in step (A), the reaction temperature is 10 to 40°C, and the temperature is 5°C or less lower than the boiling point of the solvent, and the reaction time is 0.1 to 12 hours.

[0170] Technical solution 84. The manufacturing method according to any one of technical solutions 73 to 83, characterized in that in step (A), the reaction temperature is 15 to 35 °C, and the temperature is 5 °C or lower lower than the boiling point of the solvent, and the reaction time is 0.5 to 6 hours.

[0171] Technical solution 85. The manufacturing method according to any one of technical solutions 73 to 84, characterized in that in step (A), the reaction temperature is 20 to 30 °C, the temperature is 5 °C or lower lower than the boiling point of the solvent, and the reaction time is 1 to 3 hours.

[0172] Technical solution 86. An intermediate of the compound of formula (I’),

[0173]

Chemical formula

[0174] R1 is a C 1-6 alkyl group, M is K + , Na + , Li + , Cs + and has a structural formula characterized by being an intermediate of the compound of formula (I’).

[0175] Technical solution 87. An intermediate of the compound of formula (I’),

[0176]

Chemical formula

[0177] R1 is a methyl group or an ethyl group, M is K + , Na + , Li + , Cs + and has a structural formula characterized by being an intermediate of the compound of formula (I’).

[0178] Technical solution 88.

[0179]

Chemical formula

[0180] An intermediate characterized by having the following structure.

[0181] The manufacturing methods disclosed in WO2019062733A1 and WO2020182076A1 use an intermediate such as a 1,2-dihydro-2-oxo-3-cyano-1,7-naphthyridine-4-ol compound to undergo a halogenation reaction with a halogenating agent. In contrast, the manufacturing method of the present invention allows for the use of an intermediate such as a 1,2-dihydro-2-oxo-3-cyano-1,7-naphthyridine-4-yl alkali metal salt compound to undergo a halogenation reaction with a halogenating agent. As illustrated in the following examples, the present invention can reduce the amount of toxic and harmful halogenating agents (e.g., phosphorus oxychloride) used. [Examples]

[0182] The above-described content of the present invention will be explained in more detail below with reference to specific examples, but the scope of the present invention should not be understood as being limited to the following examples. Any technology realized based on the above content of the present invention falls within the scope of the present invention.

[0183] The abbreviations used herein are as follows: "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. "DIPEA" refers to N,N-diisopropylethylamine.

[0184] [ka]

[0185] It was prepared by referring to compound 23 and example 14 of WO2009093032A1.

[0186] Example 1: Preparation of the compound of formula (I)

[0187]

Chem.

[0188] Step 1a: Synthesis of Ethyl 6-ethyl-3-(cyanoacetamido)pyridine-4-carboxylate

[0189]

Chem.

[0190] The intermediate ethyl 6-ethyl-3-aminopyridine-4-carboxylate (100 g, 514.84 mmol, 1.0 eq) was dissolved in dichloromethane (1.00 L), cyanoacetic acid (52.55 g, 617.81 mmol, 1.2 eq) was added under ice bath conditions, and EDCI (148.03 g, 772.26 mmol, 1.5 eq) was added in multiple portions. The reaction was carried out at 25 °C for 2 hours, and it was detected by LC-MS that the reaction was complete. H2O (1.00 L) was added to the reaction solution, and after liquid separation, the organic phase was washed with H2O (2 × 500 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the crude product was slurried with methyl tert-butyl ether (300 mL) to obtain the product (128 g, yield 95.15%).

[0191] Step 1b: Synthesis of Ethyl 6-ethyl-3-(cyanoacetamido)pyridine-4-carboxylate The intermediate ethyl 6-ethyl-3-aminopyridine-4-carboxylate (500 g, 2.57 mmol, 1.0 eq) was dissolved in dichloromethane (6.00 L), and cyanoacetic acid (262.76 g, 3.09 mol, 1.2 eq) was added under ice bath conditions. EDCI (740.23 g, 3.86 mol, 1.5 eq) was added in multiple batches, and the mixture was reacted at 25°C for 2 hours. The completion of the reaction was detected by LC-MS. H2O (5.00 L) was added to the reaction mixture, and the liquid-liquid was separated. The aqueous phase was extracted with DCM (2 × 500 mL), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, filtered by suction, and the filtrate was concentrated to 1.0 L. This filtrate was added dropwise to 5.0 L of n-heptane, and a large amount of solid precipitated. The solid was collected by suction filtration and dried at 50°C to obtain the product (658 g, yield 98%).

[0192] Step 2a: Synthesis of 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-4-potassium alkoxide

[0193] [ka]

[0194] Potassium methoxide (2.95 g, 42.10 mmol, 1.1 eq) was dispersed in n-heptane (200 mL), and the system was heated to 80°C. Subsequently, the intermediate ethyl 6-ethyl-3-(cyanoacetamide)pyridine-4-carboxylate (10 g, 38.27 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL) and added dropwise to the heated system. After the addition was complete, the reaction was carried out at 80°C for 2 hours, and the completion of the reaction was detected by LC-MS. Heating was stopped, the reaction system was allowed to cool naturally to room temperature, and the mixture was filtered by suction. The filtered cake was dried to obtain the crude product (10.4 g, yield 107.29%).

[0195] Step 2b: Synthesis of 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-4-sodium alkoxide

[0196] [ka]

[0197] Sodium ethoxide (2.86 g, 42.10 mmol, 1.1 eq) was dispersed in n-heptane (200 mL), and the system was heated to 80°C. Subsequently, the intermediate ethyl 6-ethyl-3-(cyanoacetamide)pyridine-4-carboxylate (10 g, 38.27 mmol, 1.0 eq) was dissolved in tetrahydrofuran (30 mL) and added dropwise to the heated system. After the addition was complete, the reaction was carried out at 80°C for 2 hours, and the completion of the reaction was detected by LC-MS. Heating was stopped, the reaction system was allowed to cool naturally to room temperature, and the mixture was filtered by suction. The filtered cake was dried to obtain the crude product (10.3 g, yield 113.43%).

[0198] Step 3a: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0199] [ka]

[0200] The intermediate 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-4-potassium alkoxide (5 g, 19.74 mmol, 1.0 eq) was dissolved in acetonitrile (50 mL), phosphorus oxychloride (4.54 g, 29.61 mmol, 1.5 eq) was added at room temperature, and the mixture was reacted at 100 °C for 8 hours. The reaction mixture was cooled, concentrated, and H₂O (50 mL) was added. The pH was adjusted to approximately 6 with 10% sodium hydroxide, and a large amount of yellow solid precipitated. The mixture was filtered by suction and dried to obtain 3.87 g of crude product (yield 83.95%).

[0201] Step 3b: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0202] [ka]

[0203] The intermediate 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-4-potassium alkoxide (5 g, 19.74 mmol, 1.0 eq) was dissolved in acetonitrile (50 mL), phosphorus oxychloride (3.63 g, 23.69 mmol, 1.2 eq) was added at room temperature, and the reaction was carried out at 100 °C for 8 hours. The reaction mixture was cooled, concentrated, and H₂O (50 mL) was added. The pH was adjusted to approximately 6 with 10% sodium hydroxide, and a large amount of yellow solid precipitated. The mixture was filtered by suction and dried to obtain 3.47 g of crude product (yield 75.27%).

[0204] Step 3c: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0205] [ka]

[0206] The intermediate 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-4-potassium alkoxide (10 g, 39.5 mmol, 1.0 eq) was dissolved in acetonitrile (100 mL), and phosphorus oxychloride (13.93 g, 90.85 mmol, 2.3 eq) was added in several portions at room temperature. The mixture was reacted at 100 °C for 8 hours. The reaction mixture was cooled, concentrated, and H₂O (500 mL) was added. The pH was adjusted to approximately 6 with 10% sodium hydroxide, and a large amount of yellow solid precipitated. The mixture was filtered by suction and dried to obtain 7.18 g of crude product (yield 77.87%).

[0207] Step 3d: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0208] [ka]

[0209] The intermediate 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-naphthyridine-4-sodium alkoxide (5 g, 21.08 mmol, 1.0 eq) was dissolved in acetonitrile (50 mL), phosphorus oxychloride (4.85 g, 31.62 mmol, 1.5 eq) was added at room temperature, and the reaction was carried out at 100 °C for 8 hours. The reaction mixture was cooled, concentrated, and H₂O (50 mL) was added. The pH was adjusted to approximately 6 with 10% sodium hydroxide, and a large amount of yellow solid precipitated. The mixture was filtered by suction and dried to obtain 3.72 g of crude product (yield 75.46%).

[0210] Step 3e: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0211] [ka]

[0212] The intermediate 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-naphthyrizine-4-potassium alkoxide (120 g, 473.7 mmol, 1.0 eq) was dissolved in acetonitrile (1200 mL), and phosphorus oxychloride (73.36 g, 478.48 mmol, 1.01 eq) was added in several portions at room temperature, and the mixture was reacted at 100 °C for 8 hours. The reaction mixture was cooled and concentrated, 1200 mL of H2O was added, and the pH was adjusted to approximately 6 with 10% sodium hydroxide. A large amount of yellow solid precipitated, which was filtered by suction and dried to obtain the crude product. 2350 mL of tetrahydrofuran (THF) was added to the crude product, activated carbon was added, and the mixture was heated, refluxed, and filtered. The filtrate was evaporated with isopropyl acetate to remove the THF, and after cooling to room temperature, a large amount of solid precipitated. The solid was collected and dried to obtain 80.45 g of yellow solid (yield 72.7%).

[0213] Step 4a: Synthesis of 6-ethyl-4-(4-methoxy-4-methylpiperidine-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0214] [ka]

[0215] The intermediates 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrilate (91 g, 390.3 mmol, 1.0 eq) and 4-methyl-4-methoxypiperidine hydrochloride (70.89 g, 429.43 mmol, 1.1 eq) were dissolved in ethanol (1365 mL), DIPEA (151.36 g, 1171.17 mmol, 3.0 eq) were added, and the mixture was reacted at 80°C for 2 hours. The completion of the reaction was detected by LC-MS. Approximately 75% ethanol was removed by vacuum distillation, water (2L) was added, the mixture was stirred at 25°C for 1 hour, and the mixture was filtered by suction. The filtered cake was completely refluxed with ethanol (4L), filtered by suction, concentrated to approximately 1L, cooled to approximately 10°C, filtered by suction, and the filtered cake was dried to obtain the product (69g, yield 54.15%).

[0216] 1 HNMR (400 MHz, DMSO-d6) δ(ppm): 11.90 (s, 1H), 8.58 (s, 1H), 7.40 (s, 1H), 3.59-3.61 (m, 4H), 3.19 (s, 3H), 2.78-2.84 (m, 2H), 1.89-1.93 (m, 2H), 1.77-1.82 (m, 2H), 1.22-1.26 (m, 6H).

[0217] Molecular formula:C 18 H 22 N4O2 molecular weight: 326.40 LC-MS(Pos, m / z)=327.59[M+H] + .

[0218] Step 4b: Synthesis of 6-ethyl-4-(4-methoxy-4-methylpiperidine-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile

[0219] [ka]

[0220] The intermediates 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile (15 g, 64.2 mmol, 1.0 eq) and 4-methyl-4-methoxypiperidine hydrochloride (11.7 g, 70.62 mmol, 1.1 eq) were dissolved in ethanol (150 mL), triethylamine (14.29 g, 141.23 mmol, 2.2 eq) was added, and the mixture was reacted at 80°C for 2 hours. The completion of the reaction was detected by LC-MS. Approximately 75% ethanol was removed by distillation under reduced pressure, water (300 mL) was added, the mixture was stirred at 25°C for 1 hour, filtered by suction, and the filter cake was completely dissolved under reflux in ethanol (600 mL). Activated carbon (2 g) was added, and the mixture was refluxed for 0.5 hours. The filtrate was filtered by suction, concentrated to approximately 400 mL, cooled to room temperature, filtered by suction, and the filtered cake was dried to obtain the product (17.10 g, yield 81.6%).

[0221] Example 2 In step 1, 6-ethyl-3-(cyanoacetamide)pyridine-4-carboxylate ethyl can be obtained by replacing EDCI with 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or dicyclohexylcarbodiimide, and dichloromethane with N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran.

[0222] In step 2a, the corresponding product can be obtained by replacing potassium methoxide with sodium ethoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide, and by replacing tetrahydrofuran with ethanol, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide.

[0223] In step 2b, the corresponding product can be obtained by replacing sodium ethoxide with potassium methoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide, and by replacing tetrahydrofuran with ethanol, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide.

[0224] In steps 3a, 3b, 3c, and 3d, acetonitrile can be replaced with tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, or 1,2-dichloroethane, and phosphorus oxychloride can be replaced with thionyl chloride, sulfuryl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, or oxalyl chloride to obtain 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile.

[0225] In step 4a, 6-ethyl-4-(4-methoxy-4-methylpiperidine-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitriel can be obtained by replacing N,N-diisopropylethylamine with triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, and replacing ethanol with tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide.

[0226] In step 4b, by replacing triethylamine with N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, and replacing ethanol with tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide, 6-ethyl-4-(4-methoxy-4-methylpiperidine-1-yl)-2-oxo-1,2-dihydro-1,7-naphthyridine-3-carbonitrile can be obtained.

[0227] The novel manufacturing method according to the present invention has the following advantages: (1) Compared to the prior art, the present invention can significantly reduce the amount of halogenating reagents such as phosphorus oxychloride added while maintaining the same or even higher yield. That is, when the same or even higher amount of the target product is obtained, a smaller amount of halogenating reagents such as phosphorus oxychloride can be used. This reduces manufacturing costs and also significantly reduces the amount of waste generated, namely exhaust gas, wastewater, and solid waste.

[0228] (2) In large-scale factory production, the large-scale use of certain halogenating reagents such as phosphorus oxychloride can instantaneously generate a large amount of heat during the quenching of the post-processing process, and if the processing is not carried out properly, there is a risk of explosion. The present invention significantly reduces the amount of halogenating reagents such as phosphorus oxychloride added, correspondingly reduces the generation of thermal energy in the post-processing process, improves the safety of the post-processing system, and is more suitable for large-scale factory production.

[0229] The foregoing are merely preferred embodiments of the present invention and do not limit it. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should all be included within the scope of the claims.

Claims

1. A method for producing the compound of formula (I), 【Chemistry 1】 Step (C') involves reacting (I-4) with a halogenating reagent in an organic solvent to obtain (I-5), 【Chemistry 2】 It is produced by step (D') in which (I-5) is subjected to a nucleophilic substitution reaction with (I-6) and a base in an organic solvent to obtain (I), 【Transformation 3】 Of these, X is a halogen atom and M is an alkali metal ion. X １ CH is, X ２ N is X ３ CR ３ X ４ CH is, R ３ is selected from hydrogen, an amino group, a cyano group, a halogen, a carboxyl group, C １－４ alkyl group, C １－４ alkoxy group, C １－４ alkylamino group, (C １－４ alkyl) ２ amino group, morpholinyl group, C ２－６ alkenyl group, C １－４ alkylcarbonyl group, C １－４ alkylaminocarbonyl group, (C １－６ alkyl) ２ aminocarbonyl group, C １－４ alkylsulfonyl group, C １－４ alkylthio group, aminocarbonyl group, cyclopropyl group, azetidinyl group and piperazinyl group, a) Of these, C １－４ alkyl group, C １－４ Alkoxy group, C １－４ Alkylamino group, (C １－４ Alkyl) ２ amino group, C ２－６ Alkenyl group, C １－４ Alkylcarbonyl group, C １－４ Alkylaminocarbonyl group, (C １－６ Alkyl) ２ aminocarbonyl group, C １－４ Alkyl sulfonyl group, C １－４ Alkylthio groups and aminocarbonyl groups are either unsubstituted or are hydroxyl groups, amino groups, halogens, or C １－４ alkyl group, C １－４ Alkoxy group, C １－４ Alkylamino group, (C １－４ Alkyl) ２ Amino group, cyclopropyl group, C １－４ Alkylcarbonyloxy group, and unsubstituted or C １－４ The group is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from 4-6 member heterocyclyl groups substituted with alkyl groups, under conditions that satisfy valence equilibrium. b) Of these, the cyclopropyl group, azetidinyl group, morpholinyl group and piperazinyl group are either unsubstituted or contain a hydroxyl group, halogen, C １－４ alkyl group, C １－４ Alkoxy group, cyclopropyl group, amino group, C １－４ Alkylamino group, (C １－４ Alkyl) ２ amino group and C １－４ The alkylcarbonyloxy group is optionally substituted with one, two, three, four, or five groups independently selected from the alkylcarbonyloxy group, under conditions that satisfy valence equilibrium. L is a bond, Ring A is a 4- to 7-membered monoheterocyclyl group or a 7- to 12-membered spiroheterocyclyl group, wherein the heteroatoms of the 4- to 7-membered monoheterocyclyl group are selected from N, and the heteroatoms of the 7- to 12-membered spiroheterocyclyl group are selected from one or two combinations of O and N, and the 7- to 12-membered spiroheterocyclyl group contains at least one N, and ring A is linked to L via an N atom. Each R １ C is hydrogen, hydroxyl group, cyano group, halogen, C １－４ alkyl group, C １－４ A group is independently selected from an alkoxy group, a pyrazolyl group, a thiazolyl group, and a triazolyl group, and among them, the C １－４ alkyl group, C １－４ Alkoxy groups, pyrazolyl groups, thiazolyl groups, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups. m is 0, 1, or 2. R ２ It is selected from hydrogen. A manufacturing method characterized by the following features.

2. Satisfying one or more of the following conditions, In step (C'), the halogenating reagent is one or more of the following: phosphorus oxychloride, thionyl chloride, sulfonyl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride. In step (C'), the molar ratio of (I-4) to the halogenating agent is 1:(1.2-2.3). In step (D'), the base is one or more of the following: triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide. In step (D'), the molar ratio of (I-5), (I-6) to the base is 1:(0.5-2):(1-3). The manufacturing method according to claim 1, characterized in that it

3. Satisfying one or more of the following conditions, In step (C'), the organic solvent is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane. In step (D'), the organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide. In step (C'), the amount of organic solvent used is 4 to 10 times the volume of formula (I'-4), In step (D'), the amount of organic solvent used is 10 to 20 times the volume of formula (I'-5). The manufacturing method according to any one of claims 1 to 2.

4. Satisfying one or more of the following conditions, R3 is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 alkoxy group, morpholinyl group, C2-6 alkenyl group, C1-4 alkylaminocarbonyl group, (C1-4 alkyl)2 aminocarbonyl group, and aminocarbonyl group. Ring A is a 4- to 7-membered monoheterocyclyl group having a heteroatom selected from N, and ring A is linked to L via the N atom. Each R1 is independently selected from hydrogen, a C1-4 alkyl group, a C1-4 alkoxy group, a pyrazolyl group, a thiazolyl group, and a triazolyl group, of which the C1-4 alkyl group, C1-4 alkoxy group, pyrazolyl group, thiazolyl group, and triazolyl group are either unsubstituted or substituted with a hydroxyl group. In step (C'), the halogenating reagent is phosphorus oxychloride, In step (C'), the molar ratio of (I-4) to the halogenating agent is 1:1.

5. In step (D'), the base is triethylamine or N,N-diisopropylethylamine. In step (C'), the organic solvent is acetonitrile. In step (D'), the organic solvent is ethanol. The manufacturing method according to any one of claims 1 to 2.

5. Satisfying one or more of the following conditions, R3 is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 alkoxy group, C2-6 alkenyl group, C1-4 alkylaminocarbonyl group and aminocarbonyl group. Ring A is, 【Chemistry 4】 Selected from The manufacturing method according to any one of claims 1 to 2.

6. A method for producing the compound of formula (I'), 【Transformation 5】 Step (C) involves reacting (I'-4) with a halogenating reagent in an organic solvent to obtain (I'-5), 【Transformation 6】 It is produced by step (D), in which (I'-5) is subjected to a nucleophilic substitution reaction with (I'-6) and a base in an organic solvent to obtain (I'), 【Transformation 7】 Eventually, R １ is C １－６ It is an alkyl group, X is a halogen atom, M is an alkali metal ion. A manufacturing method characterized by the following features.

7. Satisfying one or more of the following conditions, In step (C), the halogenating reagent is one or more of the following: phosphorus oxychloride, thionyl chloride, sulfonyl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride. In step (C), the molar ratio of (I'-4) to the halogenating agent is 1:(1.2-2.3). In step (D), the base is one or more of the following: triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide. In step (D), the molar ratio of (I'-5), (I'-6) to the base is 1:(0.5-2):(1-3). The manufacturing method according to claim 6.

8. Satisfying one or more of the following conditions, The halogenating reagent is phosphorus oxychloride, In step (C), the molar ratio of (I'-4) to the halogenating agent is 1:1.

5. In step (D), the base is triethylamine or N,N-diisopropylethylamine. The manufacturing method according to claim 6 or 7, characterized by the above.

9. Satisfying one or more of the following conditions, In step (C), the organic solvent is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane. In step (D), the organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide. In step (C), the amount of organic solvent used is 4 to 10 times the volume of formula (I'-4), In step (D), the amount of organic solvent used is 10 to 20 times the volume of formula (I'-5). The manufacturing method according to any one of claims 6 to 7, characterized by...

10. Satisfying one or more of the following conditions, In step (C), the organic solvent is acetonitrile. In step (D), the organic solvent is ethanol. The manufacturing method according to claim 6 or 7, characterized by the above.

11. The process further includes step (B), in which (I'-3) is condensed with a base in an organic solvent to obtain (I'-4), 【Transformation 8】 R １ C １－６ It is an alkyl group, R2 is C １－６ It is an alkyl group, M is K ＋ Na ＋ Li ＋ , Cs ＋ That is The manufacturing method according to claim 6.

12. Satisfying one or more of the following conditions, In step (B), the base is one or more of the following: potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, potassium methoxide. The manufacturing method according to claim 11, characterized in that in step (B), the molar ratio of (I'-3) to the base is 1:(1-5).

13. Satisfying one or more of the following conditions, In step (B), the organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide. In step (B), the amount of organic solvent used is 3 to 12 times the volume of formula (I'-3). The manufacturing method according to any one of claims 11 to 12.

14. In step (B), the base is one or more of potassium methoxide and sodium ethoxide, The organic solvent is tetrahydrofuran. The manufacturing method according to claim 12, characterized in that it is a feature of the present invention.

15. The method further comprises step (A), in which formulas (I'-1) and (I'-2) are condensed with a coupling reagent in an organic solvent to obtain (I'-3), 【Chemistry 9】 R １ C １－６ It is an alkyl group, R2 is C １－６ It is an alkyl group The manufacturing method according to claim 11, characterized in that it

16. R1 is a methyl group or an ethyl group, R2 is either a methyl group or an ethyl group. The manufacturing method according to claim 15, characterized in that it

17. Satisfying one or more of the following conditions, In step (A), the coupling reagent is one or more of the following: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and dicyclohexylcarbodiimide. In step (A), the molar ratio of (I'-1), (I'-2) to the coupling reagent is 1:(0.5-2):(1-2). The manufacturing method according to claim 15, characterized in that it

18. Satisfying one or more of the following conditions, In step (A), the organic solvent is one or more of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran. In step (A), the amount of organic solvent used is 5 to 12 times the volume of formula (I'-1). The manufacturing method according to any one of claims 15 to 17, characterized by...

19. A manufacturing intermediate for the compound of formula (I'), It has the following structural formula, 【Chemistry 10】 R １ C １－６ It is an alkyl group, M is K ＋ Na ＋ Li ＋ , Cs ＋ That is A manufacturing intermediate characterized by the following features.

20. The manufacturing intermediate according to claim 19, characterized in that R1 is a methyl group or an ethyl group.

21. The structure is, 【Chemistry 11】 The manufacturing intermediate according to claim 19, characterized in that it is the same as the manufacturing intermediate according to claim 19.

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