Process for the preparation of phosphodiesterase inhibitors

Abstract

The application belongs to the technical field of medicine, and particularly relates to a preparation process and an intermediate of a compound shown in formula (I) and (I'). The preparation process is lower in production cost and less in three-waste generation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the preparation method of phosphodiesterase inhibitors and preparation intermediates. Background Technology

[0002] Phosphodiesterase 9 (PDE) is an important member of the PDE family and has very high selectivity for cGMP. Its inhibitors are used to treat cognitive impairment caused by central nervous system disorders, such as Alzheimer's disease and schizophrenia, as well as neurodegenerative diseases of the brain.

[0003] 6-Ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile (i.e., compound 107 in Example 71 of WO2019062733A1) is an inhibitor of PDE9.

[0004] Example 71 of WO2019062733A1 discloses the following preparation method, which includes the following steps:

[0005]

[0006] Introducing substituents at positions 4 and 6 of the 1,7-diazanaphthalene ring requires coupling and nucleophilic substitution reactions, resulting in a long reaction process and low overall yield. In the preparation of compound 107, the intermediate 4,6-dichloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile (structure shown below) is required as the starting point for synthesis.

[0007]

[0008] Preparation Example 2 of WO2019062733A1 discloses a method for preparing the intermediate 4,6-dichloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile.

[0009]

[0010] This requires 15 mL of phosphorus oxychloride (density 1.64 g / cm³). 3 The molecular weight is 153.33 g / mol, which is equivalent to 24.6 g, 0.16 mol, or 7 equivalents, yielding approximately 0.7 equivalents of the target product. In other words, to obtain 1 equivalent of 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile, the method disclosed in WO2019062733A1 requires approximately 30 equivalents of phosphorus oxychloride.

[0011] WO2020182076A1 discloses the same method for preparing the intermediate 4,6-dichloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile (page 28, Preparation Example 1, Step 3).

[0012] WO2020182076A1 also discloses a method for preparing 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxylonitrile (page 29, Preparation Example 2, Step 3). According to this method, to prepare 1 equivalent of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxylonitrile, 5.13 equivalents of phosphorus oxychloride are required, and chromatographic separation is also necessary.

[0013] Phosphorus oxychloride is highly toxic, explosive, and causes significant environmental pollution. Therefore, it is desirable to minimize its use in the synthesis process. In actual pharmaceutical manufacturing, a shorter process flow and avoidance of purification operations are also desirable to improve yield. Therefore, further research into scale-up synthesis will require improvements to the synthesis process to further reduce production costs, minimize waste generation, and enhance process safety. Summary of the Invention

[0014] The object of the present invention is to provide a method for preparing a compound of formula (I) and a preparation intermediate, and further, to provide a method for preparing a compound of formula (I') and a preparation intermediate.

[0015] This invention provides a method for preparing the compound of formula (I), which is prepared by the following steps:

[0016]

[0017] Step (C'): In an organic solvent, (I-4) undergoes a halogenation reaction with a halogenating agent to give (I-5):

[0018]

[0019] Step (D'): In an organic solvent, (I-5) reacts with (I-6) and a base in a nucleophilic substitution reaction to give (I'):

[0020]

[0021] Where X is a halogen atom; M is an alkali metal ion;

[0022] X1 is CH, X2 is N, X3 is CR3, and X4 is CH;

[0023] R3 is selected from hydrogen, amino, cyano, halogen, carboxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Alkylamino, (C 1-4 alkyl)2-amino, morpholino, C 2-6 alkenyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 Alkyl thio, amino carbonyl, cyclopropyl, aziridine, and piperazine.

[0024] a) wherein C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, (C 1-4 alkyl)2amino, C 2-6 alkenyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 The alkyl thio group and amino carbonyl group are unsubstituted or optionally selected independently from hydroxyl, amino, halogen, C by one or more (e.g., 1, 2, 3, 4 or 5, provided that valence equilibrium is satisfied). 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino, cyclopropyl, C 1-4 Alkyl carbonyl groups, and unsubstituted or C-substituted groups 1-4 Alkyl-substituted 4-6 membered heterocyclic groups are substituted.

[0025] b) wherein the cyclopropyl, aziridine, morpholino, and piperazine groups are unsubstituted or optionally selected independently by one or more (e.g., 1, 2, 3, 4, or 5, provided that valence balance is satisfied) hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino, and C 1-4 Substitution of the alkyl carbonyl group;

[0026] Preferably, R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, morpholino, C 2-6 alkenyl, C 1-4 Alkylamine carbonyl, (C 1-4 alkyl)2-aminocarbonyl and aminocarbonyl,

[0027] a) wherein C 1-4 Alkyl, C1-4 Alkoxy, C 2-6 alkenyl, C 1-4 Alkylamine carbonyl, (C 1-4 The alkyl)2-aminocarbonyl and aminocarbonyl groups are unsubstituted or optionally selected independently from hydroxyl, C, and N, by one or more (e.g., 1, 2, 3, 4, or 5, provided that valence equilibrium is satisfied). 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino, and unsubstituted or C-substituted 1-4 Alkyl-substituted 4-6 membered heterocyclic groups are substituted.

[0028] b) wherein the morpholino group is unsubstituted or optionally selected independently from one or more (e.g., 1, 2, 3, 4 or 5, provided that valence equilibrium is satisfied) hydroxyl, C 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino, (C 1-4 Substitution of alkyl)2-amino groups;

[0029] More preferably, R3 is selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 alkenyl, C 1-4 Alkylaminocarbonyl and aminocarbonyl,

[0030] Wherein C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 alkenyl, C 1-4 The alkane carbonyl and amino carbonyl groups are unsubstituted or optionally selected independently from one or more (e.g., 1, 2, 3, 4, or 5, provided that valence equilibrium is satisfied) hydroxyl, C 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino, and unsubstituted or C-substituted 1-4 Alkyl-substituted groups of 4-6 membered heterocyclic groups;

[0031] L represents the bond;

[0032] Ring A is a 4-7 member monoheterocyclic group or a 7-12 member spiroheterocyclic group. The heteroatom of the 4-7 member monoheterocyclic group is selected from N. The heteroatom of the 7-12 member spiroheterocyclic group is selected from one or a combination of O and N. The 7-12 member spiroheterocyclic group contains at least one N atom. Ring A is connected to L through an N atom.

[0033] Preferably, ring A is a 4-7 member monoheterocyclic group, wherein the heteroatom of the 4-7 member monoheterocyclic group is selected from N, and ring A is connected to L through N atoms;

[0034] More preferably, ring A is selected from

[0035] More preferably, ring A is

[0036] Each R1 is independently selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, pyrazolyl, thiazolyl, and triazolyl groups, wherein the C group is... 1-4 Alkyl, C 1-4 The alkoxy, pyrazolyl, thiazolyl, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups;

[0037] Preferably, each R1 is independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, pyrazolyl, thiazolyl, and triazolyl, wherein the C 1-4 Alkyl, C 1-4 The alkoxy, pyrazolyl, thiazolyl, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups;

[0038] m is 0, 1, or 2;

[0039] R2 is selected from hydrogen.

[0040] This invention provides a method for preparing a compound of formula (I'), which is prepared by the following steps:

[0041]

[0042] Step (C): In an organic solvent, (I'-4) undergoes a halogenation reaction with a halogenating agent to give (I'-5):

[0043]

[0044] Step (D): In an organic solvent, (I'-5) reacts with (I'-6) and a base in a nucleophilic substitution reaction to give (I'):

[0045]

[0046] Where R1 is C 1-6 alkyl;

[0047] X is a halogen atom;

[0048] M is an alkali metal ion.

[0049] In one embodiment of the present invention, the preparation method of compound (I') comprises the following steps:

[0050] Step (C): In an organic solvent, (I'-4) undergoes a halogenation reaction with a halogenating agent to give (I'-5):

[0051]

[0052] Step (D): In an organic solvent, (I'-5) reacts with (I'-6) and a base in a nucleophilic substitution reaction to give (I'):

[0053]

[0054] Where R1 is C 1-6 alkyl;

[0055] X is a halogen atom;

[0056] M is K + Na + Li + Cs + .

[0057] In one embodiment of the present invention, the method for preparing the compound of formula (I') further includes step (B).

[0058] In an organic solvent, (I'-3) undergoes a condensation reaction with a base to give (I'-4):

[0059]

[0060] R1 is C 1-6 Alkyl; preferably methyl or ethyl;

[0061] R2 is C 1-6 Alkyl; preferably methyl or ethyl;

[0062] M is K + Na + Li + Cs + K is preferred + Na + .

[0063] In one embodiment of the present invention, the method for preparing the compound of formula (I') further includes step (A).

[0064] In an organic solvent, formulas (I'-1) and (I'-2) undergo a condensation reaction with a coupling agent to give (I'-3):

[0065]

[0066] R1 is C 1-6 Alkyl; preferably methyl or ethyl;

[0067] R2 is C1-6 Alkyl; preferably methyl or ethyl.

[0068] In one embodiment of the present invention

[0069] The coupling reagent described in step (A) is one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and dicyclohexylcarbodiimide;

[0070] The alkali mentioned in step (B) is one or more of potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium methoxide.

[0071] The halogenated reagents mentioned in steps (C') and (C) are one or more of phosphorus oxychloride, thionyl chloride, sulfonyl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride;

[0072] The base mentioned in steps (D') and (D) is one or more of triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0073] In one embodiment of the present invention

[0074] The base described in steps (D') and (D) is triethylamine.

[0075] In one embodiment of the present invention

[0076] The organic solvent mentioned in step (A) is one or more of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran; preferably dichloromethane.

[0077] The organic solvent mentioned in step (B) is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide; preferably tetrahydrofuran;

[0078] The organic solvents mentioned in steps (C') and (C) are one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane; preferably acetonitrile.

[0079] The organic solvents mentioned in steps (D') and (D) are one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide; preferably ethanol.

[0080] In one embodiment of the present invention

[0081] The coupling agent described in step (A) is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0082] The base mentioned in step (B) is one or more of potassium methoxide and sodium ethoxide;

[0083] The halogenated reagent mentioned in steps (C') and (C) is phosphorus oxychloride;

[0084] The base mentioned in steps (D') and (D) is triethylamine or N,N-diisopropylethylamine.

[0085] In one embodiment of the present invention

[0086] In step (A), the amount of organic solvent used is 2-20 times the volume of formula (I'-1), preferably 5-12 times the volume;

[0087] In step (B), the amount of organic solvent used is 2-20 times the volume of formula (I'-3), preferably 3-12 times the volume;

[0088] In step (C'), the amount of organic solvent used is 2-20 times the volume of formula (I-4), preferably 4-10 times the volume;

[0089] In step (C), the amount of organic solvent used is 2-20 times the volume of formula (I'-4), preferably 4-10 times the volume;

[0090] In step (D'), the amount of organic solvent used is 2-20 times the volume of formula (I-5), preferably 10-20 times the volume.

[0091] In step (D), the amount of organic solvent used is 2-20 times the volume of formula (I'-5), preferably 10-20 times the volume.

[0092] In one embodiment of the present invention

[0093] The molar ratio of (I'-1), (I'-2) and the coupling reagent in step (A) is 1:(0.5-2):(1-2);

[0094] The molar ratio of (I'-3) and base in step (B) is 1:(1-5);

[0095] The molar ratio of (I-4) and the halogenated reagent in step (C') is 1:(1-5);

[0096] The molar ratio of (I'-4) and the halogenated reagent in step (C) is 1:(1-5);

[0097] The molar ratio of (I-5), (I-6) and alkali in step (D') is 1:(0.5-2):(1-3);

[0098] The molar ratio of (I'-5), (I'-6) and base in step (D) is 1:(0.5-2):(1-3).

[0099] In one embodiment of the present invention

[0100] The molar ratio of (I-4) and the halogenated reagent in step (C') is 1:(1-3);

[0101] The molar ratio of (I'-4) and the halogenated reagent in step (C) is 1:(1-3).

[0102] In one embodiment of the present invention

[0103] The molar ratio of (I-4) and the halogenated reagent in step (C') is 1:1, 1:1.1, 1:1.2, 1:1.5 or 1:2.3;

[0104] The molar ratio of (I'-4) and the halogenated reagent in step (C) is 1:1, 1:1.1, 1:1.2, 1:1.5 or 1:2.3.

[0105] The present invention also provides a preparation intermediate of the compound of formula (I') having the following structural formula:

[0106]

[0107] R1 is C 1-6 Alkyl; preferably methyl or ethyl;

[0108] M is K + Na + Li + Cs + .

[0109] In one embodiment of the present invention, the preparation intermediate has the following structure:

[0110]

[0111] The present invention also provides preparation intermediates of compounds of formula (I') that can be used for the synthesis of drugs for the treatment or prevention of PDE9-mediated diseases. Detailed Implementation

[0112] The "C" described in this invention 1-6"Alkyl" refers to a straight-chain or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and 1-methyl-2-methylpropyl, etc. 1-4 "Alkyl" refers to the above examples containing 1 to 4 carbon atoms.

[0113] The "C" described in this invention 1-4 "Alkoxy" refers to the "C" defined above. 1-4 An alkyl group is a group that is attached to the parent molecule by an oxygen atom, i.e., a C18 group. 1-4 Alkyl-O-" groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy.

[0114] The invention described in "C" 1-4 Alkylamino, (C 1-4 Alkyl)2amino", (C) 1-4 alkyl)2-aminocarbonyl", C 1-4 alkylsulfonyl, C 1-4 "alkyl thio" refers to C 1-4 Alkyl-NH-, (C 1-4 Alkyl)(C 1-4 Alkyl)N-, (C 1-4 Alkyl)(C 1-4 Alkyl)NC(O)-, C 1-4 Alkyl-S(O)2-, C 1-4 Alkyl-S-.

[0115] The “4-6 membered heterocyclic group” mentioned in this invention refers to a non-aromatic cyclic group in which at least one cyclic carbon atom of a 4-6 member is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms, and the carbon atom, nitrogen atom, and sulfur atom can be oxidized.

[0116] The "halogen" mentioned in this invention refers to fluorine, chlorine, bromine, iodine, etc.

[0117] The "alkali" described in this invention includes both organic and inorganic alkalis. Organic alkalis include, but are not limited to, sodium tert-butoxide, potassium tert-butoxide, LiHMDS, sodium methoxide, sodium ethoxide, and potassium methoxide. Inorganic alkalis include, but are not limited to, potassium hydroxide, sodium hydroxide, magnesium hydroxide, and rubidium hydroxide.

[0118] The "alkali metals" mentioned in this invention refer to the six metallic elements in Group IA of the periodic table, excluding hydrogen (H), namely lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), and francium (Fr).

[0119] The term "times of volume" as used in this invention refers to the volume (mL) of solvent required to dissolve 1g of a substance. For example, if 10mL of solvent is required to dissolve 1g of compound (I'-1), it is called 10 times the volume.

[0120] In particular, the present invention provides the following technical solutions:

[0121] Technical Solution 1. A method for preparing the compound of formula (I), characterized in that it is prepared by the following steps:

[0122]

[0123] Step (C'): In an organic solvent, (I-4) undergoes a halogenation reaction with a halogenating agent to give (I-5):

[0124]

[0125] Step (D'): In an organic solvent, (I-5) reacts with (I-6) and a base in a nucleophilic substitution reaction to give (I):

[0126]

[0127] Where X is a halogen atom; M is an alkali metal ion;

[0128] X1 is CH, X2 is N, X3 is CR3, and X4 is CH;

[0129] R3 is selected from hydrogen, amino, cyano, halogen, carboxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino, morpholino, C 2-6 alkenyl, C 1-4 Alkyl carbonyl, C 1-4 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 Alkyl thio, amino carbonyl, cyclopropyl, aziridine, and piperazine.

[0130] a) wherein C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, (C 1-4 alkyl)2amino, C 2-6 alkenyl, C1-4 Alkyl carbonyl, C 1-4 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-4 alkylsulfonyl, C 1-4 The alkyl thio group and amino carbonyl group are unsubstituted or optionally selected independently from hydroxyl, amino, halogen, C by one or more (e.g., 1, 2, 3, 4 or 5, provided that valence equilibrium is satisfied). 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino, cyclopropyl, C 1-4 Alkyl carbonyl groups and unsubstituted or C-shaped groups 1-4 Alkyl-substituted 4-6 membered heterocyclic groups are substituted.

[0131] b) wherein the cyclopropyl, aziridine, morpholino, and piperazine groups are unsubstituted or optionally selected independently by one or more (e.g., 1, 2, 3, 4, or 5, provided that valence balance is satisfied) hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino and C 1-4 Substitution of the alkyl carbonyl group;

[0132] L represents the bond;

[0133] Ring A is a 4-7 member monoheterocyclic group or a 7-12 member spiroheterocyclic group. The heteroatom of the 4-7 member monoheterocyclic group is selected from N. The heteroatom of the 7-12 member spiroheterocyclic group is selected from one or a combination of O and N. The 7-12 member spiroheterocyclic group contains at least one N atom. Ring A is connected to L through an N atom.

[0134] Each R1 is independently selected from hydrogen, hydroxyl, cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, pyrazolyl, thiazolyl, and triazolyl groups, wherein the C group is... 1-4 Alkyl, C 1-4 The alkoxy, pyrazolyl, thiazolyl, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups;

[0135] m is 0, 1, or 2;

[0136] R2 is selected from hydrogen.

[0137] Technical Solution 2. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0138] R3 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4Alkoxy, morpholino, C 2-6 alkenyl, C 1-4 Alkylamine carbonyl, (C 1-4 alkyl)2-aminocarbonyl and aminocarbonyl,

[0139] a) wherein C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 alkenyl, C 1-4 Alkylamine carbonyl, (C 1-4 The alkyl)2-aminocarbonyl and aminocarbonyl groups are unsubstituted or optionally selected independently from hydroxyl, C, and N, by one or more (e.g., 1, 2, 3, 4, or 5, provided that valence equilibrium is satisfied). 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino and unsubstituted or C 1-4 Alkyl-substituted 4-6 membered heterocyclic groups are substituted.

[0140] b) wherein the morpholino group is unsubstituted or optionally selected independently from one or more (e.g., 1, 2, 3, 4 or 5, provided that valence equilibrium is satisfied) hydroxyl, C 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino and (C 1-4 Substitution of alkyl)2-amino groups;

[0141] Technical Solution 3. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0142] R3 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 alkenyl, C 1-4 Alkylaminocarbonyl and aminocarbonyl,

[0143] Wherein C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 alkenyl, C 1-4 The alkane carbonyl and amino carbonyl groups are unsubstituted or optionally selected independently from one or more (e.g., 1, 2, 3, 4, or 5, provided that valence equilibrium is satisfied) hydroxyl, C 1-4 Alkoxy, cyclopropyl, amino, C 1-4 Alkylamino, (C 1-4 alkyl)2-amino and unsubstituted or C 1-4 Alkyl-substituted 4-6 membered heterocyclic groups are substituted.

[0144] Technical Solution 4. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0145] Ring A is a 4-7 member monoheterocyclic group, wherein the heteroatom of the 4-7 member monoheterocyclic group is selected from N, and ring A is connected to L through N atoms.

[0146] Technical Solution 5. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0147] Ring A is selected from

[0148] Technical Solution 6. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0149] Ring A is

[0150] Technical Solution 7. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0151] Each R1 is independently selected from hydrogen, C, and C. 1-4 Alkyl, C 1-4 Alkoxy, pyrazolyl, thiazolyl, and triazolyl, wherein the C 1-4 Alkyl, C 1-4 The alkoxy, pyrazolyl, thiazolyl, and triazolyl groups are either unsubstituted or substituted with hydroxyl groups.

[0152] Technical Solution 8. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0153] In step (C'), the halogenated reagent is one or more of phosphorus oxychloride, thionyl chloride, sulfonyl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride.

[0154] Technical Solution 9. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0155] In step (C'), the halogenated reagent is phosphorus oxychloride.

[0156] Technical Solution 10. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0157] In step (C'), the molar ratio of (I-4) to the halogenated reagent is 1:(1-5).

[0158] Technical Solution 11. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0159] In step (C'), the molar ratio of (I-4) to the halogenated reagent is 1:(1-3).

[0160] Technical Solution 12. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0161] In step (C'), the molar ratio of (I-4) to the halogenated reagent is 1:(1.2-2.3).

[0162] Technical Solution 13. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0163] In step (C'), the molar ratio of (I-4) to the halogenated reagent is approximately 1:1.5.

[0164] Technical Solution 14. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0165] In step (D'), the base is one or more of triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0166] Technical Solution 15. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0167] In step (D'), the base is triethylamine or N,N-diisopropylethylamine.

[0168] Technical Solution 16. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0169] In step (D'), the base is triethylamine.

[0170] Technical Solution 17. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0171] In step (D'), the base is N,N-diisopropylethylamine.

[0172] Technical Solution 18. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0173] In step (D'), the molar ratio of (I-5), (I-6) and base is 1:(0.5-2):(1-3).

[0174] Technical Solution 19. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0175] In step (C'), the organic solvent is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane.

[0176] Technical Solution 20. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0177] In step (C'), the organic solvent is acetonitrile.

[0178] Technical Solution 21. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0179] In step (D'), the organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0180] Technical Solution 22. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0181] In step (D'), the organic solvent is ethanol.

[0182] Technical Solution 23. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0183] In step (C'), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-4).

[0184] Technical Solution 24. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0185] In step (C'), the amount of organic solvent used is 4-10 times the volume of formula (I'-4).

[0186] Technical Solution 25. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0187] In step (D'), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-5).

[0188] Technical Solution 26. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0189] In step (D'), the amount of organic solvent used is 10-20 times the volume of formula (I'-5).

[0190] Technical Solution 27. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0191] In step (C'), the reaction temperature is 40-160℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 1-36 hours.

[0192] Technical Solution 28. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0193] In step (C'), the reaction temperature is 60-140℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 2-24 hours.

[0194] Technical Solution 29. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0195] In step (C'), the reaction temperature is 80-120℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 4-12 hours.

[0196] Technical Solution 30. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0197] In step (D'), the reaction temperature is 40-120℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.1-12 hours.

[0198] Technical Solution 31. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0199] In step (D'), the reaction temperature is 50-110℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.5-6 hours.

[0200] Technical Solution 32. The preparation method according to any one of the foregoing technical solutions, characterized in that,

[0201] In step (D'), the reaction temperature is 60-100℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 1-3 hours.

[0202] Technical solution 33. A method for preparing the compound of formula (I'), characterized in that it is prepared by the following steps:

[0203]

[0204] Step (C): In an organic solvent, (I'-4) undergoes a halogenation reaction with a halogenating agent to give (I'-5):

[0205]

[0206] Step (D): In an organic solvent, (I'-5) reacts with (I'-6) and a base in a nucleophilic substitution reaction to give (I'):

[0207]

[0208] Where R1 is C 1-6 alkyl;

[0209] X is a halogen atom;

[0210] M is an alkali metal ion.

[0211] Technical Solution 34. The preparation method according to Technical Solution 33 is characterized in that, in step (C), the halogenated reagent is one or more of phosphorus oxychloride, thionyl chloride, sulfonyl chloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, phosphorus oxybromide, triphosgene, and oxalyl chloride.

[0212] Technical Solution 35. The preparation method according to any one of Technical Solutions 33-34, characterized in that in step (C), the halogenated reagent is phosphorus oxychloride.

[0213] Technical Solution 36. The preparation method according to any one of Technical Solutions 33-35, characterized in that in step (C), the molar ratio of (I'-4) and the halogenated reagent is 1:(1-5).

[0214] Technical Solution 37. The preparation method according to any one of Technical Solutions 33-36, characterized in that in step (C), the molar ratio of (I'-4) to the halogenated reagent is 1:(1-3).

[0215] Technical Solution 38. The preparation method according to any one of Technical Solutions 33-37, characterized in that in step (C), the molar ratio of (I'-4) to the halogenated reagent is 1:(1.2-2.3).

[0216] Technical Solution 39. The preparation method according to any one of Technical Solutions 33-38, characterized in that in step (C), the molar ratio of (I'-4) to the halogenated reagent is about 1:1.5.

[0217] Technical Solution 40. The preparation method according to any one of Technical Solutions 33-39, characterized in that in step (D), the alkali is one or more of triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

[0218] Technical Solution 41. The preparation method according to any one of Technical Solutions 33-40, characterized in that in step (D), the base is triethylamine or N,N-diisopropylethylamine.

[0219] Technical Solution 42. The preparation method according to any one of Technical Solutions 33-41, characterized in that in step (D), the base is triethylamine.

[0220] Technical Solution 43. The preparation method according to any one of Technical Solutions 33-42, characterized in that in step (D), the base is N,N-diisopropylethylamine.

[0221] Technical Solution 44. The preparation method according to any one of Technical Solutions 33-43, characterized in that in step (D), the molar ratio of (I'-5), (I'-6) and the base is 1:(0.5-2):(1-3).

[0222] Technical Solution 45. The preparation method according to any one of Technical Solutions 33-44, characterized in that in step (C), the organic solvent is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane.

[0223] Technical Solution 46. The preparation method according to any one of Technical Solutions 33-45, characterized in that in step (C), the organic solvent is acetonitrile.

[0224] Technical Solution 47. The preparation method according to any one of Technical Solutions 33-46, 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.

[0225] Technical Solution 48. The preparation method according to any one of Technical Solutions 33-47, characterized in that in step (D), the organic solvent is ethanol.

[0226] Technical Solution 49. The preparation method according to any one of Technical Solutions 33-48, characterized in that in step (C), the amount of organic solvent used is 2-20 times the volume of formula (I'-4).

[0227] Technical Solution 50. The preparation method according to any one of Technical Solutions 33-49, characterized in that in step (C), the amount of organic solvent used is 4-10 times the volume of formula (I'-4).

[0228] Technical Solution 51. The preparation method according to any one of Technical Solutions 33-50, characterized in that in step (D), the amount of organic solvent used is 2-20 times the volume of formula (I'-5).

[0229] Technical Solution 52. The preparation method according to any one of Technical Solutions 33-51, characterized in that in step (D), the amount of organic solvent used is 10-20 times the volume of formula (I'-5).

[0230] Technical Solution 53. The preparation method according to any one of technical solutions 33-52, characterized in that,

[0231] In step (C), the reaction temperature is 40-160℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 1-36 hours.

[0232] Technical Solution 54. The preparation method according to any one of technical solutions 33-53, characterized in that,

[0233] In step (C), the reaction temperature is 60-140℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 2-24 hours.

[0234] Technical Solution 55. The preparation method according to any one of Technical Solutions 33-54, characterized in that,

[0235] In step (C), the reaction temperature is 80-120℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 4-12 hours.

[0236] Technical Solution 56. The preparation method according to any one of technical solutions 33-55, characterized in that,

[0237] In step (D), the reaction temperature is 40-120℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.1-12 hours.

[0238] Technical Solution 57. The preparation method according to any one of technical solutions 33-56, characterized in that,

[0239] In step (D), the reaction temperature is 50-110℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.5-6 hours.

[0240] Technical Solution 58. The preparation method according to any one of Technical Solutions 33-57, characterized in that,

[0241] In step (D), the reaction temperature is 60-100℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 1-3 hours.

[0242] Technical Solution 59. The preparation method according to any one of Technical Solutions 1-58, characterized in that it further includes step (B),

[0243] In an organic solvent, (I'-3) undergoes a condensation reaction with a base to give (I'-4):

[0244]

[0245] R1 is C 1-6 alkyl;

[0246] R2 is C 1-6 alkyl;

[0247] M is K + Na + Li+ Cs + .

[0248] Technical solution 60. The preparation method described in technical solution 59, wherein R1 is methyl or ethyl.

[0249] Technical Solution 61. The preparation method according to any one of Technical Solutions 59-60, wherein R2 is methyl or ethyl.

[0250] Technical solution 62. The preparation method according to any one of technical solutions 59-61, characterized in that M is K + Or Na + .

[0251] Technical solution 63. The preparation method according to any one of technical solutions 59-62, characterized in that in step (B), the alkali is one or more of potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium methoxide.

[0252] Technical Solution 64. The preparation method according to any one of Technical Solutions 59-63, characterized in that in step (B), the alkali is potassium methoxide and / or sodium ethoxide.

[0253] Technical solution 65. The preparation method according to any one of technical solutions 59-64, characterized in that in step (B), the molar ratio of (I'-3) to alkali is 1:(1-5).

[0254] Technical Solution 66. The preparation method of any one of Technical Solutions 59-65, 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.

[0255] Technical Solution 67. The preparation method of any one of Technical Solutions 59-66, characterized in that in step (B), the organic solvent is tetrahydrofuran.

[0256] The preparation method according to any one of technical solutions 68 and 59-67 is characterized in that, in step (B), the amount of organic solvent used is 2-20 times the volume of formula (I'-3).

[0257] Technical solution 69. The preparation method according to any one of technical solutions 59-68, characterized in that in step (B), the amount of organic solvent used is 3-12 times the volume of formula (I'-3).

[0258] Technical solution 70. The preparation method according to any one of technical solutions 59-69, characterized in that,

[0259] In step (B), the reaction temperature is 40-120℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.1-12 hours.

[0260] Technical Solution 71. The preparation method according to any one of Technical Solutions 59-70, characterized in that,

[0261] In step (B), the reaction temperature is 50-120℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.5-6 hours.

[0262] Technical solution 72. The preparation method according to any one of technical solutions 59-71, characterized in that,

[0263] In step (B), the reaction temperature is 60-100℃ and not higher than 5℃ lower than the boiling point of the solvent, and the reaction time is 1-3 hours.

[0264] Technical Solution 73. The preparation method according to any one of Technical Solutions 59-72, characterized in that it further includes step (A),

[0265] In an organic solvent, formulas (I'-1) and (I'-2) undergo a condensation reaction with a coupling agent to give (I'-3):

[0266]

[0267] R1 is C 1-6 alkyl;

[0268] R2 is C 1-6 alkyl.

[0269] Technical Solution 74. The preparation method described in Technical Solution 73, characterized in that,

[0270] R1 is methyl or ethyl;

[0271] Technical solution 75. The preparation method according to any one of technical solutions 73-74, characterized in that,

[0272] R2 is methyl or ethyl.

[0273] Technical solution 76. The preparation method according to any one of technical solutions 73-75, characterized in that,

[0274] In step (A), the coupling agent is one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and dicyclohexylcarbodiimide.

[0275] Technical solution 77. The preparation method according to any one of technical solutions 73-76, characterized in that,

[0276] In step (A), the coupling agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0277] Technical solution 78. The preparation method according to any one of technical solutions 73-77, characterized in that in step (A), the molar ratio of (I'-1), (I'-2) and the coupling reagent is 1:(0.5-2):(1-2).

[0278] Technical solution 79. The preparation method according to any one of technical solutions 73-78, characterized in that,

[0279] In step (A), the organic solvent is one or more of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran.

[0280] Technical solution 80. The preparation method according to any one of technical solutions 73-79, characterized in that,

[0281] In step (A), the organic solvent is dichloromethane.

[0282] Technical Solution 81. The preparation method according to any one of Technical Solutions 73-80, characterized in that,

[0283] In step (A), the amount of organic solvent used is 2 to 20 times the volume of formula (I'-1).

[0284] Technical solution 82. The preparation method according to any one of technical solutions 73-81, characterized in that,

[0285] In step (A), the amount of organic solvent used is 5-12 times the volume of formula (I'-1).

[0286] Technical solution 83. The preparation method according to any one of technical solutions 73-82, characterized in that,

[0287] In step (A), the reaction temperature is 10-40℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.1-12 hours.

[0288] Technical solution 84. The preparation method according to any one of technical solutions 73-83, characterized in that,

[0289] In step (A), the reaction temperature is 15-35℃ and not higher than 5℃ below the boiling point of the solvent, and the reaction time is 0.5-6 hours.

[0290] Technical solution 85. The preparation method according to any one of technical solutions 73-84, characterized in that,

[0291] In step (A), the reaction temperature is 20-30°C and not higher than 5°C below the boiling point of the solvent, and the reaction time is 1-3 hours.

[0292] Technical solution 86. An intermediate of the compound of formula (I'), characterized in that it has the following structural formula:

[0293]

[0294] R1 is C 1-6 alkyl;

[0295] M is K + Na + Li + Cs + .

[0296] Technical solution 87. An intermediate of the compound of formula (I'), characterized in that it has the following structural formula:

[0297]

[0298] R1 is methyl or ethyl;

[0299] M is K + Na + Li + Cs + .

[0300] Technical solution 88. An intermediate, characterized in that its structure is as follows:

[0301]

[0302] The preparation methods disclosed in WO2019062733A1 and WO2020182076A1 use a class of 1,2-dihydro-2-oxo-3-cyano-1,7-diazanaphthalene-4-ol compounds as intermediates for halogenation with a halogenating agent. In contrast, the preparation method according to the present invention can use a class of 1,2-dihydro-2-oxo-3-cyano-1,7-diazanaphthalene-4-ol alkali metal salt compounds as intermediates for halogenation with a halogenating agent. As illustrated in the following examples, the present invention can reduce the amount of toxic and harmful halogenating agents (such as phosphorus oxychloride) used.

[0303] Example

[0304] The following detailed description of specific embodiments further illustrates the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0305] The abbreviations used in this article are as follows:

[0306] “EDCI” refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0307] "DIPEA" refers to N,N-diisopropylethylamine.

[0308] Compound 23 of WO2009093032A1 was prepared in Example 14.

[0309] Example 1 Preparation of compound (I)

[0310]

[0311] Step 1a: Synthesis of ethyl 6-ethyl-3-(cyanoacetamido)pyridine-4-carboxylate

[0312]

[0313] The intermediate ethyl 6-ethyl-3-aminopyridine-4-carboxylate (100 g, 514.84 mmol, 1.0 eq) was dissolved in dichloromethane (1.00 L), and cyanoacetic acid (52.55 g, 617.81 mmol, 1.2 eq) was added under ice bath conditions. EDCI (148.03 g, 772.26 mmol, 1.5 eq) was added in portions, and the reaction was carried out at 25 °C for 2 hours. The reaction was confirmed to be complete by LC-MS. H2O (1.00 L) was added to the reaction solution, and the mixture was separated. The organic phase was washed with H2O (2 × 500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was slurried with methyl tert-butyl ether (300 mL) to obtain the final product (128 g, yield: 95.15%).

[0314] Step 1b: Synthesis of ethyl 6-ethyl-3-(cyanoacetamido)pyridine-4-carboxylate

[0315] The intermediate ethyl 6-ethyl-3-aminopyridine-4-carboxylate (500 g, 2.57 mol, 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 portions, and the reaction was carried out at 25 °C for 2 hours. The reaction was confirmed to be complete by LC-MS. H₂O (5.00 L) was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with DCM (2 × 500 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to 1.0 L. The filtrate was then added dropwise to 5.0 L of n-heptane, resulting in the precipitation of a large amount of solid. The solid was collected by filtration and dried at 50 °C to obtain the product (658 g, yield: 98%).

[0316] Step 2a: Synthesis of potassium 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-4-ol

[0317]

[0318] 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. Then, the intermediate ethyl 6-ethyl-3-(cyanoacetamido)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 reaction was confirmed to be complete by LC-MS. The heating was turned off, and the reaction system was allowed to cool naturally to room temperature. The mixture was filtered, and the filter cake was dried to obtain the crude product (10.4 g, yield: 107.29%).

[0319] Step 2b: Synthesis of sodium 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-4-ol

[0320]

[0321] 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. Then, the intermediate ethyl 6-ethyl-3-(cyanoacetamido)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 reaction was confirmed to be complete by LC-MS. The heating was turned off, and the reaction system was allowed to cool naturally to room temperature. The mixture was filtered, and the filter cake was dried to obtain the crude product (10.3 g, yield: 113.43%).

[0322] Step 3a: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile

[0323]

[0324] Potassium 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-4-ol (5 g, 19.74 mmol, 1.0 eq) was dissolved in acetonitrile (50 mL), and phosphorus oxychloride (4.54 g, 29.61 mmol, 1.5 eq) was added at room temperature. The reaction mixture was then reacted at 100 °C for 8 hours. The reaction solution was cooled, concentrated, and H₂O (50 mL) was added. The pH was adjusted to approximately 6 with 10% sodium hydroxide, resulting in the precipitation of a large amount of yellow solid. The solid was filtered and dried to obtain 3.87 g of crude product (yield: 83.95%).

[0325] Step 3b: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile

[0326]

[0327] Potassium 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-4-ol (5 g, 19.74 mmol, 1.0 eq) was dissolved in acetonitrile (50 mL), and phosphorus oxychloride (3.63 g, 23.69 mmol, 1.2 eq) was added at room temperature. The reaction mixture was then reacted at 100 °C for 8 hours. The reaction solution was cooled, concentrated, and H₂O (50 mL) was added. The pH was adjusted to approximately 6 with 10% sodium hydroxide, resulting in the precipitation of a large amount of yellow solid. The solid was filtered and dried to obtain 3.47 g of crude product (yield: 75.27%).

[0328] Step 3c: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile

[0329]

[0330] Potassium 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-4-ol (10 g, 39.5 mmol, 1.0 eq) was dissolved in acetonitrile (100 mL). Phosphorus oxychloride (13.93 g, 90.85 mmol, 2.3 eq) was added in portions at room temperature, and the reaction was carried out at 100 °C for 8 hours. The reaction solution was cooled, concentrated, and H2O (500 mL) was added. The pH was adjusted to about 6 with 10% sodium hydroxide, and a large amount of yellow solid precipitated. The solid was filtered and dried to give 7.18 g of crude product (yield: 77.87%).

[0331] Step 3d: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile

[0332]

[0333] The intermediate 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-4-ol sodium (5 g, 21.08 mmol, 1.0 eq) was dissolved in acetonitrile (50 mL), and phosphorus oxychloride (4.85 g, 31.62 mmol, 1.5 eq) was added at room temperature. The reaction mixture was then reacted at 100 °C for 8 hours. The reaction solution was cooled, concentrated, and H2O (50 mL) was added. The pH was adjusted to approximately 6 with 10% sodium hydroxide, resulting in the precipitation of a large amount of yellow solid. The solid was filtered and dried to obtain 3.72 g of crude product (yield: 75.46%).

[0334] Step 3e: Synthesis of 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile

[0335]

[0336] Potassium 3-cyano-6-ethyl-2-oxo-1,2-dihydro-1,7-diazanaphthalene-4-ol (120 g, 473.7 mmol, 1.0 eq) was dissolved in acetonitrile (1200 mL). Phosphorus oxychloride (73.36 g, 478.48 mmol, 1.01 eq) was added in portions at room temperature, and the reaction was carried out at 100 °C for 8 hours. The reaction solution was cooled, concentrated, and H2O (1200 mL) was added. The pH was adjusted to about 6 with 10% sodium hydroxide, and a large amount of yellow solid precipitated. The solid was filtered and dried to obtain the crude product. 2350 mL of tetrahydrofuran (THF) was added to the crude product, followed by activated carbon. The mixture was heated and refluxed for filtration. The filtrate was distilled with isopropyl acetate to remove THF. After cooling to room temperature, a large amount of solid precipitated. The solid was collected, dried, and 80.45 g of yellow solid was obtained (yield: 72.7%).

[0337] Step 4a: Synthesis of 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile

[0338]

[0339] Intermediate 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile (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), and DIPEA (151.36 g, 1171.17 mmol, 3.0 eq) was added. The mixture was reacted at 80 °C for 2 hours, and the reaction was confirmed to be complete by LC-MS. Approximately 75% of the ethanol was removed by vacuum distillation, and water (2 L) was added. The mixture was stirred at 25 °C for 1 hour, filtered, and the filter cake was completely dissolved by reflux with ethanol (4 L). The mixture was then filtered again, and the filtrate was concentrated to approximately 1 L. The solution was cooled to approximately 10 °C, filtered again, and the filter cake was dried to obtain the product (69 g, yield: 54.15%).

[0340] 1 HNMR(400MHz,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).

[0341] Molecular formula: C 18 H 22 N4O2 molecular weight: 326.40 LC-MS (Pos, m / z) = 327.59 [M+H] + .

[0342] Step 4b: Synthesis of 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile

[0343]

[0344] Intermediate 6-ethyl-4-chloro-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile (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), and triethylamine (14.29 g, 141.23 mmol, 2.2 eq) was added. The reaction was carried out at 80 °C for 2 hours, and the reaction was confirmed to be complete by LC-MS. Approximately 75% of the ethanol was removed by vacuum distillation, and water (300 mL) was added. The mixture was stirred at 25 °C for 1 hour, filtered, and the filter cake was completely dissolved by reflux with ethanol (600 mL). Activated carbon (2 g) was added, and the mixture was refluxed for 0.5 h. The mixture was filtered, and the filtrate was concentrated to approximately 400 mL. The solution was cooled to room temperature, filtered again, and the filter cake was dried to obtain the product (17.10 g, yield: 81.6%).

[0345] Example 2

[0346] In step 1, EDCI is replaced with 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, or dicyclohexylcarbodiimide, and dichloromethane is replaced with N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran to obtain ethyl 6-ethyl-3-(cyanoacetamido)pyridine-4-carboxylate.

[0347] In step 2a, potassium methoxide is replaced with sodium ethoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide, and tetrahydrofuran is replaced with ethanol, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide to obtain the corresponding products.

[0348] In step 2b, sodium ethoxide is replaced with potassium methoxide, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium tert-butoxide, or potassium tert-butoxide, and tetrahydrofuran is replaced with ethanol, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide to obtain the corresponding products.

[0349] In steps 3a, 3b, 3c, and 3d, acetonitrile is replaced with tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, or 1,2-dichloroethane; and phosphorus oxychloride is replaced with thionyl chloride, sulfonyl 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-diazanaphthalene-3-carboxynitrile.

[0350] In step 4a, N,N-diisopropylethylamine is replaced with triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, and ethanol is replaced with tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide to obtain 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile.

[0351] In step 4b, triethylamine is replaced with N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide, and ethanol is replaced with tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide to obtain 6-ethyl-4-(4-methoxy-4-methylpiperidin-1-yl)-2-oxo-1,2-dihydro-1,7-diazanaphthalene-3-carboxynitrile.

[0352] The novel preparation method of the present invention has the following advantages:

[0353] (1) Compared with the prior art, the present invention can significantly reduce the amount of halogenated reagents such as phosphorus oxychloride while maintaining the same or even higher yield. That is, less amount of halogenated reagents such as phosphorus oxychloride can be used to obtain the same or even higher amount of target product. This reduces production costs and significantly reduces the amount of waste generated.

[0354] (2) In large-scale factory production, the use of large quantities of certain halogenated reagents such as phosphorus oxychloride can cause a huge amount of heat to be generated instantaneously during the quenching process in the post-processing, which poses an explosion risk if not handled properly. The present invention significantly reduces the amount of such halogenated reagents such as phosphorus oxychloride used, thereby correspondingly reducing the heat generated in the post-processing, improving the safety of the post-processing system, and making it more suitable for large-scale factory production.

[0355] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing the compound of formula (I), characterized in that, It is prepared through the following steps: (I) Step (C'): In an organic solvent, (I-4) undergoes a halogenation reaction with a halogenating agent to give (I-5): ， The halogenated reagent is one or more of phosphorus oxychloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, and phosphorus oxybromide; The molar ratio of (I-4) to the halogenated reagent is 1:(1-2.3); The organic solvent is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane; Step (D'): In an organic solvent, (I-5) reacts with (I-6) and a base in a nucleophilic substitution reaction to give (I): ， The alkali is one or more of triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. The molar ratio of (I-5), (I-6) and the base is 1:(0.5-2):(1-3); The organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide; wherein X is chlorine, bromine; M is K + , Na + , Li + , Cs + ; X1 is CH, X2 is N, X3 is CR3, and X4 is CH; R3is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, a) wherein said C 1-4 alkyl, C 1-4 alkoxy is unsubstituted or optionally substituted with one to more groups independently selected from the group consisting of hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl, b) wherein said cyclopropyl is unsubstituted or optionally substituted with one to more groups independently selected from hydroxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyclopropyl; L represents the bond; Ring A is selected from , and ; each R1is independently selected from hydrogen, hydroxyl, halogen, C 1-4 alkyl or C 1-4 alkoxy, wherein said C 1-4 alkyl and C 1-4 alkoxy is unsubstituted or substituted with hydroxyl; m is 0, 1, or 2; R2 is hydrogen.

2. The preparation method according to claim 1, characterized in that, Ring A is .

3. The preparation method according to claim 1, characterized in that, In step (C'), the halogenated reagent is phosphorus oxychloride; In step (C'), the molar ratio of (I-4) to the halogenated reagent is 1:(1.2-2.3); In step (D'), the base is triethylamine or N,N-diisopropylethylamine.

4. The preparation method according to claim 1, characterized in that, In step (C'), the molar ratio of (I-4) to the halogenated reagent is 1:1.

5.

5. The preparation method according to claim 1, characterized in that, In step (C'), the organic solvent is acetonitrile; In step (D'), the organic solvent is ethanol; In step (C'), the amount of organic solvent used is 4-10 times the volume of formula (I-4); In step (D'), the amount of organic solvent used is 10-20 times the volume of formula (I-5).

6. The preparation method according to claim 1, characterized in that, Compound (I') is prepared via the following steps: (I') Step (C): In an organic solvent, (I'-4) undergoes a halogenation reaction with a halogenating agent to give (I'-5): The halogenated reagent is one or more of phosphorus oxychloride, phosphine trichloride, phosphine pentachloride, phosphorus tribromide, or phosphorus oxychloride. The molar ratio of (I'-4) to the halogenated reagent is 1:(1-2.3); The organic solvent is one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, and 1,2-dichloroethane; Step (D): In an organic solvent, (I'-5) reacts with (I'-6) and a base in a nucleophilic substitution reaction to give (I'): ； The alkali is one or more of triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. The molar ratio of (I'-5), (I'-6) and the base is 1:(0.5-2):(1-3); The organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide; wherein R1is C 1-4 alkyl; X represents chlorine or bromine; M is K + , Na + , Li + , Cs + .

7. The preparation method according to claim 6, characterized in that, In step (C), the halogenated reagent is phosphorus oxychloride; In step (C), the molar ratio of (I'-4) to the halogenated reagent is 1:(1.2-2.3); In step (D), the base is triethylamine or N,N-diisopropylethylamine.

8. The preparation method according to claim 7, characterized in that, In step (C), the molar ratio of (I'-4) to the halogenated reagent is 1:1.

5.

9. The preparation method according to claim 6, characterized in that, In step (C), the organic solvent is acetonitrile; In step (D), the organic solvent is ethanol; In step (C), the amount of organic solvent used is 4-10 times the volume of formula (I'-4); In step (D), the amount of organic solvent used is 10-20 times the volume of formula (I'-5).

10. The preparation method according to any one of claims 1-9, characterized in that, It also includes step (B), In an organic solvent, (I'-3) undergoes a condensation reaction with a base to give (I'-4): ； The alkali mentioned is one or more of potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium methoxide. The organic solvent is one or more of ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and N,N-dimethylacetamide; R1 is methyl or ethyl; R2 is methyl or ethyl; M is K + or Na + .

11. The preparation method according to claim 10, characterized in that, In step (B), the base is one or more of potassium methoxide and sodium ethoxide; In step (B), the molar ratio of (I'-3) to the base is 1:(1-5).

12. The preparation method according to claim 10, characterized in that, In step (B), the organic solvent is tetrahydrofuran; In step (B), the amount of the organic solvent used is 3-12 times the volume of formula (I'-3).

13. The preparation method according to claim 10, characterized in that, It also includes step (A), In an organic solvent, formulas (I'-1) and (I'-2) undergo a condensation reaction with a coupling agent to give (I'-3): ； R1 is methyl or ethyl; R2 is methyl or ethyl; The coupling reagent is one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and dicyclohexylcarbodiimide; The organic solvent is dichloromethane.

14. The preparation method according to claim 13, characterized in that, In step (A), the coupling agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; In step (A), the molar ratio of (I'-1), (I'-2) and the coupling reagent is 1:(0.5-2):(1-2).

15. The preparation method according to claim 13, characterized in that, In step (A), the amount of organic solvent used is 5-12 times the volume of formula (I'-1).

16. An intermediate, characterized in that, It has the following structural formula: R1 is methyl or ethyl; M is K + 、Na + 、Li + 、Cs + 。 17. The intermediate as described in claim 16, characterized in that, Its structure is as follows: , , or .

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