Process for the synthesis of 1,3-dihydro-imidazo[4,5-b]pyridin-2-one and / or its derivatives

Abstract

The present invention relates to a novel process for preparing a compound of formula (I) from a compound of formula (II) by a novel cyclization process, as well as a process for preparing an acid adduct of a compound of formula (I), JPEG2024516134000018.jpg28170 wherein L represents a leaving group; R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain; a substituted or unsubstituted aromatic or heteroaromatic group; a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain; or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain.

Description

Technical Field

[0001] The present invention relates to a method for producing a compound of formula (I), in particular a 1,3-dihydro-imidazo[4,5-b]pyridin-2-one derivative. In particular, the present invention relates to a novel method for producing a compound of formula (Ia) from a compound of formula (IIa) by a novel cyclization process, as well as a method for producing an acid addition salt of a compound of formula (I), derivatives of 3-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one:

[0002]

Chemical Formula

[0003] In the formula, L represents a leaving group, R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, and R' represents hydrogen, a substituent, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain.

Background Art

[0004] 1,3-Dihydro-imidazo[4,5-b]pyridin-2-one and its derivatives are precursors of many active pharmaceutical ingredients that are already on the market or are currently under development. The therapeutic areas of these substances of interest cover a wide range, including cancer, erectile dysfunction, diabetes, the treatment of migraine, use as an antithrombotic agent, use as an analgesic agent, etc. That is, telcagepant, rimegepant, imiglyptin ((R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile), FR-238831 (1-(3-chloro-4-methoxybenzyl)-3-(4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-carbonitrile), CJS-3678 (1-(4-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)phenyl)urea), CJS-3255 (7-(4-(1-(4-chloro-3-(trifluoromethyl)phenylamino)vinylamino)phenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one), or AA-012 (1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea), and various other active pharmaceutical ingredients mainly in the group of CGRP (calcitonin gene-related peptide) receptor antagonists are examples of active pharmaceutical ingredients having one of 1,3-dihydro-imidazo[4,5-b]pyridin-2-one or its derivatives as a substructure.

[0005] Rimegepant and imiglyptin are examples of substances in which 1,3-dihydro-imidazo[4,5-b]pyridin-2-one or its derivatives are important precursors in their synthesis. Rimegepant is an active pharmaceutical compound used to treat migraine in adults, while imiglyptin is used to treat diabetes.

[0006] There is an increasing demand for access to ecologically and economically viable precursors and suitable manufacturing methods. State of the art There are few industrially viable manufacturing methods for 1,3-dihydro-imidazo[4,5-b]pyridin-2-one.

[0007] Manufacturing methods using carboyldiimidazole (CDI) are widely used in the pharmaceutical industry and are disclosed in various patents and patent applications. For example, in Patent Documents 1 to 4, 2,3-diamino-pyridine derivatives are used as starting materials. Patent Document 5 discloses a synthesis in which COCl2 is used instead of CDI.

[0008] Non-Patent Document 1 discloses a synthetic route from tert-butyl 4-(2-aminopyridin-3-ylamino)piperidine-1-carboxylate to tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate. The authors use carboyldiimidazole (CDI) as the key reagent therein. Patent Document 6 describes a cyclization process of different molecules that requires high temperatures and results in a 10.3% yield. Similarly, a method using similar molecules with aromatic leaving groups is disclosed in Patent Document 7, but the yield is low, and even assuming a quantitative step for preparing the leaving group compared to the current one (not realistic), it ranges from 33.2% for compounds 5a to 5b, 44.5% for compounds 1f to 3b via compound 3a, and 50.2% for compounds 2a to 2-1. Another similar method using the same compounds is disclosed in Non-Patent Document 2, but this method uses a large amount of DBU, which is an expensive and toxic base. Furthermore, the method of Non-Patent Document 2 (Zhaoguang et al.) was considered disadvantageous because TEA and Cu(II) could be attributed to the aromatic side chains in the free substances therein (page 3264, right column, page 3265, left column), and it is quite different.

[0009] However, it is desirable to establish a sustainable synthetic route that operates under mild reaction conditions, uses reagents that are less toxic and more environmentally friendly, is readily available and accessible, and achieves a yield that is sufficiently high or even higher than that of the prior art.

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Non-Patent Documents

[0011]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0012] Accordingly, an object of the present invention is to provide a method for producing a compound of formula (I), such as 1,3-dihydro-imidazo[4,5-b]pyridin-2-one or a derivative thereof, as a precursor of various pharmaceutical compounds.

Means for Solving the Problems

[0013] The present invention provides a novel method for the synthesis of a compound of formula (I) (wherein R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain).

[0014]

Chemical formula

[0015] The inventors of the present application have found such a novel synthetic method that uses readily available reagents and has ecological and economic advantages over currently used manufacturing processes. The innovative method provides high yields under mild reaction conditions. In particular, according to certain embodiments, the low boiling point of the solvent found to be suitable in the present invention enables easy recycling of the solvent and an environmentally friendly closed circuit. The disclosed invention avoids complexes or complexes handling catalysts, especially expensive metal catalysts based on palladium. This novel method also reduces the amount of by-products and impurities caused by the reagents used in the final product and which are difficult to remove.

[0016] In a first aspect, the present invention is a method for producing a compound of formula (I) from a compound of formula (II), the method comprising: reacting a compound of formula (II) in a solvent or solvent mixture with a Cu catalyst and a diamine additive optionally with a base, particularly an inorganic base to form a compound of formula (I),

[0017]

Chemical formula

[0018] wherein L represents a leaving group, and R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain.

[0019] Furthermore, a method for producing an acid addition salt of a compound of formula (I) from a compound of formula (II) is disclosed, the method comprising: - reacting a compound of formula (II) in a solvent or solvent mixture with a Cu catalyst and a diamine additive optionally with a base, particularly an inorganic base to form a compound of formula (I),

[0020]

Chemical formula

[0021] (In the formula, L represents a leaving group, and R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain), - a step of reacting the compound of formula (I) with an acid, comprises.

[0022] Further aspects and embodiments of the present invention are disclosed in the dependent claims and can be understood from the following description, drawings and examples, but are not limited thereto.

Mode for Carrying Out the Invention

[0023] Definition Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0024] Quantities within the scope of the present invention are given in weight %, unless otherwise specified or not apparent from the context. Within the scope of the present disclosure, the copper catalyst / Cu catalyst is not particularly limited and includes Cu itself and its compounds, such as Cu salts and Cu complexes, preferably Cu salts, particularly Cu(I) and / or Cu(II) salts.

[0025] In the structural formula, Bn is a benzyl group and BOC is a tert-butyloxycarbonyl group. Before exemplarily and in detail explaining the present invention, it should be understood that the present invention is not limited to specific component parts of the process steps of the methods described herein, and such methods can be modified. It should also be understood that the terms used herein are for the sole purpose of describing specific embodiments and are not intended to be limiting. When used in this specification and the appended claims, the singular forms "a", "an", and "the" should be noted to include the singular and / or plural referents unless the context clearly dictates otherwise. For example, the term "a" as used herein can be understood as a single entity or in the sense of "one or more" entities. The plural form should also be understood to include the singular and / or plural referents unless the context clearly dictates otherwise. Further, when a parameter range delimited by numerical values is given, it should be understood that the range is considered to include these limiting values.

[0026] In a first aspect, the present invention is a method for producing a compound of formula (I) from a compound of formula (II), the method comprising: reacting the compound of formula (II) in a solvent or solvent mixture with a Cu catalyst and a diamine additive and optionally a base, particularly an inorganic base in the presence of to form a compound of formula (I).

[0027]

Chemical formula

[0028] In the formula, L represents a leaving group, and R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain.

[0029] In the method of the present invention, the cyclization of the compound of formula (II) to the compound of formula (I), for example, the cyclization of a specific 1-(pyridin-3-yl)urea compound to a specific 1H-imidazo[4,5-b]pyridin-2(3H) compound can generally be described by the following reaction scheme 1: Scheme 1:

[0030]

Chemical formula

[0031] In the formula: L represents a leaving group, and R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain.

[0032] Accordingly, the present invention particularly relates to a method for producing 1,3-dihydro-imidazo[4,5-b]pyridin-2-one or a derivative thereof starting from a 1-(pyridin-3-yl)urea compound, i.e., 1-(pyridin-3-yl)urea or a derivative thereof, preferably 1-(2-halopyridin-3-yl)urea or a derivative thereof, in the presence of a copper catalyst, particularly a copper(I) or copper(II) compound, particularly a copper(I) or copper(II) salt, as a catalyst, further in the presence of a diamine additive, and optionally in the presence of a base, particularly an inorganic base.

[0033] In the compound of formula (II), the leaving group L is not particularly limited and may be any chemical group that can act as a leaving group. Any suitable leaving group can be used, for example, a nitro group, an ester group of an alkyl and / or aryl sulfonic acid such as mesyl or tosyl, an ester group of an alkyl and / or aryl carboxylic acid, a halogen, -CN, -N3, -OCN, -NCO, -CNO, -SCN, -NCS, -SeCN, or other pseudo-halogen groups selected therefrom. According to a particular embodiment, the leaving group L is a halogen, particularly F, Cl, Br or I, for example Cl or Br. According to a particular embodiment, the leaving group L is chloride.

[0034] In the compound of formula (II), and thus also in the compound of formula (I), the group R is hydrogen, preferably a substituted or unsubstituted linear, branched and / or cyclic alkyl group having 1 to 40 C atoms, particularly 1 to 20 C atoms, which may contain one or more heteroatoms in a linear, branched and / or cyclic alkyl chain, preferably a substituted or unsubstituted aromatic group having 6 to 40 C atoms, particularly 6 to 20 C atoms, preferably a substituted or unsubstituted heteroaromatic group having 2 to 40 C atoms, particularly 3 to 20 C atoms, wherein the heteroatom of the heteroaromatic group is particularly N, A substituted or unsubstituted linear, branched and / or cyclic aralkyl group (wherein the aryl group is bonded to a linear, branched and / or cyclic alkanediyl chain), which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, preferably having 7 to 40 carbon atoms, particularly 7 to 20 carbon atoms. A substituted or unsubstituted linear, branched and / or cyclic heteroaromatic alkyl group (having a heteroaromatic group bonded to a linear, branched and / or cyclic alkanediyl chain), which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, preferably having 3 to 40 carbon atoms, particularly 4 to 20 carbon atoms, and wherein the heteroatom of the heteroaromatic group is particularly N. A substituted or unsubstituted alkylaryl group having at least one linear, branched and / or cyclic alkyl residue, which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, preferably having 7 to 40 carbon atoms, particularly 7 to 20 carbon atoms. A substituted or unsubstituted alkylheteroaryl group having at least one linear, branched and / or cyclic alkyl residue, which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, preferably having 7 to 40 carbon atoms, particularly 7 to 20 carbon atoms, and wherein the heteroatom of the heteroaromatic group is particularly N. represents.

[0035] In the scope of the present application, the R group of a specific target represents the entire structure of the active pharmaceutical ingredient in question, in particular telcagepant, rimegepant, imiglyptin ((R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile), FR-238831 (1-(3-chloro-4-methoxybenzyl)-3-(4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-carbonitrile), CJS-3678 (1-(4-chlorophenyl)-3-(3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)phenyl)urea), CJS-3255 (7-(4-(1-(4-chloro-3-(trifluoromethyl)phenylamino)vinylamino)phenoxy)-3-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one), or AA-012 (1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea), or a moiety representing any of the precursors enabling the construction of said products. Examples are groups having a substituted or unsubstituted straight-chain and / or branched-chain alkyl group, cycloalkyl group, aryl group, heteroaryl group or a mixture of these elements. The group may contain one or several heteroatoms from the group of N, P, O, S, halogen (e.g., F, Cl, Br, and / or I). The R group is characterized in particular by the fact that it remains unchanged during the conversion in the process of the present invention.

[0036] In the residue R having one or more heteroatoms in a straight-chain, branched-chain and / or cyclic alkyl chain, the heteroatoms in the straight-chain, branched-chain and / or cyclic alkyl chain are not particularly limited and are preferably at least one of N, O, S, Se and / or P, particularly N.

[0037] At residue R, and at residue R' discussed herein, the substituents, when present, are not particularly limited. In particular, according to certain embodiments, the substituents are selected from the following: -alkoxycarbonyl, alkenoxycarbonyl, and aralkyloxycarbonyl groups -(CO)-O-R 1 , in particular straight-chain, branched and / or cyclic alkoxycarbonyl groups having from 1 to 10, in particular from 1 to 4, C atoms (i.e., R 1 is a straight-chain, branched and / or cyclic alkyl residue having from 1 to 10, in particular from 1 to 4, C atoms), for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butyloxycarbonyl, etc.; straight-chain, branched and / or cyclic alkenoxycarbonyl groups having from 2 to 10, in particular from 2 to 4, C atoms (i.e., R 1 is a straight-chain, branched and / or cyclic alkenyl residue having from 2 to 10, in particular from 2 to 4, C atoms), for example, allyloxycarbonyl; straight-chain, branched and / or cyclic aryloxycarbonyl groups having from 6 to 40, in particular from 6 to 20, C atoms (i.e., R 1 is an aromatic residue having from 6 to 40, in particular from 6 to 20, C atoms), or straight-chain, branched and / or cyclic aralkyloxycarbonyl groups having from 7 to 40, in particular from 7 to 20, C atoms (i.e., R 1 is a straight-chain, branched and / or cyclic aralkyl residue having from 7 to 40, in particular from 7 to 20, C atoms); for example, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, etc.; more particularly straight-chain, branched and / or cyclic alkoxycarbonyl groups having from 1 to 10, in particular from 1 to 4, C atoms; -alkylcarbonyloxy groups -O(CO)-R 2 , in particular straight-chain, branched and / or cyclic alkylcarbonyloxy groups having from 1 to 10, in particular from 1 to 4, C atoms (i.e., R 2is a linear, branched and / or cyclic alkyl residue having from 1 to 10, especially 1 to 4, C atoms), an arylcarbonyloxy group having from 6 to 40, especially 6 to 20, C atoms (i.e., R 2 is an aromatic residue having from 6 to 40, especially 6 to 20, C atoms), or a linear, branched and / or cyclic aralkylcarbonyloxy group having from 7 to 40, especially 7 to 20, C atoms (i.e., R 2 is a linear, branched and / or cyclic aralkyl residue having from 7 to 40, especially 7 to 20, C atoms); -alkoxy group -OR 3 , especially a linear, branched and / or cyclic alkoxy group having from 1 to 10, especially 1 to 4, C atoms (i.e., R 3 is a linear, branched and / or cyclic alkyl residue having from 1 to 10, especially 1 to 4, C atoms), for example, methoxy group, ethoxy group, propoxy group, butoxy group, tert-butoxy group, an aryloxy group having from 6 to 40, especially 6 to 20, C atoms (i.e., R 3 is an aromatic residue having from 6 to 40, especially 6 to 20, C atoms), or a linear, branched and / or cyclic aralkyloxy group having from 7 to 40, especially 7 to 20, C atoms (i.e., R 3 is a linear, branched and / or cyclic aralkyl residue having from 7 to 40, especially 7 to 20, C atoms); -alkylamide group -(CO)NR 4 R 5 , especially a linear, branched and / or cyclic alkylamide group having from 1 to 10, especially 1 to 4, C atoms (wherein R 4 and R 5 may be the same or different, provided that at least one of R 4 and R 5 is not H); -sulfone group -(SO2)-R 6 , especially (wherein R 6is selected from a linear, branched and / or cyclic alkyl residue having from 1 to 10, especially 1 to 4, C atoms, an aryl group having from 6 to 40, especially 6 to 20, C atoms, or a linear, branched and / or cyclic aralkyl group having from 7 to 40, especially 7 to 20, C atoms); -sulfoxide group -(SO)-R 7 , especially (wherein R 7 is selected from a linear, branched and / or cyclic alkyl residue having from 1 to 10, especially 1 to 4, C atoms, an aryl group having from 6 to 40, especially 6 to 20, C atoms, or a linear, branched and / or cyclic aralkyl group having from 7 to 40, especially 7 to 20, C atoms); -thioether group -SR 8 , especially (wherein R 8 is selected from a linear, branched and / or cyclic alkyl residue having from 1 to 10, especially 1 to 4, C atoms, an aryl group having from 6 to 40, especially 6 to 20, C atoms, or a linear, branched and / or cyclic aralkyl group having from 7 to 40, especially 7 to 20, C atoms); -carboxamide group -(CO)-NR 9 R 10 , especially (wherein R 9 and R 10 are each independently selected from H, a linear, branched and / or cyclic alkyl residue having from 1 to 10, especially 1 to 4, C atoms, an aryl group having from 6 to 40, especially 6 to 20, C atoms, and / or a linear, branched and / or cyclic aralkyl group having from 7 to 40, especially 7 to 20, C atoms, and R 9 and R 10 may be the same or different); -carboxylic acid group -COOR 11 , especially (wherein R 11 is selected from a linear, branched and / or cyclic alkyl residue having from 1 to 10, especially 1 to 4, C atoms, an aryl group having from 6 to 40, especially 6 to 20, C atoms, or a linear, branched and / or cyclic aralkyl group having from 7 to 40, especially 7 to 20, C atoms); - A halogen, for example, F, Cl, Br, I, especially Cl and / or Br, more particularly Cl; - NH2; or - OH.

[0038] According to a particular embodiment, the substituent is a tert - butyloxycarbonyl (Boc) group. According to a particular embodiment, the group R in the compound of formula (II) and thus similarly in the compound of formula (I) represents hydrogen.

[0039] According to a particular embodiment, in the compound of formula (II) and thus similarly in the compound of formula (I), the group R is preferably a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in a linear, branched and / or cyclic alkyl chain having 1 to 40 C atoms, especially 1 to 20 C atoms, for example, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert - butyl, cyclobutyl, cyclohexyl, piperidin - 4 - yl, 1 - (tert - butoxycarbonyl)piperidin - 4 - yl (1 - Boc - piperidin - 4 - yl) and the like. According to a particular embodiment, the group R in the compound of formula (II) and thus similarly in the compound of formula (I) represents a 1 - substituted or unsubstituted piperidin - 4 - yl group, especially a 1 - (tert - butoxycarbonyl)piperidin - 4 - yl group.

[0040] According to a particular embodiment, in the compound of formula (II) and thus similarly in the compound of formula (I), the group R is preferably a substituted or unsubstituted aromatic group having 6 to 40 C atoms, especially 6 to 20 C atoms, for example, a substituted or unsubstituted phenyl or naphthyl group.

[0041] According to certain embodiments, in the compounds of formula (II), and thus also in the compounds of formula (I), the group R preferably represents a substituted or unsubstituted linear, branched and / or cyclic aralkyl group, which may contain one or more heteroatoms in a linear, branched and / or cyclic alkanediyl chain having 7 to 40 C atoms, especially 7 to 20 C atoms, such as benzyl, phenethyl, phenylpropyl, naphthylmethyl, 1-benzylpiperidin-4-yl group and the like. According to certain embodiments, the group R in the compounds of formula (II), and thus also in the compounds of formula (I), represents a substituted or unsubstituted 1-benzylpiperidin-4-yl group, especially an unsubstituted 1-benzylpiperidin-4-yl group.

[0042] According to certain embodiments, in the compounds of formula (II), and thus also in the compounds of formula (I), the group R preferably represents a substituted or unsubstituted alkylaryl group, which may contain one or more heteroatoms in a linear, branched and / or cyclic alkanediyl chain having 7 to 40 C atoms, especially 7 to 20 C atoms, such as substituted or unsubstituted methylphenyl, ethylphenyl, propylphenyl, isopropylphenyl and the like groups.

[0043] According to certain embodiments, R is hydrogen, or a substituted or unsubstituted linear, branched and / or cyclic alkyl or aralkyl group having 1 to 12 carbons, which may or may not contain heteroatoms, and may contain one or more heteroatoms. Preferably, R is a piperidine group - especially a piperidin-4-yl group, an N-substituted piperidine derivative - especially an N-substituted piperidin-4-yl group, a 1-benzylpiperidin-4-yl group, or benzyl. Preferably, R is a piperidine, especially a piperidin-4-yl group N-substituted (1-substituted) by tert-butyloxycarbonyl, or a 1-benzylpiperidin-4-yl group.

[0044] A schematic diagram of the preferred reaction of the compound of formula (IIa) to the compound of formula (Ia) in the preferred method is shown in Scheme 2 below. Scheme 2

[0045]

Chem.

[0046] In the formula, L represents a leaving group, and R' is hydrogen, a substituent defined above, a substituted or unsubstituted straight-chain, branched-chain, and / or cyclic alkyl group which may contain one or more heteroatoms in the straight-chain, branched-chain, and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted straight-chain, branched-chain, and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the straight-chain, branched-chain, and / or cyclic alkane diyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one straight-chain, branched-chain, and / or cyclic alkyl residue which may contain one or more heteroatoms in the straight-chain, branched-chain, and / or cyclic alkyl chain, In particular, in the formula, R' is hydrogen, a substituent defined above, a substituted or unsubstituted straight-chain, branched-chain, and / or cyclic alkyl group which may contain one or more heteroatoms in the straight-chain, branched-chain, and / or cyclic alkyl chain having 1 to 35 C atoms, preferably 1 to 15 C atoms, particularly 1 to 4 C atoms, a substituted or unsubstituted aromatic group having 6 to 35 C atoms, preferably 6 to 20 C atoms, particularly 6 to 12 C atoms, a substituted or unsubstituted heteroaromatic group having 2 to 35 C atoms, preferably 3 to 15 C atoms, particularly 3 to 12 C atoms, and the heteroatom of the heteroaromatic group is particularly N, a substituted or unsubstituted straight-chain, branched-chain, and / or cyclic aralkyl group which may contain one or more heteroatoms in the straight-chain, branched-chain, and / or cyclic alkane diyl chain having 7 to 35 C atoms, preferably 7 to 15 C atoms, particularly 7 to 12 C atoms, A substituted or unsubstituted linear, branched and / or cyclic heteroaromatic alkyl group which preferably has 3 to 35 C atoms, in particular 4 to 15 C atoms, and may contain one or more heteroatoms in a linear, branched and / or cyclic alkanediyl chain, wherein the heteroatom of the heteroaromatic group is in particular N, A substituted or unsubstituted alkylaryl group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in an alkyl chain having 7 to 35 C atoms, preferably 7 to 15 C atoms, in particular 7 to 12 C atoms, or A substituted or unsubstituted alkylheteroaryl group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in a linear, branched and / or cyclic alkyl chain having 7 to 35 C atoms, preferably 7 to 15 C atoms, in particular 7 to 20 C atoms, wherein the heteroatom of the heteroaromatic group is in particular N having the substituents described above, represents an alkylheteroaryl group, in particular represents either a benzyl group or a tert-butyloxycarbonyl group.

[0047] In the process of the present invention, the Cu catalyst is not particularly limited. In particular, the origin of the copper catalyst is not particularly limited. According to certain embodiments, as the copper catalyst, any salt of copper(I) or copper(II) can be used. Preferably, the catalyst is a copper(I) and / or copper(II) salt having the formula CuX, Cu2Y, CuX2 or CuY, wherein X is a halogen or any other monovalent anion, preferably a halogen or OAc (Ac is the acetyl group (CO)CH3), Y is a divalent anion, and neither is particularly limited. Preferably, X is a halogen, especially Cl, Br or I, such as Cl or I; or OAc; and Y is sulfate. According to certain embodiments, the Cu catalyst is CuI, CuCl, CuBr, Cu(OAc)2, and / or CuSO4, especially CuCl, CuBr, CuI, and / or CuSO4. According to certain embodiments, the Cu catalyst is CuCl, CuBr, CuI, Cu(OAc)2, or CuSO4, especially CuCl, CuBr, CuI, or CuSO4, such as CuCl, CuI, or CuSO4.

[0048] The amount of the copper catalyst is not particularly limited. According to certain embodiments, the copper catalyst is added in an amount of 0.1 equivalent to 0.7 equivalent, preferably in an amount of 0.1 equivalent to 0.5 equivalent, including 0.1 equivalent and 0.7 equivalent with respect to the compound of formula (II), respectively the compound of formula (IIa).

[0049] This method is carried out in the presence of a diamine additive. The nature of the diamine additive is not particularly limited. It can be, for example, N,N'-dimethyl-ethylenediamine (DMEDA), ethylenediamine (EDA), propylenediamine (PDA), butylenediamine, pentylenediamine, 1,2-diaminocyclopentane, trans-1,2-diaminocyclohexane (DACH), phenylenediamine, such as o-phenylenediamine or diaminotoluene, such as 2,3-diaminotoluene, 3,4-diaminotoluene, or diaminonaphthalene, such as 1,8-diaminonaphthalene, or 1,10-phenanthroline or a mixture thereof. According to a particular embodiment, the diamine additive is a bidentate ligand, in particular one in which both nitrogen atoms enable binding to the copper of the catalyst. Without being bound by any theory, it is believed that the bidentate ligand enables the cyclization reaction by assisting in effective ring formation.

[0050] According to a particular embodiment, the diamine additive is selected from the group consisting of N,N'-dimethyl-ethylenediamine (DMEDA), ethylenediamine (EDA), propylenediamine (PDA), or trans-1,2-diaminocyclohexane (DACH), or a mixture thereof. According to a preferred embodiment, the diamine additive is selected from EDA, PDA, and DACH, more preferably EDA and PDA, and particularly ethylenediamine (EDA).

[0051] The amount of the diamine additive is from 0.1 equivalent to 9.0 equivalents, preferably from 0.2 equivalent to 9.0 equivalents, more preferably from 0.25 equivalent to 7.5 equivalents, including 0.1 equivalent and 9.0 equivalents, with respect to the compound of formula (II) (each compound of formula (IIa)). According to a particular embodiment, the equivalent of the diamine additive is equal to or greater than the equivalent of the copper catalyst. The diamine additive is preferably added in an amount less than 9.0 equivalents with respect to the compound of formula (II), each (respectively) compound of formula (IIa).

[0052] When adding a base in the method of the present invention, the base is not particularly limited. According to a specific embodiment, a base, particularly an inorganic base, is added. According to a specific embodiment, the process is carried out in the presence of an inorganic base, and its nature is not particularly limited. According to a specific embodiment, the base is a salt of an alkaline earth metal and / or an alkali metal, for example, a salt of an alkaline earth metal or a salt of an alkali metal.

[0053] According to a specific embodiment, the base is a salt selected from the group consisting of carbonates or bicarbonates, preferably from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate, more preferably from potassium carbonate and sodium carbonate, but not limited thereto.

[0054] The amount of the base in the reaction is not particularly limited. The preferred amount of the inorganic base is, according to a specific embodiment, from 0 equivalent to 5.0 equivalents, including 0 equivalent and 5.0 equivalents for the compound of formula (II), respectively for the compound of formula (IIa), for example, from 2.0 equivalents to 5.0 equivalents, including 2.0 equivalents and 5.0 equivalents, preferably 3.5 equivalents or less, for example 3.0 equivalents or less, more preferably from 2.0 equivalents to 3.0 equivalents.

[0055] In the method of the present invention, the solvent or solvent mixture is not particularly limited. The solvent can include an organic solvent, such as at least alcohol, ketone, ether, amide, sulfone, sulfoxide, and / or hydrocarbon, such as aromatic hydrocarbon; for example, ether, amide, sulfone, sulfoxide, and / or hydrocarbon, such as aromatic hydrocarbon, as a single solvent or as a mixture thereof. The solvent mixture can contain any organic solvent, such as at least alcohol, ketone, ether, amide, sulfone, sulfoxide, hydrocarbon, such as aromatic hydrocarbon, etc.; for example, ether, amide, sulfone, sulfoxide, hydrocarbon, such as aromatic hydrocarbon, or a mixture of a plurality of these and water.

[0056] According to certain embodiments, the solvent or solvent mixture contains at least a polar solvent, in particular water; alcohols such as methanol, ethanol, propanol, butanol; amides such as dimethylformamide (DMF) or dimethylacetamide; sulfones such as sulfolane; sulfoxides such as dimethylsulfoxide. When a solvent mixture is used in the method of the present invention, it is preferred to use at least one organic solvent, in particular a mixture of one organic solvent and water as disclosed above. Preferably, the solvent mixture contains water. In such a solvent mixture, the amount of water is not particularly limited.

[0057] The ether is not particularly limited and can be any ether, such as dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran (THF), dioxane (especially 1,4-dioxane), or a mixture thereof, especially an ether having a boiling point above 90 °C, preferably dioxane, especially 1,4-dioxane. The amide is not particularly limited and can be any amide, such as formamide, dimethylformamide, acetamide, etc., for example dimethylformamide. Also, the hydrocarbon is not particularly limited and can be, for example, linear, branched and / or cyclic alkanes, and / or aromatic hydrocarbons, such as benzene, toluene, ethylbenzene, xylene (as a mixture of isomers or as pure isomers (o-, m- and / or p-xylene)), preferably an aromatic hydrocarbon, especially toluene. Also, the sulfone is not particularly limited, but sulfolane is preferred. Also, the sulfoxide is not particularly limited, but can preferably be dimethylsulfoxide (DMSO).

[0058] According to certain embodiments, the cyclization reaction is carried out in a solvent or solvent mixture that enables at least partial dissolution, for example complete dissolution, of all the reagents used in the method of the present invention. According to certain embodiments, the solvent or solvent mixture enables at least partial dissolution, for example, dissolution of at least 5% by weight, preferably at least 10% by weight, more preferably at least 15% by weight, or even complete dissolution of the total amount of the inorganic base, based on the total amount of the inorganic base. For this purpose, it is preferable to add a strongly polar solvent such as water, or at least use a solvent such as an ether that can dissolve salts, for example dioxane (especially 1,4 - dioxane); an amide, for example DMF; a sulfone, for example sulfolane; a sulfoxide, for example dimethyl sulfoxide; a ketone, etc. In a solvent mixture containing one or more organic solvents, the amount of water is not particularly limited, but it is preferably 50% by volume or less and / or 10% by volume or more with respect to the solvent mixture.

[0059] According to certain embodiments, the solvent is an organic solvent containing up to 50% by volume of water, or a mixture of organic solvents containing up to 50% by volume of water. According to certain embodiments, dioxane (especially 1,4 - dioxane) is used as the sole solvent. According to certain embodiments, a mixture of a hydrocarbon and water, especially an aromatic hydrocarbon and water, especially a mixture of toluene and water, or a mixture of an ether and water, especially a mixture of dioxane (especially 1,4 - dioxane) and water, is used as the solvent mixture.

[0060] In the method of the present invention, the reaction conditions are not particularly limited. For example, in the method of the present invention, the reaction temperature is not particularly restricted. According to certain embodiments, it is at least 50°C, at least 70°C, at least 80°C, or even at least 90°C. According to certain embodiments, the reaction is carried out under reflux.

[0061] A further second aspect of the present invention relates to a method for producing an acid addition product of a compound of formula (I) from a compound of formula (II), the method comprising: - a compound of formula (II) in a solvent or solvent mixture, with a Cu catalyst, a diamine additive, and optionally, a base, in particular an inorganic base, and reacting in the presence thereof to form a compound of formula (I),

[0062] [Chemical formula]

[0063] (wherein L represents a leaving group, and R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain), - reacting the compound of formula (I) with an acid, is included.

[0064] In this method of the second aspect, the first step of reacting a compound of formula (II) in a solvent or solvent mixture in the presence of a Cu catalyst, a diamine additive, and optionally a base, in particular an inorganic base, to form a compound of formula (I) corresponds to the method of the first aspect, and thus all embodiments and descriptions regarding the first aspect can also be applied to this step in the method of the second aspect.

[0065] In the method of the second aspect, the step of reacting the compound of formula (I) with an acid is not particularly limited. In particular, the acid is not limited and can be an organic acid or an inorganic acid. According to a specific embodiment, the acid is an inorganic acid, in particular HCl.

[0066] The above embodiments can be combined as appropriate and arbitrarily. Further possible embodiments and implementations of the present invention also include combinations of features not explicitly mentioned either previously or subsequently with respect to the examples of the present invention. In particular, those skilled in the art will also add individual aspects as improvements or additions to each basic form of the present invention.

Example

[0067] Hereinafter, the present invention will be described in more detail with reference to some of its examples. However, these examples are illustrative and do not limit the scope of the present invention. General method According to Scheme 3, a general method for producing a 1,3-dihydro-imidazo[4,5-b]pyridin-2-one compound of formula (III) from a compound of formula (IV) (wherein in a specific example, R’ represents either a benzyl group or a tert-butyloxycarbonyl group).

[0068] A 1-(2-chloropyridin-3-yl)urea compound of formula (IV) (1.0 equivalent) is placed in a flask. A diamine additive, optionally a base, and a copper catalyst are added in appropriate amounts. The reaction mixture is heated to a desired temperature, for example, under reflux or at sealed pressure, and held at this temperature for an appropriate time. After completion of the reaction, the reaction mixture is sampled and analyzed.

[0069] Scheme 3

[0070]

Chemical formula

[0071] Reference example: Preparation of the starting material, i.e., a compound of formula (IV) where R’ is benzyl or Boc. Generally, the compound of formula (IV) can be prepared from 3 - amino - 2 - chloropyridine using reductive amination with the respective N - derivatives of 4 - piperidone followed by reaction with chlorosulfonyl isocyanate (CSI), as shown in Schemes 4 and 5 below (including the final reaction of the method of the present invention).

[0072] Scheme 4

[0073]

Chemical formula

[0074] Scheme 5

[0075]

Chemical formula

[0076] Synthesis of tert - butyl 4 - (1 - (2 - chloropyridin - 3 - yl)ureido)piperidine - 1 - carboxylate 2 - Chloropyridine - 3 - amine (502 g, 3.92 mol), tert - butyl - 4 - oxopiperidine - 1 - carboxylate (930 g, 4.67 mol) were stirred in ethyl acetate (7.5 L) at 0 - 5 °C or below, treated with trifluoroacetic acid (887 g, 7.78 mol), and then sodium triacetoxyborohydride (1240 g, 5.85 mol) was added at 10 °C or below. The reaction mixture was warmed to room temperature, stirred for 2 hours, and quenched with water (1.5 L). The pH was adjusted to 10 - 11 with sodium hydroxide solution (20%), and the phases were separated. The organic layer was washed with water (3 × 5 L) and concentrated under vacuum to a volume of about 1.5 L. n - Heptane (5 L) was added at 40 °C, the resulting slurry was cooled to 5 °C or below, and aged for 1 hour. The slurry was filtered, the cake was washed with n - heptane (1.5 L), and dried under vacuum at 50 °C for 12 hours. tert - Butyl 4 - (2 - chloropyridin - 3 - yl)piperidine - 1 - carboxylate (1170 g, 3.75 mol) was obtained as an off - white solid.

[0077] Chlorosulfonyl isocyanate (60.2 g, 0.425 mol) was added to tetrahydrofuran (THF, 300 mL) at room temperature. The mixture was cooled to -10 °C. A solution of tert-butyl 4-(2-chloropyridin-3-ylamino)piperidine-1-carboxylate (102.0 g, 0.327 mol) in a 1:1 mixture of THF and ethyl acetate (200 mL) was added dropwise over 20 minutes. After 10 minutes at -10 °C, water (50 mL) was added dropwise over 10 minutes. The mixture was warmed to room temperature and aged for 30 minutes. The pH was adjusted to 8 - 9 with sodium hydroxide solution (10%), and the suspension was distilled under reduced pressure to remove THF. The same amount of ethyl acetate was added, the residue was filtered, washed with ethyl acetate, and dried in vacuo to obtain the title compound (120 g, 0.338 mol, yield: 96.7%).

[0078] The structure was proven by comparing the NMR with the literature data shown in Non-Patent Document 1 (Leahy K.D. et al., Organic Process Research & Development, 2012, Vol.16, Issue2, pp244 - 249).

[0079] Synthesis of 1-(1-benzylpiperidin-4-yl)-1-(2-chloropyridin-3-yl)urea 2-Chloropyridin-3-amine (12.8 g, 0.1 mol), 1-benzyl-4-piperidone (25.6 g, 0.12 mol), PTSA (p-toluenesulfonic acid, 0.12 g, 1 wt%), and toluene (46 mL) were added to a flask. The mixture was heated to reflux, and the water formed was immediately separated with a Dean-Stark trap. When no more water was recovered, the reaction mixture was cooled. The resulting imine solution was used in the next step.

[0080] To a flask containing MeOH (100 mL), NaBH4 (38 g, 1 mol) was added portionwise at 5 - 20 °C. The imine solution was added dropwise at a temperature below 20 °C. After the addition was complete, the reaction mixture was stirred at room temperature overnight. 50 g of water was added to quench the reaction mixture. Methanol was distilled off, and phase separation occurred. The organic phase was concentrated. The residual solid was recrystallized from n-heptane (95 g). After filtration, the wet product was dried at 50 °C overnight. N-(1-Benzylpiperidin-4-yl)-2-chloropyridine-3-amine (27.4 g, 0.091 mol) was obtained in a 91% yield. The HPLC purity was 93.2%.

[0081] Following the procedure described for the conversion of tert-butyl 4-(2-chloropyridin-3-ylamino)piperidine-1-carboxylate to tert-butyl 4-(1-(2-chloropyridin-3-yl)ureido)piperidine-1-carboxylate, N-(1-benzylpiperidin-4-yl)-2-chloropyridine-3-amine was further converted to 1-(1-benzylpiperidin-4-yl)-1-(2-chloropyridin-3-yl)urea.

[0082] Specific Examples A-01 to A-12 Synthesis and Isolation of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (R’ = Boc) Into a flask, 15.25 g of tert-butyl 4-(1-(2-chloropyridin-3-yl)ureido)piperidine-1-carboxylate (0.048 mol), 18.5 g of diaminoethane (EDA, 0.308 mol), 13.1 g of potassium carbonate (0.095 mol), 1.1 g of copper(I) iodide (0.0058 mol), 87 mL of dioxane and 37 mL of water were added. The mixture was heated to reflux (96 °C) and stirred at this temperature for 72 hours. The aqueous layer was separated at 90 °C. The organic phase was cooled to room temperature (22 °C). The suspension was filtered to remove the inorganic solid. The mother liquor was concentrated to dryness. The pH of the residue was adjusted to about 6 with dilute HCl. The suspension was filtered off and washed with water. The wet product was dried at 50 °C to obtain 11.8 g of the title compound (0.037 mol, corresponding to 77% of the theoretical yield).

[0083] The structure was proven by comparing the NMR data with the literature data shown in Non-Patent Document 1 (Leahy K.D. et al., Organic Process Research & Development, 2012, Vol.16, Issue2, pp244~249).

[0084] Examples A-02 to A-12 were carried out in the same manner as Example A-01, using the reagents, amounts and reaction conditions shown in Table 1, and only analyzing the crude product using HPLC and NMR without performing the final work-up of the product. The results are shown together in Table 1.

[0085] Specific Examples B-01 to B-07 Synthesis and Isolation of 1-(1-Benzylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (R’ = Bn) Into a flask, 10.0 g of 1-(1-benzylpiperidin-4-yl)-1-(2-chloropyridin-3-yl)urea (0.0291 mol), 15.2 g of diaminoethane (EDA, 0.253 mol), 8.0 g of potassium carbonate (0.058 mol), 1.4 g of copper(I) iodide (0.00735 mol), 45 mL of dioxane and 5 mL of water were added. The resulting mixture was heated to reflux (96 °C). The mixture was stirred at this temperature for 72 hours. The aqueous layer was separated at 90 °C. The organic phase was cooled to room temperature and analyzed by HPLC. The suspension was filtered off. The mother liquor was concentrated to dryness. The pH of the residue was adjusted to about 6 with dilute HCl. The suspension was filtered off and washed with water. The wet product was dried at 50 °C. 8.5 g of the title compound was obtained (0.0278 mol, corresponding to 88% of the theoretical yield).

[0086] Analysis Hydrogenation of 1-(1-benzylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one to 1H-imidazo[4,5-b]pyridin-2(3H)-one. To confirm the structure, the NMR data was compared with the data from Non-Patent Document 1 (Leahy K.D. et al., Organic Process Research & Development, 2012, Vol.16, Issue2, pp244~249).

[0087] Into an autoclave, 0.45 g of 1-(1-benzylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (1.460 mmol) from Example 2, 60 mL of methanol and 0.4 g of palladium on charcoal were charged. The reaction mixture was stirred at 40 °C overnight under a hydrogen pressure of 35 bar (3.5 MPa). The resulting solution was concentrated to give an oily solid. The oily solid was dissolved in 10 mL of ethanol. 1 mL of 32% hydrochloric acid was added to the precipitate. The suspension was filtered and the wet cake was dried to give 0.25 g of 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (0.865 mmol). The structure was confirmed as described above by comparing the NMR data with the data from the literature.

[0088] For Examples B-02 to B-07, without performing the final work-up of the product, only the analysis of the crude product using HPLC and NMR was carried out in the same manner as in Example B-01 using the reagents, amounts, and reaction conditions shown in Table 2. The results are shown together in Table 2.

[0089] Comparative Example C-01 The comparative example following the general method without adding an amino additive gave a yield of 0% as given by the reaction conditions, reagents, and their amounts in Table 3.

[0090]

Table 1

[0091]

Table 2

[0092]

Table 3

[0093] In Tables 1 to 3, the following apply. RF: At reflux temperature DMEDA: N,N'-dimethyl-ethylenediamine EDA: Ethylenediamine PDA: Propylenediamine DACH: trans-1,2-diaminocyclohexane

Claims

1. A method for producing a compound of formula (I) from a compound of formula (II), said method comprising: reacting a compound of formula (II) in a solvent or solvent mixture in the presence of a Cu catalyst, a diamine additive, and an inorganic base to form a compound of formula (I) 【Chemical 1】 wherein L represents a leaving group, and R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted linear, branched and / or cyclic aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain) comprising a method wherein the inorganic base is a carbonate or bicarbonate.

2. The method according to claim 1, wherein the leaving group L is halogen.

3. The method according to claim 1 or claim 2, wherein the leaving group L is chloride.

4. The method according to claim 1 or claim 2, wherein the Cu catalyst is a copper(I) salt or a copper(II) salt.

5. wherein the Cu catalyst is CuI, CuCl, CuBr, Cu(OAc) ２ , and / or CuSO ４ , and the method according to claim 1 or claim 2

6. The method according to claim 1 or claim 2, wherein the amount of the Cu catalyst is 0.1 equivalent to 0.6 equivalent based on the compound of formula (II).

7. The method according to claim 1 or claim 2, wherein the solvent is an organic solvent or a mixture of organic solvents containing 0 wt% to 50 wt% of water.

8. The method according to claim 1 or claim 2, wherein the diamine additive is a bidentate ligand.

9. The method according to claim 8, wherein the diamine additive is selected from the group consisting of N,N'-dimethyl-ethylenediamine (DMEDA), ethylenediamine (EDA), propylenediamine (PDA), or trans-1,2-diaminocyclohexane (DACH), or a mixture thereof.

10. The method according to claim 9, wherein the diamine additive is selected from EDA and PDA.

11. The method according to claim 1 or claim 2, wherein the inorganic base is present in an amount of less than 5.0 equivalents based on the compound of formula (II).

12. A method for producing an acid addition salt of a compound of formula (I) from a compound of formula (II), said method comprising: reacting a compound of formula (II) in a solvent or solvent mixture in the presence of a Cu catalyst, a diamine additive, and an inorganic base to form a compound of formula (I), [Chemical 2] wherein L represents a leaving group, and R represents hydrogen, a substituted or unsubstituted linear, branched and / or cyclic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain, a substituted or unsubstituted aromatic or heteroaromatic group, a substituted or unsubstituted aralkyl or heteroaromatic alkyl group which may contain one or more heteroatoms in the linear, branched and / or cyclic alkanediyl chain, or a substituted or unsubstituted alkylaryl or alkylheteroaromatic group having at least one linear, branched and / or cyclic alkyl residue which may contain one or more heteroatoms in the linear, branched and / or cyclic alkyl chain), reacting the compound of formula (I) with an acid, and wherein the inorganic base is a carbonate or bicarbonate.

Images