Process for the preparation of 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol

Abstract

The present invention relates to a process for producing (3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]-6,7-dihydrotriazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol, which is useful as a pharmaceutically active compound.

Description

Technical Field

[0001] The present invention relates to a method for producing 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol, which is useful as a pharmaceutically active compound.

Background Art

[0002] The compound 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol, which is a compound of formula (VI) described in International Publication No. WO 2013 / 068306, has been shown to be a useful pharmaceutical compound as a CB2 receptor agonist. Interest in CB2 receptor agonists has been steadily increasing over the past decade (currently 30 - 40 patent applications / year) because several of the lead compounds have been shown to have beneficial effects in preclinical models of several human diseases including chronic pain (Beltramo, M. Mini Rev Med Chem 2009, 9(1), 11 - 25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20 Suppl 1, 53 - 7), bone mass regulation (Bab, I. et al. Br J Pharmacol 2008, 153(2), 182 - 8), neuroinflammation (Cabral, G. A. et al. J Leukoc Biol 2005, 78(6), 1192 - 7), ischemia / reperfusion injury (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252 - 62), systemic fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129 - 36; Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050 - 6), and liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742 - 55; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475 - 83). Without wishing to be bound by theory, the use of azide in a flow reactor may prevent and / or reduce the accumulation of explosive components commonly seen in typical syntheses involving azide. For example, since there is no headspace in a tubular flow reactor, volatile HN3 may not accumulate in significant amounts. For example, in a batch process, there is a risk of HN3 accumulating and condensing in the headspace, a risk of heavy metal azides depositing, a risk of HN3 exposing personnel, and / or the use of a restricted temperature range is required.In contrast, in a continuous flow process, due to the lack of a headspace, HN3 accumulation in the reactor is minimized (e.g., in a tubular reactor), the reactor volume is small, access to a variety of temperature ranges including higher ranges compared to batch processes is possible, and / or the process allows for in-line quenching of excess azide residues and other harmful azide wastes. HN3 is a known by-product and is generally formed when azide reagents are used under acidic conditions.

[0003] HN3 is a very volatile compound (bp = 37 °C) and has been reported to form explosive gas-phase mixtures with air and / or nitrogen at low concentrations of 8 - 15 volume %. Undiluted HN3 is extremely explosive, shock-sensitive, and highly toxic (e.g., according to the National Institute for Occupational Safety and Health (NIOSH), the recommended airborne exposure limit for hydrazoic acid is 0.11 ppm (0.3 mg / m as sodium azide)). The fluidity of the reaction and the ability to quench unreacted azide and / or HN3 before removing the reaction mixture from the flow reactor significantly reduce and / or eliminate the risk of potential explosion and exposure. Thus, the production method of the present invention can minimize and / or eliminate the possibility of large amounts of HN3 accumulating in either gaseous or liquid form.

[0004] The present invention is carried out in the presence of a solvent or a mixture of two or more solvents. More specifically, the solvent may be an ether-like solvent (e.g., tetrahydrofuran, acetonitrile, diisopropyl ether, tert-butyl methyl ether or dibutyl ether, more specifically acetonitrile), an alcohol solvent (e.g., methanol, n-butanol, s-butanol, tert-butanol or ethanol, more specifically t-butanol), an aliphatic hydrocarbon solvent (e.g., hexane, heptane or pentane), a saturated alicyclic hydrocarbon solvent (e.g., cyclohexane or cyclopentane) or an aromatic solvent (e.g., toluene or t-butylbenzene), a polar aprotic solvent (e.g., acetonitrile, DMSO, sulfolane), water or an organic solvent such as a combination thereof. More specifically, in some steps of the present invention, the specific solvent for a particular purpose is acetonitrile, and in other steps of the present invention, the specific solvent for a particular purpose is ethyl acetate.

Summary of the Invention

[0005] A first aspect of the present invention is a method for producing a compound of formula (II)

Chemical Formula

Chemical Formula

[0006] A second aspect of the present invention is a method for producing a compound of formula (III)

Chemical Formula

Chemical Formula

[0007] The third aspect of the present invention is a compound of formula (IV)

Chemical formula

Chemical formula

[0008] The fourth aspect of the present invention is a compound of formula (V)

Chemical formula

Chemical formula

[0009] The fifth aspect of the present invention is a compound of formula (VI)

Chemical formula

Chemical formula

Chemical formula

Brief description of the drawings

[0010]

Fig. 1A - B

Fig. 2

Embodiments for Carrying Out the Invention

[0011] Unless otherwise specified, the following terms used in this specification and the claims have the meanings shown below.

[0012] "Ambient conditions" or "room temperature" refers to conditions experienced in a standard laboratory, for example, ambient temperature of 18°C to 28°C under atmospheric pressure, air, Ar or N2.

[0013] "Compound of formula (VI)"

Chem.

[0014] "Compound of formula (VI)" is also known as rac-(3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol. In this specification, the name or reference of the compound of formula (VI)' can be used interchangeably.

[0015] The term "inorganic base" means an alkali base such as an alkali carbonate, alkali bicarbonate, alkali borate, alkali phosphate, alkali hydroxide, etc. More preferred basic aqueous solutions are solutions of sodium carbonate, sodium phosphate, potassium carbonate, lithium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium bicarbonate or lithium bicarbonate, particularly NaOH, KHCO3, NaHCO3, K2CO3, Na2CO3, sodium phosphate, KOH and lithium hydroxide, more specifically selected from KHCO3, NaHCO3, K2CO3, Na2CO3, sodium phosphate or mixtures thereof. The most preferred basic aqueous solution is a solution of KHCO3, NaHCO3, or a mixture thereof.

[0016] The term "organic base" refers to an organic Bronsted-Lowry base. Examples of organic bases are triethylamine, 4-pyrrolidinopyridine, dimethylaminopyridine (DMAP), N-methylmorpholine, N-ethylmorpholine, pyridine, dialkylaniline, 1,1,3,3-tetramethylguanidine (TMG), 2-picoline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium acetate, potassium acetate, 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), potassium acetate, imidazole, diisopropylamine, diisopropylcyclohexylamine, and in particular, according to the present invention, the organic base is 1,1,3,3-tetramethylguanidine (TMG), pyridine, 2-picoline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium acetate, potassium acetate, 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), potassium acetate, imidazole or diisopropylamine, more specifically 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or pyridine.

[0017] The term "Bronsted-Lowry base" refers to any chemical species that can accept a proton.

[0018] The term "base" refers to any Bronsted-Lowry base, any organic base, or any inorganic base. Examples of bases are 1,1,3,3-tetramethylguanidine (TMG), 2-picoline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium acetate, potassium acetate, 1,5-diazabicyclo(4.3.0)nona-5-ene (DBN), potassium acetate, imidazole, diisopropylamine, pyridine, KHCO3, NaHCO3, K2CO3, Na2CO3, or sodium phosphate.

[0019] The term "tautomer" means a constitutional isomer that undergoes rapid interconversion such that it cannot be isolated independently.

[0020] The term "pivaloyl source" refers to a molecule that can generate an electrophilic pivaloyl. Examples of pivaloyl sources are pivalic acid, pivaloyl chloride, or pivalic anhydride, particularly pivaloyl chloride.

[0021] The term "salt" means a salt formed from an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, formic acid, acetic acid, phosphoric acid, and an organic acid selected from the classes of aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, and in particular, the salt refers to a salt formed from hydrochloric acid and citric acid.

[0022] The terms "hydroxyl" and "hydroxy" alone or in combination mean an -OH group.

[0023] The term "telescoping" means performing a plurality of reaction steps (including quenching and other work-up operations) without directly isolating the intermediate.

[0024] The term "chlorine source" means any chemical reagent that can be used to add chlorine atoms to other chemical substances. In particular, the chlorine source can be POCl3, PCl3, calcium hypochlorite, oxalyl chloride, PCl5, Cl2, thionyl chloride, trichloroisocyanuric acid, and more specifically, the chlorine source is oxalyl chloride or POCl3.

[0025] The azide source refers to a metal azide or an organic azide. In particular, the metal azide can be an alkali metal such as potassium, sodium, lithium, rubidium or cesium. The metal can be, but is not limited to, a transition metal such as iron, cobalt, nickel, copper or zinc. It is understood that certain metal azides can be formed in solution by mixing sodium azide and the like with a metal salt. In particular, a transition metal salt such as copper sulfate. The azide of the present invention may be an organic azide or ammonium azide. Some metal azides such as Cu(N3)2 and Pb(N3)2 are explosive, and care should be taken when such azides are used (for example, copper-containing fittings such as brass or bronze should not be used). Examples of azides according to the present invention are selected from sodium azide, trimethylsilyl azide, tetrabutylammonium azide, or benzenesulfonyl azide or combinations thereof, particularly sodium azide.

[0026] As used herein, the terms “continuous flow process,” “continuous flow process,” “flow process,” “continuous process,” and “semicontinuous process” are used interchangeably to refer to chemical processes that utilize flow chemistry and techniques. Both single-step and multi-step chemical reactions can be carried out using flow chemistry. One of ordinary skill in the art will recognize that flow chemistry involves the use of channels or tubes for carrying out chemical reactions (or a series of chemical reactions) in a continuous flow, rather than in discrete batches using conventional vessels such as reaction flasks. One of ordinary skill in the art will also recognize the various types of continuous flow reactors in which flow chemistry can be carried out, such as tubular reactors (including spinning tube reactors), microreactors, spinning disk reactors, multi-cell flow reactors, CSTRs, oscillatory flow reactors, hex reactors, and aspirator reactors. A continuous flow process can be scaled up or down and thus does not necessarily imply a particular continuous flow reactor size. In various embodiments, the channels or tubes of a continuous flow reactor have a cross-sectional size (e.g., the diameter of a tube having a circular cross-section) in the range of 1.5 mm to about 51 mm. Thus, examples of cross-sectional sizes (e.g., diameters) of channels or tubes of a continuous flow reactor include about 1.5 mm or greater, about 3 mm or greater, about 6 mm or greater, about 9 mm or greater, about 13 mm or greater, about 25 mm or greater, about 51 mm or less, about 25 mm or less, about 22 mm or less, about 19 mm or less, about 16 mm or less, about 13 mm or less, about 9 mm or less, or about 6 mm or less. One of ordinary skill in the art will understand that the foregoing description of channel or tube sizes provides descriptions within appropriate combinations, e.g., in the range of about 3 mm to about 6 mm. The terms used herein with respect to continuous flow processes, flow chemistry, and flow equipment are to be understood to have their ordinary meanings known to one of ordinary skill in the art. In particular, see M.B. Plutschack et al., ‘‘The Hitchhiker’s Guide to Flow Chemistry’’ Chem. Rev. (June 2017), which is incorporated herein by reference for the purpose of describing various continuous flow processes, flow chemistry, flow techniques, and flow equipment.For any given continuous flow process, scale-up or scale-down can be achieved by using continuous flow reactors with larger or smaller pipe diameters, respectively. Scale-up or scale-down can also be achieved by increasing or decreasing the number of continuous flow reactors used to carry out the continuous flow. Reactor technologies and conditions such as mixing, pressure, temperature, flow rate, reaction rate, reaction time, and / or degree of reaction can be controlled and / or monitored using known technologies and equipment such as vessels, CSTRs, piping, pumps, valves, mixers, back pressure regulators (BPRs), coolers, heaters, temperature sensors, temperature controllers, reaction monitors (such as in-line flow infrared (IR) monitors), photoreactors (equipped with UV sources such as mercury lamps or 365 nm UV LEDs), membrane separators, and computers. One of ordinary skill in the art can control and monitor the state of the reactor using routine experimentation informed by the detailed guidance and examples provided herein.

[0027] "Batch reaction" or "batch" means that the reactants are mixed together and reacted until the reactants are completely converted to products.

[0028] "Batch reactor" means a vessel suitable for carrying out a batch reaction in a stirred tank. One of ordinary skill in the art is also familiar with the various types of batch reactors in which batch chemistry can be carried out as described in the art.

[0029] In some embodiments, the method of forming the tetrazole of formula (II) is carried out in a flow reactor. Flow reactors are known to those skilled in the art. Flow reactors may be provided in various configurations and may include several components for utilizing the methods described herein. Non-limiting components of a flow reactor include an inlet (e.g., for reactants, solvents, quenchants, etc.), a reaction tube and / or chamber (e.g., where the reaction takes place), an outlet, a pressure controller (e.g., a back pressure regulator), and a temperature control device (e.g., a heating device and / or a cooling device). Non-limiting examples of flow reactors are shown in FIGS. 1A and 1B and will be described in more detail herein.

[0030] In another embodiment, the present invention provides a method for producing a compound of formula (II)

Chemical formula

Chemical formula

[0031] In another embodiment, the present invention provides a method for producing a compound of formula (III)

Chemical formula

Chemical formula

[0032] In another embodiment, the present invention provides a method for producing a compound of formula (IV)

Chemical formula

Chemical formula

[0033] In another embodiment, the present invention provides a method for producing a compound of formula (V)

Chemical formula

Chemical formula

[0034] In another embodiment, the present invention provides a method for producing a compound of formula (VI)

Chemical formula

Chemical formula

Chemical formula

[0035] In another embodiment, the present invention provides a method for producing a compound of formula (VI)

Chemical formula

Chemical formula

[0036] In another embodiment, the present invention relates to a method for producing a compound of formula (VI) [Chemical formula] which includes reacting the compound of formula (VIII) [Chemical formula] with the compound of formula (VII) [Chemical formula] A production method is provided which includes reacting them.

[0037] In another embodiment, the present invention relates to a method for producing a compound of formula (VI) [Chemical formula] which includes reacting the compound of formula (V) [Chemical formula] with a chlorine source, particularly oxalyl chloride or POCl₃ to form [Chemical formula] the compound, and then reacting the compound of formula (VIII) with the compound of formula (VII) [Chemical formula] A production method including reacting with a compound of

[0038] In another embodiment, the present invention relates to a compound of formula (VI)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0039] In another embodiment, the present invention relates to a compound of formula (VI)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0040] In another embodiment, the present invention relates to a method for producing a compound of formula (VI)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0041] In another embodiment, the present invention relates to a method for producing a compound of formula (VI) [Chemical formula] which comprises reacting a compound of formula (I) [Chemical formula] in the presence of an azide source to form a compound of formula (II) [Chemical formula] reacting the compound of formula (II) with 2-cyanoacetamide to form a compound of formula (III) [Chemical formula] reacting the compound of formula (III) with a pivaloyl source to form a compound of formula (IV); [Chemical formula] reacting the compound of formula (IV) with a base to form a compound of formula (V) [Chemical formula] to form a compound of formula (V), and reacting the compound of formula (V) in the presence of a chlorine source, particularly oxalyl chloride or POCl3, to form a compound of formula (III)

Chemical formula

Chemical formula

[0042] In certain embodiments, the present invention provides a multi-step synthetic route as shown in Scheme 1. Scheme 1:

Chemical formula

[0043] In more specific embodiments, the present invention provides a multi-step synthetic route in which the routes A to B and C to D described in Scheme 1 are nested.

[0044] In more specific embodiments, the present invention provides a multi-step synthetic route in which the route F to G described in Scheme 1 is nested.

[0045] In even more specific embodiments, as described in Scheme 1, steps A, B, and D are carried out in continuous flow mode, and most specifically, step A is carried out in continuous flow mode.

[0046] In another embodiment, the present invention provides a method for producing a compound of formula (III)

Chemical formula

Chemical formula

Chemical formula

[0047] In another embodiment, the present invention relates to a method for producing a compound of formula (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0048] In another embodiment, the present invention relates to a method for producing a compound of formula (V)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0049] In another embodiment, the present invention relates to a method for producing a compound of formula (VI)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0050] In a specific embodiment of the present invention, one or more of the production methods described herein are implemented as a continuous flow process, and in particular, the continuous flow process is implemented in a flow reactor.

[0051] In other embodiments, one or more of the production methods described herein are implemented as a semi - continuous or continuous flow process.

[0052] In a specific embodiment of the present invention, the azide source is selected from sodium azide, trimethylsilyl azide, tetrabutylammonium azide, or benzenesulfonyl azide, or a combination thereof, and in particular, sodium azide.

[0053] In another embodiment, the present invention provides a production method of a compound of formula (II), which includes reacting a compound of formula (I) in the presence of an azide source and in the presence of a solvent selected from water, dimethyl sulfoxide (DMSO), sulfolane, acetonitrile, tetrahydrofuran (THF), 2 - methyltetrahydrofuran (MeTHF), EtOH, MeOH, N - methyl - 2 - pyrrolidone (NMP), N - ethylpentedrone (NEP), dimethylacetamide (DMA) and dimethylformamide (DMF), or a mixture of two solvents, and in particular, a mixture of water and EtOH.

[0054] In another embodiment, the present invention provides a method for producing a compound of formula (II) comprising reacting a compound of formula (I) in the presence of an azide source, wherein the reaction time is 1 to 20 minutes, particularly 1 to 6 minutes, more specifically 4 minutes.

[0055] In another embodiment, the present invention provides a method for producing a compound of formula (II) comprising reacting a compound of formula (I) in the presence of an azide source, wherein the reaction temperature is 50°C to 150°C, particularly 70°C to 120°C, more specifically 90°C to 120°C.

[0056] In a specific embodiment of the present invention, the present invention provides a method for producing a compound of formula (II) comprising reacting a compound of formula (I) in the presence of an azide source and being carried out as a continuous flow process.

[0057] In a specific embodiment of the present invention, the present invention provides a method for producing a compound of formula (II) comprising reacting a compound of formula (I) in the presence of an azide source, wherein the reaction time is 30 seconds to 15 minutes, particularly 2 to 10 minutes, more specifically 3 to 7 minutes.

[0058] In another embodiment, the present invention provides a method for producing a compound of formula (III) comprising reacting a compound of formula (II) with 2-cyanoacetamide in the presence of a solvent selected from DMSO, sulfolane, acetonitrile, water, THF, MeTHF, EtOH, NMP, NEP, MeOH, DMA, TMG, DMF or a mixture of two solvents, particularly a mixture of TMG and EtOH.

[0059] In another embodiment, the present invention provides a method for producing a compound of formula (III) comprising reacting a compound of formula (II) with 2-cyanoacetamide and being carried out as a continuous flow process (Figure 1A).

[0060] In a more specific embodiment, the present invention provides a method for producing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide and is carried out as a batch process (Figure 1B).

[0061] In another embodiment, the present invention provides a method for producing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide and is carried out at 0 °C to 70 °C, particularly 30 °C to 50 °C, more specifically 40 °C ± 5 °C.

[0062] In another embodiment, the present invention provides a method for producing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide, and the reaction time is 5 to 20 minutes, particularly 8 to 15 minutes, more specifically 10 to 15 minutes (Figure 1A) or 0.5 hour to 28 days, particularly 12 hours to 5 days, more specifically 1 to 2 days (Figure 1B).

[0063] In another embodiment, the present invention provides a method for producing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide in the presence of a base selected from TMG, pyridine, 2-picoline, DBU, and NaHCO3, particularly TMG, pyridine, and 2-picoline, more specifically TMG.

[0064] In another embodiment, the present invention provides a method for producing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source in the presence of acetonitrile, pyridine, 1,3-dimethylimidazolidin-2-one (DMI), ethyl acetate, sulfolane, diethyl carbonate, methyl t-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran.

[0065] In another embodiment, the present invention provides a method for producing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source in the presence of acetonitrile, pyridine, ethyl acetate, sulfolane, diethyl carbonate, methyl t-butyl ether, isopropyl acetate, n-propyl acetate, or tetrahydrofuran or a mixture thereof, particularly in the presence of pyridine and acetonitrile.

[0066] In a more specific embodiment, the present invention provides a method for producing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source in the presence of DMI.

[0067] In another embodiment, the present invention provides a method for producing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source, wherein the pivaloyl source is selected from pivalic acid, pivaloyl chloride, or pivalic anhydride, particularly pivaloyl chloride.

[0068] In another embodiment, the present invention provides a method for producing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source, and the reaction temperature is 100°C to 250°C, particularly 130°C to 230°C, more specifically 150°C to 200°C.

[0069] In another embodiment, the present invention provides a method for producing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source, and the reaction time is 5 to 45 minutes, particularly 8 to 25 minutes, more specifically 10 to 20 minutes.

[0070] In another embodiment, the present invention provides a method for producing a compound of formula (V), which comprises reacting a compound of formula (IV) with a base, wherein the base is selected from a Bronsted-Lowry base, any organic base, or any inorganic base, and in particular, the base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, sodium acetate, potassium acetate, DBN, KHCO3, NaHCO3, K2CO3, Na2CO3, potassium acetate, imidazole, sodium phosphate, triethylamine, diisopropylamine, and more specifically, the base is DBU or pyridine.

[0071] In another embodiment, the present invention provides a method for producing a compound of formula (V), which comprises reacting a compound of formula (IV) with a base, and the reaction is carried out at a temperature of 100 °C to 250 °C, particularly 120 °C to 230 °C, and more specifically 150 °C to 200 °C.

[0072] In another embodiment, the present invention provides a method for producing a compound of formula (VI), which comprises reacting a compound of formula (V) with a compound of formula (VII) in the presence of DMF, DMSO, DMA, pyridine, acetonitrile, ethyl acetate, diethyl carbonate, diethyl ether, methyl t-butyl ether, isopropyl acetate, n-propyl acetate, or tetrahydrofuran, or a mixture thereof, and in particular, in the presence of DMF and acetonitrile.

[0073] In another embodiment, the present invention provides a production method as shown in Scheme 2. Scheme 2

Chemical formula

[0074] In another embodiment, the present invention provides a process as shown in Scheme 3. Scheme 3 [ka] In the formula, the amount of the compound of formula (III) is 1 equivalent, the amount of the pivaloyl chloride is 0.8 to 3 equivalents, particularly 1.25 equivalents, and the amount of the pyridine is 0.2 to 3 equivalents, particularly 0.5 equivalents.

[0075] In another embodiment, the present invention provides a process as shown in Scheme 6. Scheme 6 [ka] In the formula, the compound of formula (III) is used in an amount of 1 equivalent, and pivaloyl chloride is used in an amount of 0.8 to 3 equivalents, particularly 1.5 equivalents.

[0076] In another embodiment, the present invention provides a process as shown in Scheme 4. Scheme 4 [ka] In the formula, the compound of formula (IV) is 1 equivalent, and DBU is 1 to 5 equivalents, particularly 3 equivalents.

[0077] In certain embodiments, the present invention provides a multi-step synthetic route as shown in Scheme 5. Scheme 5: [ka]

[0078] In a more specific embodiment, the present invention provides a multi-step synthetic route in which Routes A-B and C-D as depicted in Scheme 5 are nested.

[0079] In even more specific embodiments, as described in Scheme 5, steps A, B, and D are carried out in continuous flow mode, and most particularly, step A is carried out in continuous flow mode.

[0080] Starting materials, reagents and catalysts that do not have those synthetic routes explicitly disclosed herein, in particular compounds of formula (I), are generally available from commercial sources or can be readily prepared using methods known to those skilled in the art.

[0081] In another embodiment, the present invention provides a compound of formula (III)

Chemical formula

[0082] In another embodiment, the present invention provides a compound of formula (IV)

Chemical formula

[0083] In another embodiment, the present invention provides a compound of formula (V)

Chemical formula

[0084] Generally, the nomenclature used in this application is based on MDL.Draw.Editor 22.1.3, a Biovia Draw computerized system for the generation of IUPAC systematic nomenclature. The chemical structures shown herein were created using MDL.Draw.Editor 22.1.3.1260. Any open valence appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0085] The following examples are provided for purposes of illustration of the invention. They should not be construed as limiting the scope of the invention, but rather should be understood as merely representative of it.

[0086] In this application, the following abbreviations and definitions are used: br (broad); CDCl3 (deuterochloroform); d (doublet); DMA (dimethylacetamide); DMAP (4-dimethylaminopyridine); TMG (1,1,3,3-tetramethylguanidine); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DBN (1,5-diazabicyclo(4.3.0)nona-5-ene); DMSO (dimethylsulfoxide); THF (tetrahydrofuran); MeTHF (2-methyltetrahydrofuran); EtOH (ethanol); NEP (N-ethylpentedrone); DMF (dimethylformamide); eq. (equivalent); g (gram); GC (gas chromatography); h (hour); H2O (water); HPLC (high performance liquid chromatography); iPrOH (isopropanol); KOH (potassium hydroxide); LCMS (liquid chromatography - mass spectrometry); M (mole); m (multiplet); MeOH (methanol); MS (mass spectrometry); mL (milliliter); NaOH (sodium hydroxide); NMP (N-methyl-2-pyrrolidone); NMR (nuclear magnetic resonance); s (singlet); sec (second); t (triplet); THF (tetrahydrofuran);.

[0087] Example 1: Synthesis of 5-amino-1-[(1-methyltetrazol-5-yl)methyl]-1,2,3-triazole-4-carboxamide

Chemical formula

[0088] Preparation of feeds: 1.30 M 5-(Chloromethyl)-1-methyl-1H-tetrazole (Cl-tetrazole): In a 250 mL volumetric flask, Cl-tetrazole (43.08 g, 325.01 mmol) was dissolved and filled to the 250 mL mark with ethanol. 2.00 M NaN3: In a 100 mL volumetric flask, sodium azide (13.13 g, 622.77 mmol) was dissolved and filled to the 100 mL mark with water. Additionally, 20 μL of NaOH was added to ensure pH > 8.

[0089] Reaction: In a 100 mL batch reactor 2, 2-cyanoacetamide (5.642 g, 1.30 equivalents), followed by TMG (6.2428 g, 1.05 equivalents) and ethanol (45 mL) were added to form a light suspension. The reaction mixture was heated to 40 °C.

[0090] Into reactor 1, the addition of the Cl-tetrazole feed solution (0.35 mL / min, 1.0 equivalent) and NaN3 (0.25 mL / min, 1.1 equivalents) was started. Reactor 1 consists of a T-shaped component (PEEK, inner diameter 0.8 mm). The output of the mixer was connected to a residence time unit (5 min, PFA tube, inner diameter 0.8 mm). The temperature of reactor 1 JT was 100 °C and the residence time was 5 min. The output of reactor 1 was connected to a backpressure regulator (Zaiput BPR-10) set to 3 - 4 bar. The output of reactor 1 was directed to waste for 30 min and then to reactor 2 over 100 min. The IT in reactor 2 was 40 °C. After the addition was complete, reactor 2 was stirred at 40 °C for an additional 0 - 5 h. Process control (IPC) was measured to confirm complete conversion.

[0091] Workup and separation: Water (30 mL) was added to the reaction mixture in reactor 2. The formed suspension was cooled to 0 °C and stirred at this temperature for about 2 h. The suspension was filtered through a 3a glass filter and washed with water (30 g) to obtain a light pink product (III) (9.28 g, 81%).

[0092] Example 2: Synthesis of 5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]-6H-triazolo[4,5-d]pyrimidin-7-one [Chemical formula] A 500 mL round-bottom flask equipped with a magnetic stir bar was charged with 5-amino-1-(1-methyl-1H-tetrazol-5-yl)methyl-1H-1,2,3-triazole-4-carboxamide (39.06 g, 175 mmol) and acetonitrile (150 mL - to form a suspension). Pyridine (6.92 g, 0.5 eq, 87.5 mmol) was added to the stirred suspension. Pivaloyl chloride (27.43 g, 1.3 eq, 227.5 mmol) was added dropwise over 15 minutes using a dropping funnel. The addition funnel was rinsed with acetonitrile (25 mL). A reflux condenser was attached to the round-bottom flask and the mixture was heated to reflux using an oil bath (bath temperature 95 °C). The reaction mixture became clear after about 2 hours at reflux, forming a slightly yellow homogeneous solution. After 6 hours, the reaction was cooled to room temperature using a water bath. [Chemical formula]

[0093] A single feed solution was pumped at 1.33 mL / min using a Knauer HPLC pump (10 mL pump head) (Figure 2). As the residence time unit, a 20 mL stainless steel coil attached to a Uniqsis coil heater heated to 190 °C was used (residence time 15 minutes). After passing through the residence time unit, heating of the reaction mixture was enabled using a Swagelok BPR set to 20 bar.

[0094] Collection of fractions: One unsteady-state fraction was collected 10 - 25 minutes after switching on the pump. Two steady-state fractions (each corresponding to 80 mmol) were collected directly into a stirred 250 mL round-bottom flask (equipped with a stir bar) charged with an aqueous citric acid solution (3.2 M, 60 mL) quenching solution. Division 1: 25 to 145 minutes after the start. Division 2: 145 to 265 minutes after the start.

[0095] During the recovery into the citric acid solution, precipitation of white crystalline substances began to occur around 5 minutes before the start of the recovery. After that, another non-steady state fraction was collected (265 - 280 minutes). After 260 minutes, the feed was switched to acetonitrile as the carrier solvent.

[0096] Preliminary work: The solvent was evaporated under reduced pressure (40 °C water bath temperature, pressure = 70 mbar). To avoid the crystalline solid adhering to the flask, 20 mL of water was added. The suspension was cooled to 4 °C overnight. The crystals were filtered and washed with 2 × 30 mL of water, 2 × 30 mL of i-PrOH, and 3 × 40 mL of petroleum ether. The collected white crystalline solid was dried under reduced pressure at 50 °C overnight. From the combined steady state fractions, 5-(tert-butyl)-3-((1-methyl-1H-tetrazol-5-yl)methyl)-3,6-dihydro-7H-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (337.88 g, yield 82.1%) was obtained. Approximately 0.74 g (1.6%) of the product remained in the mother liquor (by HPLC analysis).

[0097] Example 3: Synthesis of (3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol 5-tert-Butyl-3-[(1-methyltetrazol-5-yl)methyl]-6H-triazolo[4,5-d]pyrimidin-7-one (1.0 eq, 10.0 g) is mixed with CH3CN (90 mL) and DMF (6.7 mL) at 20 °C. The mixture is warmed to 38 °C and oxalyl chloride (9.7 g, 2.2 eq) is added over 15 minutes. The mixture is diluted with CH3CN (7 mL). The mixture is stirred at 38 °C for at least 4 hours and then cooled to 20 °C. The reaction mixture is added to a mixture of n-PrOAc (50 mL) and 8% KH2PO4 solution (60 mL). The phases are stirred before settling for phase separation. The organic phase is washed with 8% KH2PO4 (60 mL). The phases are stirred before settling for phase separation. The organic phase is washed with 5% NaHCO3 (60 mL). The phases are stirred before settling for phase separation. The organic solution is distilled under reduced pressure, always exchanging CH3CN with n-PrOAc. To the resulting solution, DIPEA (20.0 mL, 1.3 eq) and n-PrOAc (20 mL) are added at 30 °C, followed by addition of an aqueous solution (20 mL) of (3S)-pyrrolidin-3-ol (3.22 g, 1.07 eq). The mixture is stirred at 30 °C until the starting material is completely consumed. The phases are separated and the organic phase is washed with water (2 × 30 mL). After phase separation, the organic layer is distilled under reduced pressure to a volume of 45 mL and n-heptane (16.7 g) is added. The mixture is warmed to 65 °C until all solids dissolve and then cooled to 0 - 5 °C. The resulting suspension is filtered and the filter cake is washed with n-PrOAc / n-heptane (3:2). The product is dried at 60 °C under reduced pressure to give the title compound as a white powder (10.2 g, 82% yield).

[0098] Example 4: Synthesis of the compound of formula (IV)

Chemical formula

[0099] Example 5: Synthesis of the compound of formula (V)

Chemical formula

[0100] Aspects of the present invention Aspect 1. A method for producing a compound of formula (II) [Chemical formula] which comprises reacting a compound of formula (I) [Chemical formula] in the presence of an azide source.

[0101] Aspect 2. A method for producing a compound of formula (III) [Chemical formula] which comprises reacting a compound of formula (II) [Chemical formula] with 2-cyanoacetamide.

[0102] Aspect 3. A method for producing a compound of formula (IV) [Chemical formula] which comprises reacting a compound of formula (III) [Chemical formula] with a pivaloyl source.

[0103] Aspect 4. A method for producing a compound of formula (V) [Chemical formula] which comprises reacting a compound of formula (IV) [Chemical formula] with a base.

[0104] Aspect 5. Formula (VI)

Chem.

Chem.

Chem.

[0105] Aspect 6. Formula (III)

Chem.

Chem.

[0106] Aspect 7. Formula (V)

Chem.

Chem.

[0107] Aspect 8. Formula (VI)

Chem.

[0108] Embodiment 9. Formula (II) [Chemical formula] which further comprises producing the compound of formula (II) wherein this production comprises reacting the compound of formula I [Chemical formula] The production method according to embodiment 6.

[0109] Embodiment 10. Formula (III) [Chemical formula] which further comprises producing the compound of formula (III) wherein this production comprises reacting the compound of formula (II) [Chemical formula] with 2-cyanoacetamide. The production method according to embodiment 6.

[0110] Embodiment 11. Formula (IV) [Chemical formula] which further comprises producing the compound of formula (IV) wherein this production comprises reacting the compound of formula (III) [Chemical formula] The production method according to embodiment 5, which comprises reacting the compound of with a pivaloyl source.

[0111] Embodiment 12. Formula V [Chemical formula] which further comprises producing the compound of , wherein this production comprises reacting the compound of formula (IV) [Chemical formula] with a base. The production method according to embodiment 5.

[0112] Embodiment 13. The production method according to any one of embodiments 1, 2, 4, 6, 7, 9, 10 or 12, wherein the method is carried out in a flow mode, particularly in a flow reactor.

[0113] Embodiment 14. The production method according to any one of embodiments 1, 2, 4, 6, 7, 9, 10 or 12, wherein the method is carried out in a batch mode, particularly in a batch reactor.

[0114] Embodiment 15. The production method according to embodiment 1 or 9, wherein the azide source is selected from sodium azide, trimethylsilyl azide, tetrabutylammonium azide, or benzenesulfonyl azide, or a combination thereof, particularly sodium azide.

[0115] Embodiment 16. The production method according to any one of embodiments 1, 9 or 15, in the presence of a solvent selected from water, DMSO, sulfolane, acetonitrile, THF, MeTHF, EtOH, MeOH, NMP, NEP, DMA and DMF, or a mixture of two solvents, particularly a mixture of water and EtOH.

[0116] Aspect 17. The production method according to any one of Aspects 1, 9, 15 or 16, wherein the reaction time is 1 to 20 minutes, particularly 1 to 6 minutes, more specifically 4 minutes.

[0117] Aspect 18. The production method according to any one of Aspects 1, 9, 15 to 17, wherein the reaction temperature is 50°C to 150°C, particularly 70°C to 120°C, more specifically 90°C to 120°C.

[0118] Aspect 19. The production method according to any one of Aspects 2, 6 or 10, in the presence of a solvent selected from DMSO, sulfolane, acetonitrile, water, THF, MeTHF, EtOH, NMP, NEP, MeOH, DMA, DMF, particularly EtOH, or a mixture of two solvents.

[0119] Aspect 20. The production method according to any one of Aspects 2, 6, 10 or 19, wherein the production method is carried out at 0°C to 70°C, particularly 30°C to 50°C, more specifically 40°C ± 5°C.

[0120] Aspect 21. The production method according to any one of Aspects 2, 6, 10, 19 or 20, wherein the reaction time is 5 to 20 minutes, particularly 8 to 15 minutes, more specifically 10 to 15 minutes.

[0121] Aspect 22. The production method according to any one of Aspects 2, 6, 10, 19, or 20, wherein the reaction time is 0.5 hours to 28 days in a batch process, particularly 12 hours to 5 days, more specifically 1 to 2 days.

[0122] Aspect 23. The production method according to Aspects 2, 6, 10, 19 to 21, in the presence of a base selected from TMG, pyridine, 2-picoline, DBU and NaHCO3, specifically TMG, pyridine and 2-picoline, more specifically TMG.

[0123] Aspect 24. The production method according to Aspect 3 or 11 to 23 in the presence of acetonitrile, pyridine, DMI, ethyl acetate, sulfolane, diethyl carbonate, methyl t-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran.

[0124] Aspect 25. The production method according to Aspect 3, 11 to 24 in the presence of acetonitrile, pyridine, ethyl acetate, sulfolane, diethyl carbonate, methyl t-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran or a mixture thereof, particularly in the presence of pyridine and acetonitrile.

[0125] Aspect 26. The production method according to claims 3, 11 to 24 in the presence of DMI.

[0126] Aspect 27. The production method according to any one of Aspect 3, 11 to 26, wherein the pivaloyl source is selected from pivalic acid, pivaloyl chloride, or pivalic anhydride, particularly pivaloyl chloride.

[0127] Aspect 28. The production method according to any one of Aspect 3, 11 to 27, wherein the reaction temperature for the process according to Aspect 3, 11 or 24 is 100 °C to 250 °C, particularly 130 °C to 230 °C, more specifically 150 °C to 200 °C.

[0128] Aspect 29. The production method according to any one of Aspect 3, 11, 24 to 28, wherein the reaction time for the process according to Aspect 3, 11 or 24 is 5 to 45 minutes, particularly 8 to 25 minutes, more specifically 10 to 20 minutes.

[0129] Aspect 30. The production method according to any one of Aspect 4, 7 to 29, wherein the base for the process according to Aspect 4, 7 or 12 is selected from DBU, pyridine, sodium acetate, potassium acetate, DBN, KHCO3, NaHCO3, K2CO3, Na2CO3, potassium acetate, imidazole, sodium phosphate, triethylamine, diisopropylamine, particularly DBU or pyridine.

[0130] Aspect 31. The manufacturing method according to any one of Aspects 4, 7 to 29, wherein the method is carried out at 100°C to 250°C, particularly 120°C to 230°C, more specifically 180°C to 200°C, for the steps described in Aspect 4, 7 or 12.

[0131] Aspect 32. The manufacturing method according to Aspect 5 or 8, in the presence of a chlorine source, particularly oxalyl chloride or POCl3.

[0132] Aspect 33. The manufacturing method according to Aspect 5 or 8, in the presence of a solvent selected from DMF, DMSO, DMA, pyridine, acetonitrile, ethyl acetate, diethyl carbonate, diethyl ether, methyl t-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran, or a mixture of two solvents, particularly a mixture of DMF and acetonitrile.

[0133] Aspect 34. A compound of formula (III)

Chemical formula

[0134] Aspect 35. A compound of formula (IV)

Chemical formula

[0135] Aspect 36. A compound of formula (V)

Chemical formula

[0136] Aspect 37. A compound of formula (III)

Chemical formula

[0137] Aspect 38. Formula (IV) [Chemical formula] of the compound, or a salt thereof.

[0138] Aspect 39. Formula (V) [Chemical formula] of the compound.

Claims

1. Equation (VI) 【Chemistry 1】 A method for producing the compound, Equation (I) 【Chemistry 2】 The compound is reacted in the presence of an azide source to obtain equation (II). 【Transformation 3】 To form the compound, The compound of formula (II) is reacted with 2-cyanoacetamide to obtain formula (III). 【Chemistry 4】 To form the compound, The compound of formula (III) is reacted with a pivaloyl source to obtain formula (IV). 【Transformation 5】 To form the compound, The compound of formula (IV) is reacted with a base to obtain formula (V). 【Transformation 6】 To form the compound, The compound of formula (V) above, formula (VII) 【Transformation 7】 Reacting with the compound to form the compound of formula (VI) A manufacturing method that includes this.

2. Formula (II) 【Transformation 8】 A method for producing the compound, Equation (I) 【Chemistry 9】 A method for producing a compound, comprising reacting the compound in the presence of an azide source.

3. Formula (III) 【Chemistry 10】 A method for producing the compound, Formula (II) 【Chemistry 11】 A method for producing a compound comprising reacting it with 2-cyanoacetamide.

4. Formula (IV) 【Chemistry 12】 A method for producing the compound, Formula (III) 【Chemistry 13】 A method for producing a compound, comprising reacting it with a pivaloyl source.

5. Formula (V) 【Chemistry 14】 A method for producing the compound, Formula (IV) 【Chemistry 15】 A method for producing a compound, comprising reacting it with a base.

6. Equation (VI) 【Chemistry 16】 A method for producing the compound, Formula (V) 【Chemistry 17】 The compound of formula (VII) [Chemistry 18] A method for producing a compound, which includes reacting it with the compound.

7. Formula (III) 【Chemistry 19】 Further comprising the production of the compound, This manufacturing is formula (II) 【Chemistry 20】 The method for producing the compound according to claim 2, comprising reacting the compound with 2-cyanoacetamide.

8. Formula (V) 【Chemistry 21】 Further comprising the production of the compound, This manufacturing process is based on formula (IV) 【Chemistry 22】 The manufacturing method according to claim 3, comprising reacting the compound with a base.

9. Equation (VI) 【Chemistry 23】 Further comprising the production of the compound, This manufacturing process is based on formula (V) 【Chemistry 24】 The compound of formula (VII) 【Chemistry 25】 The method for producing the product according to claim 4, comprising reacting it with a compound.

10. Formula (II) 【Chemistry 26】 Further comprising the production of the compound, This manufacturing process is based on Formula I 【Chemistry 27】 The method for producing the compound according to claim 7, comprising reacting the compound in the presence of an azide source.

11. Formula III 【Chemistry 28】 Further comprising the production of the compound, This manufacturing is Type II 【Chemistry 29】 The method for producing the compound according to claim 7, comprising reacting the compound with 2-cyanoacetamide.

12. Formula IV 【Transformation 30】 Further comprising the production of the compound, This manufacturing is Formula III 【Chemistry 31】 The method for producing the compound according to claim 6, comprising reacting the compound with a pivaloyl source.

13. Formula V 【Chemistry 32】 Further comprising the production of the compound, This manufacturing is formula IV 【Transformation 33】 The manufacturing method according to claim 6, comprising reacting the compound with a base.

14. The manufacturing method according to any one of claims 1 to 8, 10, 11, or 13, wherein the manufacturing method is carried out in a flow manner, and in particular, the manufacturing method is carried out in a flow reactor.

15. The manufacturing method according to any one of claims 1, 2, 3, 5, 7, 8, 10, 11, or 13, wherein the manufacturing method is carried out in a batch manner, and in particular, the manufacturing method is carried out in a batch reactor.

16. The manufacturing method according to any one of claims 1, 2, or 10, wherein the azide source is selected from sodium azide, trimethylsilyl azide, tetrabutylammonium azide, or benzenesulfonyl azide, or a combination thereof, particularly sodium azide.

17. A method for producing a product according to any one of claims 1 to 3 or 10, in the presence of a solvent selected from DMSO, sulfolane, acetonitrile, water, THF, MeTHF, EtOH, NMP, NEP, MeOH, DMA, DMF, and especially EtOH, or a mixture of two solvents.

18. The manufacturing method according to any one of claims 1, 2, or 10, wherein the reaction time is 1 to 20 minutes, particularly 1 to 6 minutes, and more specifically 4 minutes.

19. The manufacturing method according to any one of claims 1, 2, or 10, wherein the reaction temperature is 50°C to 150°C, particularly 70°C to 120°C, and more specifically 90°C to 120°C.

20. The method for producing according to any one of claims 3, 7, or 11, in the presence of a solvent selected from DMSO, sulfolane, acetonitrile, water, THF, MeTHF, EtOH, NMP, NEP, MeOH, DMA, DMF, and especially EtOH, or a mixture of two solvents.

21. The manufacturing method according to any one of claims 3, 7, or 11, wherein the manufacturing method is carried out at a temperature of 0°C to 70°C, particularly 30°C to 50°C, and more specifically 40°C ± 5°C.

22. The manufacturing method according to any one of claims 3, 7, or 11, wherein the reaction time is 5 to 20 minutes, particularly 8 to 15 minutes, and more specifically 10 to 15 minutes.

23. The manufacturing method according to any one of claims 3, 7, or 11, wherein the reaction time in a batch process is 0.5 hours to 28 days, particularly 12 hours to 5 days, and more specifically 1 to 2 days.

24. TMG, pyridine, 2-picoline, DBU, and NaHCO ３ The method for producing the product according to any one of claims 3, 7, or 11, particularly in the presence of a base selected from TMG, pyridine, and 2-picoline, more specifically from TMG.

25. The method for producing the product according to claim 4 or 12, in the presence of acetonitrile, pyridine, DMI, ethyl acetate, sulfolane, diethyl carbonate, methyl t-butyl ether, isopropyl acetate, n-propyl acetate, or tetrahydrofuran.

26. The method for producing the product according to claim 4 or 12, in the presence of acetonitrile, pyridine, ethyl acetate, sulfolane, diethyl carbonate, methyl t-butyl ether, isopropyl acetate, n-propyl acetate, or tetrahydrofuran or a mixture thereof, particularly in the presence of pyridine and acetonitrile.

27. The manufacturing method according to claim 4 or 12, in the presence of DMI.

28. The method for producing according to any one of claims 1, 4, or 12, wherein the pivaloyl source is selected from pivalic acid, pivaloyl chloride, or pivalic anhydride, particularly pivaloyl chloride.

29. The manufacturing method according to any one of claims 4 or 12, wherein the reaction temperature is 100°C to 250°C, particularly 130°C to 230°C, and more specifically 150°C to 200°C.

30. The manufacturing method according to any one of claims 4 or 12, wherein the reaction time is 5 to 45 minutes, particularly 8 to 25 minutes, and more specifically 10 to 20 minutes.

31. The base is DBU, pyridine, sodium acetate, potassium acetate, DBN, KHCO ３ NaHCO ３ _K ２ CO ３ Na ２ CO ３ A method for producing a product according to any one of claims 1, 5, 8, or 13, wherein potassium acetate, imidazole, sodium phosphate, triethylamine, diisopropylamine, and especially DBU or pyridine are selected.

32. The manufacturing method according to any one of claims 5, 8, or 13, wherein the manufacturing method is carried out at a temperature of 100°C to 250°C, particularly 120°C to 230°C, and more specifically 180°C to 200°C.

33. Chlorine sources, especially oxalyl chloride or POCl ３ The manufacturing method according to any one of claims 1, 6, or 9, in the presence of

34. The method for producing the product according to claim 6 or 9, in the presence of a solvent selected from DMF, DMSO, DMA, pyridine, acetonitrile, ethyl acetate, diethyl carbonate, diethyl ether, methyl t-butyl ether, isopropyl acetate, n-propyl acetate, or tetrahydrofuran, or a mixture of two solvents, particularly a mixture of DMF and acetonitrile.

35. Formula (III) 【Transformation 34】 A compound or salt thereof.

36. Formula (IV) 【Chemistry 35】 A compound or salt thereof.

37. Formula (V) 【Transformation 36】 A compound or salt thereof.

Images