Process for 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 the preparation of (3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl) methyl]-6, 7-dihydrotriazolo [4, 5-d] pyrimidin-7-yl] pyrrolidin-3-ol, which can be used as a pharmaceutically active compound.

Description

[0001] The present invention relates to a process for preparing 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.

[0002] As described in WO2013 / 068306, 1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol, the compound of formula (VI) has been shown to be a valuable pharmaceutical compound as a CB2 receptor agonist. Over the past decade, interest in CB2 receptor agonists has been steadily increasing (currently 30 to 40 patent applications per year) as several early compounds have been shown to have beneficial effects in preclinical models of a number of 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 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), 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).

[0003] Without wishing to be bound by theory, the use of azides in flow reactors can prevent and / or reduce the accumulation of explosive components commonly found in typical syntheses involving azides. For example, due to the lack of head space in a tubular flow reactor, volatile HN3 may not accumulate in any significant amount. For example, for a batch process, there is a risk of HN3 accumulation and condensation in the head space, the risk of heavy metal azide deposition, the risk of personnel being exposed to HN3 and / or the requirement of using a restricted temperature range. In contrast, for a continuous flow process, due to the lack of head space, the HN3 accumulation in a reactor (e.g., a tubular reactor) is minimized, the reactor volume is small, various temperature ranges (including higher ranges compared to a batch process) can be reached, and / or the method allows online quenching of excess azide residues and other dangerous azide wastes.

[0004] HN3 is a known byproduct that is typically formed when using an azide reagent under acidic conditions. HN3 is an extremely volatile compound (bp = 37°C) and is reported to form explosive gas phase mixtures with air and / or nitrogen (at concentrations as low as 8-15% by volume). Pure HN3 is extremely explosive, shock-sensitive, and highly toxic (e.g., according to the National Institute for Occupational Safety and Health (NIOSH) of the United States, the recommended air exposure limit for hydrazoic acid is 0.11 ppm (0.3 mg / m as sodium azide). Due to the fluidity of the reaction and the ability to quench any unreacted azide and / or HN3 before removing the reaction mixture from the flow reactor, the risk of potential explosion and exposure is greatly reduced and / or eliminated. Therefore, the method of the present invention can minimize and / or eliminate the possibility of large amounts of HN3 accumulation in gaseous or liquid form.

[0005] The present invention is carried out in the presence of a solvent or a mixture of two or more solvents. In particular, the solvent can be an organic solvent, such as an ether solvent (e.g. tetrahydrofuran, acetonitrile, diisopropyl ether, tert-butyl methyl ether or dibutyl ether, in particular acetonitrile), an alcohol solvent (e.g. methanol, n-butanol, sec-butanol, tert-butanol or ethanol, in particular tert-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 tert-butyl-benzene), a polar aprotic solvent (e.g. acetonitrile, DMSO, sulfolane), water or a combination thereof. More particularly, in some steps of the present invention, the solvent of particular interest is acetonitrile, while in other steps of the present invention, the solvent of particular interest is ethyl acetate.

[0006] A first aspect of the present invention provides a method for preparing a compound of formula (II),

[0007]

[0008] The method comprises treating a compound of formula (I)

[0009]

[0010] The reaction is carried out in the presence of an azide source.

[0011] A second aspect of the present invention provides a method for preparing a compound of formula (III),

[0012]

[0013] The method comprises making a compound of formula (II)

[0014]

[0015] Reaction with 2-cyanoacetamide.

[0016] A third aspect of the present invention provides a method for preparing a compound of formula (IV),

[0017]

[0018] The method comprises treating a compound of formula (III)

[0019]

[0020] React with a pivaloyl source.

[0021] A fourth aspect of the present invention provides a method for preparing a compound of formula (V),

[0022]

[0023] The method comprises treating a compound of formula (IV)

[0024]

[0025] Reacts with base.

[0026] A fifth aspect of the present invention provides a method for preparing a compound of formula (VI),

[0027]

[0028] The method comprises treating a compound of formula (V)

[0029]

[0030] Reaction with a compound of formula (VII)

[0031] BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1A and 1B The flow process of the synthesis from the compound of formula I to the compound of formula III is shown. 1 and T 2 refers to the temperature in °C. According to the present invention, T 1 T may be between 50°C and 150°C, particularly between 70°C and 120°C, more particularly between 90°C and 120°C. 2 It may be between 0°C and 70°C, particularly between 30°C and 50°C, more particularly at 40°C.

[0033] R 1 , R 2 and R 3 Refers to the injection rate in mL / min. According to the present invention, R 1 The flow rate may be between 0.05 mL / min and 1.5 mL / min, in particular between 0.25 mL / min and 1 mL / min, R 2 The flow rate may be between 0.05 mL / min and 1.5 mL / min, in particular between 0.1 mL / min and 0.75 mL / min, R 3 It may be between 0.05 mL / min and 2 mL / min, in particular between 0.4 mL / min and 1.7 mL / min. Figure 1A ).

[0034] L 1 and L 2 Refers to the reaction time in minutes. According to the present invention, L 1 The time may be between 1 and 20 minutes, in particular between 1 and 6 minutes, more particularly 4 minutes. 2 The time may be between 5 and 20 minutes, in particular between 8 and 15 minutes, more in particular between 10 and 15 minutes ( Figure 1A ); or L 2 It may be between 0.5 hours and 28 days, in particular between 12 hours and 5 days, more particularly between 1 and 2 days ( Figure 1B ).

[0035] M 1 、M 2 、M 3 、M 4 and M 5 refers to the molar concentration expressed as M. According to the present invention, M 1 It can be between 0.5M and 2M, especially between 1M and 2M, M 2 It can be between 1M and 3M, especially between 2M and 3M, M 3 It can be between 1M and 3M, especially between 2M and 3M, M4 It can be between 0.5M and 2M, especially between 1M and 2M, M 5 It can be between 0.5M and 2M, especially between 1M and 2M,

[0036] The compound of formula (I) is 1 equivalent, NaN3 is between 0.6 and 3 equivalents, especially 1.05 equivalents, 2-cyanoacetamide is between 1 and 5 equivalents, especially 1.3 equivalents, and TMG is between 0.2 and 2 equivalents, especially 1.05 equivalents.

[0037] Figure 2 The flow process of the synthesis from the compound of formula IV to the compound of formula V is shown. 3 refers to the temperature in °C. According to the present invention, T 3 It may be between 100°C and 250°C, particularly between 120°C and 230°C, and more particularly between 150°C and 200°C. 3 Refers to the reaction time in minutes. According to the present invention, L 3 It may be between 1 and 20 minutes, in particular between 5 and 20 minutes, more in particular 15 minutes.

[0038] M 6 With M 7 refers to the molar concentration expressed as M. According to the present invention, M 6 It can be between 0.05M and 2M, particularly between 1M and 2M, more particularly 0.5M, M 7 It may be between 1M and 4M, particularly between 3M and 4M, more particularly 3.2M.

[0039] In particular, between 1.0 and 5.0 equivalents of DBU are used relative to the compound of formula (IV), in particular 3.0 equivalents are used.

[0040] Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

[0041] "Ambient conditions" or "room temperature" refer to conditions experienced in a standard laboratory, such as atmospheric pressure, air, Ar, or N2, at an ambient temperature between 18°C ​​and 28°C.

[0042] "Compound of formula (VI)" means

[0043]

[0044] The "compound of formula (VI)" is also referred to as rac-(3S)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol. Herein, the names or references to the compounds of formula (VI) may be used interchangeably.

[0045] The term "inorganic base" means an alkali metal base, such as an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal borate, an alkali metal phosphate, an alkali metal hydroxide. A more preferred alkaline aqueous solution is selected from a solution of sodium carbonate, sodium phosphate, potassium carbonate, lithium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, potassium bicarbonate or lithium bicarbonate, in particular NaOH, KHCO3, NaHCO3, K2CO3, Na2CO3, sodium phosphate, KOH and lithium hydroxide, more particularly KHCO3, NaHCO3, K2CO3, Na2CO3, sodium phosphate or a mixture thereof. The most preferred alkaline aqueous solution is a solution of KHCO3, NaHCO3 or a mixture thereof.

[0046] The term "organic base" refers to organic Brønsted-Lowry Base. Examples of organic bases are triethylamine, 4-pyrrolidinylpyridine, dimethylaminopyridine (DMAP), N-methylmorpholine, N-ethylmorpholine, pyridine, dialkylaniline, 1,1,3,3-tetramethylguanidine (TMG), 2-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium acetate, potassium acetate, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), potassium acetate, imidazole, diisopropylamine, diisopropylcyclohexylamine, in particular According to the present invention, the organic base is 1,1,3,3-tetramethylguanidine (TMG), pyridine, 2-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium acetate, potassium acetate, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), potassium acetate, imidazole or diisopropylamine, more particularly 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or pyridine.

[0047] The term "Brønsted-Lowry base" refers to any chemical species that is capable of accepting a proton.

[0048] 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-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium acetate, potassium acetate, 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), potassium acetate, imidazole, diisopropylamine, KHCO3, NaHCO3, K2CO3, Na2CO3 or sodium phosphate.

[0049] The term "tautomers" refers to structural isomers that undergo rapid interconversion such that they cannot be independently separated.

[0050] The term "pivaloyl source" refers to a molecule capable of generating an electrophilic pivaloyl group. Examples of pivaloyl sources are pivalic acid, pivaloyl chloride or pivalic anhydride, in particular pivaloyl chloride.

[0051] The term "salt" means those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, formic acid, acetic acid, phosphoric acid and organic acids selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and p-toluenesulfonic acid, and in particular, salts refer to salts formed with hydrochloric acid and citric acid.

[0052] The term "hydroxyl" or "hydroxy", alone or in combination, refers to a -OH group.

[0053] The term "telescoping" means performing multiple reaction steps (including quenching and other work-up operations) without direct isolation of intermediates.

[0054] The term "chlorine source" refers to any chemical reagent that can be used to add chlorine atoms to other chemicals. In particular, the chlorine source can be POCl3, PCl3, calcium hypochlorite, oxalyl chloride, PCl5, Cl2, thionyl chloride, trichloroisocyanuric acid, more particularly, the chlorine source is oxalyl chloride or POCl3.

[0055] Azide source refers to metal azide or organic azide. In particular, metal azide can be an alkali metal, such as potassium, sodium, lithium, rubidium or cesium. Metal can be a transition metal, such as but not limited to iron, cobalt, nickel, copper or zinc. It should be understood that some metal azides can be formed in solution by mixing sodium azide, etc. with metal salts. In particular, it is a transition metal salt, such as copper sulfate. The azide of the present invention can also be an organic azide or ammonium azide. Some metal azides (such as Cu (N3) 2 and Pb (N3) 2) are explosive, and if such azides are used, precautions should be taken (for example, copper-containing accessories such as brass or bronze should not be used). The example of the azide according to the present invention is selected from sodium azide, trimethylsilane azide, tetrabutylammonium azide or benzenesulfonyl azide or a combination thereof, particularly sodium azide.

[0056] As used herein, the terms "continuous flow process", "continuous flow processes", "flow process", "continuous process" and "semi-continuous process" are used interchangeably to refer to chemical processes that utilize flow chemistry and technology. Both single-step and multi-step chemical reactions can be performed using flow chemistry. Those skilled in the art recognize that flow chemistry involves performing a chemical reaction (or series of chemical reactions) in a continuous flow using a channel or pipe, rather than performing it in a separate batch using a traditional vessel (such as a reaction flask). Those skilled in the art are also aware of various continuous flow reactors in which flow chemistry can be performed, such as tubular reactors (including rotating tube reactors), microreactors, rotating disk reactors, multi-pool flow reactors, CSTRs, oscillating flow reactors, hexagonal reactors, and aspiration reactors. Continuous flow processes can be scaled up or down, and therefore do not necessarily mean a specific continuous flow reactor size. In various embodiments, the channel or pipe of the continuous flow reactor has a cross-sectional size (e.g., the diameter of a tube with a circular cross-section) in the range of 1.5 mm to about 51 mm. Thus, examples of cross-sectional dimensions (e.g., diameters) of the channels or tubes of the continuous flow reactor include the following: 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. It will be appreciated by those skilled in the art that the above description of channel or tube dimensions provides a description of the range between suitable combinations (e.g., about 3 mm to about 6 mm). The terms used herein for continuous flow processes, flow chemistry, and flow devices should be understood to have ordinary meanings known to those skilled in the art. See MB Plutschack et al., "The Hitchhiker's Guide to Flow Chemistry" Chem. Rev. (June 2017), which is incorporated herein by reference and in particular for the purpose of describing various continuous flow processes, flow chemistry, flow techniques, and flow devices. For any particular continuous flow process, scaling up or down can be accomplished by utilizing continuous flow reactors with larger or smaller conduit diameters, respectively. Scaling up or down can also be accomplished by increasing or decreasing the number of continuous flow reactors used to perform the continuous flow.Reactor techniques and conditions (such as mixing, pressure, temperature, flow rate, reaction rate, reaction time, and / or extent of reaction) can be controlled and / or monitored using known techniques and equipment (such as vessels, CSTRs, piping, pumps, valves, mixers, back pressure regulators (BPRs), coolers, heaters, temperature sensors, temperature regulators, reaction monitors (such as online flow infrared (IR) monitors), photoreactors (e.g., equipped with a UV source such as a mercury lamp or a 365 nm UV LED), membrane separators, and computers). Those skilled in the art can control and monitor reactor conditions using routine experimentation informed by the detailed guidance and working examples provided herein.

[0057] "Batch reaction" or "batch" means that the reactants are mixed together and allowed to react until complete conversion of the reactants to products.

[0058] "Batch reactor" means a vessel suitable for conducting batch reactions in a stirred tank. Those skilled in the art are also aware of various batch reactors in which batch chemical reactions can be conducted as described in the art.

[0059] In some embodiments, the method for forming tetrazolyl formula (II) is carried out in a flow reactor. Flow reactors will be known to those of ordinary skill in the art. Flow reactors can be provided in various configurations and can be equipped with many components to utilize the methods described herein. Non-limiting components of flow reactors include inlets (e.g., for reactants, solvents, quenchers, etc.), reaction tubes and / or chambers (e.g., where the reaction occurs), outlets, pressure controllers (e.g., back pressure regulators) and temperature control devices (e.g., heating devices and / or cooling devices). Non-limiting examples of flow reactors are shown in Figure 1A and 1B and described in more detail herein.

[0060] In another embodiment, the present invention provides a process for preparing a compound of formula (II),

[0061]

[0062] The method comprises treating a compound of formula (I)

[0063]

[0064] The reaction is carried out in the presence of an azide source.

[0065] In another embodiment, the present invention provides a process for preparing a compound of formula (III),

[0066]

[0067] The method comprises making a compound of formula (II)

[0068]

[0069] Reaction with 2-cyanoacetamide.

[0070] In another embodiment, the present invention provides a process for preparing a compound of formula (IV),

[0071]

[0072] The method comprises treating a compound of formula (III)

[0073]

[0074] React with a pivaloyl source.

[0075] In another embodiment, the present invention provides a process for preparing a compound of formula (V),

[0076]

[0077] The method comprises treating a compound of formula (IV)

[0078]

[0079] Reacts with base.

[0080] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0081]

[0082] The method comprises treating a compound of formula (V)

[0083]

[0084] Reaction with a compound of formula (VII)

[0085]

[0086] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0087]

[0088] The method comprises treating a compound of formula (V)

[0089]

[0090] Reaction with a compound of formula (VII)

[0091]

[0092] The reaction is carried out in the presence of a chlorine source, particularly oxalyl chloride or POCl3.

[0093] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0094]

[0095] The method comprises treating a compound of formula (VIII)

[0096]

[0097] Reaction with a compound of formula (VII)

[0098]

[0099] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0100]

[0101] The method comprises:

[0102] The compound of formula (V)

[0103]

[0104] reacting in the presence of a chlorine source, particularly oxalyl chloride or POCl3 to form a compound of formula (VIII);

[0105]

[0106] The compound of formula (VIII) is reacted with the compound of formula (VII)

[0107]

[0108] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0109]

[0110] The method comprises:

[0111] The compound of formula (IV)

[0112]

[0113] reacting with a base to form a compound of formula (V);

[0114]

[0115] reacting the compound of formula (V) in the presence of a chlorine source, in particular oxalyl chloride or POCl3, to form a compound of formula (VIII);

[0116]

[0117] The compound of formula (VIII) is reacted with the compound of formula (VII)

[0118]

[0119] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0120]

[0121] The method comprises:

[0122] The compound of formula (III)

[0123]

[0124] reacting with a pivaloyl source to form a compound of formula (IV);

[0125]

[0126] reacting the compound of formula (IV) with a base to form a compound of formula (V);

[0127]

[0128] reacting the compound of formula (V) in the presence of a chlorine source, in particular oxalyl chloride or POCl3, to form a compound of formula (VIII);

[0129]

[0130] The compound of formula (VIII) is reacted with the compound of formula (VII)

[0131]

[0132] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0133]

[0134] The method comprises:

[0135] The compound of formula (II)

[0136]

[0137] reacting with 2-cyanoacetamide to form a compound of formula (III);

[0138]

[0139] reacting the compound of formula (III) with a pivaloyl source to form a compound of formula (IV);

[0140]

[0141] reacting the compound of formula (IV) with a base to form a compound of formula (V);

[0142]

[0143] reacting the compound of formula (V) in the presence of a chlorine source, in particular oxalyl chloride or POCl3, to form a compound of formula (VIII);

[0144]

[0145] The compound of formula (VIII) is reacted with the compound of formula (VII)

[0146]

[0147] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0148]

[0149] The method comprises:

[0150] The compound of formula (I)

[0151]

[0152] reacting in the presence of an azide source to form a compound of formula (II);

[0153]

[0154] reacting the compound of formula (II) with 2-cyanoacetamide to form a compound of formula (III);

[0155]

[0156] reacting the compound of formula (III) with a pivaloyl source to form a compound of formula (IV);

[0157]

[0158] reacting the compound of formula (IV) with a base to form a compound of formula (V);

[0159]

[0160] reacting the compound of formula (V) in the presence of a chlorine source, in particular oxalyl chloride or POCl3, to form a compound of formula (VIII);

[0161]

[0162] The compound of formula (VIII) is reacted with the compound of formula (VII)

[0163]

[0164] In a specific embodiment, the present invention provides a multi-step synthetic route as shown in Scheme 1. Scheme 1:

[0165]

[0166] In a more specific embodiment, the present invention provides a multi-step synthetic route wherein stages AB and CD are performed in tandem as depicted in Scheme 1.

[0167] In a more specific embodiment, the present invention provides a multi-step synthetic route in which stages FG are performed in series as described in Scheme 1.

[0168] In even more specific embodiments, steps A, B and D as described in Scheme 1 are performed in a continuous flow mode, most specifically, step A is performed in a continuous flow mode.

[0169] In another embodiment, the present invention provides a process for preparing a compound of formula (III),

[0170]

[0171] The method comprises:

[0172] The compound of formula (I)

[0173]

[0174] reacting in the presence of an azide source to form a compound of formula (II);

[0175]

[0176] The compound of formula (II) is reacted with 2-cyanoacetamide to form a compound of formula (III).

[0177] In another embodiment, the present invention provides a process for preparing a compound of formula (IV),

[0178]

[0179] The method comprises:

[0180] The compound of formula (I)

[0181]

[0182] reacting in the presence of an azide source to form a compound of formula (II);

[0183]

[0184] reacting the compound of formula (II) with 2-cyanoacetamide to form a compound of formula (III);

[0185]

[0186] The compound of formula (III) is reacted with a pivaloyl source to form a compound of formula (IV).

[0187] In another embodiment, the present invention provides a process for preparing a compound of formula (V),

[0188]

[0189] The method comprises:

[0190] The compound of formula (I)

[0191]

[0192] reacting in the presence of an azide source to form a compound of formula (II);

[0193]

[0194] reacting the compound of formula (II) with 2-cyanoacetamide to form a compound of formula (III);

[0195]

[0196] reacting the compound of formula (III) with a pivaloyl source to form a compound of formula (IV);

[0197]

[0198] The compound of formula (IV) is reacted with a base to form a compound of formula (V).

[0199] In another embodiment, the present invention provides a process for preparing a compound of formula (VI),

[0200]

[0201] The method comprises:

[0202] The compound of formula (I)

[0203]

[0204] reacting in the presence of an azide source to form a compound of formula (II);

[0205]

[0206] reacting the compound of formula (II) with 2-cyanoacetamide to form a compound of formula (III);

[0207]

[0208] reacting the compound of formula (III) with a pivaloyl source to form a compound of formula (IV);

[0209]

[0210] reacting the compound of formula (IV) with a base to form a compound of formula (V);

[0211]

[0212] The compound of formula (V) is reacted with the compound of formula (VII)

[0213]

[0214] To form the compound of formula (VI).

[0215] In certain embodiments of the invention, one or more of the methods described herein are performed as a continuous flow process, in particular, the continuous flow process is performed in a flow reactor.

[0216] In other embodiments, one or more of the methods described herein are performed as a semi-continuous or continuous flow process.

[0217] In a particular embodiment of the present invention, the azide source is selected from sodium azide, trimethylsilyl azide, tetrabutylammonium azide or benzenesulfonyl azide or a combination thereof, in particular sodium azide.

[0218] In another embodiment, the present invention provides a method for preparing a compound of formula (II), which comprises 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-ethylpentanone (NEP), dimethylacetamide (DMA) and dimethylformamide (DMF) or a mixture of two solvents, in particular in the presence of a mixture between water and EtOH.

[0219] In another embodiment, the present invention provides a method for preparing a compound of formula (II), which comprises reacting a compound of formula (I) in the presence of an azide source, wherein the reaction time is between 1 and 20 minutes, particularly between 1 and 6 minutes, more particularly 4 minutes.

[0220] In another embodiment, the present invention provides a method for preparing a compound of formula (II), which comprises reacting a compound of formula (I) in the presence of an azide source, wherein the reaction temperature is between 50°C and 150°C, particularly between 70°C and 120°C, more particularly between 90°C and 120°C.

[0221] In a specific embodiment of the present invention, the present invention provides a process for preparing a compound of formula (II), the process comprising reacting a compound of formula (I) in the presence of an azide source, wherein the process is performed as a continuous flow process.

[0222] In a specific embodiment of the present invention, the present invention is used to provide a method for preparing a compound of formula (II), which comprises reacting a compound of formula (I) in the presence of an azide source, wherein the reaction time is between 30 seconds and 15 minutes, particularly between 2 and 10 minutes, more particularly between 3 and 7 minutes.

[0223] In another embodiment, the present invention provides a method for preparing a compound of formula (III), which comprises 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, in particular in the presence of a mixture between TMG and EtOH.

[0224] In another embodiment, the present invention provides a process for preparing a compound of formula (III), comprising reacting a compound of formula (II) with 2-cyanoacetamide, wherein the process is carried out as a continuous flow process ( Figure 1A ).

[0225] In a more specific embodiment, the present invention provides a process for preparing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide, wherein the process is carried out as a batch process ( Figure 1B ).

[0226] In another embodiment, the present invention provides a process for preparing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide, wherein the process is carried out between 0°C and 70°C, particularly between 30°C and 50°C, more particularly at 40°C±5°C.

[0227] In another embodiment, the present invention provides a method for preparing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide, wherein the reaction time is between 5 and 20 minutes, particularly between 8 and 15 minutes, more particularly between 10 and 15 minutes ( Figure 1A ) or 0.5 hours to 28 days, in particular between 12 hours and 5 days, more in particular between 1 and 2 days ( Figure 1B ).

[0228] In another embodiment, the present invention provides a method for preparing a compound of formula (III), which comprises reacting a compound of formula (II) with 2-cyanoacetamide in the presence of a base selected from the group consisting of TMG, pyridine, 2-picoline, DBU and NaHCO3, particularly TMG, pyridine and 2-picoline, more particularly TMG.

[0229] In another embodiment, the present invention provides a method for preparing 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-dimethylimidazolin-2-one (DMI), ethyl acetate, sulfolane, diethyl carbonate, methyl tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran.

[0230] In another embodiment, the present invention provides a process for preparing 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 tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran or a mixture thereof, particularly in the presence of pyridine and acetonitrile.

[0231] In a more particular embodiment, the present invention provides a process for preparing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source in the presence of DMI.

[0232] In another embodiment, the present invention provides a process for preparing a compound of formula (IV), comprising reacting a compound of formula (III) with a pivaloyl source, wherein the pivaloyl source is selected from pivalic acid, pivaloyl chloride or pivalic anhydride, in particular pivaloyl chloride.

[0233] In another embodiment, the present invention provides a method for preparing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source, wherein the reaction temperature is between 100°C and 250°C, particularly between 130°C and 230°C, more particularly between 150°C and 200°C.

[0234] In another embodiment, the present invention provides a method for preparing a compound of formula (IV), which comprises reacting a compound of formula (III) with a pivaloyl source, wherein the reaction time is between 5 and 45 minutes, particularly between 8 and 25 minutes, more particularly between 10 and 20 minutes.

[0235] In another embodiment, the present invention provides a method for preparing a compound of formula (V), which comprises reacting a compound of formula (IV) with a base, wherein the base is selected from Bronsted-Lowry base, any organic base or any inorganic base, 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, more particularly, wherein the base is DBU or pyridine.

[0236] In another embodiment, the present invention provides a process for preparing a compound of formula (V), which comprises reacting a compound of formula (IV) with a base, wherein the process is carried out between 100°C and 250°C, particularly between 120°C and 230°C, more particularly between 150°C and 200°C.

[0237] In another embodiment, the present invention provides a process for preparing 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 tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran or a mixture thereof, particularly in the presence of DMF and acetonitrile.

[0238] In another embodiment, the present invention provides a method as shown in Scheme 2

[0239] Solution 2

[0240]

[0241] inThe compound of formula (I) is 1 equivalent, NaN3 is between 0.6 and 3 equivalents, especially 1.05 equivalents, 2-cyanoacetamide is between 1 and 5 equivalents, especially 1.3 equivalents, and TMG is between 0.2 and 2 equivalents, especially 1.05 equivalents.

[0242] In another embodiment, the present invention provides a method as shown in Scheme 3

[0243]

[0244] The compound of formula (III) is 1 equivalent, pivaloyl chloride is between 0.8 and 3 equivalents, especially 1.25 equivalents, and pyridine is between 0.2 and 3 equivalents, especially 0.5 equivalent.

[0245] In another embodiment, the present invention provides a method as shown in Scheme 6

[0246] Solution 6

[0247]

[0248] The compound of formula (III) is 1 equivalent, and the pivaloyl chloride is between 0.8 and 3 equivalents, especially 1.5 equivalents.

[0249] In another embodiment, the present invention provides a method as shown in Scheme 4

[0250] Solution 4

[0251]

[0252] The compound of formula (IV) is 1 equivalent, and DBU is between 1 and 5 equivalents, especially 3 equivalents.

[0253] In certain embodiments, the present invention provides a multi-step synthetic route as shown in Scheme 5.

[0254] Solution 5:

[0255]

[0256] In a more specific embodiment, the present invention provides a multi-step synthetic route wherein stages AB and CD are performed in tandem as depicted in Scheme 5.

[0257] In even more specific embodiments, steps A, B and D as described in Scheme 5 are performed in a continuous flow mode, most specifically, step A is performed in a continuous flow mode.

[0258] Starting materials, reagents and catalysts, particularly compounds of formula (I), whose synthetic routes are not explicitly disclosed herein, are generally available from commercial sources or can be readily prepared using methods known to those skilled in the art.

[0259] In another embodiment, the present invention provides a compound of formula (III) or a salt thereof

[0260]

[0261] In another embodiment, the present invention provides a compound of formula (IV) or a salt thereof

[0262]

[0263] In another embodiment, the present invention provides a compound of formula (V) or a salt thereof

[0264]

[0265] In general, the nomenclature used in this application is based on MDL.Draw.Editor 22.1.3, which is a Biovia Draw computerized system for generating IUPAC systematic nomenclature. The chemical structures shown herein were prepared 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.

[0266] The following examples are provided to illustrate the present invention. They should not be considered as limiting the scope of the invention, but are merely representative.

[0267] In this application, the following abbreviations and definitions are used: br (broad sense); CDCl3 (deuterated chloroform); 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)non-5-ene); DMSO (dimethyl sulfoxide); THF (tetrahydrofuran); MeTHF (2-methyltetrahydrofuran); EtOH (ethanol); NEP (N-ethylpentanone) ); 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).

[0268] Example 1: Synthesis of 5-amino-1-[(1-methyltetrazol-5-yl)methyl]triazole-4-carboxamide

[0269]

[0270] exist Figure 1A The process setup for forming (III) in a continuous flow manner is shown in Figure 1B The formation of (II) in a continuous flow and (III) in a batch reactor are shown in Figure 2. Further laboratory procedures report scenarios such as Figure 1B Described in.

[0271] Feed preparation:

[0272] 1.30M 5-(Chloromethyl)-1-methyl-1H-tetrazole (Cl-tetrazole): In a 250 mL volumetric flask, dissolve Cl-tetrazole (43.08 g, 325.01 mmol) and fill to the 250 mL mark with ethanol.

[0273] 2.00M NaN3: In a 100 mL volumetric flask, dissolve sodium azide (13.13 g, 622.77 mmol) and fill to the 100 mL mark with water. Add an additional 20 μL of NaOH to ensure pH>8.

[0274] reaction:

[0275] In a 100 mL batch reactor 2, 2-cyanoacetamide (5.642 g, 1.30 equiv) was added followed by TMG (6.2428 g, 1.05 equiv) and ethanol (45 mL) to form a light suspension. The reaction mixture was warmed to JT 40°C.

[0276] Addition of Cl-tetrazole feed solution (0.35 mL / min, 1.0 equiv) and NaN3 (feed (0.25 mL / min, 1.1 equiv)) was started in Reactor 1. Reactor 1 consisted of a T-piece (PEEK, 0.8 mm inner diameter). The output of the mixer was connected to a residence time unit (5 min, PFA tubing, 0.8 mm inner diameter). The IT of Reactor 1 was 100°C and the residence time was 5 minutes. The output of Reactor 1 was connected to a back pressure regulator (Zaiput BPR-10) set to 3-4 bar. The output of Reactor 1 was directed to waste for 30 minutes and then to Reactor 2 over 100 minutes. The IT in Reactor 2 was 40°C. After the addition was complete, Reactor 2 was further stirred at 40°C for 0-5 h. An in-process control (IPC) was measured to confirm complete conversion.

[0277] Post-processing and separation:

[0278] Water (30 mL) was added to the reaction mixture in reactor 2. The resulting suspension was cooled to 0°C and stirred at this temperature for about 2 hours. 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%).

[0279] Example 2: Synthesis of 5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]-6H-triazolo[4,5-d]pyrimidin-7-one

[0280]

[0281] A 500 mL round-bottom flask equipped with a magnetic stir bar was charged with 5-amino-1-(1-methyl-1H-tetrazolyl-5-yl)methyl-1H-1,2,3-triazole-4-carboxamide (39.06 g, 175 mmol) and acetonitrile (150 mL - the resulting suspension). Pyridine (6.92 g, 0.5 equiv., 87.5 mmol) was added to the stirred suspension. Pivaloyl chloride (27.43 g, 1.3 equiv., 227.5 mmol) was added over 15 minutes using a dropping funnel. The addition funnel was washed with acetonitrile (25 mL). The round-bottom flask was equipped with a reflux condenser and heated to reflux using an oil bath (bath temperature 95 °C). After about 2 h of reflux, the reaction mixture became clear and a light yellow homogeneous solution was formed. After 6 h, the reaction was cooled to room temperature using a water bath.

[0282]

[0283] A single feed solution ( Figure 2 As residence time unit, a 20 mL stainless steel coil mounted on a Uniqsis coil heater heated to 190° C. was used (15 min residence time). After passing through the residence time unit, the reaction mixture was allowed to superheat using a Swagelok BPR set to 20 bar.

[0284] Collection of fractions:

[0285] One non-steady-state fraction was collected 10-25 minutes after turning on the pump. Two steady-state fractions (each corresponding to 80 mmol) were collected directly into stirred 250 mL round-bottom flasks (equipped with a stir bar), each charged with an aqueous citric acid (3.2 M, 60 mL) quench solution.

[0286] Fraction 1: 25–145 min after onset.

[0287] Fraction 2: 145-265 min after the start.

[0288] During collection into the citric acid solution, precipitation of a white crystalline product began to occur approximately 5 minutes after the start of collection.

[0289] Another non-steady-state fraction was then collected (265-280 min).After 260 min, the feed was switched to acetonitrile as the carrier solvent.

[0290] Post-processing:

[0291] The solvent was evaporated under vacuum (40°C water bath temperature, pressure = 70mbar). 20mL of water was added to avoid the crystalline solid from adhering to the flask. The suspension was cooled to 4°C overnight. The crystals were filtered and washed with 2x 30mL water, 2x 30mL i-PrOH and 3x40mL petroleum ether. The collected white crystalline solid was dried overnight at 50°C under vacuum. The combined steady-state fractions produced 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 (3 37.88g, 82.1% yield). Approximately 0.74g (1.6%) of the product remained in the mother liquor (analyzed by HPLC).

[0292] 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

[0293] 5-tert-Butyl-3-[(1-methyltetrazol-5-yl)methyl]-6H-triazolo[4,5-d]pyrimidin-7-one (1.0 eq, 10.0 g) was mixed with CH3CN (90 mL) and DMF (6.7 mL) at 20°C. The mixture was warmed to 38°C and oxalyl chloride (9.7 g, 2.2 eq) was added during 15 min. The mixture was diluted with CH3CN (7 mL). The mixture was stirred at 38°C for at least 4 h and then cooled to 20°C. The reaction mixture was added to a mixture of n-PrOAc (50 mL) and 8% KH2PO4 solution (60 mL). The phases were stirred before standing for phase separation. The organic phase was washed with 8% KH2PO4 (60 mL). The phases were stirred before standing for phase separation. The organic phase was washed with 5% NaHCO3 (60 mL). The phases were stirred before standing for phase separation. The organic solution was distilled under reduced pressure and CH3CN was constantly exchanged for n-PrOAc. At 30 ° C, DIPEA (20.0 mL, 1.3 eq) and n-PrOAc (20 ml) were added to the resulting solution, followed by a solution of (3S)-pyrrolidin-3-ol (3.22 g, 1.07 eq) in water (20 mL). The mixture was stirred at 30 ° C until the starting material was completely consumed. The phases were separated and the organic phase was washed with water (2x 30 ml). After phase separation, the organic layer was distilled under reduced pressure to a volume of 45 mL and normal heptane (16.7 g) was added. The mixture was warmed to 65 ° C until all solids dissolved and then cooled to 0-5 ° C. The suspension formed was filtered and the filter cake was washed with n-PrOAc / normal heptane (3: 2). The product was dried at 60 ° C under reduced pressure to obtain the title compound, which was a white powder (10.2 g, yield 82%).

[0294] Example 4: Synthesis of compound of formula (IV)

[0295]

[0296] The compound of formula (III) (70 g, 313.6 mmol, 1.00 eq) was suspended in ethyl acetate (299 g) and 1,3-dimethylimidazolin-2-one (DMI) (87.1 g) and pivaloyl chloride (56.7 g, 470.4 mmol, 1.5 eq) was added. The mixture was heated to TR = 80 ° C and stirred for at least 7 h. The mixture was cooled to TR = 20 ° C and quenched with methanol (10.1 g, 313.6 mmol, 1.00 eq). The mixture was transferred to a suspension of sodium citrate (40.5 g, 137.61 mmol) in ethyl acetate (126 g) and treated with 25% aqueous ammonia (26.4 g, 188.2 mmol). The solvent was distilled under reduced pressure. The residue was heated to TR = 65 ° C and water (210 g) was slowly charged. The mixture was cooled to TR = 55 ° C and seeded. An aqueous sodium citrate solution was slowly added. The suspension was cooled to TR = 3 ° C. The solid was isolated by filtration and washed with cold water. The wet product was dried under reduced pressure to obtain a yield of about 87%.

[0297] Example 5 Synthesis of Compound of Formula (V)

[0298]

[0299] The compound of formula (IV) (60.2 g, 183.53 mmol, 1.00 eq) was dissolved in acetonitrile (141.48 ml) and DBU (47.5 g, 312 mmol, 1.70 eq) at ambient temperature. The reaction was carried out in a batch microwave vial (laboratory) or a flow-through microwave (pilot / facility) for 5-8 min at IT = 210 ° C and a pressure of about 20-25 bar. After cooling to ambient temperature, an aqueous solution of citric acid (422.1 mmol, 2.30 eq) was added and the compound of formula (V) was crystallized from the solution. Acetonitrile (103 g) was distilled off. The suspension was cooled to IT = 0 ° C. The crystals were filtered off, washed with water (150 g) and 2-PrOH (35.1 g) and dried under vacuum (10 mbar, 45 ° C) until the weight was constant to obtain the compound of formula (V) as a white solid with a yield of 89%.

[0300] Aspects of the invention:

[0301] Aspect 1. A method for preparing a compound of formula (II),

[0302]

[0303] The method comprises treating a compound of formula (I)

[0304]

[0305] The reaction is carried out in the presence of an azide source.

[0306] Aspect 2. A method for preparing a compound of formula (III),

[0307]

[0308]

[0309] The method comprises making a compound of formula (II)

[0310]

[0311] Reaction with 2-cyanoacetamide.

[0312] Aspect 3. A method for preparing a compound of formula (IV),

[0313]

[0314] The method comprises treating a compound of formula (III)

[0315]

[0316] React with a pivaloyl source.

[0317] Aspect 4. A method for preparing a compound of formula (V),

[0318]

[0319] The method comprises treating a compound of formula (IV)

[0320]

[0321] Reacts with base.

[0322] Aspect 5. A method for preparing a compound of formula (VI),

[0323]

[0324] The method comprises treating a compound of formula (V)

[0325]

[0326] Reaction with a compound of formula (VII)

[0327]

[0328] Aspect 6. The method according to aspect 1, further comprising preparing a compound of formula (III),

[0329]

[0330] The preparation comprises making a compound of formula (II)

[0331]

[0332] Reaction with 2-cyanoacetamide.

[0333] Aspect 7. The method according to aspect 2 or 6, further comprising preparing a compound of formula (V),

[0334]

[0335] The preparation comprises making a compound of formula (IV)

[0336]

[0337] Reacts with base.

[0338] Aspect 8. The method according to aspect 3 or 7, further comprising preparing a compound of formula (VI),

[0339]

[0340] The preparation comprises making a compound of formula (V)

[0341]

[0342] Reaction with a compound of formula (VII)

[0343]

[0344] Aspect 9. The method according to aspect 6, further comprising preparing a compound of formula (II),

[0345]

[0346] The preparation comprises making a compound of formula I

[0347]

[0348] The reaction is carried out in the presence of an azide source.

[0349] Aspect 10. The method according to aspect 6, further comprising preparing a compound of formula III,

[0350]

[0351] The preparation comprises making a compound of formula II

[0352]

[0353] Reaction with 2-cyanoacetamide.

[0354] Aspect 11. The method according to aspect 5, further comprising preparing a compound of formula IV,

[0355]

[0356] The preparation comprises making a compound of formula III

[0357]

[0358] React with a pivaloyl source.

[0359] Aspect 12. The method according to aspect 5, further comprising preparing a compound of formula V,

[0360]

[0361] The preparation comprises making a compound of formula IV

[0362]

[0363] Reacts with base.

[0364] Aspect 13. The method according to any one of aspects 1, 2, 4, 6, 7, 9, 10 or 12, wherein the method is carried out in a flow mode, in particular, wherein the method is carried out in a flow reactor.

[0365] Aspect 14. The method according to any one of aspects 1, 2, 4, 6, 7, 9, 10 or 12, wherein the method is carried out in a batch mode, in particular, wherein the method is carried out in a batch reactor.

[0366] Aspect 15. The method according to any one of aspects 1 or 9, wherein the azide source is selected from sodium azide, trimethylsilyl azide, tetrabutylammonium azide or benzenesulfonyl azide or a combination thereof, in particular sodium azide.

[0367] Aspect 16. A method according to any one of aspects 1, 9 or 15, which is carried out in the presence of a solvent or a mixture of two solvents selected from water, DMSO, sulfolane, acetonitrile, THF, MeTHF, EtOH, MeOH, NMP, NEP, DMA and DMF, in particular in the presence of a mixture between water and EtOH.

[0368] Aspect 17. The method according to any one of aspects 1, 9, 15 or 16, wherein the reaction time is between 1 and 20 minutes, in particular between 1 and 6 minutes, more particularly 4 minutes.

[0369] Aspect 18. The method according to any one of aspects 1, 9, 15 to 17, wherein the reaction temperature is between 50°C and 150°C, particularly between 70°C and 120°C, more particularly between 90°C and 120°C.

[0370] Aspect 19. A method according to any one of aspects 2, 6 or 10, which is carried out in the presence of a solvent selected from DMSO, sulfolane, acetonitrile, water, THF, MeTHF, EtOH, NMP, NEP, MeOH, DMA, DMF or a mixture of two solvents, in particular in the presence of EtOH.

[0371] Aspect 20. The method according to any one of aspects 2, 6, 10 or 19, wherein the method is carried out at between 0°C and 70°C, particularly between 30°C and 50°C, more particularly at 40°C±5°C.

[0372] Aspect 21. The method according to any one of aspects 2, 6, 10, 19 or 20, wherein the reaction time is between 5 and 20 minutes, in particular between 8 and 15 minutes, more in particular between 10 and 15 minutes.

[0373] Aspect 22. The method according to any one of aspects 2, 6, 10, 19 or 20, wherein the reaction time in a batch process is between 0.5 hours and 28 days, in particular between 12 hours and 5 days, more particularly between 1 and 2 days.

[0374] Aspect 23. The method according to aspects 2, 6, 10, 19 to 21, in the presence of a base selected from the group consisting of TMG, pyridine, 2-methylpyridine, DBU and NaHCO3, in particular TMG, pyridine and 2-methylpyridine, more in particular TMG.

[0375] Aspect 24. The method according to aspects 3 or 11 to 23, which is in the presence of acetonitrile, pyridine, DMI, ethyl acetate, sulfolane, diethyl carbonate, methyl tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran.

[0376] Aspect 25. The method according to aspects 3, 11 to 24, in the presence of acetonitrile, pyridine, ethyl acetate, sulfolane, diethyl carbonate, methyl tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran or a mixture thereof, in particular in the presence of pyridine and acetonitrile.

[0377] Aspect 26. The method of claims 3, 11 to 24, in the presence of DMI.

[0378] Aspect 27. The method according to any one of aspects 3, 11 to 26, wherein the pivaloyl source is selected from pivaloyl acid, pivaloyl chloride or pivaloyl anhydride, in particular pivaloyl chloride.

[0379] Aspect 28. The method according to any one of aspects 3, 11 to 27, wherein the reaction temperature used in the step mentioned in aspect 3, 11 or 24 is between 100°C and 250°C, particularly between 130°C and 230°C, and more particularly between 150°C and 200°C.

[0380] Aspect 29. A method according to any one of aspects 3, 11, 24 to 28, wherein the reaction time for the step mentioned in aspect 3, 11 or 24 is between 5 and 45 minutes, in particular between 8 and 25 minutes, more particularly between 10 and 20 minutes.

[0381] Aspect 30. A method according to any one of aspects 4, 7 to 29, wherein the base used in the step mentioned in 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, in particular DBU or pyridine.

[0382] Aspect 31. The method according to any one of aspects 4, 7 to 29, wherein for the step mentioned in aspect 4, 7 or 12, the method is carried out between 100°C and 250°C, particularly between 120°C and 230°C, and more particularly between 180°C and 200°C.

[0383] Aspect 32. The method according to aspect 5 or 8, which is in the presence of a chlorine source, in particular oxalyl chloride or POCl3.

[0384] Aspect 33. The method according to aspect 5 or 8, which is carried out in the presence of a solvent or a mixture of two solvents selected from DMF, DMSO, DMA, pyridine, acetonitrile, ethyl acetate, diethyl carbonate, diethyl ether, methyl tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran, in particular in the presence of a mixture between DMF and acetonitrile.

[0385] Aspect 34. A compound of formula (III) or a salt thereof

[0386]

[0387] Aspect 35. A compound of formula (IV) or a salt thereof

[0388]

[0389] Aspect 36. A compound of formula (V) or a salt thereof

[0390]

[0391] Aspect 37. A compound of formula (III)

[0392]

[0393] Aspect 38. A compound of formula (IV)

[0394]

[0395] Aspect 39. A compound of formula (V)

Claims

1. A method for preparing a compound of formula (VI), The method comprises: The compound of formula (I) reacting in the presence of an azide source to form a compound of formula (II); reacting the compound of formula (II) with 2-cyanoacetamide to form a compound of formula (III); reacting the compound of formula (III) with a pivaloyl source to form a compound of formula (IV); reacting the compound of formula (IV) with a base to form a compound of formula (V); The compound of formula (V) is reacted with the compound of formula (VII) To form the compound of formula (VI).

2. A method for preparing a compound of formula (II), The method comprises treating a compound of formula (I) The reaction is carried out in the presence of an azide source.

3. A method for preparing a compound of formula (III), The method comprises making a compound of formula (II) Reaction with 2-cyanoacetamide.

4. A method for preparing a compound of formula (IV), The method comprises treating a compound of formula (III) React with a pivaloyl source.

5. A method for preparing a compound of formula (V), The method comprises treating a compound of formula (IV) Reacts with base.

6. A method for preparing a compound of formula (VI), The method comprises treating a compound of formula (V) Reaction with a compound of formula (VII) 7. The method according to claim 2, further comprising the preparation of a compound of formula (III), The preparation comprises making a compound of formula (II) Reaction with 2-cyanoacetamide.

8. The method according to claim 3 or 7, further comprising the preparation of a compound of formula (V), The preparation comprises making a compound of formula (IV) Reacts with base.

9. The method according to claim 4 or 8, further comprising the preparation of a compound of formula (VI), The preparation comprises making a compound of formula (V) Reaction with a compound of formula (VII) 10. The method according to claim 7, further comprising the preparation of a compound of formula (II), The preparation comprises making a compound of formula I The reaction is carried out in the presence of an azide source.

11. The method according to claim 7, further comprising the preparation of a compound of formula III, The preparation comprises making a compound of formula II Reaction with 2-cyanoacetamide.

12. The method according to claim 6, further comprising the preparation of a compound of formula IV, The preparation comprises making a compound of formula III React with a pivaloyl source.

13. The method according to claim 6, further comprising the preparation of a compound of formula V, The preparation comprises making a compound of formula IV Reacts with base.

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

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

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

17. The process according to any one of claims 1 to 3, 10 or 16, which is carried out in the presence of a solvent selected from DMSO, sulfolane, acetonitrile, water, THF, MeTHF, EtOH, NMP, NEP, MeOH, DMA, DMF or a mixture of two solvents, in particular in the presence of EtOH.

18. The method according to any one of claims 1, 2, 10, 16 or 17, wherein the reaction time is between 1 minute and 20 minutes, in particular between 1 minute and 6 minutes, more in particular 4 minutes.

19. The process according to any one of claims 1, 2, 10, 16 to 18, wherein the reaction temperature is between 50°C and 150°C, in particular between 70°C and 120°C, more in particular between 90°C and 120°C.

20. The process according to any one of claims 3, 7 or 11, which is carried out in the presence of a solvent selected from DMSO, sulfolane, acetonitrile, water, THF, MeTHF, EtOH, NMP, NEP, MeOH, DMA, DMF or a mixture of two solvents, in particular in the presence of EtOH.

21. The method according to any one of claims 3, 7, 11 or 20, wherein the method is carried out at between 0°C and 70°C, in particular between 30°C and 50°C, more in particular at 40°C ± 5°C.

22. The method according to any one of claims 3, 7, 11, 20 or 21, wherein the reaction time is between 5 and 20 minutes, in particular between 8 and 15 minutes, more in particular between 10 and 15 minutes.

23. The process according to any one of claims 3, 7, 11, 20 or 21, wherein in a batch process the reaction time is between 0.5 hours and 28 days, in particular between 12 hours and 5 days, more in particular between 1 day and 2 days.

24. The process according to claims 3, 7, 11, 20 to 22, which is carried out in the presence of a base selected from the group consisting of TMG, pyridine, 2-picoline, DBU and NaHCO3, in particular TMG, pyridine and 2-picoline, more in particular TMG.

25. The method according to claim 4 or 12, which is carried out in the presence of acetonitrile, pyridine, DMI, ethyl acetate, sulfolane, diethyl carbonate, methyl tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran.

26. The process according to claim 4, 12 or 25, which is carried out in the presence of acetonitrile, pyridine, ethyl acetate, sulfolane, diethyl carbonate, methyl tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran or a mixture thereof, in particular in the presence of pyridine and acetonitrile.

27. The method of claim 4, 12 or 25, which is performed in the presence of DMI.

28. A process according to any one of claims 1, 4, 12 or 25 to 27, wherein the pivaloyl source is selected from pivalic acid, pivaloyl chloride or pivalic anhydride, in particular pivaloyl chloride.

29. The process according to any one of claims 4, 12, 25, 26 or 27, wherein the reaction temperature is between 100°C and 250°C, in particular between 130°C and 230°C, more in particular between 150°C and 200°C.

30. The method according to any one of claims 4, 12, 25 to 29, wherein the reaction time is between 5 and 45 minutes, in particular between 8 and 25 minutes, more in particular between 10 and 20 minutes.

31. The process according to any one of claims 1, 5, 8 or 13, wherein the base is selected from DBU, pyridine, sodium acetate, potassium acetate, DBN, KHCO3, NaHCO3, K2CO3, Na2CO3, potassium acetate, imidazole, sodium phosphate, triethylamine, diisopropylamine, in particular DBU or pyridine.

32. The method according to any one of claims 5, 8, 13 or 31, wherein the method is carried out between 100°C and 250°C, in particular between 120°C and 230°C, more in particular between 180°C and 200°C.

33. The process according to claim 1, 6 or 9, which is carried out in the presence of a chlorine source, in particular in the presence of oxalyl chloride or POCl3.

34. The process according to claim 6 or 9, which is carried out in the presence of a solvent or a mixture of two solvents selected from DMF, DMSO, DMA, pyridine, acetonitrile, ethyl acetate, diethyl carbonate, diethyl ether, methyl tert-butyl ether, isopropyl acetate, n-propyl acetate or tetrahydrofuran, in particular in the presence of a mixture of DMF and acetonitrile.

35. A compound of formula (III) or a salt thereof 36. A compound of formula (IV) or a salt thereof 37. A compound of formula (V) or a salt thereof

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