A new method for preparing soluble guanylate cyclase stimulants

Abstract

This disclosure relates to novel methods for preparing compounds that can be used as stimulators of soluble guanylate cyclases (sGC). These methods are suitable for large-scale preparation and production of stable 3-(2-pyrimidinyl)pyrazoles of formula I, including compound I, in high purity and yield. The invention has the added advantage of readily available reaction conditions, making it suitable for scale-up for large-scale production. This disclosure also provides novel intermediates that can be used to prepare said compounds.

Description

Technical Field

[0001] This disclosure relates to novel methods for preparing compounds that can be used as soluble guanylate cyclase (sGC) stimulators. These methods are suitable for large-scale preparation and production of stable 3-(2-pyrimidinyl)pyrazoles of formula I with high purity and yield. An additional advantage of this invention is that it relates to simple reaction conditions that are easily scaled up for large-scale manufacturing. This disclosure also provides novel intermediates that can be used to prepare said compounds.

[0002]

[0003] In one respect, compounds of formula I and their pharmaceutically acceptable salts are sGC stimulants that can be used to treat diseases or conditions that benefit from sGC stimulation or from increased concentrations of nitric oxide (NO) and / or cyclic guanosine monophosphate (cGMP). In another respect, compounds of formula I are useful intermediates for the preparation of other sGC stimulants, including other compounds of formula I. Background Technology

[0004] sGC is the main NO receptor in the body. sGC can be activated through both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine-5'-triphosphate (GTP) to the second messenger cGMP. Increased cGMP levels, in turn, regulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels.

[0005] In vivo, NO is synthesized from arginine and oxygen via various nitric oxide synthases (NOS) and the continuous reduction of inorganic nitrates. Three distinct NOS isoforms have been identified: inducible NOS (iNOS or NOSII) found in activated macrophages; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long-term potentiation; and constitutive endothelial NOS (eNOS or NOS III), regulating smooth muscle relaxation and blood pressure. Experimental and clinical evidence suggests that decreased NO concentration or bioavailability and / or responsiveness to endogenous NO contribute to disease progression.

[0006] Compared to NO-independent and heme-independent sGC activators, NO-independent and heme-dependent sGC stimulators exhibit several important differentiating characteristics. These include a significant dependence on the presence of a reduced pseudoheme moiety, strong coenzyme activation when combined with NO, and NO-independent stimulation of cGMP synthesis via direct stimulation of sGC. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Subsequently, additional sGC stimulators with improved potency and specificity for sGC have been developed.

[0007] Compounds that stimulate sGC in a NO-independent manner offer significant advantages over other current alternative therapies targeting aberrant NO pathways. There is a need to develop novel sGC stimulants. Furthermore, there is a need to develop efficient methods suitable for large-scale manufacturing for the synthesis of these novel sGC stimulants, particularly for compounds of formula I. Efficient methods suitable for large-scale manufacturing are required, providing stable sGC stimulants in high purity and high yield. Summary of the Invention

[0008] This article describes a new method for preparing compounds of formula I.

[0009]

[0010] Some Formula I compounds and their pharmaceutically acceptable salts are sGC stimulants, which can be used to treat diseases or conditions that benefit from sGC stimulation or from increased NO and / or cGMP concentrations. Other Formula I compounds can be used as intermediates in the synthesis of other sGC stimulants, including other Formula I compounds.

[0011] For compounds of formula I, the following definitions apply:

[0012] R 1 It is an unsubstituted phenyl or 5- to 6-membered heteroaryl ring containing three independent cyclic heteroatoms selected from N, O, or S;

[0013] R 2 It is either phenyl or a 6-membered heteroaryl group, either of which may be selectively bound by up to three R groups. 5 Group substitution; wherein the 6-membered heteroaryl ring contains a maximum of 2 nitrogen ring atoms;

[0014] R 4 Is it halogen or -NR? 6 R 7 ;

[0015] Each R 5 Selected independently from C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0016] R 6 Is it hydrogen or composed of 0-3 Rs? 8 Replacement C 1-6 alkyl;

[0017] R 7 Is it hydrogen or composed of 0-3 Rs? 8 Replacement C 1-6 Alkyl; and

[0018] Each R 8 Independently selected from -OH, C 1-3 Halogenated alkyl groups or halogens.

[0019] This article also discloses a new intermediate that can be used to prepare compounds of formula I. Invention Details

[0021] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the appended structures and molecular formulas. While the invention will be described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. The invention is not limited to the methods and materials described herein, but includes any methods and materials similar to or equivalent to those described herein that can be used in the practice of the invention. If any of the incorporated references, patents, or similar materials differ from or contradict this application, including but not limited to defined terminology, usage of terms, described techniques, etc., this application shall prevail.

[0022] Definitions and general terms

[0023] For the purposes of this disclosure, chemical elements are identified according to the CAS version of the periodic table and the Handbook of Chemistry and Physics (75th edition). Furthermore, the general principles of organic chemistry are described in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito: 1999, and *March's Advanced Organic Chemistry*, 5th Ed., Smith, MB and March, J., eds. John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0024] The selection of substituents and combinations contemplated in this disclosure are only those that result in the formation of stable or chemically viable compounds. These selections and combinations are readily apparent to those skilled in the art and can be determined without extensive experimentation. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions permissible for its production, testing, and, in some embodiments, for the recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound is one that remains substantially unchanged when kept at 25°C or lower for at least one week in the absence of moisture or other chemically reactive conditions. Chemically viable compounds are those prepared by those skilled in the art based on the compounds disclosed herein, supplemented by relevant knowledge in the art if necessary.

[0025] Compounds, such as those of Formula I or other compounds disclosed herein, may exist in their free form (e.g., amorphous, crystalline, or polymorphic). Under certain conditions, compounds may also form co-forms. As used herein, the term co-form is synonymous with the term multicomponent crystalline form. When one component of a co-form significantly transfers or loses a proton, the resulting co-form is called a “salt.” Salt formation depends on the magnitude of the difference in pKas between the ligands forming the mixture.

[0026] Throughout this document, the term "compound" also includes pharmaceutically acceptable salts of the compound, regardless of whether the phrase "pharmaceutically acceptable salt" is actually used. As used herein, "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compound described herein. Pharmaceutically acceptable salts of the compound described herein are used in medicine. However, non-pharmaceutically acceptable salts can be used to prepare the compound described herein or other pharmaceutically acceptable salts. A pharmaceutically acceptable salt comprises an atom or molecule that acts as a counterion. The counterion can be any organic or inorganic part that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. In some cases, the counterions may be the same. In other cases, they may be different for each charged atom. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0027] Pharmaceutically acceptable salts of the compounds described herein include those derived from the reaction of the compounds described herein with inorganic or organic bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments, the salts can be prepared from the free form of the compounds described herein in a separate synthetic step.

[0028] Berg et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977: 66: 1-19, provide a more comprehensive description of the preparation of the above-mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts, the entire contents of which are incorporated herein by reference.

[0029] Unless a single isomer is specifically drawn or named, the structures described herein also imply all stereoisomers (e.g., enantiomers, diastereomers, configurational isomers, and cis-trans isomers) of that structure; for example, R and S configurations for each asymmetry center, Ra and Sa configurations for each asymmetry axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers of the compounds of this invention, as well as mixtures of racemic, enantiomers, diastereomers, and cis-trans isomers (double bonds or conformations), are within the scope of this invention.

[0030] Unless otherwise stated, all tautomer forms of the compounds disclosed herein are also within the scope of this invention. As an example, the substituents are as follows:

[0031]

[0032] Where R can be hydrogen, including the two compounds shown below:

[0033]

[0034] This disclosure also includes isotopically labeled compounds, which are the same as those described herein, but because one or more atoms are replaced by atoms with atomic masses or mass numbers different from those found in nature. All isotopes of any particular atom or element indicated are covered within the scope of the compounds of this invention and their uses. Exemplary isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, respectively. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Certain isotope-labeled compounds of the present invention (e.g., those labeled with...) 3 H and 14 C-labeled compounds can be used for the determination of compound and / or substrate tissue distribution. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are useful due to their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2H) substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., prolonged half-life or reduced dose requirement) and may therefore be preferred in some cases. Positron-emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of this invention can generally be prepared by replacing the non-isotopically labeled reagents with isotopically labeled reagents, following methods similar to those disclosed in the schemes and / or examples below.

[0035] As used in this article, the terms “appropriate” and “suitable” are used interchangeably.

[0036] As used herein, if more than one instance of a substituent is permitted at a time, then each instance of that substituent is selected independently in each case. For example, if a phenyl group can be expressed by two R groups... 100 Instance replacement, and R 100 Selected from halogens and methyl groups, this means R 100 Each instance is selected from either a halogen or a methyl group; for example, an R 100 It can be fluorine, one can be methyl, or both can be chlorine, etc.

[0037] A group can be substituted by "at most" Z instances of substituents, where "n" is an integer. For example, if "Z" is 3, the group can be substituted by 0, 1, 2, or 3 substituents. Unless otherwise stated, each "Z" instance is always chosen independently.

[0038] As used herein, the term "alkyl" (such as "alkyl chain" or "alkyl group") refers to a saturated straight-chain or branched monovalent hydrocarbon group. x An alkyl group is an alkyl chain containing x carbon atoms, where x is an integer not equal to 0. "C x-y "alkyl", where x and y are two distinct integers, neither of which is 0, represents an alkyl chain containing x carbon atoms and y carbon atoms, including the end values. For example, C 1-6 Alkyl is any number of alkyl groups containing 1 to 6 carbon atoms as defined above. Examples of alkyl groups include, but are not limited to, methyl (C1 alkyl), ethyl (C2 alkyl), n-propyl (C3 alkyl), isopropyl (C3 alkyl), n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc.

[0039] As used herein, the term "aryl" (such as "aryl ring" or "aryl group") refers to a carbocyclic system that is aromatic and has a single-point connection to the rest of the molecule. An example of an aromatic ring is the phenyl group.

[0040] The term "heteroaryl" (such as "heteroaromatic group" or "heteroaryl ring") refers to an aromatic ring containing one or more heteroatoms, which has a single connection point to the rest of the molecule. In some embodiments, the heteroaryl ring is a 5- to 6-membered heteroaryl ring. In other embodiments, it is a 5-membered heteroaryl ring. In still other embodiments, it is a 6-membered heteroaryl ring. Examples of heteroaryl rings include, but are not limited to, the following monocyclic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl. 4-Thiazolyl, 5-Thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl.

[0041] The term "cyclic atom" refers to an atom such as C, N, O, or S that is part of a phenyl or heteroaryl ring. A "substitutable cyclic atom" is a cyclic carbon or nitrogen atom bonded to at least one hydrogen atom. Hydrogen atoms may optionally be substituted with suitable substituents. A "substitutable cyclic atom" does not include a cyclic carbon or nitrogen atom when the structure indicates that they are already attached to one or more parts other than hydrogen and no hydrogen is available for substitution. When a ring, group, or chain is optionally substituted, it should be understood that it may be substituted in any, some, or all of its substitutable cyclic atoms.

[0042] "Heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, any basic nitrogen in a quaternized form, or a substituted nitrogen heterocycle or heteroaryl ring, such as N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrroleyl groups).

[0043] As used herein, the term "halogen" or "halogen" refers to F, Cl, Br, or I.

[0044] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogen atoms. For example, C 1-3Halogenated alkyl groups can be -CFHCH2CHF2. The term "fluoroalkyl" refers to an alkyl group substituted with one or more fluorine atoms. This term includes perfluorinated alkyl groups, such as -CF3 and -CF2CF3.

[0045] As used herein, the term "alkoxy" refers to an alkyl group as defined above, connected by an oxygen atom to a molecule or another chain or ring. An "alkoxy" can be described as -OC x-y Alkyl or C x-y Alkyl group.

[0046] The term "hydroxyl" or "hydroxyl" refers to -OH.

[0047] As used herein, the term "solvent" refers to a single solvent or a mixture of solvents that results in the desired properties of the solvent mixture. For example, "aprotic organic solvent" or "aprotic solvent" as defined below can be toluene, or it can be a mixture of toluene and another aprotic solvent such as DMF. Therefore, as used herein, the term "aprotic organic solvent" or "aprotic solvent" can also include toluene / DMF mixtures, provided that the resulting mixture has properties characteristic of an aprotic solvent. As another example, a protic solvent as defined below can include water or a mixture of water and methanol.

[0048] As used herein, a "protic solvent" is a solvent having hydrogen atoms bonded to polar groups, such as oxygen (as in hydroxyl groups) or nitrogen (as in amine groups). In general, any solvent containing unstable H atoms... + Solvents that readily donate protons (H+) to reagents are called proton solvents. + Conversely, "aprotic solvents" cannot readily provide hydrogen. Protic solvents are typically polar solvents because they have a high dielectric constant and high polarity. Aprotic solvents are generally classified as polar aprotic or nonpolar (or nonpolar) aprotic based on the value of their dielectric constant.

[0049] The terms "aprotic solvent" and "aprotic organic solvent" are used interchangeably.

[0050] Some common characteristics of protic solvents are their ability to exhibit hydrogen bonding, the presence of acidic hydrogen atoms (although they can be very weak acids, such as ethanol), and their ability to dissolve salts. Non-limiting examples include water, most alcohols (e.g., methanol, ethanol, propanol, butanol, isopropanol, isobutanol, etc.), formic acid, hydrogen fluoride, nitromethane, acetic acid, and ammonia.

[0051] Some common characteristics of aprotic solvents are that they can accept hydrogen bonds, do not possess acidic hydrogen, and are sometimes only able to dissolve salts. These criteria are relative and highly qualitative. For aprotic solvents, a range of acidities is identified. Their ability to dissolve salts depends largely on the nature of the salt.

[0052] Polar aprotic solvents are generally soluble in salts. They lack acidic hydrogen. Therefore, they are not hydrogen bond donors. These solvents typically have moderate dielectric constants and polarity. While the term "polar aprotic" is discouraged, IUPAC describes solvents with high dielectric constants and high dipole moments, such as acetonitrile. Other solvents that meet IUPAC criteria include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), hexamethylphosphoramide (HMPA), tetrahydrofuran, ethyl acetate, acetone, acetonitrile (MeCN), and dimethyl sulfoxide (DMSO).

[0053] Nonpolar or nonpolar aprotic solvents typically have a small dielectric constant. Some examples of nonpolar or nonpolar aprotic (organic) solvents are hexane, pentane, decane and other alkanes, benzene, toluene, 1,4-dioxane, chloroform, ethers such as diethyl ether, dichloromethane, dichloroethane, etc.

[0054] When discussing the amount of reagents used, the term "equivalent" as used herein refers to "molar equivalent." For example, for every mole of reagent B, one equivalent of reagent A means that one mole of reagent A is used for every mole of reagent B in the reaction. A mole is defined as the quantity produced when the total weight of the substances used is divided by the molecular weight of the substances, both weights being in the same unit (e.g., grams).

[0055] The compounds of this invention are defined herein by their chemical structure and / or chemical name. A compound is determined by its chemical structure and chemical name; in the event of a conflict between the two, the chemical structure determines the properties of the compound.

[0056] Substituent R n It is usually defined at the time of introduction and the definition is retained throughout the specification and in all independent and dependent claims. Detailed Implementation

[0057] This article describes a new method for preparing compounds of formula I.

[0058]

[0059] Some Formula I compounds and their pharmaceutically acceptable salts are sGC stimulants, which can be used to treat diseases or conditions that benefit from sGC stimulation or from increased NO and / or cGMP concentrations. Other Formula I compounds can be used as intermediates in the synthesis of other sGC stimulants, including other Formula I compounds. For Formula I compounds, the following definitions apply:

[0060] R 1 It is an unsubstituted phenyl or 5- to 6-membered heteroaryl ring containing up to 3 independently selected cyclic heteroatoms chosen from N, O or S;

[0061] R 2 It is a phenyl or a 6-membered heteroaryl group, both of which may be optionally substituted by up to three R5 groups; wherein the 6-membered heteroaryl ring contains up to two nitrogen ring atoms;

[0062] R 4 Is it halogen or -NR? 6 R 7 ;

[0063] Each R 5 Selected independently from C 1-6 Alkyl, C 1-6 Alkyl or halogen;

[0064] R 6 Is it hydrogen or composed of 0-3 Rs? 8 Replacement C 1-6 alkyl;

[0065] R 7 Is it hydrogen or composed of 0-3 Rs? 8 Replacement C 1-6 Alkyl; and

[0066] Each R 8 Independently selected from -OH, C 1-3 Halogenated alkyl groups or halogens.

[0067] In one aspect, this document describes a method for preparing compounds of formula II as follows, the method comprising the following steps:

[0068] i) At a suitable temperature and in the presence of a suitable amount of a suitable catalyst, react the raw material (1) with a suitable amount of oxalyl chloride or an equivalent reagent in a suitable aprotic organic solvent to amidate the raw material (1); then at a suitable temperature, in a suitable mixture of water and aprotic organic solvent, under anhydrous or aqueous conditions, in the presence of a suitable excess of a suitable base, add an appropriate amount of N,O-dimethylhydroxylamine hydrochloride to obtain amide (2);

[0069]

[0070] Where R 1 It is an unsubstituted phenyl or 5- to 6-membered heteroaryl ring containing up to three independent cyclic heteroatoms selected from N, O or S;

[0071] ii) In a suitable aprotic organic solvent, at a suitable temperature, and in the presence of a suitable base, the intermediate amide (2) is alkylated with a suitable amount of ethyl propynate to obtain β-enamine ketone ester (3).

[0072]

[0073] iii) Add β-enamine ketone ester (3) to an appropriate amount of formula R 2 The condensation of hydrazine or its HCl salt of -CH2-NH-NH2, optionally in the presence of a suitable base (to neutralize the acid from it), in a suitable protic solvent, at a suitable temperature, using hydrazine hydrochloride when hydrazine hydrochloride is used, yields the pyrazolite intermediate (4); wherein R 2 It is either phenyl or 6-heteroaryl, either of which may be optionally bound by at most three Rs. 5 Group substitution; wherein the 6-membered heteroaryl ring contains a maximum of 2 nitrogen ring atoms;

[0074]

[0075] iv) In a suitable aprotic organic solvent, at a suitable temperature, in the presence of a suitable amount of trimethylaluminum, the pyrazole ester intermediate (4) is aminated with a suitable amount of ammonium chloride to obtain amidine (5A), or after treatment with a suitable aqueous inorganic acid, amidine salt (5B) is obtained.

[0076]

[0077] v) Condensate amidine (5A) or amidine salt (5B) and an appropriate amount of fluoromalonate (optionally in the presence of an appropriate amount of a suitable base) in a suitable protic solvent at a suitable temperature, and after treatment with an appropriate amount of a suitable inorganic acid, to obtain diol (6).

[0078]

[0079] vi) At a suitable temperature, in a suitable aprotic organic solvent, optionally in the presence of a suitable base, with a suitable amount of phosphoryl chloride diol (6), to obtain dichloropyrimidine (7);

[0080]

[0081] vii) At a suitable temperature and in a suitable protic solvent, dichloropyrimidine is monomethoxylated with an appropriate amount of sodium methoxide (7) to obtain methoxypyrimidine (8);

[0082]

[0083] viii) At a suitable temperature, in a suitable organic solvent, in the presence of a suitable base, methoxypyrimidine (8) is dechlorinated with hydrogen or a transfer hydrogenating agent and optionally a suitable metal catalyst to provide fluoromethoxypyrimidine (9).

[0084]

[0085] ix) At an appropriate temperature, fluoromethoxypyrimidine (9) is methanolized by reacting with an appropriate amount of acidic aqueous solution in a suitable protic solvent to obtain fluorohydroxypyrimidine (10);

[0086] and

[0087] x) In a suitable aprotic organic solvent, fluorinated hydroxypyrimidine (10) is chlorinated with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base to obtain chloropyrimidine of formula II;

[0088]

[0089] On the other hand, this article describes an alternative method for synthesizing compounds of formula II, comprising the following steps:

[0090] 1) At a suitable temperature, in the presence of a suitable amount of a suitable phase transfer catalyst, in a suitable mixture of aprotic and protic solvents, dichloropyrimidine (7) is monohydroxylated with an appropriate amount of sodium hydroxide to provide hydroxypyrimidine (8B).

[0091]

[0092] 2) At a suitable temperature, in a suitable organic solvent, and in the presence of a suitable base, hydroxypyrimidine (8B) is dechlorinated with hydrogen or a transfer hydrogenating agent and optionally a suitable metal catalyst to provide fluorohydroxypyrimidine (10).

[0093] and

[0094] 3) In a suitable aprotic organic solvent, fluorohydroxypyrimidine (10) is chlorinated with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base to obtain chloropyrimidine of formula II;

[0095]

[0096] Compound of formula 8B can be used as an intermediate in the preparation of compound of formula II.

[0097] On the other hand, this paper describes an alternative one-step method for synthesizing compounds of formula II, which involves the direct and selective dechlorination of dichloropyrimidine (7) using hydrogen or a transfer hydrogenating agent, and optionally, at a suitable temperature, in a suitable organic solvent, in the presence of a suitable base, the addition of a suitable metal catalyst to obtain monochloropyrimidine of formula II.

[0098] In some embodiments of the above-described method for preparing compound II, for compound II and for intermediates (1) to (10) and (8B), R 1It is an unsubstituted 5-membered heteroaryl ring containing three heteroatoms independently selected from N, O, or S. In a further embodiment, R 1 It is an isoxazolyl group. In other embodiments, R 1 It is 3-isooxazolyl.

[0099] In other embodiments of the above-described method for preparing compounds of formula II, for compounds of formula II and intermediates (1) to (10) and (8B), R 1 It is an unsubstituted phenyl or 6-membered heteroaryl ring containing at most three nitrogen atoms. In some embodiments, R 1 It is pyridine or pyrimidine. In other embodiments, R 1 It is phenyl.

[0100] In some embodiments of the above-described method for preparing compounds of formula II, for compounds of formula II, intermediates (4) to (10) and (8B), and formula R 2 -CH2-NH-NH2 hydrazine, or its corresponding hydrochloride, R 2 It can be selected by up to three Rs. 5 Example of a substituted 6-membered heteroaryl group. In other embodiments, R 2 It can be selected by up to three Rs. 5 Substituted phenyl groups. In other embodiments, R 2 It was by an R 5 A phenyl group substituted with a radical. In a further embodiment, R 2 It was by an R 5 Group-substituted phenyl, R 5 It is a halogen. In other embodiments, R 2 It was by an R 5 Group-substituted phenyl, R 5 It is fluorine. In other embodiments, R 2 It is 2-fluorophenyl. In other embodiments, R 2 It was by two Rs 5 Example of a substituted phenyl group. In other embodiments, R 2 It was by two Rs 5 Examples of substituted phenyl groups, and R 5 Each instance is independently selected from halogens. In other implementations, R 2 It was by two Rs 5 Examples of substituted phenyl groups, and R 5 Each instance is fluorine.

[0101] On the other hand, this paper describes a method for preparing compounds of formula III:

[0102]

[0103] The one-step method for preparing the compound of formula III comprises the step of coupling an appropriate amount of amine (13) with a chloropyrimidine of formula II in the presence of an appropriate amount of a suitable base at a suitable temperature to produce the compound of formula III.

[0104]

[0105] On the other hand, this article describes an alternative method for preparing compounds of formula III, including the following steps:

[0106] A) In a suitable aprotic organic solvent, at a suitable temperature, and in the presence of a suitable base, a suitable amount of amine (13) is coupled with dichloropyrimidine (7) to obtain intermediate VII.

[0107] and

[0108] B) At a suitable temperature, in a suitable organic solvent, in the presence of a suitable base, the intermediate of formula VII is dechlorinated with hydrogen or a transfer hydrogenating agent and optionally a suitable metal catalyst to provide the compound of formula III.

[0109] In some embodiments of the above-described method for preparing compounds of formula III, for compounds of formula III and intermediates of formulas II and VII, R 1 It is an unsubstituted 5-membered heteroaryl ring that independently contains up to three cyclic heteroatoms selected from N, O, or S. In a further embodiment, R 1 It is an isoxazolyl group. In other embodiments, R 1 It is 3-isooxazolyl.

[0110] In other embodiments of the above-described method for preparing compounds of formula III, for compounds of formula III and intermediates of formulas II and VII, R 1 It is an unsubstituted phenyl or 6-membered heteroaryl group containing at most three cyclic nitrogen atoms. In other embodiments, R 1 It is a pyrimidine. In other embodiments, R 1 It is pyridine. In other embodiments, R 1 It is phenyl.

[0111] In some embodiments of the above-described method for preparing compounds of formula III, for compounds of formula III and intermediates of formulas II and VII, R 2 It can be selected by up to three Rs. 5 The substituted 6-membered heteroaryl group. In other embodiments, R 2 It can be selected by up to three Rs. 5 Substituted phenyl groups. In other embodiments, R 2It was by an R 5 A phenyl group substituted with a radical. In a further embodiment, R 2 It was by an R 5 Group-substituted phenyl, R 5 It is a halogen. In other embodiments, R 2 It was by an R 5 Group-substituted phenyl, R 5 It is fluorine. In other embodiments, R 2 It is 2-fluorophenyl. In other embodiments, R 2 It was by two Rs 5 Example of a substituted phenyl group. In other embodiments, R 2 It was by two Rs 5 Examples of substituted phenyl groups, and R 5 Each instance is independently selected from halogens. In other implementations, R 2 It was by two Rs 5 Examples of substituted phenyl groups, and R 5 Each instance is fluorine.

[0112] In some embodiments of the above-described method for preparing compound III, R 6 It is an intermediate (13), the hydrogen, methyl, or ethyl group in compounds of formula III and intermediates of formula VII. In some embodiments of the method for preparing compounds of formula III, R 6 It is an intermediate (13), hydrogen in the compound of formula III and the intermediate of formula VII.

[0113] In some embodiments of the above-described method for preparing compounds of formula III, R 7 C is in intermediate (13) 1-6 Alkyl groups and compounds of formula III and intermediates of formula VII, and C 1-6 Alkyl groups are formed by at most 3 Rs 8 Instance replacement. In other implementations, R 7 It can be hit by a maximum of 3 Rs 8 Replacement C 1-2 Alkyl group. In other embodiments, R 7 It is an ethyl group, surrounded by 3 R groups. 8 Instance replacement.

[0114] In some embodiments of the above-described method for preparing compounds of formula III, for compounds of formula III, intermediates of formula VII, and intermediate (13), R 8 One example is -OH. In other implementations, R 8 One instance is -OH, and the other two instances are independently C. 1-3 Halogenated alkyl group. In other embodiments, R 8One example is -OH, and two other examples are trifluoromethyl.

[0115] In some embodiments of the above-described method for preparing compound III, R 7 It is the ethyl group in intermediate (13), intermediate of formula VII and compound of formula III, the ethyl group being formed by 3 R groups. 8 Instance replacement, R 8 One of the three examples is -OH. In other implementations, R 7 It is by 3 Rs 8 Ethyl groups substituted with groups, and R 8 One example is -OH, and R 8 The other two instances are C independently. 1-3 Halogenated alkyl groups. In some embodiments, R 8 One example is -OH, R 8 Two other examples are trifluoromethyl.

[0116] On the other hand, this article describes a method for preparing compounds of formula IV, which includes the following steps:

[0117] i) At a suitable temperature, in the presence of a suitable amount of a suitable catalyst, react with a suitable amount of oxalyl chloride or an equivalent reagent in a suitable aprotic organic solvent to amidate the raw material (1'); then at a suitable temperature, in a suitable mixture of water and aprotic organic solvent, in the presence of a suitable excess of a suitable base, add a suitable amount of N,O-dimethylhydroxylamine hydrochloride to obtain amide (2').

[0118]

[0119] ii) In a suitable aprotic organic solvent, at a suitable temperature, and in the presence of a suitable base, the intermediate amide (2') is alkylated with a suitable amount of ethyl propynate to give β-enamine ketone ester (3');

[0120]

[0121] iii) At a suitable temperature, in a suitable protic solvent, optionally in the presence of an appropriate amount of a suitable base (in order to neutralize the acid from hydrazine hydrochloride when hydrazine is used in the form of hydrochloric acid), condense β-enamine ketone ester (3') with an appropriate amount of hydrazine of the formula NH2NH-CH2-(2-fluorophenyl) or its HCl salt to give pyrazolite intermediate (4').

[0122]

[0123] iv) In a suitable aprotic organic solvent, at a suitable temperature, in the presence of a suitable amount of trimethylaluminum, the pyrazole ester intermediate (4') is aminated with a suitable amount of ammonium chloride to give amidine (5'A), or after treatment with an aqueous solution of a suitable inorganic acid, the amidine salt (5'B) is given.

[0124]

[0125] v) In a suitable protic solvent, at a suitable temperature, optionally in the presence of a suitable base, condense amidine (5'A) or amidine salt (5'B) with a suitable amount of fluoromalonate, and after treatment with a suitable amount of a suitable inorganic acid, to obtain diol (6').

[0126]

[0127] vi) At a suitable temperature, in a suitable aprotic organic solvent, optionally in the presence of a suitable base, with a suitable amount of phosphoryl chloride diol (6'), to obtain dichloropyrimidine (7');

[0128]

[0129] vii) Monomethoxylated dichloropyrimidine (7') is reacted with an appropriate amount of sodium methoxide at a suitable temperature in a suitable protic solvent to obtain methoxypyrimidine (8');

[0130]

[0131] viii) At a suitable temperature, in a suitable organic solvent, in the presence of a suitable base, methoxypyrimidine (8') is dechlorinated with hydrogen or a transfer hydrogenating agent and optionally a suitable metal catalyst to provide fluoromethoxypyrimidine (9').

[0132]

[0133] ix) At a suitable temperature and in a suitable protic solvent, fluoromethoxypyrimidine (9') is deformylated by reacting it with an appropriate amount of aqueous acid solution to give an alcohol (10');

[0134] and

[0135] x) At a suitable temperature, in a suitable aprotic organic solvent, with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base chlorinated alcohol (10'), chloropyrimidine of formula IV is obtained.

[0136]

[0137] On the other hand, this article describes an alternative method for synthesizing compound IV, including the following steps:

[0138] 1) At a suitable temperature, in the presence of a suitable amount of a suitable phase transfer catalyst, in a suitable mixture of aprotic solvent and protic solvent, dichloropyrimidine (7') is monohydroxylated with an appropriate amount of sodium hydroxide to obtain hydroxypyrimidine (8'B);

[0139]

[0140] 2) At a suitable temperature, in a suitable organic solvent, in the presence of a suitable base, hydroxypyrimidine (8'B) is dechlorinated with hydrogen or a transfer hydrogenating agent and optionally a suitable metal catalyst to provide fluorohydroxypyrimidine (10').

[0141] and

[0142] 3) In a suitable aprotic organic solvent, with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base chlorinated alcohol (10'), chloropyrimidine of formula IV is obtained;

[0143]

[0144] On the other hand, this paper describes another one-step method for synthesizing compounds of formula IV, including the direct and selective dechlorination of dichloropyrimidine (7') with hydrogen or a transfer hydrogenating agent; and optionally, at a suitable temperature, in a suitable organic solvent, in the presence of a suitable base, with the addition of a suitable metal catalyst, to obtain monochloropyrimidine of formula IV.

[0145] For steps i) of synthesizing compounds of formula II or IV:

[0146] Suitable equivalents to oxalyl chloride are, for example, thionyl chloride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC). A suitable amount of oxalyl chloride or its equivalent is at least one equivalent of oxalyl chloride per amount of raw material (1) or raw material (1'). In some embodiments, a suitable amount is about 1 to about 3 equivalents. In other embodiments, a suitable amount is about 1 to about 2 equivalents. In other embodiments, a suitable amount is about 1 to about 1.5 equivalents. In other embodiments, a suitable amount is about 1.1 to about 1.3 equivalents. In other embodiments, a suitable amount is about 1.1 equivalents or about 1.2 equivalents.

[0147] Suitable aprotic organic solvents are, for example, toluene. Other suitable solvents are, for example, dichloromethane or tetrahydrofuran.

[0148] A suitable catalyst is DMF.

[0149] The appropriate amount of DMF is a catalytic amount, i.e., less than one equivalent of DMF per unit amount of feedstock (1) or feedstock (1'). In some embodiments, the appropriate amount is about 0.01 to about 0.09 equivalents. In other embodiments, it is about 0.01 to about 0.07 equivalents. In other embodiments, it is about 0.02 to about 0.07 equivalents. In other embodiments, it is about 0.04 to about 0.06 equivalents.

[0150] The suitable temperature for reacting raw material (1) or raw material (1') with oxalyl chloride or thionyl chloride is a temperature of about 45°C to about 60°C. In some embodiments, the suitable temperature is about 45°C to about 50°C. In other embodiments, the temperature is about 50°C.

[0151] The suitable temperature for reacting reactant (1) or reactant (1') with EDAC is a temperature of about -10°C to about 25°C. In some embodiments, the suitable temperature is about -10°C to about 20°C. In some embodiments, the suitable temperature is about -10°C to about 0°C. In some embodiments, the suitable temperature is about -10°C to about -5°C.

[0152] A suitable amount of N,O-dimethylhydroxylamine hydrochloride is at least 1 equivalent of N,O-dimethylhydroxylamine hydrochloride per equimolar amount of raw material (1) or raw material (1'). In other embodiments, a suitable amount of N,O-dimethylhydroxylamine hydrochloride is about 1 equivalent to about 2 equivalents per equimolar amount of raw material (1) or raw material (1'). In other embodiments, it is about 1 equivalent to about 1.5 equivalents. In other embodiments, it is about 1 equivalent to about 1.2 equivalents. In other embodiments, it is about 1.1 equivalents to about 1.2 equivalents.

[0153] Suitable bases are, for example, K₂CO₃ or NaOH. Other suitable inorganic bases are, for example, NaHCO₃, KHCO₃, Et₃N, or Hunig base.

[0154] A suitable amount of the base is at least 1.1 equivalents of base per unit amount of N,O-dimethylhydroxylamine hydrochloride used. In some embodiments, a suitable amount is about 1.1 to about 5 equivalents of base per unit amount of N,O-dimethylhydroxylamine hydrochloride. In some embodiments, a suitable amount is about 1.2 to about 5 equivalents of base per unit amount of N,O-dimethylhydroxylamine hydrochloride. In other embodiments, it is about 2 to about 3 equivalents. In other embodiments, it is about 2 to about 4 equivalents. In other embodiments, it is about 1.2 to about 3 equivalents. In other embodiments, it is about 1.2 to about 3 equivalents. In other embodiments, it is about 1.5 to about 3 equivalents. In other embodiments, it is about 1.2 to about 4 equivalents. In other embodiments, it is about 1.5 to about 4 equivalents. In other embodiments, it is about 1.5 to about 4 equivalents. In other embodiments, it is about 1.2 to about 2 equivalents.

[0155] The suitable temperature for the reaction of N,O-dimethylhydroxylamine hydrochloride with a suitable base is from about -10°C to about 25°C. In some embodiments, the suitable temperature is from about -10°C to about 20°C. In some embodiments, the suitable temperature is from about -10°C to about 0°C. In some embodiments, the suitable temperature is from about -10°C to about -5°C.

[0156] Suitable solvents for water / aprotic solvent mixtures are, for example, dichloromethane (DCM). Other suitable solvents are, for example, ethyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0157] For steps ii) of synthesizing compounds of formula II or IV:

[0158] A suitable amount of ethyl propargyl is at least one equivalent of ethyl propargyl for each amount of intermediate (2) or intermediate (2'). In some embodiments, a suitable amount of ethyl propargyl is about 1 to about 2 equivalents. In other embodiments, it is about 1 to about 1.8 equivalents. In other embodiments, it is about 1 to about 1.6 equivalents. In other embodiments, it is about 1.1 to about 1.5 equivalents. In other embodiments, it is about 1.1 equivalents. In other embodiments, it is about 1.5 equivalents.

[0159] Suitable aprotic organic solvents are anhydrous organic solvents. For example, a suitable solvent is anhydrous tetrahydrofuran (THF). Other suitable solvents in this step are, for example, 2-methyltetrahydrofuran and toluene.

[0160] A suitable temperature is between approximately -75°C and -30°C. In some embodiments, a suitable temperature is between approximately -70°C and -50°C. In some embodiments, a suitable temperature is between approximately -65°C and -50°C. In other embodiments, a suitable temperature is between approximately -65°C and -55°C. In still other embodiments, a suitable temperature is between approximately -70°C and -60°C.

[0161] Suitable bases are, for example, sodium bis(trimethylsilyl)amino (NaHMDS). Other suitable bases are, for example, lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, and lithium diisopropylamino.

[0162] A suitable amount of base is about 1 equivalent to about 1.65 equivalents per unit amount of intermediate (2) or intermediate (2'). In some embodiments, it is about 1 equivalent to about 1.5 equivalents. In some embodiments, it is about 1 equivalent to about 1.3 equivalents. In other embodiments, it is about 1.1 equivalent to about 1.65 equivalents. In other embodiments, it is about 1.1 equivalent to about 1.5 equivalents. In other embodiments, it is about 1.1 equivalent to about 1.4 equivalents. In other embodiments, it is 1.1 equivalent to about 1.3 equivalents.

[0163] For steps iii) of synthesizing compounds of formula II or IV:

[0164] A suitable amount of hydrazine is at least one equivalent of hydrazine per unit amount of intermediate (3) or intermediate (3'). In some embodiments, a suitable amount of hydrazine is about 1 equivalent to about 2 equivalents. In other embodiments, it is about 1 equivalent to about 1.5 equivalents. In other embodiments, it is about 1 equivalent to about 1.3 equivalents. In other embodiments, it is about 1.1 equivalent to about 1.4 equivalents. In other embodiments, it is 1.1 equivalent to about 1.3 equivalents.

[0165] A suitable, optional base is, for example, potassium carbonate (K₂CO₃). Other suitable, optional organic bases in this step are, for example, sodium acetate (NaOAc), sodium carbonate (Na₂CO₃), sodium bicarbonate (NaHCO₃), and potassium bicarbonate (KHCO₃).

[0166] When using hydrazine in hydrochloride form, a suitable amount of base is the amount that can neutralize the acid from hydrazine hydrochloride. For example, about 0.5 to about 1.1 equivalents of base per unit amount of hydrazine hydrochloride. In other embodiments, a suitable amount is about 0.5 to about 0.9 equivalents. In other embodiments, it is about 0.65 equivalents.

[0167] Suitable proton solvents are, for example, anhydrous ethanol or isopropanol. Other solvents that can be used in this step are, for example, dichloromethane, isopropanol, and methanol.

[0168] A suitable temperature is between about 0°C and about 40°C. In other embodiments, a suitable temperature is between about 0°C and about 30°C. In some embodiments, it is between about 0°C and about 25°C. In other embodiments, it is between about 0°C and about 15°C. In other embodiments, it is between about 0°C and about 10°C. In other embodiments, it is between about 10°C and about 25°C.

[0169] For the synthesis of compounds of formula II or IV, step iv):

[0170] A suitable amount of ammonium chloride is about 2.5 to about 6 equivalents of ammonium chloride per amount of intermediate (4) or intermediate (4'). In some embodiments, a suitable amount is about 2.5 to about 5.5 equivalents. In some embodiments, a suitable amount is about 3.5 to about 4 equivalents. In other embodiments, a suitable amount is about 3.8 equivalents. In other embodiments, a suitable amount is about 3.5 equivalents. In some embodiments, a suitable amount is about 4.5 to 5.0 equivalents. In other embodiments, a suitable amount is about 4.8 equivalents. A suitable amount of trimethylaluminum is about 2.5 to about 5.5 equivalents of trimethylaluminum per amount of intermediate (4) or intermediate (4'). In some embodiments, a suitable amount is about 3.5 to about 5.5 equivalents. In other embodiments, a suitable amount is about 3.5 to about 4.5 equivalents. In other embodiments, a suitable amount is about 3.5 to about 4 equivalents. In other embodiments, a suitable amount is about 3.5 equivalents.

[0171] Suitable aprotic organic solvents are, for example, toluene. Other suitable solvents include, for example, xylene.

[0172] The suitable temperature for toluene is from about 60°C to about 115°C. In some embodiments, the suitable temperature is from about 70°C to about 110°C. In other embodiments, it is between about 70°C and about 110°C. In other embodiments, it is between about 80°C and about 110°C. In other embodiments, it is between about 90°C and about 110°C.

[0173] The suitable temperature for xylene is from about 70°C to about 130°C.

[0174] Suitable aqueous solutions of inorganic acids are concentrated HCl, such as 3N HCl or 37% by weight HCl. Other suitable inorganic acids that can be used to induce precipitation of intermediate (4) or intermediate (4') are, for example, H2SO4.

[0175] For steps v) of synthesizing compounds of formula II or IV:

[0176] A suitable amount of fluoromalonate is at least one equivalent of fluoromalonate for each amount of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In some embodiments, it is about 1 equivalent to about 2 equivalents of fluoromalonate. In other embodiments, it is about 1.2 equivalents to about 2 equivalents. In other embodiments, it is about 1.3 to about 1.9 equivalents. In other embodiments, it is 1.4 to 1.6 equivalents. In other embodiments, it is about 1.7 to 1.9 equivalents.

[0177] A suitable base is, for example, sodium methoxide (NaOMe). Typically, NaOMe is added as a MeOH solution. For example, a 23 wt% MeOH solution can be used. In other embodiments, a 30 wt% MeOH solution can be used. Alternatively, a 5.4 M MeOH solution can be used. Other bases that can be used in this step include EtONa.

[0178] The appropriate amount of alkali is an excess relative to the amount of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In some embodiments, the appropriate amount is about 3 to about 10 equivalents of NaOMe per unit amount of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In other embodiments, the appropriate amount is about 3 to about 6 equivalents. In other embodiments, it is about 3 to about 5 equivalents. In other embodiments, it is about 4 to about 5 equivalents. In other embodiments, the appropriate amount is about 4.5 equivalents.

[0179] A suitable proton solvent is, for example, MeOH. Other suitable solvents that can be used for this step include EtOH.

[0180] A suitable temperature is between about 10°C and about 40°C. In some embodiments, a suitable temperature is between about 15°C and about 35°C. In other embodiments, a suitable temperature is between about 15°C and about 30°C. In other embodiments, a suitable temperature is between about 20°C and about 35°C. In other embodiments, a suitable temperature is between about 20°C and about 30°C.

[0181] A suitable inorganic acid is, for example, 1.5N HCl. Other suitable inorganic acids that can be used in this step include sulfuric acid.

[0182] The appropriate amount of inorganic acid is an amount that is at least in excess of the appropriate amount of base used. In some embodiments, the appropriate amount is at least one equivalent of inorganic acid per unit amount of base (e.g., NaOMe). In some embodiments, the appropriate amount is about 1.1 equivalents of inorganic acid per unit amount of base. In some embodiments, the appropriate amount of inorganic acid is about 4.5 to about 5.5 equivalents of inorganic acid per unit amount of intermediate (5B) or intermediate (5'B). In other embodiments, the appropriate amount of inorganic acid is about 4.7 to about 5.0 equivalents. In other embodiments, it is about 4.9 equivalents.

[0183] For the synthesis of compounds of formula II or IV, step vi):

[0184] A suitable amount of POCl3 is at least two equivalents of POCl3 per amount of intermediate (6) or intermediate (6'). In some embodiments, a suitable amount of POCl3 is at least four equivalents. In some embodiments, a suitable amount is at least five equivalents. In other embodiments, a suitable amount is about six equivalents of POCl3 per amount of intermediate (6) or intermediate (6').

[0185] A suitable temperature is from about 60°C to about 90°C. In some embodiments, a suitable temperature is from about 65°C to about 90°C. In other embodiments, a suitable temperature is from about 70°C to about 90°C. In other embodiments, a suitable temperature is from about 75°C to about 90°C. In other embodiments, a suitable temperature is from about 70°C to about 80°C.

[0186] Suitable aprotic organic solvents are, for example, acetonitrile (CNMe). The reaction can also be carried out in pure POCl3 in the absence of any solvent.

[0187] A suitable optional base is, for example, N,N-dimethylaniline. The reaction can also proceed without a base.

[0188] A suitable amount of base is about 0.2 to about 2 equivalents of base per unit amount of intermediate (6) or intermediate (6') used. In some embodiments, a suitable amount of base is about 1.5 to about 1.8 equivalents. In other embodiments, it is about 0.8 equivalents to about 1.2 equivalents. In other embodiments, it is about 1 equivalent.

[0189] For step vii) of synthesizing compounds of formula II or IV:

[0190] A suitable amount of sodium methoxide (NaOMe) is about 1 equivalent of NaOMe per 100g of intermediate (7) or intermediate (7'). In some embodiments, a suitable amount of NaOMe is a slightly excess of NaOMe per 100g of intermediate (7) or intermediate (7'). In some embodiments, a suitable amount of NaOMe is 1.1 to 1.3 equivalents per 100g of intermediate (7) or intermediate (7'). In other embodiments, a suitable amount is about 1.2 equivalents.

[0191] A suitable temperature is from about 15°C to about 30°C. In some embodiments, a suitable temperature is from about 20°C to about 30°C. In other embodiments, it is between about 15°C and about 28°C. In other embodiments, it is between about 20°C and about 28°C. In other embodiments, it is between about 23°C and about 27°C.

[0192] A suitable proton solvent is, for example, methanol (MeOH).

[0193] For step viii) of synthesizing compounds of formula II or IV:

[0194] A suitable transfer hydrogenation reagent is HCOOH. HCOOH is most commonly used in the presence of organic / inorganic bases such as Et3N, NaOH, NaHCO3, etc. HCOONH4, HCOONa, HCOOK, isopropanol, triethylsilane, and cyclohexadiene can also be used. A suitable metal catalyst is palladium on activated carbon, for example, 10% Pd on activated carbon.

[0195] A suitable amount of the suitable metal catalyst is a catalytic amount, i.e., less than 1 equivalent of Pd per amount of intermediate (8) or intermediate (8'). In some embodiments, a suitable amount of the suitable metal catalyst is 0.01 to 0.03 equivalents of Pd per amount of intermediate (8) or intermediate (8'). In other embodiments, a suitable amount of the suitable metal catalyst is 0.01 to 0.025 equivalents of Pd per amount of intermediate (8) or intermediate (8'). In other embodiments, a suitable amount of the suitable metal catalyst is 0.015 to 0.025 equivalents of Pd per amount of intermediate (8) or intermediate (8'). In other embodiments, a suitable amount of the suitable metal catalyst is 0.01 to 0.02 equivalents of Pd per amount of intermediate (8) or intermediate (8').

[0196] A suitable base is triethylamine (Et3N). Other suitable bases that can be used are, for example, Hunig base, NaHCO3, KHCO3, and sodium acetate.

[0197] The appropriate amount of base is at least one equivalent of base per unit amount of intermediate (8) or intermediate (8'). In some embodiments, the appropriate amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.

[0198] A suitable temperature is from about 35°C to about 60°C. A suitable temperature is from about 35°C to about 55°C. In some embodiments, a suitable temperature is from about 40°C to about 50°C.

[0199] Suitable organic solvents are, for example, THF. Other solvents that can be used are, for example, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran, or mixtures thereof.

[0200] For the synthesis of compounds of formula II or IV, step ix):

[0201] A suitable aqueous acid is HCl. Other acids that can be used include, for example, methanesulfonic acid (MeSO3H) or HBr.

[0202] The suitable amount of acid is about 3 to about 6 equivalents. In some embodiments, the suitable amount is about 4 to about 6 equivalents. In other embodiments, it is about 4.5 equivalents to about 6 equivalents. In other embodiments, it is about 4.90 to about 5 equivalents. For example, HCl can be provided in the form of concentrated HCl (e.g., 37 wt% HCl).

[0203] Suitable proton solvents are, for example, MeOH. Other suitable proton solvents are EtOH and iPrOH.

[0204] A suitable temperature is between about 50°C and about 70°C. In some embodiments, a suitable temperature is between about 55°C and about 65°C. In other embodiments, a suitable temperature is between about 60°C and about 65°C. In still other embodiments, a suitable temperature is between about 62°C and about 65°C.

[0205] For step x) of synthesizing compounds of formula II or IV:

[0206] A suitable amount of POCl3 is at least 2 equivalents of POCl3 per amount of intermediate (10) or intermediate (10'). In some embodiments, a suitable amount of POCl3 is at least 4 equivalents. In some embodiments, a suitable amount is at least 3 equivalents. In some embodiments, a suitable amount is at least 2 equivalents. In some embodiments, a suitable amount is at least 1 equivalent. In other embodiments, a suitable amount is about 1 to about 4 equivalents of POCl3 per amount of intermediate (10) or intermediate (10').

[0207] A suitable temperature is from about 50°C to about 90°C. In some embodiments, a suitable temperature is from about 60°C to about 90°C. In some embodiments, a suitable temperature is from about 65°C to about 90°C. In other embodiments, a suitable temperature is from about 70°C to about 90°C. In other embodiments, a suitable temperature is from about 75°C to about 90°C. In other embodiments, a suitable temperature is from about 75°C to about 85°C. In other embodiments, a suitable temperature is from about 75°C to about 80°C.

[0208] Suitable aprotic solvents are, for example, acetonitrile (CNMe). The reaction can also be carried out in pure POCl3 in the absence of any solvent.

[0209] A suitable optional base is, for example, N,N-dimethylaniline. The reaction can also proceed without a base.

[0210] A suitable amount of base is about 0.2 to about 2 equivalents of base per unit amount of intermediate (10) or intermediate (10'). In some embodiments, a suitable amount of base is about 1.3 to about 1.6 equivalents. In some embodiments, a suitable amount of base is about 1.2 to about 1.8 equivalents. In other embodiments, it is about 1 equivalent.

[0211] For steps 1) of synthesizing compounds of formula II or IV:

[0212] A suitable amount of sodium hydroxide (NaOH) is about 2 to about 2.5 equivalents of NaOH per unit amount of intermediate (7) or intermediate (7'). In other embodiments, a suitable amount is about 2.2 equivalents.

[0213] The suitable temperature is from about 45°C to about 70°C. In some embodiments, the suitable temperature is from about 50°C to about 65°C. In other embodiments, it is between about 55°C and about 60°C.

[0214] A suitable phase transfer catalyst is tetrabutylammonium hydroxide. Other suitable phase transfer catalysts that can be used include benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltrioctylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride. A suitable amount of a suitable phase transfer catalyst is a catalytic amount, i.e., less than one equivalent of phase transfer catalyst per unit amount of intermediate (7) or intermediate (7'). In some embodiments, the catalytic amount is about 0.1 to about 0.5 equivalents. In other embodiments, it is about 0.1 to about 2.5 equivalents. In other embodiments, it is about 0.1 to about 0.15 equivalents.

[0215] A suitable protic solvent is, for example, water. A suitable aprotic solvent is, for example, tetrahydrofuran.

[0216] For step 2 of the synthesis of compounds of formula II or IV:

[0217] A suitable transfer hydrogenation reagent is HCOOH. HCOOH is most commonly used in the presence of organic / inorganic bases such as Et3N, NaOH, NaHCO3, etc. HCOONH4, HCOONa, HCOOK, isopropanol, triethylsilane, and cyclohexadiene can also be used. A suitable metal catalyst is palladium on activated carbon, for example, 10% Pd on activated carbon.

[0218] The suitable amount of a suitable metal catalyst is a catalytic amount, i.e., less than 1 equivalent of Pd per unit amount of intermediate (8B) or intermediate (8'B). In some embodiments, the suitable amount of a suitable metal catalyst is 0.01 to 0.02 equivalents of Pd per unit amount of intermediate (8B) or intermediate (8'B).

[0219] A suitable base is triethylamine (Et3N). Other suitable bases that can be used are, for example, Hunig base, NaHCO3, KHCO3, and sodium acetate.

[0220] A suitable amount of base is at least one equivalent of base per unit amount of intermediate (8B) or intermediate (8'B). In some embodiments, a suitable amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.

[0221] A suitable temperature is from about 15°C to about 60°C. In some embodiments, a suitable temperature is from about 15°C to about 55°C. In some embodiments, a suitable temperature is from about 35°C to about 55°C. In other embodiments, a suitable temperature is from about 40°C to about 50°C. In other embodiments, a suitable temperature is from about 15°C to about 25°C. In other embodiments, a suitable temperature is from about 20°C to about 30°C. In other embodiments, a suitable temperature is from about 20°C to about 25°C.

[0222] Suitable organic solvents are, for example, THF. Other solvents that can be used are, for example, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran, or mixtures thereof.

[0223] For steps 3) of synthesizing compounds of formula II or IV:

[0224] A suitable amount of POCl3 is at least 2 equivalents of POCl3 per amount of intermediate (10) or intermediate (10'). In some embodiments, a suitable amount of POCl3 is at least 4 equivalents. In some embodiments, a suitable amount is at least 3 equivalents. In some embodiments, a suitable amount is at least 2 equivalents. In some embodiments, a suitable amount is at least 1 equivalent. In other embodiments, a suitable amount is about 1 to about 4 equivalents of POCl3 per amount of intermediate (10) or intermediate (10').

[0225] A suitable temperature is between about 50°C and about 80°C. In some embodiments, a suitable temperature is between about 60°C and about 80°C. In some embodiments, a suitable temperature is between about 65°C and about 80°C. In other embodiments, a suitable temperature is between about 70°C and about 80°C. In other embodiments, a suitable temperature is between about 75°C and about 80°C.

[0226] Suitable aprotic solvents are, for example, acetonitrile (CNMe). The reaction can also be carried out in pure POCl3 in the absence of any solvent.

[0227] A suitable optional base is, for example, N,N-dimethylaniline. The reaction can also proceed without a base.

[0228] A suitable amount of base is about 0.2 to about 2 equivalents of base per unit amount of intermediate (10) or intermediate (10'). In some embodiments, a suitable amount of base is about 1.3 to about 1.6 equivalents. In some embodiments, a suitable amount of base is about 1.2 to about 1.8 equivalents. In other embodiments, it is about 1 equivalent.

[0229] For the above one-step method for synthesizing compounds of formula II or formula IV:

[0230] A suitable transfer hydrogenation reagent is HCOOH. HCOOH is most commonly used in the presence of organic / inorganic bases such as Et3N, NaOH, NaHCO3, etc. HCOONH4, HCOONa, HCOOK, isopropanol, triethylsilane, and cyclohexadiene can also be used. A suitable metal catalyst is palladium on activated carbon, for example, 10% Pd on activated carbon.

[0231] The suitable amount of a suitable metal catalyst is a catalytic amount, i.e., less than 1 equivalent of Pd per unit amount of intermediate (7) or intermediate (7'). In some embodiments, the suitable amount of a suitable metal catalyst is 0.01 to 0.02 equivalents of Pd per unit amount of intermediate (7) or intermediate (7').

[0232] A suitable base is triethylamine (Et3N). Other suitable bases that can be used are, for example, Hunig base, NaHCO3, KHCO3, and sodium acetate.

[0233] A suitable amount of base is at least one equivalent of base per unit amount of intermediate (7) or intermediate (7'). In some embodiments, a suitable amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.

[0234] A suitable temperature is from about 35°C to about 60°C. A suitable temperature is from about 35°C to about 55°C. In some embodiments, a suitable temperature is from about 40°C to about 50°C.

[0235] Suitable organic solvents are, for example, THF. Other solvents that can be used are, for example, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran, or mixtures thereof.

[0236] On the other hand, this paper describes a one-step method for preparing compound V.

[0237]

[0238] The one-step preparation of compound V involves coupling an appropriate amount of amine (13) with chloropyrimidine of formula IV at a suitable temperature in a suitable aprotic organic solvent, optionally in the presence of an appropriate amount of a suitable base, to obtain compound V.

[0239]

[0240] On the other hand, this article describes an alternative method for preparing compound V, including the following steps:

[0241] A) In a suitable aprotic organic solvent, at a suitable temperature, and in the presence of a suitable base, an appropriate amount of amine (13) is coupled with dichloropyrimidine (7') to obtain the intermediate product of formula VIII.

[0242] and

[0243] B) At a suitable temperature, in a suitable organic solvent, and in the presence of a suitable base, use hydrogen or transfer hydrogenation test.

[0244] An agent and, optionally, a suitable amount of metal catalyst, dechlorinate the intermediate of formula VIII to provide a compound of formula V.

[0245] Compounds of formula VIII can be used as intermediates in the preparation of compounds of formula V.

[0246] In some embodiments of the above-described method for preparing compound V, R 6 It is hydrogen, methyl, or ethyl in intermediate (13), compound of formula V, and intermediate of formula VIII. In some embodiments of the method for preparing compound of formula V, R 6 It is hydrogen in intermediate (13), compound of formula V and intermediate of formula VIII.

[0247] In some embodiments of the above-described method for preparing compound V, R 7 It is the intermediate (13), the intermediate of formula VIII, and the C in the compound of formula V. 1-6 Alkyl, and C 1-6 Alkyl groups are formed by at most 3 Rs 8 Instance replacement. In other implementations, R 7 It is C 1-2 Alkyl groups, with at most 3 R groups 8 Instance replacement. In other implementations, R 7 It is an ethyl group, with at most 3 R groups. 8 Instance replacement.

[0248] In some embodiments of the above-described method for preparing compound V, for compound V, intermediate of formula VIII and intermediate (13), R 8 One example is -OH. In other implementations, R 8 One instance is -OH, and the other two instances are independently selected from C. 1-3 Halogenated alkyl group. In other embodiments, R 8 One example is -OH, and two other examples are trifluoromethyl.

[0249] In some embodiments of the above-described method for preparing compound V, R 7 In intermediate (13), the ethyl group in intermediate of formula VIII and compound of formula V, the ethyl group is formed by 3 R groups. 8 Group substitution, and one of the R groups 8 Three examples are -OH. In other implementations, R 7 It is an ethyl group, surrounded by 3 R groups. 8 Group substitution, and R 8 One example is -OH, and R 8 The other two instances are independently selected from C 1-3 Halogenated alkyl groups. In some embodiments, R 8 One example is -OH, R 8 Two other examples are trifluoromethyl.

[0250] On the other hand, this paper describes a one-step method for preparing compound VI.

[0251]

[0252] The one-step preparation of compound VI involves coupling an appropriate amount of amine (14) with chloropyrimidine of formula II at a suitable temperature in a suitable aprotic organic solvent, optionally in the presence of a suitable amount of a suitable base, to obtain compound VI.

[0253]

[0254] On the other hand, this article describes an alternative method for preparing compound VI, including the following steps:

[0255] A) At a suitable temperature, in a suitable aprotic organic solvent, and optionally in the presence of a suitable base, a suitable amount of amine (14) is coupled with dichloropyrimidine (7) to obtain intermediate of formula IX;

[0256] and

[0257] B) At a suitable temperature, in a suitable organic solvent, in the presence of a suitable base, the intermediate of formula IX is dechlorinated with hydrogen or a transfer hydrogenating agent and optionally in a suitable amount of a suitable metal catalyst to provide the compound of formula VI.

[0258] Compounds of formula IX can be used as intermediates for the preparation of compounds of formula VI.

[0259] On the other hand, this paper describes another method for preparing compound VI.

[0260] The method for preparing compound VI includes the following steps:

[0261] a) At a suitable temperature, in a suitable aprotic organic solvent, ethylene oxide (12) is amination with an appropriate amount of ammonium hydroxide to obtain amine (14);

[0262] and

[0263] b) At a suitable temperature, in a suitable aprotic organic solvent, and optionally in the presence of a suitable base, a suitable amount of amine (14) is coupled with chloropyrimidine of formula II to obtain the compound of formula VI.

[0264] In some embodiments of the above-described method for preparing compound VI, for compound VI and intermediates of formula II and formula IX, R 1 It is an unsubstituted 5-membered heteroaryl ring containing up to three cyclic heteroatoms independently selected from N, O, or S. In a further embodiment, R 1 It is an isoxazolyl group. In other embodiments, R 1 It is 3-isooxazolyl.

[0265] In other embodiments of the above-described method for preparing compound VI, for compounds of formula VI and intermediates of formula II and formula IX, R 1 It is an unsubstituted phenyl or 6-membered heteroaryl ring containing at most three cyclic nitrogen atoms. In other embodiments, R 1 It is phenyl.

[0266] In some embodiments of the above-described method for preparing compound VI, for compound VI and intermediates of formula II and formula IX, R 2 It can be selected by up to three Rs. 5 Examples of substituted 6-membered heteroaryl groups. In other embodiments, R 2 It can be selected by up to three Rs. 5 Substituted phenyl groups. In other embodiments, R 2 It was by an R 5 A phenyl group substituted with a radical. In a further embodiment, R 2 It was by an R 5 Group-substituted phenyl, R 5 It is a halogen. In other embodiments, R 2 It was by an R 5 Group-substituted phenyl, R 5 It is fluorine. In other embodiments, R 2 It is 2-fluorophenyl. In other embodiments, R 2 It was by two Rs 5 Example of substituted phenyl group.

[0267] In other implementations, R 2 It was by two Rs 5 A phenyl group substituted with a radical, and R 5 Each group is independently a halogen. In other embodiments, R 2 It was by two Rs 5 Examples of substituted phenyl groups, and R 5 Each instance is fluorine.

[0268] On the other hand, this paper describes a one-step method for preparing compound I (1,1,1,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)prop-2-ol). Compound I has the structure described below. Compound I is an sGC stimulant, which has been shown to be effective in treating many NO-related conditions in preclinical models.

[0269]

[0270] In one embodiment, the one-step preparation of compound I comprises coupling an appropriate amount of amine (14) with chloropyrimidine of formula IV at a suitable temperature in a suitable aprotic organic solvent, optionally in the presence of an appropriate amount of a suitable base, to obtain compound I.

[0271] The above one-step method for preparing compounds of formula III, V, VI, or I by reacting an intermediate of formula II or IV with an amine (13), or by reacting an intermediate of formula II or IV with an amine (14):

[0272] A suitable amount of amine (13) or amine (14) is at least one equivalent of amine (13) or amine (14) per amount of compound of formula II or formula IV. In some embodiments, an excess of amine (13) or amine (14) may be used. In some embodiments, an amount of about 1 to about 5 equivalents of amine (13) or amine (14) may be used. In other embodiments, a suitable amount is about 1 to about 4 equivalents. In other embodiments, it is about 1 to about 3 equivalents.

[0273] Suitable alternative bases are, for example, Hunig bases. Other suitable alternative bases are, for example, Et3N, NaHCO3, and KHCO3. Amines (13) or amines (14) can also be used as bases themselves.

[0274] A suitable amount of base is at least one equivalent of the optional base per equivalent of intermediate of formula II or formula IV. In some embodiments, a suitable amount is about two equivalents.

[0275] A suitable aprotic organic solvent is dimethyl sulfoxide (DMSO). Other suitable aprotic organic solvents are, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tert-butanol (t-BuOH).

[0276] A suitable temperature is between about 100°C and about 135°C. In some embodiments, a suitable temperature is between about 120°C and about 130°C. In other embodiments, a suitable temperature is between about 125°C and about 130°C.

[0277] On the other hand, this article describes an alternative method for preparing compound I, comprising the following steps:

[0278] A) In a suitable aprotic organic solvent, optionally in the presence of a suitable base, at a suitable temperature, a suitable amount of amine (14) is coupled with dichloropyrimidine (7') to obtain an intermediate of formula X;

[0279]

[0280] B) At a suitable temperature, in a suitable organic solvent, in the presence of an appropriate amount of a suitable base, the intermediate of formula X is dechlorinated with hydrogen or a transfer hydrogenating agent and optionally a suitable amount of metal catalyst to provide compound I.

[0281] On the other hand, another method for preparing compound I includes the following steps:

[0282] a) At a suitable temperature, in a suitable aprotic organic solvent, ethylene oxide (12) is amination with an appropriate amount of ammonium hydroxide to obtain amine (14);

[0283] and

[0284] b) At a suitable temperature, in a suitable aprotic organic solvent, and optionally in the presence of a suitable base, an appropriate amount of amine (14) is coupled with chloropyrimidine of formula IV to give compound I.

[0285] For step a) of the above method for preparing compound VI or compound I:

[0286] A suitable amount of ammonium hydroxide is at least 3 equivalents of ammonium hydroxide per unit amount of intermediate (12). In some embodiments, a suitable amount is about 3 equivalents to about 12 equivalents. In other embodiments, it is about 4 equivalents to about 10 equivalents. In other embodiments, it is about 6 equivalents to about 12 equivalents. In other embodiments, it is about 8 equivalents to about 10 equivalents. In some embodiments, it is about 10 equivalents.

[0287] Suitable aprotic organic solvents are, for example, dialkyl ethers. In some embodiments, the ether is methyl tert-butyl ether. Other ethers that can be used include, for example, diisopropyl ether. Other aprotic organic solvents that can be used are, for example, dichloromethane and ethyl acetate. Suitable temperatures are between about 15°C and about 35°C. In some embodiments, suitable temperatures are between about 20°C and about 30°C. In other embodiments, suitable temperatures are between about 23°C and about 28°C.

[0288] For step b) in the above method for preparing compound VI or compound I:

[0289] A suitable amount of amine (14) is at least 1 equivalent of amine (14) per amount of compound II or compound IV. In some embodiments, an excess of amine (14) may be used. In some embodiments, an amount of about 1 to about 5 equivalents of amine (14) may be used. In other embodiments, a suitable amount is about 1 to about 4 equivalents. In other embodiments, it is about 1 to about 3 equivalents.

[0290] Suitable alternative bases are, for example, Hunig bases. Other suitable alternative bases are, for example, Et3N, NaHCO3, and KHCO3. Amines (14) can also be used as bases themselves.

[0291] A suitable amount of base is at least one equivalent of the optional base per equivalent of intermediate of formula II or formula IV. In some embodiments, a suitable amount is about two equivalents.

[0292] A suitable aprotic organic solvent is dimethyl sulfoxide (DMSO). Other suitable aprotic organic solvents are, for example, DMF, DMA, and t-BuOH.

[0293] A suitable temperature is between about 100°C and about 135°C. In some embodiments, a suitable temperature is between about 120°C and about 130°C. In other embodiments, a suitable temperature is between about 125°C and about 130°C.

[0294] For step A) of the above method for preparing compounds of formula III, V, VI, or I:

[0295] An appropriate amount of amine (13) or amine (14) is at least one equivalent of amine (13) or amine (14) per unit amount of intermediate (7) or intermediate (7'). In some embodiments, an excess of amine (13) or amine (14) may be used. In some embodiments, an amount of about 1 to about 3 equivalents of amine (13) or amine (14) may be used. In other embodiments, a suitable amount is about 1 to about 2.9 equivalents. In other embodiments, it is about 1 to about 2.7 equivalents. In other embodiments, it is about 2.6 equivalents.

[0296] Suitable alternative bases are, for example, bases of Hunig. Other suitable alternative bases are, for example, Et3N, NaHCO3, and KHCO3. When used in excess, amines (13) or amines (14) themselves may also be used as bases.

[0297] The appropriate amount of base is at least one equivalent of optional base per unit amount of intermediate (7) or intermediate (7'). In some embodiments, the appropriate amount is about 2 equivalents.

[0298] A suitable aprotic organic solvent is dimethyl sulfoxide (DMSO). Other suitable aprotic organic solvents are, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tert-butanol (t-BuOH).

[0299] A suitable temperature is from about 50°C to about 90°C. In some embodiments, a suitable temperature is from about 55°C to about 65°C. In other embodiments, a suitable temperature is from about 75°C to about 90°C. In other embodiments, a suitable temperature is from about 55°C to about 85°C. In other embodiments, a suitable temperature is from about 75°C to about 85°C. In other embodiments, a suitable temperature is from about 50°C to about 70°C.

[0300] For step B) of the above method for preparing compounds of formula III, V, VI, or I:

[0301] A suitable transfer hydrogenation reagent is HCOOH. HCOOH is most commonly used in the presence of organic / inorganic bases such as Et3N, NaOH, and NaHCO3. HCOONH4, HCOONa, HCOOK, isopropanol, triethylsilane, and cyclohexadiene can also be used.

[0302] A suitable metal catalyst is palladium on activated carbon, such as 10% Pd on activated carbon.

[0303] A suitable amount of metal catalyst is a catalytic amount, i.e., less than 1 equivalent of Pd per amount of intermediate of formula VII, VIII, IX or X. In some embodiments, a suitable amount of metal catalyst is 0.01 to 0.02 equivalents of Pd per amount of intermediate of formula VII, VIII, IX or X.

[0304] A suitable base is triethylamine (Et3N). Other suitable bases that can be used are, for example, Hunig base, NaHCO3, KHCO3, and sodium acetate.

[0305] A suitable amount of base is at least one equivalent of base per unit amount of intermediate of formula VII, VIII, IX, or X. In some embodiments, a suitable amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.

[0306] A suitable temperature is from about 35°C to about 60°C. A suitable temperature is from about 35°C to about 55°C. In some embodiments, a suitable temperature is from about 40°C to about 50°C.

[0307] Suitable organic solvents are, for example, THF. Other solvents that can be used are, for example, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran, or mixtures thereof.

[0308] The method described herein has the advantage of allowing the preparation of sGC stimulants and intermediates of Formula I in high yield and purity. Another advantage of the invention is the simple reaction conditions that are easy to scale up for large-scale production.

[0309] In one embodiment of the above method, the compound of formula I is a compound of formula II. In another embodiment, the compound of formula I is a compound of formula IV. In another embodiment, the compound of formula I is a compound of formula III. In another embodiment, it is a compound of formula V. In another embodiment, the compound of formula I is a compound of formula VI. In other embodiments, the compound of formula I is compound I (1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5)-(isoxazo-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)prop-2-ol).

[0310] Alternative methods for preparing compounds of formulas II and IV have previously been described in US8748442B2, WO2013101830 and WO2014144100.

[0311] In those publications, intermediates (4) and (4') are synthesized according to scheme 1 described below, with intermediate (4') used as an example.

[0312]

[0313] Option 1

[0314] According to scheme 1, the synthesis of intermediates (4) and (4') can be carried out in two steps. For example, for compound (4'), the first step involves the reaction of ketone (19) with diethyl oxalate to give intermediate (20). In the second step, intermediate (20) is reacted with a suitably substituted hydrazine or its corresponding hydrochloride. In the specific case of compound (4'), the hydrazine is one of the formula NH2NH-CH2-(2-fluorophenyl).

[0315] This article describes the preparation of compounds (4) and (4') according to scheme 2, such as compound (4') described below.

[0316]

[0317] Option 2

[0318] It has been found that the preparation of intermediate (4) or (4') according to Scheme 2 has several advantages compared to the preparation according to Scheme 1. Although the synthesis according to Scheme 2 introduces an additional step, the synthesis according to Scheme 2 is more suitable for large-scale manufacturing scale-up compared to the synthesis according to Scheme 1, resulting in higher overall yield and higher purity. Scheme 2 uses compound (1') as the starting material in step i). This starting material is solid at room temperature and is inexpensive and available from commercial sources. Compound (19), used as the starting material in Scheme 1, is liquid at room temperature, which makes it difficult to handle in large-scale operations. Compound (19) is also much more expensive than the commercially available compound (1').

[0319] Another advantage of the synthesis according to Scheme 2 is that the intermediate (3') generated in step ii) can be recrystallized and obtained with high purity. The intermediate (20) of Scheme 1 is used in the second step of the reaction without further purification, resulting in a lower purity final product and a more complex purification method. Furthermore, the second step in the synthesis according to Scheme 1 to prepare compound (4) or compound (4') occurs in cases where the regioselectivity of the desired regioisomer of (4) or (4') is very low, as described in the above scheme. The less desirable regioisomers of structures (4B) and (4'B) are shown below. The low regioselectivity observed during the synthesis according to Scheme 1 results in a loss of overall yield of the desired isomer and requires lengthy and inefficient purification methods to separate the pure desired isomer.

[0320]

[0321] In US8748442B2, WO2013101830 and WO2014144100, compounds of formula II or formula IV are prepared from intermediate amidine (5A) or (5A') or intermediate amidine salt (5B) or (5'B), according to scheme 3, by forming intermediate (10'), as shown in the final compound of formula IV below.

[0322]

[0323] Option 3

[0324] This document discloses the preparation of compounds of formula II or formula IV from the corresponding amidine (5A) or (5A') or amidine salt (5B) or (5B') by one of several alternative methods. These are examples of the final formula IV compounds in scheme 4 below.

[0325]

[0326] Option 4

[0327] It has been found that the preparation of compounds of formula II or IV according to scheme 4 has several advantages compared to the preparation according to scheme 3. Although the process summarized in scheme 3 is very short, like scheme 4, it is not suitable for large-scale manufacturing. The preparation of intermediate (10) or (10') using asymmetric reagents (25) and (26) or similar reagents results in the formation of a large number of impurities. These impurities need to be separated before proceeding to the next step to avoid being carried over into the final product. This involves lengthy and complex purification and low yield.

[0328] The method summarized in Scheme 4, which utilizes the reaction of the symmetric reagent (27) as the first step, has the advantage of providing symmetric intermediates (6) or (6') in high purity and yield. This intermediate can then be converted into compounds of formula II or IV via several alternative methods: a five-step method via steps vi) to x); a one-step method directly yielding the final product; or a four-step process via steps vi) and 1) to 3). In all cases, each resulting step is in high yield, and the intermediates are all separated in high purity and yielded after simple precipitation or crystallization, avoiding the use of chromatography. Therefore, the entire process is highly efficient and suitable for large-scale manufacturing.

[0329] This article also describes a novel method for preparing compounds of formula III, V, VI, or compound I using intermediate (7) or intermediate (7'), which is itself generated from intermediates (6) and (6'). This method is summarized in Scheme 5 below. The method is illustrated by way of preparing compound V below. Similar methods can be used to prepare compounds of formulas III and VI, as well as compound I.

[0330]

[0331] Option 5

[0332] This method is superior to alternative methods for preparing compounds of formulas III, V, VI, and I because it uses a symmetrical intermediate (7) or (7') as a starting material. As described above, starting from this symmetrical intermediate, the production from symmetrical intermediates (6) and (6') results in high overall yield and purity of subsequent steps. Two high-yield steps produce the final amine of formula V. The entire process is suitable for large-scale manufacturing.

[0333] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the invention. As used herein, the singular forms “a,” “an,” and “the” are also intended to include the plural forms unless the context clearly indicates otherwise. It will be further understood that the terms “comprising” (and any form of inclusion, e.g., “comprising”), “having” (and any form of having, e.g., “having”), “including” (and any form of inclusion, e.g., “comprising”), “containing” (and any form of containing, e.g., “containing”), and any other grammatical variations are open-connecting verbs. As a result, a method or apparatus that “comprising,” “having,” “comprising,” or “containing” one or more steps or elements possesses, but is not limited to, possessing only those one or more steps or elements. Similarly, a method or element of an apparatus that “comprising,” “having,” “comprising,” or “containing” one or more features possesses, but is not limited to, possessing only those features or one or more features. Further functionality. In addition, the apparatus or structure configured in a certain way is configured at least in this manner, but may also be configured in ways not listed.

[0334] As used herein, the terms “contains,” “has,” “includes,” “contains,” and other grammatical variations include the terms “composed of” and “substantially composed of.”

[0335] When used herein, the phrase “consistently of…” or its grammatical variations shall be regarded as specifying the said feature, integer, step or component, but does not preclude the addition of one or more additional features, integers, steps, components or groups thereof, only if such additional features, integers, steps, components or groups do not substantially alter the essential and novel features of the claimed composition, apparatus or method.

[0336] All publications cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated as incorporated herein by reference, as if fully explained.

[0337] Unless otherwise expressly stated, the subject matter incorporated by reference is not considered a substitute for any claim limitation.

[0338] Where one or more ranges are referenced throughout the specification, each range is intended to be a simplified format for presenting information, wherein the range is understood to contain every discrete point within that range, as fully explained herein.

[0339] While several aspects and embodiments of the invention have been described and depicted herein, those skilled in the art can influence alternative aspects and embodiments to achieve the same purpose. Therefore, this disclosure and the appended claims are intended to cover all such further and alternative aspects and embodiments that fall within the true spirit and scope of the invention.

[0340] Example

[0341] The following preparation examples are provided to provide a more complete understanding of the invention. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0342] method

[0343] HPLC analysis

[0344] equipment:

[0345] A. HPLC analysis was performed using an Agilent 1100 / 1200 series HPLC system, which consists of a pump, ChemStation UV VWD or DAD detector, autoinjector, and column heater or equivalent. ChemStation software was installed on a GX270 or equivalent. The column was a HALO C18 150 × 4.6 mm.

[0346] B. Column: HALO C18 150×4.6mm 2.7 micrometers or equivalent

[0347] C. Autosampler vials, silicone / Teflon septum, 12x32mm

[0348] D. 100-mL Grade A volumetric flask

[0349] E. Weighing funnel

[0350] F. Spatulas

[0351] G. Disposable glass Pasteur straws

[0352] H. A balance capable of accurately weighing 0.01 milligrams.

[0353] 1.2 x 2-L solvent containers

[0354] Reagents:

[0355] A. Water, HPLC grade or equivalent

[0356] B. Acetonitrile (ACN), HPLC grade or equivalent

[0357] C. Trifluoroacetic acid (TFA) HPLC grade or equivalent

[0358] D. Intermediate test samples

[0359] E. Actual intermediate materials or reference standards (if any)

[0360] Solvents and diluents:

[0361] A. Solvent A: 0.1% TFA aqueous solution (i.e., 1 mL in 1 L of water)

[0362] B. Solvent B: 0.1% TFA in acetonitrile (i.e., 1 mL in 1 L ACN)

[0363] C. Diluent: Acetonitrile / Water

[0364] Column temperature: 40℃

[0365] schedule:

[0366] Time (minutes) % Solvent A % Solvent B 0 85 15 10 5 95 15 5 95

[0367] Retention time of selected compounds

[0368] compound Approximate retention time (Min) Isoxazole-3-carboxylic acid (1') 1.8 Compound (2') 3.1 Compound (3') 6.2 Compound (4') 8.6 Compound (5') 5.1 Compound (6') 6.2 Compound (7') 10.3 Compound (8') 10.0 Compound (9') 8.8 Compound (10') 7.0 Formula IV 9.3 Compound I 8.9

[0369] Nuclear magnetic resonance spectroscopy

[0370] All compounds were recorded on a BRUKER NMR spectrometer operating at 500 MHz at room temperature. 1 1H NMR spectra. The sample dissolved in CDCl3 is referenced against the residual solvent peak at 7.27 ppm. The sample dissolved in DMSO-d6 is referenced against the residual solvent peak at 2.50 ppm. The resulting FIDs were transferred to a PC and processed using ACD / Labs NMR processing software.

[0371] Example 1

[0372] i): Coupling of compound (1') with N,O-dimethylhydroxylamine yields N-methoxy-N-methylisoxazole-3-carboxyl Amine (2')

[0373]

[0374] Isoxazol-3-carboxylic acid ((1'), 241.6 g, 2137 mmol, 1.0 equivalent), toluene (1450 mL), and DMF (7.8 g, 107 mmol, 0.05 equivalent) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The resulting slurry was heated to 45–50 °C. Oxaloyl chloride (325 g, 2559 mmol, 1.2 equivalent) was then added over 2 hours via a feeding funnel while maintaining the reaction temperature between 45 and 50 °C, and vigorous gas escape was observed. A brown mixture was obtained after the addition. The brown mixture was heated to 87–92 °C over 1 hour and stirred at 87–92 °C for 1 hour. The reaction was completed as shown by HPLC. During heating, the brown mixture turned into a dark solution. The reaction was monitored by quenching a portion of the reaction mixture into piperidine and monitoring the piperidine amide by HPLC. The dark mixture was cooled to 20–25 °C and then filtered through a sintered glass funnel to remove any insoluble matter. The black filtrate was concentrated under reduced pressure to a volume of 400 mL of dark oil.

[0375] Potassium carbonate (413 g, 2988 mmol, 1.4 equivalents) and water (1000 mL) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction solution was cooled to -10 to -5 °C. N,O-dimethylhydroxylamine hydrochloride (229 g, 2348 mmol, 1.1 equivalents) was added to a suitable reaction vessel and dissolved in water (1000 mL). Then the N,O-dimethylhydroxylamine solution and dichloromethane (2500 mL) were added to the potassium carbonate solution.

[0376] The above-mentioned dark oily substance (400 mL) was then slowly added through a feeding funnel while maintaining the reaction temperature at -10 to 0 °C. The addition was slightly exothermic, resulting in a brown mixture. The mixture was stirred at 0 to 5 °C for 20 minutes. The temperature was then raised to 20 to 25 °C. The bottom organic layer and the top aqueous solution were collected. The aqueous layer was extracted with dichloromethane (400 mL). The combined organic layers were washed with a 15% sodium chloride solution (1200 mL). The organic layer was dried with magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give intermediate (2'), a dark oily substance (261.9 g, 97 wt%, 76% yield, 3 wt% toluene). 1 H-NMR, 0.04 wt% water content, KF). 1 H-NMR (500MHz, CDCl3) δppm8.48(s,1H); 6.71(s,1H); 3.78(s,3H); 3.38(s,3H).

[0377] ii): Alkylation of compound (2') and ethyl propargylate yields (E)-4-(isoxazo-3-yl)-2-(methoxy) (Methyl)amino)-4-oxobut-2-enoic acid ethyl ester (3')

[0378]

[0379] Intermediate (2') (72.2 g, 96 wt%, 444 mmol, 1.0 equivalent), ethyl propargyl ester (65.7 g, 670 mmol, 1.5 equivalent), and anhydrous THF (650 mL) were added to the appropriate reaction vessel. The vessel was equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to -65 to -55 °C. Then, a THF solution of bis(trimethylsilyl)amide (1 M, 650 mL, 650 mmol, 1.46 equivalent) was slowly added through a feeding funnel while maintaining the reaction temperature at -65 to -55 °C. The mixture was stirred below -55 °C for 10 minutes. After the addition was complete, 1 N HCl (650 mL, 650 mmol, 1.46 equivalent) was added to quench the reaction while maintaining the reaction temperature below -20 °C, followed immediately by the addition of ethyl acetate (1500 mL) and water (650 mL). The top ethyl acetate layer was collected, and the bottom aqueous layer was extracted with ethyl acetate (800 mL). The combined organic layers were washed with 10% citric acid (1000 mL) and saturated sodium chloride solution (650 mL). The organic layers were concentrated under reduced pressure to obtain a dark oily substance.

[0380] A dark oily substance was dissolved in a solution of dichloromethane / ethyl acetate / heptane (150 mL / 100 mL / 100 mL). The solution was loaded onto a silica gel pad (410 g), and the pad was eluted with ethyl acetate / heptane (1 / 1 v / v). The filtrate (~3000 mL) was collected and concentrated under reduced pressure to 150 mL. After standing, a slurry was obtained. Then, heptane (200 mL) was added to the slurry, and the slurry was concentrated under reduced pressure to 150 mL. The resulting slurry was filtered, and the filter cake was washed with heptane (150 mL). The filter cake was then air-dried overnight to give intermediate (3'), a brown solid (63.4 g, 56% yield, HPLC purity >99%). 1 H-NMR (500MHz, CDCl3) δppm8.42 (d, J = 1.53 Hz, 1H); 6.76 (d, J = 1.53 Hz, 1H); 6.18 ( s, 1H); 4.47 (q, J = 7.07Hz, 2H); 3.75 (s, 3H); 3.21 (s, 3H); 1.41 (t, J = 7.17Hz, 3H).

[0381] iii): Compound 3' and 2-fluorobenzylhydrazine are cyclized to give 1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyridine Ethyl azole-3-carboxylate (4')

[0382]

[0383] Intermediate (3') (72.9 g, 287 mmol, 1.0 equivalent) and anhydrous ethanol (730 mL) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was cooled to 0–5 °C. Then, 2-fluorobenzylhydrazine (48.2 g, 344 mmol, 1.2 equivalent) was added to the mixture. The mixture was stirred at 0–10 °C for 1 hour, then warmed to 20–25 °C and stirred at 20–25 °C for 16 hours. The reaction was completed by HPLC. Concentrated HCl (33.9 g, 37 wt%, 344 mmol, 1.2 equivalent) was added to the reaction mixture over 1 minute, and the batch temperature was exothermic from 20 °C to 38 °C. A slurry was obtained. The mixture was cooled to 0–10 °C over 1 hour and stirred at 0–10 °C for 1 hour. The resulting slurry was filtered, and the filter cake was washed with ethanol (200 mL). The filter cake was dried under vacuum at 30 to 40 °C for 16 hours to obtain intermediate (4'), which was a grayish-white solid (81.3 g, 90% yield, HPLC purity >99%). 1 H-NMR (500MHz, CDCl3) δppm8.47 (d, J = 1.68Hz, 1H); 7.15-7.26 (m, 2H); 6.94-7.08 (m, 2H); 6.77-6 .87 (m, 1H); 6.55 (d, J = 1.68Hz, 1H); 5.95 (s, 2H); 4.43 (q, J = 7.02Hz, 2H); 1.41 (t, J = 7.17Hz, 3H).

[0384] iv): Amination of compound (4') yields 1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazole-3-formamidinium salt. Salt (5'B)

[0385]

[0386] Anhydrous ammonium chloride (267 g, 4991 mmol, 5.0 equivalents) and toluene (5400 mL) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Trimethylaluminum (2 M, 2400 mL, 4800 mmol, 4.8 equivalents) in toluene was slowly added through a feeding funnel while maintaining the reaction temperature at 20–40 °C (note: methane gas was observed to escape during the addition). The mixture was then heated to 75–80 °C over 30 minutes. A clear white solution was obtained. Intermediate (4') (315 g, 999 mmol, 1.0 equivalents) was added in four equal portions to the reaction mixture over 1 hour at 75–90 °C. The reaction was stirred at 80–90 °C for 30 minutes. The mixture was then heated to 100–110 °C and stirred at 100–110 °C for 3 hours. The reaction was completed by HPLC. The reaction mixture was cooled to 10–20 °C, and methanol (461 g, 14.4 mol, 14.4 equivalents) was slowly added through a feeding funnel while maintaining the reaction temperature at 10–40 °C. Note that quenching is highly exothermic, and a significant amount of gas was observed to escape. A thick slurry was obtained. Then, 3N HCl (6400 mL, 3N, 19.2 mol, 19.2 equivalents) was slowly added through a feeding funnel while maintaining the reaction temperature at 20–45 °C. The mixture was heated to 80–85 °C and stirred at 80–85 °C for 10 minutes. A clear two-phase mixture was obtained. The mixture was cooled to 0–5 °C over 3 hours and stirred at 0–5 °C for 1 hour. The resulting slurry was filtered, and the filter cake was washed with water (3000 mL). The filter cake was vacuum dried at 40–50 °C over 24 hours to give intermediate (5'B), a grayish-white solid (292 g, 91% yield, HPLC purity >99%). 1 H-NMR (500MHz, DMSO-d6) δppm9.52 (s, 2H); 9.33 (s, 2H); 9.18 (d, J = 1.53Hz, 1H); 7.88 (s, 1H); 7.29-7.3 8(m,1H);7.19-7.25(m,1H);7.10-7.16(m,1H);7.03(d,J=1.53Hz,1H);6.92-6.98(m,1H);5.91(s,2H). MP180-185℃.

[0387] v): Compound (5'B) is cyclized with diethyl fluoromalonate to give 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isooxa) (-3-yl)-1H-pyrazol-3-yl)pyrimidin-4,6-diol (6')

[0388]

[0389] Intermediate (5'B) (224.6 g, 698 mmol, 1.0 equivalent), methanol (2250 mL), and diethyl fluoromalonate (187 g, 1050 mmol, 1.5 equivalent) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. A methanol solution of sodium methoxide (567 g, 30 wt%, 3149 mmol, 4.5 equivalent) was then added through a feeding funnel while maintaining the reaction temperature at 20–35 °C. The mixture was stirred at 20–35 °C for 30 minutes, yielding a light suspension. The reaction was confirmed by HPLC. A 1.5 N HCl solution (2300 mL, 3450 mmol, 4.9 equivalent) was added over 1 hour through a feeding funnel while maintaining the reaction temperature at 20–30 °C, yielding a white suspension. The pH of the reaction mixture was ~1 using pH paper. The slurry was stirred at 20–30 °C for 30 minutes. The filtered slurry was washed with a pre-mixed methanol and water (500 mL / 500 mL) solution, followed by washing with water (1000 mL). The filter cake was vacuum dried at 50 to 60 °C for 16 hours to give intermediate (6'), a grayish-white solid (264 g, 97% yield, HPLC purity >99%). 1 H-NMR (500MHz, DMSO-d6) δppm12.82 (br.s, 1H); 12.31 (br.s., 1H); 9.14 (d, J = 1.53Hz, 1H); 7.55 (s, 1H) ); 7.31-7.37 (m, 1H); 7.18-7.25 (m, 1H); 7.10-7.15 (m, 2H); 6.97-7.02 (t, J = 7.55Hz, 1H); 5.88 (s, 2H).

[0390] vi): Chlorinated compound (6') yields 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H- pyrazole-5-yl)isoxazole(7'))

[0391]

[0392] Intermediate (6') (264 g, 711 mmol, 1.0 equivalent), acetonitrile (4000 mL), and N,N-dimethylaniline (138 g, 1137 mmol, 1.6 equivalent) were added to a suitable reaction vessel. The slurry mixture was heated to 70–80 °C using a mechanical stirrer and a digital thermometer. Phosphorus oxychloride (655 g, 4270 mmol, 6.0 equivalent) was then added over 1 hour via a feeding funnel while maintaining the reaction temperature at 70–80 °C. The mixture was stirred at 75–80 °C for 22 hours to obtain a brown solution. The reaction was confirmed by HPLC. The mixture was then cooled to 0–5 °C, and a cotton-like solid precipitated at 25 °C. Water (3000 mL) was slowly added via a feeding funnel while maintaining the reaction temperature at 0–10 °C. The slurry was stirred at 0–10 °C for 30 minutes. The resulting slurry was filtered, and the filter cake was washed with a premixed solution of acetonitrile and water (500 mL / 500 mL). The filter cake was then vacuum dried at 35 to 45 °C for 16 hours to obtain intermediate (7'), which was a grayish-white solid (283 g, 98% yield, HPLC purity >99%). 1 H-NMR (500MHz, CDCl3) δppm8.48 (d, J = 1.68Hz, 1H) 7.44 (s, 1H) 7.19-7.25 (m ,1H)6.96-7.08(m,2H)6.81-6.88(m,1H)6.60(d,J=1.68Hz,1H)6.03(s,2H).

[0393] vii): Replacing compound (7') with a methanol salt yields 3-(3-(4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)-1- (2-Fluorobenzyl)-1H-pyrazole-5-yl)isoxazole (8')

[0394]

[0395] Methanol (3400 mL) and sodium methoxide (154 mL, 5.4 M, 832 mmol, 1.2 equivalents) in methanol were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 23–27 °C. Intermediate (7') (283 g, 693 mmol, 1.0 equivalents) was added in small portions (5–10 g per portion) to the mixture over 40 minutes while maintaining the reaction temperature at 23–27 °C. The slurry was stirred at 23–27 °C for 30 minutes. The reaction was completed by HPLC. The resulting slurry was filtered, and the filter cake was washed with methanol (850 mL) and then with water (850 mL). The filter cake was dried under vacuum at 35–45 °C over 16 hours to give intermediate (8') as a grayish-white solid (277 g, 99% yield, 97% HPLC purity). 1H-NMR (500MHz, CDCl3) δppm8.47 (d, J = 1.83Hz, 1H); 7.38 (s, 1H); 7.18-7.25 (m, 1H); 7.01-7.08 ( m, 1H); 6.94-7.00 (m, 1H); 6.81-6.88 (m, 1H); 6.60 (d, J = 1.68Hz, 1H); 6.00 (s, 2H); 4.21 (s, 3H).

[0396] viii): Hydrogenation of compound (8') yields 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)- 1H-pyrazole-5-yl)isoxazole (9')

[0397]

[0398] Intermediate (8') (226 g, 560 mmol, 1.0 equivalent), palladium (10% on activated carbon, nominally 50% wetted water, 22.6 g, 0.01 mol, 0.018 equivalent), tetrahydrofuran (3400 mL), and triethylamine (91 g, 897 mmol, 1.6 equivalent) were added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Nitrogen was bubbled into the reaction mixture through a Teflon tube over 10 minutes at 20–30 °C. The mixture was then heated to 40–50 °C and hydrogen was bubbled into the reaction mixture through a Teflon tube over 6 hours while maintaining the reaction temperature at 40–50 °C. The reaction was completed by HPLC. Nitrogen was then bubbled into the reaction mixture through a Teflon tube over 10 minutes at 40–50 °C. The reaction mixture was then purged through a HypoSupercel TM Hot filtration was performed, and the filter cake was washed with tetrahydrofuran (2000 mL). The filtrate was concentrated under reduced pressure to a volume of approximately 1300 mL to obtain a slurry. Then, the tetrahydrofuran was solvent-exchanged to methanol under reduced pressure by continuous addition of methanol (3000 mL). The final volume after solvent exchange was 1300 mL. The resulting slurry was filtered, and the filter cake was washed with methanol (500 mL). The filter cake was vacuum dried at 20–25 °C for 16 hours to give intermediate (9'), a white solid (192 g, 93% yield, HPLC purity 98%). 1 H-NMR (500MHz, CDCl3) δppm8.47 (d, J=1.68Hz, 1H); 8.41 (d, J=2.59Hz, 1H); 7.36 (s, 1H); 7.17-7.2 4(m,1H); 6.95-7.07(m,2H); 6.83-6.90(m,1H); 6.60(d,J=1.68Hz,1H); 5.99(s,2H); 4.19(s,3H).

[0399] ix: Demethylation of compound (9') yields 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H- Pyrazol-3-yl)pyrimidin-4-ol (10')

[0400]

[0401] Intermediate (9') (230 g, 623 mmol, 1.0 equivalent), MeOH (3450 mL), and concentrated hydrochloric acid. HCl (307 g, 37 wt%, 3117 mmol, 5.0 equivalent) was added to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was heated to 60–65 °C to obtain a solution. The mixture was then stirred at 60–65 °C for 17 hours to obtain a slurry. The reaction was completed by HPLC. The slurry was cooled to 20–25 °C over 2 hours and stirred at 20–25 °C for 30 minutes. The resulting slurry was filtered, and the filter cake was washed with methanol (1000 mL). The filter cake was dried under vacuum at 35–45 °C for 16 hours to give intermediate (10') as a white solid (214 g, 97% yield, HPLC purity >99%). 1 H-NMR(500MHz,DMSO-d6)δppm12.90-13.61(br.s.,1H);9.11(d,J=1.68Hz,1H);8.16(s,1H);7 .64(s,1H);7.29-7.42(m,1H);7.17-7.28(m,2H);7.08-7.15(m,1H);6.97(s,1H);5.91(s,3H).

[0402] x): Chlorinated compound (10') yields 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyridine (Azol-5-yl)isoxazole (Formula IV)

[0403]

[0404] Intermediate (10') (214 g, 602 mmol, 1.0 equivalent), acetonitrile (3000 mL), and N,N-dimethylaniline (109 g, 899 mmol, 1.5 equivalent) were added to a suitable reaction vessel. Using a mechanical stirrer and a digital thermometer, the slurry mixture was heated to 70–80 °C. Then, phosphorus oxychloride (276 g, 1802 mmol, 3.0 equivalent) was added over 30 minutes via a feeding funnel, while maintaining the reaction temperature at 70–80 °C. The mixture was stirred at 75–80 °C for 2 hours to obtain a green solution. The reaction was confirmed by HPLC. The mixture was then cooled to 0–5 °C. Water (1500 mL) was slowly added via a feeding funnel while maintaining the reaction temperature at 0–10 °C. The slurry was stirred at 0–10 °C for 30 minutes. The resulting slurry was filtered and the filter cake was washed with a premixed solution of acetonitrile and water (500 mL / 500 mL) and water (500 mL). The filter cake was dried under vacuum at 30 to 40 °C for 16 hours to give the intermediate of Formula IV, which was a grayish-white to pink solid (214 g, 95% yield, HPLC purity >99%). 1 HNMR (500MHz, CDCl3) δppm8.65 (s, 1H); 8.48 (d, J = 1.68Hz, 1H); 7.44 (s, 1H); 7.21-7. 25 (m, 1H); 6.97-7.06 (m, 2H); 6.83-6.87 (m, 1H); 6.61 (d, J = 1.68Hz, 1H); 6.03 (s, 2H).

[0405] a): Amination of compound 12 yields 2-(aminomethyl)-1,1,1,3,3,3-hexafluoroprop-2-ol (14).

[0406]

[0407] Add 354 mL of 29% (NH3) aqueous solution of ammonium hydroxide (354 mL, 5435 mmol, 9.7 equivalents) and methyl tert-butyl ether (354 mL) to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. (Note: Set the condenser temperature to -20°C and minimize the evaporation of ammonium hydroxide.) Add 2,2-bis(trifluoromethyl)ethylene oxide ((12), 101 g, 561 mmol, 1.0 equivalents) through a feeding funnel for 40 minutes. Maintain the reaction temperature at 20 to 26°C. After addition, stir the mixture at 20 to 26°C for 3 hours. Separate the mixture and extract the bottom aqueous layer with methyl tert-butyl ether (2 × 354 mL). Concentrate the combined organic layers under reduced pressure to a volume of 303 mL. Add methyl tert-butyl ether (354 mL) and concentrate the mixture under reduced pressure to a volume of 303 mL. Add heptane (303 mL) and concentrate the mixture under reduced pressure to a volume of 303 mL. Filter the slurry and wash the filter cake with heptane (100 mL). Dry the solid in a hood at 20 to 25 °C for 2 hours until constant weight to give intermediate (14), a white solid (79.5 g, 71% yield). 1 H NMR (500MHz, MeOD) δppm3.09 (s, 2H).

[0408] b): Coupling of compound IV with compound 14 yields 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2- Fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)prop-2-ol (Compound I)

[0409]

[0410] Intermediate of Formula IV (133 g, 356 mmol, 1.0 equivalent), intermediate (14) in dimethyl sulfoxide solution (352 g, 60 wt%, 1071 mmol, 3.0 equivalent), and dimethyl sulfoxide (1200 mL) were loaded into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 125–130 °C and stirred at 125–130 °C for 4 hours. The reaction was completed by HPLC. The mixture was then cooled to 20–25 °C. Methyl tert-butyl ether (3800 mL) and water (2600 mL) were then added to the reaction mixture. The organic layer was washed with saturated sodium bicarbonate solution (1000 mL) and 1 N HCl solution (1000 mL), and then concentrated to a volume of 1500 mL under reduced pressure. The organic solution was loaded onto a silica pad (800 g), and the silica pad was eluted with methyl tert-butyl ether. The clean fraction was collected and concentrated under reduced pressure to a volume of 2000 mL. The MTBE solution was heated at 45–55 °C, and heptane (2000 mL) was added over 30 minutes via a feeding funnel while maintaining the reaction temperature between 45 and 55 °C to obtain a slurry. The slurry was cooled to 20–25 °C and stirred at 20–25 °C for 30 minutes. The resulting slurry was filtered, and the filter cake was washed with a premixed solution of MTBE and heptane (400 mL / 600 mL). The filter cake was then vacuum dried over 5 hours at 45–55 °C to give compound I as a grayish-white solid (130 g, 68% yield, HPLC purity >99%). 1 H NMR (500MHz, DMSO-d6) δppm9.11(d,J=1.96Hz,1H);8.66(s,1H);8.37(d,J=3.13Hz,1H);8.11(t,J=5.87Hz,1H);7.48(s,1H);7.30 -7.37 (m, 1H); 7.17-7.24 (m, 1H); 7.21 (d, J = 1.7Hz, 1H); 7.06-7.13 (m, 1H); 7.00-7.06 (m, 1H); 5.87 (s, 2H); 4.11 (d, J = 5.87Hz, 2H).

[0411] Example 2: Kilo-scale program

[0412] i): Coupling of compound (1') with N,O-dimethylhydroxylamine yields N-methoxy-N-methylisoxazole-3-carboxyl Amine (2')

[0413] Isoxazol-3-carboxylic acid ((1'), 3.857 kg, 34.1 mol, 1.0 equivalent), toluene (19.3 L), and DMF (0.131 L, 1.692 mol, 0.05 equivalent) were mixed in a 30 L jacketed reaction vessel equipped with a nitrogen inlet, a top stirrer, thermocouples, and a feeding funnel. The resulting slurry was heated to 45–55 °C. Then, oxalyl chloride (4.8 kg, 37.8 mol, 1.11 equivalent) was added over 4 hours and 30 minutes through the feeding funnel. The reaction temperature was maintained between 45 and 55 °C, and vigorous gas escape was observed. A brown mixture was obtained after the addition. The brown mixture was maintained at 45–55 °C for 30 minutes. Then, it was heated to 85–95 °C and stirred at 85–95 °C for 1 hour. During the heating process, the brown mixture turned into a black mixture. The dark mixture was slowly cooled to 20-25°C over 4 hours. The reaction was monitored by quenching a portion of the reaction mixture into piperidine and by monitoring the disappearance of piperidine amide via HPLC until (1'): the area / area% of piperidine amide < 1.9). After the reaction was completed by HPLC, the dark mixture was filtered online into a 20 L rotary evaporator flask. The reactor was rinsed with toluene (3.9 L) and filtered online into a 20 L rotary evaporator flask. The filtered reaction mixture was concentrated under reduced pressure until most of the toluene was distilled off, yielding 4.4 kg of acyl chloride as a dark oil.

[0414] In a 100L jacketed reactor, potassium carbonate (7.06 kg, 51.1 mol, 1.5 equivalents) and water (31 L) were stirred. The reaction solution was cooled to -10 to 10°C. N,O-dimethylhydroxylamine hydrochloride (3.93 kg, 40.3 mol, 1.18 equivalents) was added to the reactor, followed by dichloromethane (39 L). The reaction mixture was cooled to -10 to 0°C. Then, under vigorous stirring, the above-mentioned dark oily acyl chloride intermediate (4.4 kg) was slowly added to the 100L jacketed reactor containing N,O-dimethylhydroxylamine in dichloromethane, while maintaining the reaction temperature between -10 and 0°C for 30 minutes. The addition was slightly exothermic, resulting in a brown mixture. The reaction mixture was stirred at -10 to 0°C for 20 minutes. Then, the temperature was raised to 15 to 25°C and stirred for 10 minutes. The layers were separated, the bottom organic layer was collected, and the top aqueous layer was extracted with dichloromethane (7.7 L). The aqueous layer was discarded, and the combined organic layers were transferred to a 100 L jacketed reactor and washed with 15 wt% sodium chloride solution (11.6 L). The layers were separated, and the bottom organic layer was collected. The top aqueous layer was extracted with dichloromethane (3.9 L). The aqueous layer was discarded, and the combined organic layers were concentrated under reduced pressure until most of the dichloromethane was removed. Tetrahydrofuran (7.7 L) was added to the dark oily substance, and the mixture was concentrated under reduced pressure until most of the tetrahydrofuran was removed, yielding intermediate (2'), a dark oily substance (4.6 kg, yield 86%, KF water content 0.01 wt%, purity 98.9%) (by HPLC).

[0415] ii): Alkylation of compound (2') and ethyl propargylate yields (E)-4-(isoxazo-3-yl)-2-(methoxy) (Methyl)amino)-4-oxobut-2-enoic acid ethyl ester (3')

[0416] Intermediate (2') (2.99 kg, 19.15 mol, 1.0 equivalent), ethyl propargyl ester (2.08 kg, 21.2 mol, 1.1 equivalent), and anhydrous THF (15 L) were mixed in a 50 L round-bottom flask. The reaction mixture was cooled to -70°C to -60°C using a mechanical stirrer and a digital thermometer. Then, a THF solution of bis(trimethylsilyl)amide (40 wt%, 9.52 kg, 21 mol, 1.1 equivalent) was slowly added through a feeding funnel while maintaining the reaction temperature at -65°C to -50°C for 1 hour and 30 minutes. After the addition, the reaction mixture was stirred below -55°C for 10 minutes. Then, 2N HCl (10.7 L, 21.6 mol, 1.14 equivalent) was added over 2 minutes. The reaction was quenched while maintaining the reaction temperature below 20°C (exothermic to -65°C to 18°C).

[0417] Separately, ethyl acetate (39 L) was pre-added to a 100 L jacketed reaction vessel, and the above reaction mixture from a 50 L round-bottom flask was rapidly transferred to the 100 L jacketed reaction vessel containing ethyl acetate. 20% citric acid (10.5 L, 10.93 mol, 0.57 equivalent) was added to adjust the batch pH to 4-5 and stirred for 5 minutes. The bottom aqueous layer was discarded, and the top ethyl acetate layer was collected and washed twice with 15 wt% sodium chloride solution (9.0 L each time). The organic layer was filtered online and concentrated to a volume of 9.0 L under reduced pressure. Ethanol (9.0 L) was added, and water was removed by azeotropic extraction under reduced pressure to a volume of 9.0 L, yielding 8.1 kg of crude product (3') as a dark brown oil in ethanol. 1 H-NMR analysis showed that 3.59 kg yielded 74%.

[0418] iii): Compound (3') is cyclized with 2-fluorobenzylhydrazine to give 1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H- Pyrazole-3-carboxylic acid ethyl ester (4') 2-Fluorobenzylhydrazine (3.234 kg, 18.3 mol, 1.3 equivalents), water (0.9 L), and anhydrous ethanol (7.2 L) were mixed in a 100 L jacketed reaction vessel. The reaction solution was cooled to 10–25 °C. Separately, potassium carbonate (1.27 kg, 9.19 mol, 0.65 equivalents) was added to a suitable reaction vessel and dissolved in water (1.8 L). The potassium carbonate solution was then added to the 100 L jacketed reaction vessel containing the 2-fluorobenzylhydrazine solution at 15–25 °C, followed by the addition of anhydrous ethanol (25.2 L). The reaction solution was cooled to 10–20 °C, and intermediate (3') (3.59 kg, 14.12 mol, 1.0 equivalents) in anhydrous ethanol was added over 5 minutes via a feeding funnel. The temperature was kept below 30 °C. This addition was slightly exothermic. After stirring at 15 to 25 °C for at least 12 hours, the reaction was completed by HPLC (area / area% (3'): (4') = 0.7). HCl (1.53 L, 37 wt%, 18.4 mol, 1.3 equivalent) was added to the reaction mixture over 1 minute. The batch temperature was exothermic from 20 °C to 38 °C. The mixture was cooled to 0 to 5 °C over 2 hours and stirred at 0 to 5 °C for 1 hour. The resulting slurry was filtered, and the filter cake was washed with a mixture of ethanol (11.5 L) and water (2.9 L), and then washed with water (28.7 L). The filter cake was dried under high vacuum at 40 °C for 16 hours to give intermediate (4'), a grayish-white solid (2.538 kg, 57% yield, HPLC purity 98.8%).

[0419] iv): Amination of compound (4') yields 1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazole-3-formamidinium hydrochloride (5'B).

[0420] An aqueous solution of ammonium chloride (1.39 kg, 26.0 mol, 3.8 equivalents) and toluene (34.1 L) were mixed in a 100 L jacketed reaction vessel. Trimethylaluminum (2 M, 12 L, 24 mol, 3.5 equivalents) in toluene was slowly added through a feeding funnel while maintaining the reaction temperature at 20–40 °C for 2 hours (Note: methane gas was observed to escape during the addition). The reaction mixture was stirred for at least 30 minutes at 20–40 °C. Toluene (6.5 L) intermediate (4') (2.16 kg, 6.85 mol, 1.0 equivalents) as a slurry was added to the reaction mixture in a single batch at 20–40 °C. The reaction mixture was heated to 70–80 °C and maintained for 30 minutes. Then, it was heated to 100–110 °C over 30 minutes and maintained at 100–110 °C for 3 hours. The reaction was confirmed by HPLC (I-4: ND vs. I-5). The reaction mixture was cooled to 20–40°C, and methanol (2.94 L, 72.6 mol, 10.6 equivalents) was slowly added through a feeding funnel while maintaining the reaction temperature at 20–40°C for 1 hour. (Note: A very exothermic quenching and significant gas escape were observed). A very thick slurry was obtained. Then, 3N HCl (26.3 L, 78.9 mol, 11.5 equivalents) was slowly added through a feeding funnel while maintaining the reaction temperature at 20–45°C. The mixture was heated to 82–85°C and stirred at 82–85°C for 10 minutes. A clear two-phase mixture was obtained. The mixture was cooled to 20–25°C over 2 hours and stirred at 20–25°C for 30 minutes. The resulting slurry was filtered, and the filter cake was washed with water (10.8 L). The filter cake was vacuum dried at 60°C for 16 hours to obtain intermediate (5'B), which was a grayish-white solid (2.015 kg, 91% yield, HPLC purity 96%).

[0421] v): Compound (5'B) is cyclized with diethyl fluoromalonate to give 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isooxa) (-3-yl)-1H-pyrazol-3-yl)pyrimidin-4,6-diol (6')

[0422] Intermediate (5'B) (3.34 kg, 10.38 mol, 1.0 equivalent), methanol (33.4 L), and diethyl fluoromalonate (2.95 L, 3.33 kg, 18.69 mol, 1.8 equivalent) were mixed in a 100 L jacketed reactor. A methanol solution of sodium methoxide (5.4 M, 8.75 L, 47.2 mol, 4.5 equivalent) was added over 1 hour and 30 minutes. The reaction temperature was maintained at 20–30 °C using a feeding funnel. The reaction mixture was stirred at 20–30 °C for 30 minutes, resulting in a light suspension. The reaction was confirmed by HPLC (I-5: ND vs. I-6). 1.5 N HCl (34 L, 51 mol, 4.9 equivalent) was added over 1 hour and 20 minutes using a feeding funnel, maintaining the reaction temperature at 20–30 °C. A white suspension was obtained. The pH of the reaction mixture was ~1 using pH paper. The slurry was stirred at 20 to 30 °C for 30 minutes. The filtered slurry was washed with a pre-mixed mixture of methanol and water (8.35 L / 8.35 L) and water (16.7 L), and then with acetonitrile (10 L). The filter cake was dried under vacuum at 60 °C for 16 hours to give intermediate (6'), a grayish-white solid (3.76 kg, 98% yield, HPLC purity >99%).

[0423] vi): The chlorination reaction of compound (6') produces 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl) y(7')-1H-pyrazole-5-yl)isoxazole

[0424] Intermediate (6') (3.6 kg, 9.695 mol, 1.00 equivalent), acetonitrile (50.4 L), and N,N-dimethylaniline (1.98 L, 15.6 mol, 1.6 equivalent) were mixed in a 100 L jacketed reactor equipped with a nitrogen inlet, thermocouple, condenser, feed funnel, and top stirrer. The mixture was then heated to 70 to 80 °C. Phosphoryl chloride (5.44 L, 8.95 kg, 58.37 mol, 6.0 equivalent) was added over 1 hour and 40 minutes through the feed funnel. The reaction temperature was maintained at 70 to 80 °C. The reaction mixture was stirred at 75 to 80 °C for 21 hours to obtain a brown solution. The reaction was confirmed by HPLC (area / area % (6'): (7')). The reaction mixture was cooled to 0 to 5 °C over 40 minutes. The solid precipitated at 28 to 30 °C under vigorous stirring. Water (39.6 L) was slowly added over 2 hours and 20 minutes via a feeding funnel. The reaction temperature was maintained between 0 and 10 °C. The slurry was stirred at 0 to 5 °C for 30 minutes. The resulting slurry was filtered through an 18-inch Buchner funnel. A solution of acetonitrile (9 L) and water (9 L) was mixed in the reactor, cooled to 10 to 15 °C, and transferred to a filter to wash the filter cake. Water (18 L) was cooled to 16 °C in the reactor and transferred to a filter to wash the filter cake. The wet filter cake was dried on the filter for 21 hours, and then vacuum dried at 50 °C for 50 hours until constant weight was obtained, yielding intermediate (7'), a grayish-white solid (3.755 kg, 95% yield, HPLC purity 99%).

[0425] vii): Replacing compound (7') with a methanol salt yields 3-(3-(4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)-1- (2-Fluorobenzyl)-1H-pyrazole-5-yl)isoxazole (8')

[0426] Methanol (45 L) and a methanol solution of sodium methoxide (2.02 L, 5.4 M, 10.91 mol, 1.19 equivalents) were mixed in a 100 L jacketed reaction vessel equipped with a nitrogen inlet, thermocouple, condenser, and top stirrer. The reaction mixture was heated to 23 to 27 °C. Intermediate (7') (3.755 kg, 9.2 mol, 1.0 equivalents) was added to the reaction mixture in small portions (40 to 60 g per portion) over 1 hour and 30 minutes. The reaction temperature was maintained at 23 to 27 °C. The slurry was stirred at 15 to 27 °C for 1 hour. The reaction was completed by HPLC (area / area% (7'): (8') = 1.8). The slurry was filtered through an 18-inch Buchner funnel. Methanol (7.5 L) was added to the reactor and then transferred to a filter to wash the filter cake. The filter cake was washed with water (11.3 L) and then with methanol (7.5 L). The wet filter cake was dried on a filter for 1 hour, and then vacuum dried at 40°C for 18 hours until constant weight was obtained to obtain intermediate (8'), which was a grayish-white solid (3.59 kg, 97% yield, HPLC purity 96.4%).

[0427] viii): Hydrogenation of compound (8') yields 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)- 1H-pyrazole-5-yl)isoxazole (9')

[0428] Intermediate (8') (1.87 kg, 4.63 mol, 1.0 equivalent), palladium (10% on activated carbon, nominally 50% wetted water, 0.188 kg, 87 mmol, 0.02 equivalent), tetrahydrofuran (26.2 L), and triethylamine (1.03 L, 7.39 mol, 1.6 equivalent) were mixed in a 30 L jacketed reaction vessel equipped with a nitrogen inlet, thermocouple, condenser, and top stirrer. Nitrogen was bubbled into the reaction mixture through a Teflon tube over 24 minutes. The reaction was carried out at 15 to 30 °C. The mixture was then heated to 40 to 50 °C and hydrogen was bubbled into the reaction mixture through a Teflon tube over 3 hours while maintaining the reaction temperature at 40 to 50 °C. The reaction was completed by HPLC (area / area% (8'): (9') = 1.7). Nitrogen was then bubbled into the reaction mixture through a Teflon tube over 25 minutes. The mixture was heated to 45-50°C at 40-50°C and then filtered. The reaction mixture was hot-filtered using a Hyflo Supercel filter. Tetrahydrofuran (11.2 L) was added to the reactor, heated to 45°C, and transferred to a filter to wash the filter cake. The filtrate was concentrated under reduced pressure to a volume of 9.4 L to obtain a slurry, which was then solvent-exchanged from tetrahydrofuran to methanol under reduced pressure by continuous addition of methanol (22.5 L). The final volume after solvent exchange was 11.2 L, and the tetrahydrofuran content was confirmed to be <1 wt% by 1H-NMR. The resulting slurry was filtered through an 18-inch Buchner funnel, and the filter cake was washed with methanol (3.7 L). The wet filter cake was dried on the filter for 25 minutes. It was then dried under vacuum at 40°C for 4 hours until constant weight was obtained to give intermediate (9'), a white solid (1.54 kg, 90% yield, HPLC purity 98.4%).

[0429] ix): Demethylation of compound (9') yields 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H- Pyrazol-3-yl)pyrimidin-4-ol (10')

[0430] Intermediate (9') (4.44 kg, 12.0 mol, 1.0 equivalent), methanol (64.4 L), and concentrated hydrochloric acid (4.88 L, 37 wt%, 59.4 mol, 4.95 equivalent) were added to a 75 L jacketed reaction vessel equipped with a nitrogen inlet-outlet, thermocouple, condenser, and top-mounted stirrer. The mixture was heated to 62-65 °C and dissolved at 63 °C. The reaction mixture was then stirred at 62-65 °C for 20 hours to obtain a slurry. The reaction was completed by HPLC (area / area% (9'): (10') = 0.4). The slurry was cooled to 20-25 °C over 50 minutes and held for 45 minutes. The resulting slurry was filtered through an 18-inch Buchner funnel. Methanol (13.3 L) was added to the reactor and then transferred to a filter to wash the filter cake. The wet filter cake was dried on the filter for 1 hour and 30 minutes. The solid was then vacuum dried at 40°C for 8 hours until constant weight was obtained to give intermediate (10'), which was a white solid (4.11 kg, 96% yield, HPLC purity 99.7%).

[0431] x): Chlorinated compound (10') yields 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyridine (Azol-5-yl)isoxazole (Formula IV)

[0432] Intermediate (10') (2.66 kg, 7.48 mol, 1.0 equivalent), acetonitrile (37.2 L), and N,N-dimethylaniline (1.41 L, 1.348 kg, 11.12 mol, 1.49 equivalent) were mixed in a 100 L jacketed reaction vessel equipped with a nitrogen inlet, thermocouple, feeding funnel, condenser, and top stirrer. The slurry was heated to 70-80 °C. Phosphorus oxychloride (2.1 L, 3.46 kg, 22.5 mol, 3.0 equivalent) was added over 1 hour and 20 minutes through the feeding funnel. The reaction temperature was maintained between 70 and 80 °C. The mixture was stirred at 75-80 °C for 2 hours to obtain a green solution. The reaction was completed by HPLC (area / area % (10'): formula IV = 0.2). The mixture was then cooled to -5 to 5 °C over 1 hour. Water (18.6 L) was slowly added over 40 minutes. The reaction temperature was maintained at -5 to 5°C using a feeding funnel. The slurry was stirred at 0 to 5°C for 30 minutes, then filtered through an 18-inch Buchner funnel. Acetonitrile (6.6 L) and water (6.6 L) were added to the reactor and stirred for 3 minutes. The mixture was then transferred to a filter to wash the cake. The water (6.6 L) was cooled to 13°C in the reactor and transferred to a filter to wash the filter cake. The wet filter cake was dried on the filter for 2 hours, then vacuum dried at 40°C for 16 hours to give intermediate formula IV, a grayish-white to pink solid (2.67 kg, 96% yield, 99.3% purity, HPLC).

[0433] a): Amination of compound (12) yields 2-(aminomethyl)-1,1,1,3,3,3-hexafluoroprop-2-ol (14).

[0434] Ammonium hydroxide (28-30% aqueous solution, 7.7 L, 57.3 mol, 4.7 equivalents) and methyl tert-butyl ether (7.7 L) were added to a 30 L jacketed reactor equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet, feed funnel, and condenser. (Note: The condenser temperature was set below -10 °C to minimize the evaporation of ammonium hydroxide). The mixture was heated to 23-28 °C. 2,2-bis(trifluoromethyl)ethylene oxide ((12), 2.2 kg, 12.22 mol, 1.0 equivalents) was added over 1 hour through the feed funnel while maintaining the reaction temperature between 20 and 30 °C. After addition, the reaction mixture was stirred at 20-30 °C for 3 hours. The layers were separated for 30 minutes. The bottom layer was extracted twice with methyl tert-butyl ether (2 × 7.7 L). The aqueous layer was discarded, and the combined organic layers were concentrated under reduced pressure to a volume of 6.6 L. 11 L of methyl tert-butyl ether was continuously added, and the mixture was concentrated to a volume of 6.6 L to obtain 2.42 L of dimethyl sulfoxide. Addition was then continued until most of the methyl tert-butyl ether was distilled to give 4.95 kg of a dimethyl sulfoxide solution of compound I-13, which has a content of 1.887 kg (14), based on 1 H-NMR determination (1.887kg, via) 1 (H-NMR determination, 78% yield).

[0435] b): Coupling of formula IV and compound 14 yields 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl) 5-(isoxazo-3-)(1H)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)prop-2-ol (Compound I)

[0436] Intermediate formula IV (1.51 kg, 4.04 mol, 1.0 equivalent), dimethyl sulfoxide (9.6 L), Hunig base (1.42 L, 8.08 mol, 2.0 equivalent), and a solution of the above intermediate (14) in dimethyl sulfoxide (4.95 kg total weight, 1.887 kg, 9.58 mol, 2.37 equivalent) were added to a 100 L reactor. The reaction mixture was heated to 125 to 130 °C and maintained for 3.5 h. The reaction was completed by HPLC (area / area % formula IV: compound I = 1.0). The reaction mixture was then cooled to 15 to 25 °C. Methyl tert-butyl ether (44 L) and water (18 L) were then added to the reaction mixture. The organic layer was washed with 1 N HCl (10.6 L, 10.6 mol, 2.6 equivalent) and then with water (9.1 L). The organic layer was then concentrated under reduced pressure to a volume of 13.6 L. 7.6 L of methyl tert-butyl ether was added and the mixture was further concentrated under reduced pressure to a volume of 13.6 L. The organic layer was then transferred to a 100 mL reactor via online filtration. 4.5 L of methyl tert-butyl ether was added to the 100 L reactor via a delivery line to bring the volume to 18.1 L. The MTBE solution was heated to 50–56 °C and heptane (18.1 L) was added. The mixture was stirred in a funnel for 1 hour and 30 minutes while maintaining the reaction temperature above 50 °C to obtain a slurry. The resulting slurry was cooled to 15–25 °C and stirred at 15–25 °C for 30 minutes. The slurry was filtered through an 18-inch Buchner funnel, and the filter cake was washed with a premixed solution of MTBE and heptane (4.5 L / 9.0 L). The filter cake was dried on a filter for 1 hour and then dried under vacuum at 40 °C for 4 hours to give compound I as a grayish-white solid (1.625 kg, 75% yield).

[0437] Example 3A: Alternative route for synthesizing compound I (small-scale)

[0438] A) Replacing (7') with an amine (14) yields 2-(((6-chloro-5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazole)-3-yl)pyrimidin-4-yl)amino)methyl)-1,1,1,3,3,3-hexafluoroprop-2-ol (Formula X).

[0439]

[0440] Compound (7') (0.2 g, 0.5 mmol, 1.0 equivalent), amine (14) (0.25 g, 1.3 mmol, 2.6 equivalent), and dimethyl sulfoxide (2 mL) were added to a reaction flask equipped with a magnetic stirrer and a digital thermometer. The reaction mixture was heated to 57–63 °C and stirred at 57–63 °C for 24 hours. The reaction was completed by HPLC. Acetonitrile (4 mL) was added at 57–63 °C, followed by water (3 mL). The resulting slurry was filtered and dried under vacuum at 35–45 °C over 16 hours to give formula X, a grayish-white solid (0.2 g, 72% yield, HPLC purity 99%). 1 H-NMR (500MHz, DMSO-d6) δppm9.11 (d, J = 1.53, 1H); 8.33 (s, 1H); 8.28 (t, J = 6.03, 1H); 7.48 (s, 1H); 7.31-7. 36 (m, 1H); 7.18-7.25 (m, 2H); 7.10 (t, J = 7.55, 1H); 6.97 (t, J = 7.17, 1H); 5.89 (s, 2H); 4.16 (d, J = 5.95, 2H).

[0441] Example 3B: Alternative Pathways for the Synthesis of Compound I (Large-Scale)

[0442] (A) Replacing (7') with an amine (14) yields 2-(((6-chloro-5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazole)-3-yl)pyrimidin-4-yl)amino)methyl)-1,1,1,3,3,3-hexafluoroprop-2-ol (Formula X).

[0443] Compound (7') (22.0 g, 53.9 mmol, 1.0 equivalent), amine (14) (24.4 g, 124 mmol, 2.3 equivalent), and dimethyl sulfoxide (220 mL) were added to a reaction flask equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 80–84 °C and stirred at 80–84 °C for 4–8 hours. The reaction was completed by HPLC. Acetonitrile (330 mL) was added over 5 minutes to dilute the reaction mixture. Water (264 mL) was then added over 5 minutes at 65–72 °C. The resulting slurry was cooled to 40–50 °C over 1 hour and stirred at 40–50 °C for 2 hours. The slurry was filtered, the solid filter cake was washed with acetonitrile / water (110 mL, 1 / 1 v / v), and dried under vacuum at 35–45 °C for 16 hours to give compound X as a grayish-white solid (27.9 g, 91% yield, 99% HPLC purity). 1H-NMR (500MHz, DMSO-d6) δppm9.11 (d, J = 1.53, 1H); 8.33 (s, 1H); 8.28 (t, J = 6.03, 1H); 7.48 (s, 1H); 7.31-7. 36 (m, 1H); 7.18-7.25 (m, 2H); 7.10 (t, J = 7.55, 1H); 6.97 (t, J = 7.17, 1H); 5.89 (s, 2H); 4.16 (d, J = 5.95, 2H).

[0444] Example 4: An alternative method for synthetic IV

[0445] 1) Replacing the intermediate (7') with a hydroxyl group yields 6-chloro-5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazol-3-yl)pyrimidin-4 alcohol (intermediate 8'B).

[0446]

[0447] Intermediate (7') (0.41 g, 1.0 mmol, 1.0 equivalence), 1 N NaOH (2.2 mL, 2.2 mmol, 2.2 equivalence), tetrabutylammonium hydroxide aqueous solution (0.1 g, 40 wt%, 0.15 mmol, 0.15 equivalence), and tetrahydrofuran (4 mL) were added to a reaction flask equipped with a magnetic stirrer and a digital thermometer. The reaction mixture was heated to 55–60 °C and stirred at 55–60 °C for 2 hours. The reaction was completed by HPLC. 1 N HCl (3 mL) was added at 45–60 °C, followed by methyl tert-butyl ether (4 mL). The resulting slurry was cooled to 20–25 °C and stirred at 20–25 °C for 20 minutes. The slurry was filtered and dried under vacuum at 35–45 °C over 16 hours to give intermediate (8'B) as a grayish-white solid (0.29 g, 73% yield, HPLC purity 99%). 1 H-NMR (500MHz, DMSO-d6) δppm13.68 (br, s, 1H); 9.11 (d, J = 1.68Hz, 1H); 7.69 (s, 1H); 7.29-7.39 (m, 1H); 7.17-7.29 (m, 2H); 7.12 (td, J = 7.55, 1.07Hz, 1H); 6.97 (td, J = 7.71, 1.53Hz, 1H); 5.93 (s, 2H).

[0448] 2) Hydrogenation of intermediate (8'B) to provide 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazo-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol intermediate (10')

[0449]

[0450] Intermediate (8'B) (0.1 g, 0.26 mmol, 1.0 equivalent), palladium (10% on activated carbon, nominally 50% wetted water, 5 mg), triethylamine (0.038 g, 0.38 mmol, 1.5 equivalent), tetrahydrofuran (2 mL), and methanol (1 mL) were added to a 25 mL round-bottom flask equipped with a magnetic stirrer. The reaction mixture was hydrogenated under a hydrogen balloon at 20–25 °C for 16 hours. HPLC showed that intermediate (10') formed in the crude reaction mixture with a purity of 73%.

Claims

1. A process for the preparation of a compound of Formula IV: ###0001### IV the process comprising the steps of: i) amidating an initial starting material (1') ###0002### 1' in a suitable non-protic organic solvent in the presence of an appropriate amount of a suitable catalyst at a suitable temperature with an appropriate amount of oxalyl chloride or an equivalent reagent; followed by the addition of an appropriate amount of N,0-dimethylhydroxylamine hydrochloride in a suitable mixture of water and a non-protic organic solvent in the presence of an appropriate excess of a suitable base at a suitable temperature to provide an amide (2') ###0003### ii) alkylating the intermediate amide (2') with an appropriate amount of ethyl propiolate in a suitable non-protic organic solvent in the presence of an appropriate amount of a suitable base at an appropriate temperature to provide a β-enaminoketo ester (3') ###0004### iii) condensing the β-enaminoketo ester (3') with an appropriate amount of a hydrazine of the formula NH2NH-CH2-(2-fluorophenyl) or its HC1 salt, optionally in the presence of an appropriate amount of a suitable base, in a suitable protic solvent at a suitable temperature to provide a pyrazole ester intermediate (4') ###0005### iv) aminating the pyrazole ester intermediate (4') with an appropriate amount of ammonium chloride in an appropriate non-protic organic solvent in the presence of an appropriate amount of trimethylaluminum at an appropriate temperature to provide a amidine (5'A) or upon treatment with an appropriate aqueous inorganic acid to provide an amidine salt (5'B) ###0006### v) condensing the amidine (5'A) or amidine salt (5'B) with an appropriate amount of fluoromalonate, optionally in the presence of an appropriate amount of a suitable base, in a suitable protic solvent at a suitable temperature or upon treatment with an appropriate amount of a suitable inorganic acid to provide a diol (6') ###0007### vi) chlorinating the diol (6') with an appropriate amount of phosphorus oxychloride in the presence of an appropriate amount of a suitable base in a suitable non-protic organic solvent at a suitable temperature to provide a dichloropyrimidine (7') ###0008### vii) monomethoxylating the dichloropyrimidine (7') with an appropriate amount of sodium methoxide in an appropriate protic solvent at an appropriate temperature to provide a methoxypyrimidine (8') ###0009### viii) dechlorinating the methoxypyrimidine (8') with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst in the presence of an appropriate amount of a suitable base in an appropriate organic solvent at a suitable temperature to provide a fluoromethoxypyrimidine (9') ###0010### ix) deformylating the fluoromethoxypyrimidine (9') by reacting it with an appropriate amount of an aqueous acid in an appropriate protic solvent at a suitable temperature to provide an alcohol (10') ###0011### x) chlorinating the alcohol (10') with an appropriate amount of phosphorus oxychloride and optionally an appropriate amount of a suitable base in a suitable non-protic organic solvent at a suitable temperature. wherein 2. A process for the preparation of a compound of Formula IV: ###0012### IV the process comprising the steps of: 1) monohydroxylating a dichloropyrimidine (7') ###0013### 7' in a mixture of an appropriate non-protic solvent and a protic solvent in the presence of an appropriate amount of a suitable phase transfer catalyst at a suitable temperature with an appropriate amount of sodium hydroxide to provide a hydroxypyrimidine (8'B) ###0014### 8'B 2) dechlorinating the hydroxypyrimidine (8'B) with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst in the presence of an appropriate amount of a suitable base in an appropriate organic solvent at a suitable temperature to provide a fluorohydroxypyrimidine (10') ###0015### ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ and ​ ​ wherein, ​ ​ ​ ​ and 3) chlorination of the alcohol (10') with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base in a suitable aprotic organic solvent at a suitable temperature; wherein the dichloropyrimidine (7') is prepared from the following steps: i) amidation of the starting material (1') at a suitable temperature in the presence of an appropriate amount of a suitable catalyst, with an appropriate amount of oxalyl chloride or an equivalent reagent in a suitable aprotic organic solvent; followed by addition of an appropriate amount of N,O-dimethylhydroxylamine hydrochloride in the presence of an appropriate excess of a suitable base in a mixture of a suitable aqueous and aprotic organic solvent at a suitable temperature to give the amide (2') ii) alkylation of the intermediate amide (2') with an appropriate amount of ethyl propiolate in the presence of an appropriate amount of a suitable base in a suitable aprotic organic solvent at a suitable temperature to give the β-enaminoketone ester (3') iii) condensation of the β-enaminoketone ester (3') with an appropriate amount of hydrazine of the formula NH2NH-CH2-(2-fluorophenyl) or its HC1 salt, optionally in the presence of an appropriate amount of a suitable base in a suitable protic solvent at a suitable temperature to provide the pyrazole ester intermediate (4') iv) amination of the pyrazole ester intermediate (4') with an appropriate amount of ammonium chloride in the presence of an appropriate amount of trimethylaluminum in a suitable aprotic organic solvent at a suitable temperature to give the amidine (5'A), or upon treatment with an appropriate aqueous inorganic acid to give the amidine salt (5'B) v) condensation of the amidine (5'A) or amidine salt (5'B) with an appropriate amount of fluoromalonate, optionally in the presence of an appropriate amount of a suitable base in a suitable protic solvent at a suitable temperature, or upon treatment with an appropriate amount of a suitable inorganic acid to give the diol (6') vi) chlorination of the diol (6') with an appropriate amount of phosphoryl chloride in the presence of an appropriate amount of a suitable base in a suitable aprotic organic solvent at a suitable temperature to give the dichloropyrimidine (7').

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