EA041479B1 - NEW METHODS FOR PRODUCING INTERMEDIATES FOR THE SYNTHESIS OF SOLUBLE GUANYLATE CYCLASE STIMULANTS - Google Patents

Description

Technical field

The present invention relates to novel methods for the preparation of intermediates useful in the synthesis of soluble guanylate cyclase (sGC) promoters. The present invention has the additional advantage that it includes effortless reaction conditions that are scalable for large scale production. The invention also provides new intermediate compounds useful in obtaining these compounds.

Background of the invention sGC is the major receptor for NO in vivo. sGC can be activated through both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine 5'-triphosphate (GTP) into the cGMP second messenger. Elevated cGMP levels, in turn, modulate the activity of downstream effectors, including protein kinases, phosphodiesterases (PDEs), and ion channels.

In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and through the sequential reduction of inorganic nitrates. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; constitutive neural NOS (nNOS or NOS I), which is involved in neurotransmission and long-term potentiation, and constitutive endothelial NOS (eNOS or NOS III), which regulates smooth muscle relaxation and blood pressure. Experimental and clinical evidence suggests that decreased NO concentrations, reduced NO bioavailability, and/or decreased sensitivity to endogenously produced NO contribute to the development of the disease.

NO-independent, heme-dependent sGC stimulators showed several important distinguishing characteristics compared to NO-independent, heme-independent sGC activators. These include the crucial dependence of their activity on the presence of a reduced prosteric heme residue, strong synergistic activation of the enzyme when combined with NO, and stimulation of cGMP synthesis by direct stimulation of sGC independent of NO. The benzylindazole compound YC-1 was the first sGC stimulant to be identified. Since then, additional sGC stimulants have been developed with increased potency and specificity for sGC.

Compounds that stimulate sGC in a NO-independent manner offer significant advantages over other current alternative therapies that target the aberrant NO pathway. There is a need to develop new sGC stimulators. There is also a need to develop efficient processes suitable for large-scale production for the synthesis of these new sGC stimulants and, in particular, for compounds of the formula. There is a need for efficient methods amenable to large scale production that provide stable sGC promoters in high purity and yields.

The essence of the invention

This document presents new methods for the preparation of compounds of formula II

F

Formula I

Where R ¹ is an unsubstituted 5-6 membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O and S;

R ² is phenyl substituted with up to three R ⁵ ; and each R ⁵ is independently selected from halogen.

New intermediates useful in the preparation of soluble guanylate cyclase (sGC) promoters are also disclosed herein.

Detailed description of the invention

The following will be a detailed description of certain embodiments of the present invention, examples of which are illustrated in the attached structures and formulas. While the invention will be described in conjunction with the listed embodiments, it should be understood that the invention is not limited to the listed embodiments. On the contrary, the invention embraces all alternatives, modifications and equivalents which may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and substances described in the present description, but includes any methods and substances similar or equivalent to those described in the present description, which can be used

- 1 041479 are called in the practice of the present invention. In the event that one or more of the included literature references, patents, or similar materials differ from or conflict with the present disclosure, including, but not limited to, certain terms, terms of use, methods described, and the like, the present disclosure takes precedence.

Definitions and general terminology.

For the purposes of the present invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, the CAS version, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, 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, M.B. and March, J., eds. John Wiley & Sons, New York: 2001, which are incorporated herein in their entirety by reference.

The selected substituents and combinations provided herein are only those that result in stable or chemically feasible compounds. Such variations and combinations will be apparent to those skilled in the art and can be determined without undue experimentation. The term stable, as used herein, refers to compounds that are substantially unchanged when subjected to conditions that enable them to be made, found, and in some embodiments, recovered, purified, and used for one or more of the purposes described herein. In some embodiments, a stable compound is one that is substantially unchanged when stored at or below 25° C., in the absence of moisture or other reactive conditions, for at least a week. A chemically feasible compound is a compound that can be obtained by a person skilled in the art on the basis of the information disclosed here, supplemented, if necessary, by appropriate knowledge in this field.

Where only one isomer is depicted and appropriately specified, structures herein are intended to also include all stereoisomeric (e.g., enantiomers, diastereomers, atropisomers, and cis-trans isomers) forms of the structure, e.g., R and S configurations. for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, individual stereochemical isomers as well as racemates and mixtures of enantiomers, diastereomers and cis-trans isomers (double bond or conformational) of the compounds of the present invention are within the scope of the present invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are also within the scope of the present invention. As an example, the substituent indicated below,

The present invention also includes isotopically labeled compounds that are identical to those described herein, with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. All isotopes of any particular atom or element are contemplated by the compounds within the scope of the present invention and their uses. Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 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, respectively. Some isotopically labeled compounds of the present invention (eg, ³ H and ¹⁴ C labeled) are used in compound and/or tissue substrate distribution assays. Tritium (ie ³ H) and carbon-14 (ie ¹⁴ C) labeled isotopes can be used to facilitate their production and detection. In addition, substitution with heavier isotopes such as deuterium (e.g., ² H) may confer certain therapeutic advantages as a result of greater metabolic stability (e.g., increased in vivo half-life or reduced dosing requirements) and therefore may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F are used in positron emission tomography (PET) assays to examine the degree of receptor occupancy by the substrate. The isotopically labeled compounds of the present invention can be prepared according to the following methods.

- 2 041479 soba, similarly to those described in the schemes and / or examples below in the present description, replacing the non-isotopically labeled reagent with an isotopically labeled reagent.

As used herein, the terms appropriate and suitable may be used interchangeably.

As used herein, if more than one substituent is provided at the same time, then each of these substituents is selected independently in each case. For example, if phenyl can be substituted with two of R ¹⁰⁰ and R ¹⁰⁰ is selected from halogen and methyl, then this means that each R ¹⁰⁰ is separately selected from halogen or methyl; for example, one R ¹⁰⁰ may be fluorine and the other may be methyl, or both may be chlorine, and so on.

The group may be substituted with up to Z substituents, where n is an integer. For example, if Z is 3, then the group may be substituted with 0, 1, 2, or 3 substituents. Unless otherwise noted, each of these Z's is always chosen independently.

As used herein, the term aryl (as in an aryl ring or aryl group) refers to a carbocyclic ring system that is aromatic and has one point of attachment to the rest of the molecule. An example of an aryl ring is phenyl.

The term heteroaryl (as heteroaromatic or heteroaryl group or heteroaryl ring) refers to a ring system that is aromatic and contains one or more heteroatoms that share a single point of attachment to the rest of the molecule. In some embodiments, the heteroaryl ring is a 5-6 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 monocycles: 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 (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (for example, 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.

The term ring atom refers to an atom, such as C, N, O, or S, that is part of the ring of a phenyl or heteroaryl ring. The ring atom to be substituted is a carbon or nitrogen ring attached to at least one hydrogen atom. Hydrogen may optionally be replaced by a suitable substituent group. The ring atom to be replaced does not include carbon or nitrogen ring atoms when the structure shows that they are already attached to one or more molecules other than hydrogen and there are no hydrogen atoms available for replacement. When a certain ring, group or chain is optionally substituted, it is to be understood that it may be substituted on any or some or all of its replaceable ring atoms.

A heteroatom refers to one or more oxygen, sulfur, or nitrogen atoms, including any oxidized form of nitrogen or sulfur, the quaternized form of any basic nitrogen, or a displaceable nitrogen of a heterocyclic or heteroaryl ring, such as N (as in 3,4-dihydro-2Hpyrrolyl), NH( as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).

As used herein, the term halogen or halo means F, Cl, Br, or I.

The term hydroxyl or hydroxy refers to -OH.

The term solvent, as used herein, refers to a single solvent or solvent mixture that results in the desired properties of the solvent mixture. For example, an aprotic organic solvent or an aprotic solvent as defined below may be toluene or a mixture of toluene and another aprotic solvent such as DMF. Thus, as used herein, the term aprotic organic solvent or aprotic solvent may also encompass a toluene/DMF mixture if the resulting mixture properties are the same as those of the aprotic solvent. As another example, the protic solvent, as defined below, may include water or a mixture of water and methanol.

As used herein, the term protic solvent is a solvent in which a hydrogen atom is bonded to a polar group such as oxygen (as in a hydroxyl group) or nitrogen (as in an amino group). In general terms, any solvent that contains a labile H+ is called a protic solvent. Molecules of such solvents easily donate protons (H+) to reagents. Conversely, aprotic solvents cannot readily donate hydrogen. Protic solvents are usually polar solvents as they have high dielectric constants and high polarity. Aprotic solvents are usually classified as either polar aprotic or non-polar (or apolar) aprotic depending on the values of their dielectric constants.

The terms aprotic solvent and aprotic organic solvent are used

- 3 041479 interchangeable.

Some common characteristics of protic solvents are the ability to exhibit hydrogen bonds having acidic hydrogens (although they can be very slightly acidic, such as ethanol) and that they are capable of dissolving salts. Non-limiting examples include water, most alcohols (eg, methanol, ethanol, propanol, butanol, isopropanol, isobutanol, etc.), formic acid, hydrogen fluoride, nitromethane, acetic acid, and ammonia.

Some common characteristics of aprotic solvents are that they can accept hydrogen bonds, do not have acidic hydrogen, and are only occasionally able to dissolve salts. These criteria are relative and very qualitative. The acidity range is recognized for aprotic solvents. Their ability to dissolve salts is highly dependent on the nature of the salt.

Polar aprotic solvents can usually dissolve salts. They lack acidic hydrogen. Therefore, they are not hydrogen bond donors. These solvents usually have intermediate dielectric constants and polarities. Although this precludes the use of the term polar aprotic, IUPAC describes such solvents as having both high dielectric constants and high dipole moments, an example of which is 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).

Apolar or nonpolar aprotic solvents generally have small dielectric constants. Some examples of non-polar or non-polar aprotic (organic) solvents are hexane, pentane, decane and other alkanes, benzene, toluene, 1,4-dioxane, chloroform, ethers such as diethyl ether, dichloromethane, dichloroethane, etc.

The term equivalent, as used herein, when discussing the amount of reagent used, refers to the molar equivalent. For example, one equivalent of reactant A for every equivalent of reactant B means that the reaction uses one mole of reactant A for every mole of reactant B. A mole is defined as the number that results when the total mass of the substance used is divided by the molecular weight of said substance, both masses are in the same units (eg grams).

Compounds of the invention are defined herein by their chemical structures and/or chemical names. If a compound is referred to by both its chemical structure and its chemical name, and the chemical structure and chemical name do not match, the chemical structure determines the identity of the compound.

Substituents R ⁿ are generally defined when introduced and retain this definition throughout the description and in all independent and dependent claims.

Embodiments of the invention.

New methods for preparing compounds of formula II are described herein.

For a compound of formula II, the following definitions apply:

R ¹ is an unsubstituted 5-6 membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O and S;

R ² is phenyl substituted with up to three R ⁵ ; and each R ⁵ is independently selected from halogen.

In one aspect, the present document describes a process for the preparation of a compound of formula II below, said process comprising the steps

i) amidation of the starting material (1) o

JJ

R ¹ ΌΗ (1) by reacting it with oxalyl chloride in a mixture of water and an aprotic organic solvent, in the presence of a catalyst; then with N,O-dimethylhydroxylamine hydrochloride in the presence of a base in a mixture of water and an aprotic solvent to give the amide (2)

- 4 041479

where R ¹ is an unsubstituted 5-6 membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O and S;

ii) alkylating the amide intermediate (2) with ethyl propiolate in an aprotic organic solvent in the presence of a base to give β-enaminoketoester (3)

iii) condensation of β-enaminoketoester (3) with hydrazine of the formula R ² -CH ₂ -NH-NH ₂ or its HCl salt in the presence of a base in a protic solvent to obtain an intermediate pyrazole ester (4)

where R ² is phenyl substituted with up to three R ⁵ , where each R ⁵ is independently halogen;

iv) amination of the pyrazole ester intermediate (4) with ammonium chloride in the presence of trimethylaluminum in an aprotic organic solvent to give the amidine (5A) or after treatment with an aqueous mineral acid solution of the amidine salt (5B):

v) condensation of an amidine (5A) or an amidine salt (5B) and a fluoromalonate in the presence of a base in a protic solvent to give, after treatment with a mineral acid, a diol (6)

vi) chlorination of diol (6) with phosphoryl chloride, in an aprotic organic solvent in the presence of a base to obtain dichloropyrimidine (7)

- 5 041479 vii) monomethoxylation of dichloropyrimidine (7) with sodium methoxide in a protic solvent to obtain methoxypyrimidine (8)

viii) dechlorination of methoxypyrimidine (8) with hydrogen gas in the presence of a metal catalyst, in the presence of a base in an organic solvent to obtain fluoromethoxypyrimidine (9)

ix) demethylation of fluoromethoxypyrimidine (9) by reacting it with an aqueous acid solution in a protic solvent to obtain alcohol (10)

x) chlorination of alcohol (10) with phosphoryl chloride and a base in an aprotic organic solvent.

In another aspect, this document describes an alternative method for the synthesis of a compound of formula II, comprising the steps

1) monohydroxylation of dichloropyrimidine (7)

sodium hydroxide in a mixture of aprotic and protic solvent in the presence of a phase transfer catalyst to obtain hydroxypyrimidine (8B)

- 6 041479

2) dechlorination of hydroxypyrimidine (8B) with gaseous hydrogen in the presence of a metal catalyst, in the presence of a base in an organic solvent to obtain fluorohydroxypyrimidine (10)

3) chlorination of fluorohydroxypyrimidine alcohol (10) with phosphoryl chloride and a base in an aprotic organic solvent.

In some embodiments of the above methods for preparing a compound of formula II, for compounds of formula II and for intermediates (1)-(10) and (8B), R ¹ is isoxazolyl. In other embodiments, R ¹ is 3-isoxazolyl.

In other embodiments of the above methods for preparing a compound of formula II, for compounds of formula II and intermediates (1)-(10) and (8B), R ¹ is a 6-membered heteroaryl ring containing up to three ring nitrogen atoms. In some embodiments, R ¹ is pyridine or pyrimidine.

In some embodiments of the above methods for preparing a compound of formula II, for compounds of formula II of intermediates (4)-(10) and (8B) and hydrazine of formula R2-CH2NH-NH2 or its corresponding hydrochloride, ^R2 is a 6-membered heteroaryl optionally substituted up to three R ⁵ . In other embodiments, R ² is phenyl optionally substituted with up to three R ⁵ . In other embodiments, R ² is phenyl substituted with one R ⁵ . In additional embodiments, R ² is phenyl substituted with one R ⁵ and R ⁵ is halogen. In other embodiments, R ² is phenyl substituted with one R ⁵ and R ⁵ is fluorine. In other embodiments, R ² is 2-fluorophenyl. In still other embodiments, R ² is phenyl substituted with two R ⁵ . In still other embodiments, R ² is phenyl substituted with two R ⁵ , and each R ⁵ is independently selected from halogen. In still other embodiments, R ² is phenyl substituted with two R ⁵ , and each R ⁵ is fluorine.

In another aspect, this document describes a method for obtaining a compound of formula IV

including stages

i) amidating the starting material (1') by reacting it with oxalyl chloride in an aprotic organic solvent in the presence of a catalyst; then N,O-dimethylhydroxylαmine hydrochloride in the presence of a base in a mixture of water and an aprotic organic solvent to give the amide (2')

- 7 041479 ii) alkylating the amide intermediate (2') with ethyl propiolate in an aprotic organic solvent in the presence of a base to give β-enaminoketoester (3')

iii) condensation of the β-enaminoketoester (3') with a hydrazine of the formula NH ₂ NH-CH ₂ -(2-fluorophenyl) or its HCl salt in the presence of a base, in a protic solvent to give the pyrazole ester intermediate (4')

iv) amination of the pyrazole ester intermediate (4') with ammonium chloride in the presence of trimethylaluminum in an aprotic organic solvent to give the amidine (5'A) or after treatment with an aqueous mineral acid solution of the amidine salt (5'B):

v) condensation of an amidine (5'A) or an amidine salt (5'B) and a fluoromalonate in the presence of a base in a protic solvent to give, after treatment with a mineral acid, a diol (6')

vi) chlorination of diol (6') with phosphoryl chloride in an aprotic organic solvent in the presence of a base to give dichloropyrimidine (7')

- 8 041479 vii) monomethoxylation of dichloropyrimidine (7') with sodium methoxide in a protic solvent to obtain methoxypyrimidine (8')

viii) dechlorination of the methoxypyrimidine (8') with hydrogen gas in the presence of a metal catalyst, in the presence of a base in an organic solvent to obtain a fluoromethoxypyrimidine (9')

ix) demethylation of the fluoromethoxypyrimidine (9') by reacting it with an aqueous acid solution in a protic solvent to give an alcohol (10')

x) chlorination of the alcohol (10') with phosphoryl chloride and a base in an aprotic organic solvent.

In another aspect, this document describes an alternative method for the synthesis of the compounds of formula IV

including stages

- 9 041479

1) monohydroxylation of dichloropyrimidine (7')

sodium hydroxide in a mixture of aprotic and protic solvent in the presence of a phase transfer catalyst to obtain hydroxypyrimidine (8'B)

2) dechlorination of hydroxypyrimidine (8'B) with gaseous hydrogen in the presence of a metal catalyst, in the presence of a base in an organic solvent to obtain fluorohydroxypyrimidine (10')

3) chlorination of alcohol (10') with phosphoryl chloride and a base in an aprotic organic solvent.

For step i) regarding the synthesis of compounds of formula II or formula IV.

A suitable equivalent reagent for oxalyl chloride is, for example, thionyl chloride or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC).

The corresponding amount of oxalyl chloride or equivalent reagent is at least one equivalent of oxalyl chloride per equivalent of starting material (1) or starting material (1'). In some embodiments, the appropriate amount is from about 1 to about 3 equivalents. In other embodiments, the appropriate amount is from about 1 to about 2 equivalents. In still other embodiments, the appropriate amount is from about 1 to about 1.5 equivalents. In still other embodiments, the appropriate amount is from about 1.1 to about 1.3 equivalents. In still other embodiments, the corresponding amount is about 1.1 equivalents or about 1.2 equivalents.

A suitable aprotic organic solvent is, for example, toluene. Other suitable solvents are, for example, methylene chloride or tetrahydrofuran.

A suitable catalyst is DMF.

The appropriate amount of DMF is the catalytic amount, i.e. less than one equivalent of DMF for each equivalent of starting material (1) or starting material (1'). In some embodiments, the appropriate amount is from about 0.01 to about 0.09 equivalents. In other embodiments, it is from about 0.01 to about 0.07 equivalents. In yet other embodiments, it is from about 0.02 to about 0.07 equivalents. In still other embodiments, it is from about 0.04 to about 0.06 equivalents.

A suitable temperature for reacting the starting material (1) or starting material (1') with oxalyl chloride or thionyl chloride is from about 45° C. to about

- 10 041479

60°C. In some embodiments, a suitable temperature is from about 45°C to about 50°C. In other embodiments, this is a temperature of approximately 50°C.

A suitable temperature for reacting the starting material (1) or starting material (1') with EDAC is from about -10°C to about 25°C. In some embodiments, a suitable temperature is from about -10°C to about 20°C. In some embodiments, a suitable temperature is from about -10°C to about 0°C. In some embodiments, a suitable temperature is from about -10°C to about -5°C.

The corresponding amount of N,O-dimethylhydroxylamine hydrochloride is at least one equivalent of N,O-dimethylhydroxylamine hydrochloride for each equivalent of starting material (1) or starting material (1'). In other embodiments, the appropriate amount of N,O-dimethylhydroxylamine hydrochloride is from about 1 equivalent to about 2 equivalents for each equivalent of starting material (1) or starting material (1'). In other embodiments, it is from about 1 equivalent to about 1.5 equivalents. In other embodiments, it is from about 1 equivalent to about 1.2 equivalents. In other embodiments, it is from about 1.1 equivalents to about 1.2 equivalents.

A suitable base is, for example, K2CO3 or NaOH. Other suitable inorganic bases are, for example, NaHCO ₃ , KHCO ₃ , Et ₃ N or Hunig's base.

A suitable excess of said suitable base is at least 1.1 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride used. In some embodiments, the appropriate amount is from about 1.1 to about 5 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride. In some embodiments, the appropriate amount is from about 1.2 to about 5 equivalents of base per equivalent of N,O-dimethylhydroxylamine hydrochloride. In other embodiments, it is about 2 to about 3 equivalents. In still other embodiments, it is from 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 yet other embodiments, it is from about 1.5 to about 4 equivalents. In other embodiments, it is about 1.2 to about 2 equivalents.

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

A suitable solvent for a water/aprotic solvent mixture is, for example, dichloromethane (DCM). Other suitable solvents are, for example, ethyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran.

For step ii) regarding the synthesis of compounds of formula II or formula IV.

The corresponding amount of ethyl propiolate is at least one equivalent of ethyl propiolate per equivalent of intermediate (2) or intermediate (2'). In some embodiments, the appropriate amount of ethyl propiolate is from about 1 to about 2 equivalents. In other embodiments, it is from about 1 to about 1.8 equivalents. In other embodiments, it is from about 1 to about 1.6 equivalents. In yet other embodiments, it is from about 1.1 to about 1.5 equivalents. In yet other embodiments, it is about 1.1 equivalents. In yet other embodiments, it is about 1.5 equivalents.

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

A suitable temperature is from about -75°C to about -30°C. In some embodiments, a suitable temperature is from about -70°C to about -50°C. In some embodiments, a suitable temperature is from about -65°C to about -50°C. In other embodiments, a suitable

- 11 041479 the temperature is from about -65°C to about -55°C. In still other embodiments, a suitable temperature is from about -70°C to about -60°C.

A suitable base is, for example, sodium bis(trimethylsilyl)amide sodium (NaHMDS). Other suitable bases are, for example, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and lithium diisopropylamide.

The appropriate amount of a suitable base is from about 1 equivalent to about 1.65 equivalents for each equivalent of intermediate (2) or intermediate (2'). In some embodiments, it is from about 1 equivalent to about 1.5 equivalents. In some embodiments, it is from about 1 equivalent to about 1.3 equivalents. In other embodiments, it is from about 1.1 equivalents to about 1.65 equivalents. In other embodiments, it is from about 1.1 equivalents to about 1.5 equivalents. In still other embodiments, it is from about 1.1 equivalents to about 1.4 equivalents. In yet other embodiments, it is from 1.1 equivalents to about 1.3 equivalents.

For step iii) regarding the synthesis of compounds of formula II or formula IV.

The corresponding amount of hydrazine is at least one equivalent of hydrazine for each equivalent of intermediate (3) or intermediate (3'). In some embodiments, the appropriate amount of hydrazine is from about 1 equivalent to about 2 equivalents. In other embodiments, it is from about 1 equivalent to about 1.5 equivalents. In yet other embodiments, it is from about 1 equivalent to about 1.3 equivalents. In still other embodiments, it is from about 1.1 equivalents to about 1.4 equivalents. In yet other embodiments, it is from 1.1 equivalents to about 1.3 equivalents.

An optional suitable base is, for example, potassium carbonate (K2CO3). Other optional suitable organic bases in this step are, for example, sodium acetate (NaOAc), sodium carbonate (Na ₂ CO ₃ ), sodium hydrogen carbonate (NaHCO ₃ ) and potassium bicarbonate (KHCO3).

An appropriate amount of a suitable base is an amount that will neutralize the acid from hydrazine hydrochloride when the hydrochloride form of hydrazine is used. For example, from about 0.5 to about 1.1 equivalents of base for each equivalent of hydrazine hydrochloride. In other embodiments, the appropriate amount is about 0.5 to about 0.9 equivalents. In yet other embodiments, it is about 0.65 equivalents.

A suitable protic solvent is, for example, absolute ethanol or isopropanol. Other solvents that can be used in this step are, for example, dichloromethane, isopropanol and methanol.

A suitable temperature is from about 0°C to about 40°C. In other embodiments, a suitable temperature is from about 0°C to about 30°C. In some embodiments, it is from about 0°C to about 25°C. In other embodiments, it is from about 0°C to about 15°C. In other embodiments, it is from about 0°C to about 10°C. In yet other embodiments, it is from about 10°C to about 25°C.

For step iv) regarding the synthesis of compounds of formula II or formula IV.

The appropriate amount of ammonium chloride is from about 2.5 to about 6 equivalents of ammonium chloride for each equivalent of intermediate (4) or intermediate (4'). In some embodiments, the appropriate amount is from about 2.5 to about 5.5 equivalents. In some embodiments, the appropriate amount is from about 3.5 to about 4 equivalents. In other embodiments, the corresponding amount is about 3.8 equivalents. In still other embodiments, the corresponding amount is about 3.5 equivalents. In some embodiments, the appropriate amount is from about 4.5 equivalents to 5.0 equivalents. In other embodiments, the corresponding amount is about 4.8 equivalents.

The appropriate amount of trimethylaluminum is from about 2.5 to about 5.5 equivalents of trimethylaluminum for each equivalent of intermediate (4) or intermediate (4'). In some embodiments, the appropriate amount is from about 3.5 to about 5.5 equivalents. In other embodiments, the appropriate amount is from about 3.5 to about 4.5 equivalents. In other embodiments, the appropriate amount is from about 3.5 to

- 12 041479 approximately 4 equivalents. In other embodiments, the corresponding amount is about 3.5 equivalents.

A suitable aprotic organic solvent is, for example, toluene. Other suitable solvents are, for example, xylene.

A suitable temperature for toluene is from about 60°C to about 115°C. In some embodiments, a suitable temperature is from about 70°C to about 110°C. In other embodiments, it is from about 70°C to about 110°C. In yet other embodiments, it is from about 80°C to about 110°C. In yet other embodiments, it is from about 90°C to about 110°C.

A suitable temperature for xylene is from about 70°C to about 130°C.

A suitable aqueous mineral acid is concentrated HCl, for example 3N. HCl or 37 wt% HCl. Other suitable mineral acids that can be used to induce precipitation of intermediate (4) or intermediate (4') are, for example, H2SO ₄ .

For step v) regarding the synthesis of compounds of formula II or formula IV.

The corresponding amount of fluoromalonate is at least one equivalent of fluoromalonate for each equivalent of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In some embodiments, it is from about 1 equivalent to about 2 equivalents of the fluoromalonate. In yet other embodiments, it is from about 1.2 equivalents to about 2 equivalents. In yet other embodiments, it is from about 1.3 to about 1.9 equivalents. In other embodiments, it is from 1.4 to 1.6 equivalents. In other embodiments, it is between about 1.7 and 1.9 equivalents.

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

The appropriate amount of a suitable base is in excess of the amount of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In some embodiments, the appropriate amount is from about 3 to about 10 equivalents of NaOMe for each equivalent of intermediate (5A) or (5B) or intermediate (5'A) or (5'B). In other embodiments, the appropriate amount is from about 3 to about 6 equivalents. In yet other embodiments, it is from about 3 to about 5 equivalents. In yet other embodiments, it is from about 4 to about 5 equivalents. In yet other embodiments, the corresponding amount is about 4.5 equivalents.

A suitable protic solvent is, for example, MeOH.

Other suitable solvents that may be used in this step include EtOH.

A suitable temperature is from about 10°C to about 40°C. In some embodiments, a suitable temperature is from about 15°C to about 35°C. In other embodiments, a suitable temperature is from about 15°C to about 30°C. In other embodiments, a suitable temperature is from about 20°C to about 35°C. In still other embodiments, a suitable temperature is from about 20°C to about 30°C.

A suitable mineral acid is, for example, 1.5N. HCl. Other suitable mineral acids which may be used in this step include sulfuric acid.

The appropriate amount of mineral acid is at least in excess of the amount of suitable base used. In some embodiments, the appropriate amount is at least one equivalent of mineral acid for each equivalent of base (eg, NaOMe) used. In some embodiments, the appropriate amount is approximately 1.1 equivalents of mineral acid for each equivalent of base. In some embodiments, the appropriate amount of mineral acid is from about 4.5 to about 5.5 equivalents of mineral acid for each equivalent of intermediate (5B) or intermediate (5'B). In other embodiments, the appropriate amount of mineral acid is from about 4.7 to about 5.0 equivalents. In yet other embodiments, it is about 4.9 equivalents.

- 13 041479

For step vi) regarding the synthesis of compounds of formula II or formula IV.

The corresponding amount of POCl ₃ is at least two equivalents of POCl ₃ for each equivalent of intermediate (6) or intermediate (6') used. In some embodiments, the corresponding amount of POCl ₃ is at least 4 equivalents. In some embodiments, the corresponding amount is at least 5 equivalents. In yet other embodiments, the appropriate amount is about 6 equivalents of POCl ₃ for each equivalent of intermediate (6) or intermediate (6').

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 yet other embodiments, a suitable temperature is from about 75°C to about 90°C. In still other embodiments, a suitable temperature is from about 70°C to about 80°C.

A suitable aprotic organic solvent is, for example, acetonitrile (CNMe). The reaction can also be carried out in pure POCl ₃ in the absence of any solvents.

A suitable optional base is, for example, N,N-dimethylaniline. The reaction also proceeds in the absence of a base.

An appropriate amount of a suitable base is from about 0.2 to about 2 equivalents of base for each equivalent of intermediate (6) or intermediate (6') used. In some embodiments, the appropriate amount of base is from about 1.5 to about 1.8 equivalents. In other embodiments, it is from about 0.8 equivalents to about 1.2 equivalents. In yet other embodiments, it is about 1 equivalent.

For step vii) regarding the synthesis of compounds of formula II or formula IV.

The corresponding amount of sodium methoxide (NaOMe) is approximately 1 equivalent of NaOMe for each equivalent of intermediate (7) or intermediate (7'). In some embodiments, the corresponding amount of NaOMe is a small excess of NaOMe for each equivalent of intermediate (7) or intermediate (7'). In some embodiments, the appropriate amount of NaOMe is 1.1 to 1.3 equivalents for each equivalent of intermediate (7) or intermediate (7'). In other embodiments, the corresponding amount is about 1.2 equivalents.

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 from about 15°C to about 28°C. In other embodiments, from about 20°C to about 28°C. In still other embodiments, from about 23°C to about 27°C.

A suitable protic solvent is, for example, methanol (MeOH).

For step viii) regarding the synthesis of compounds of formula II or formula IV.

A suitable transfer hydrogenation reagent is HCOOH. HCOOH was most often used in the presence of organic/inorganic bases such as Et ₃ N, NaOH, NaHCO ₃ and the like. HCOONH4, HCOONa, HCOOK, isopropanol, triethylsilane and cyclohexadiene can also be used.

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

The appropriate amount of a suitable metal catalyst is a catalytic amount, ie. less than one equivalent of Pd per equivalent of intermediate (8) or intermediate (8'). In some embodiments, an appropriate amount of a suitable metal catalyst is from 0.01 to 0.03 equivalents of Pd per equivalent of intermediate (8) or intermediate (8'). In other embodiments, an appropriate amount of a suitable metal catalyst is from 0.01 to 0.025 equivalents of Pd per equivalent of intermediate (8) or intermediate (8'). In still other embodiments, an appropriate amount of a suitable metal catalyst is from 0.015 to 0.025 equivalents of Pd per equivalent of intermediate (8) or intermediate (8'). In still other embodiments, an appropriate amount of a suitable metal catalyst is from 0.01 to 0.02 equivalents of Pd per equivalent of intermediate (8) or intermediate (8').

A suitable base is triethylamine (Et ₃ N). Other suitable bases that can be used are, for example, Hunig's base, NaHCO ₃ , KHCO ₃ , and sodium acetate.

The appropriate amount of a suitable base is at least one equivalent of base for each equivalent of intermediate (8) or intermediate (8'). IN

- 14 041479 In some embodiments, a suitable amount of base is at least 1.5 equivalents. In other embodiments, it is about 1.6 equivalents.

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.

A suitable organic solvent is, for example, THF. Other solvents that can be used are, for example, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran or mixtures thereof.

For step ix) regarding the synthesis of compounds of formula II or formula IV.

A suitable aqueous acid is HCl. Other acids that may be used include, for example, methylsulfonic acid (MeSO ₃ H) or HBr.

A suitable amount of acid is from about 3 to about 6 equivalents. In some embodiments, the appropriate amount is from about 4 to about 6 equivalents. In other embodiments, it is from about 4.5 equivalents to about 6 equivalents. In still other embodiments, it is about 4.90 to about 5 equivalents. HCl can be provided, for example, in the form of concentrated HCl (eg 37 wt.% HCl).

A suitable protic solvent is, for example, MeOH. Other suitable protic solvents are EtOH and iPrOH.

A suitable temperature is from about 50°C to about 70°C. In some embodiments, a suitable temperature is from about 55°C to about 65°C. In yet other embodiments, a suitable temperature is from about 60°C to about 65°C. In yet other embodiments, a suitable temperature is from about 62°C to about 65°C.

For step x) regarding the synthesis of compounds of formula II or formula IV.

The corresponding amount of POCl ₃ is at least two equivalents of POCl ₃ for each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, the corresponding amount of POCl ₃ is at least 4 equivalents. In some embodiments, the corresponding amount is at least 3 equivalents. In some embodiments, the corresponding amount is at least 2 equivalents. In some embodiments, the corresponding amount is at least 1 equivalent. In still other embodiments, the appropriate amount is from about 1 to about 4 equivalents of POCl3 for each equivalent of intermediate (10) or intermediate (10').

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 yet other embodiments, a suitable temperature is from about 75°C to about 90°C. In yet 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.

A suitable aprotic solvent is, for example, acetonitrile (CNMe). The reaction can also be carried out in pure POCl3 in the absence of any solvents.

A suitable optional base is, for example, N,N-dimethylaniline. The reaction also proceeds in the absence of a base.

An appropriate amount of a suitable base is from about 0.2 to about 2 equivalents of base for each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, the appropriate amount of base is from about 1.3 to about 1.6 equivalents. In some embodiments, the appropriate amount of base is from about 1.2 to about 1.8 equivalents. In other embodiments, it is about 1 equivalent.

For step 1) regarding the synthesis of compounds of formula II or formula IV.

A suitable amount of sodium hydroxide (NaOH) is from about 2 to about 2.5 equivalents of NaOH for each equivalent of intermediate (7) or intermediate (7'). In other embodiments, the corresponding amount is about 2.2 equivalents.

A suitable temperature is from about 45°C to about 70°C. In some embodiments, a suitable temperature is from about 50°C to about 65°C. In other embodiments, it is from about 55°C to about

- 15 041479 60°C.

A suitable phase transfer catalyst is tetrabutylammonium hydroxide. Other suitable phase transfer catalysts that can be used include benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride.

The appropriate amount of a suitable phase transfer catalyst is a catalytic amount, i. e. less than one equivalent of phase transfer catalyst per equivalent of intermediate (7) or intermediate (7'). In some embodiments, the catalytic amount is from about 0.1 to about 0.5 equivalents. In other embodiments, it is from about 0.1 to about 2.5 equivalents. In yet other embodiments, it is from about 0.1 to about 0.15 equivalents.

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

For step 2) regarding the synthesis of compounds of formula II or formula IV.

A suitable transfer hydrogenation reagent is HCOOH. HCOOH was most often used in the presence of organic/inorganic bases such as Et ₃ N, NaOH, NaHCO ₃ and the like. HCOONH ₄ , HCOONa, HCOOK, isopropanol, triethylsilane and cyclohexadiene can also be used.

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

The appropriate amount of a suitable metal catalyst is a catalytic amount, ie. less than one equivalent of Pd per equivalent of intermediate (8B) or intermediate (8'B). In some embodiments, an appropriate amount of a suitable metal catalyst is from 0.01 to 0.02 equivalents of Pd per equivalent of intermediate (8B) or intermediate (8'B).

A suitable base is triethylamine (Et ₃ N). Other suitable bases that can be used are, for example, Hunig's base, NaHCO ₃ , KHCO ₃ and sodium acetate.

The appropriate amount of a suitable base is at least one equivalent of base for each equivalent 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.

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 yet other embodiments, a suitable temperature is from about 15°C to about 25°C. In still other embodiments, a suitable temperature is from about 20°C to about 30°C. In yet other embodiments, a suitable temperature is from about 20°C to about 25°C.

A suitable organic solvent is, for example, THF. Other solvents that can be used are, for example, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran or mixtures thereof.

For step 3) regarding the synthesis of compounds of formula II or formula IV.

The corresponding amount of POCl ₃ is at least two equivalents of POCl ₃ for each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, the corresponding amount of POCl ₃ is at least 4 equivalents. In some embodiments, the corresponding amount is at least 3 equivalents. In some embodiments, the corresponding amount is at least 2 equivalents. In some embodiments, the corresponding amount is at least 1 equivalent. In yet other embodiments, the appropriate amount is from about 1 to about 4 equivalents of POCl ₃ for each equivalent of intermediate (10) or intermediate (10').

A suitable temperature is from about 50°C to about 80°C. In some embodiments, a suitable temperature is from about 60°C to about 80°C. In some embodiments, a suitable temperature is from about 65°C to about 80°C. In other embodiments, a suitable temperature is from about 70°C to about 80°C. In yet other embodiments, a suitable temperature is from about 75°C to about 80°C.

A suitable aprotic solvent is, for example, acetonitrile (CNMe). Reaction also

- 16 041479 can be carried out in pure POC13 in the absence of any solvents.

A suitable optional base is, for example, N,N-dimethylaniline. The reaction also proceeds in the absence of a base.

An appropriate amount of a suitable base is from about 0.2 to about 2 equivalents of base for each equivalent of intermediate (10) or intermediate (10') used. In some embodiments, the appropriate amount of base is from about 1.3 to about 1.6 equivalents. In some embodiments, the appropriate amount of base is from about 1.2 to about 1.8 equivalents. In other embodiments, it is about 1 equivalent.

For the above one-step processes for the synthesis of compounds of formula II or compounds of formula IV.

A suitable transfer hydrogenation reagent is. HCOOH was most often used in the presence of organic/inorganic bases such as Et3N, NaOH, NaHCO ₃ and the like. HCOONH4, HCOONa, HCOOK, isopropanol, triethylsilane and cyclohexadiene can also be used.

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

The appropriate amount of a suitable metal catalyst is a catalytic amount, ie. less than one equivalent of Pd per equivalent of intermediate (7) or intermediate (7'). In some embodiments, an appropriate amount of a suitable metal catalyst is 0.01 to 0.02 equivalents of Pd per equivalent of intermediate (7) or intermediate (7').

A suitable base is triethylamine (Et3N). Other suitable bases that can be used are, for example, Hunig's base, NaHCO ₃ , KHCO 3 and sodium acetate.

The appropriate amount of a suitable base is at least one equivalent of base for each equivalent 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.

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.

A suitable organic solvent is, for example, THF. Other solvents that can be used are, for example, methanol, ethanol, isopropanol, 2-methyltetrahydrofuran or mixtures thereof.

Alternative methods for the preparation of compounds of formula II and formula IV have previously been described in US 8748442 B2, WO 2013101830 and WO 2014144100.

In these publications, the synthesis of intermediates (4) and (4') was carried out according to Scheme 1 below, using intermediate (4') as an example.

(4')

Scheme 1

According to scheme 1, the synthesis of intermediates (4) and (4') can be carried out in two stages. For example, for compound (4'), the first step involves reacting the ketone (19) with diethyl oxalate to give intermediate (20). In the second step, intermediate (20) is reacted with an appropriately substituted hydrazine or its corresponding hydrochloride salt. In the particular case of compound (4'), the hydrazine will be one of the formula NH2NH-CH2-(2-fluorophenyl).

This describes the preparation of compounds (4) and (4') according to Scheme 2, exemplified for compound (4') shown below.

- 17 041479

Scheme 2

It has been found that the preparation of intermediate (4) or (4') according to Scheme 2 provides several advantages over their preparation according to Scheme 1. Although one additional step is introduced in the synthesis according to Scheme 2 compared to the synthesis according to Scheme 1, the synthesis according to Scheme 2 is more amenable to scale-up for large-scale production, resulting in overall higher yields and higher purity.

Scheme 2 uses compound (1') as 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 a starting material in Scheme 1 is a liquid at room temperature, which makes it difficult to process in large scale production. Compound (19) is also significantly more expensive than compound (1') from commercial sources.

Another advantage of the synthesis according to Scheme 2 is that the intermediate (3') obtained in step ii) can be recrystallized and obtained in high purity. Intermediate (20) of Scheme 1 was used without further purification in the second reaction step, resulting in a less pure end product and a more difficult purification process. In addition, the second step in the preparation of compound (4) or compound (4') in the synthesis according to scheme 1 occurs with a very low degree of regioselectivity for the desired regioisomer (4) or (4'), as shown in the above schemes. Less desirable regioisomers of structures (4B) and (4'B) are depicted below. The low regioselectivity observed during the synthesis of Scheme 1 results in a loss of overall yield of the desired isomer and also requires lengthy and less efficient purification processes to isolate the pure desired isomer.

(4V) (4'V)

In publications US 8748442B2, WO 2013101830 and WO 2014144100, the preparation of compounds of formula II or compounds of formula IV from intermediate amidines (5A) or (5A') or intermediate salts of amidine (5B) or (5'B) was carried out in accordance with scheme 3 by means of formation of intermediate compound (10') as illustrated for the final compound of formula IV below.

Scheme 3

This document discloses the preparation of compounds of formula II or compounds of formula IV from the corresponding amidines (5A) or (5A') or salts of amidines (5B) or (5B') by one of several

- 18 041479 alternative ways. They are exemplified for the final compound of formula IV in Scheme 4 below.

Scheme 4

It has been found that preparing compounds of formula II or formula IV according to Scheme 4 provides several advantages over their preparation according to Scheme 3. Although the process shown in Scheme 3 is very short, it is not as scalable for large scale production. , as scheme 4. The use of unsymmetrical reagents (25) and (26) or similar reagents to obtain intermediate compounds (10) or (10') leads to the formation of a large amount of impurities. These impurities must be separated before the next step to avoid being carried over to the final product. This includes long and complex purification processes and low yields.

The methods shown in Scheme 4, which use the reaction of the symmetrical reagent (27) as the first step, have the advantage of providing the symmetrical intermediate (6) or (6') in high purity and yields. This intermediate can then be converted to a compound of formula II or a compound of formula IV by several alternative methods: by a 5-step process with steps vi)-x); via a one-step process directly into the end product or via a four-step process with steps vi) and 1)-3). In all cases, each of the steps obtained is highly productive and all intermediates are isolated in high purity and yield after simple precipitation or crystallization, avoiding the use of chromatography. Thus, the general process is highly efficient and can be scaled up for large scale production.

The terminology used herein is only intended to describe specific embodiments and is not intended to limit the invention. As used herein, the singular forms are also intended to include plural forms, unless the context clearly indicates otherwise. In what follows, it will be understood that the terms contain (and any of its forms, such as contains and containing), have (and any of its forms, such as

- 19 041479 has or has), include (and any of its forms, such as includes and including), and contain (and any of its forms, such as contains and containing) and any other grammatical variants of them are open linking verbs. As a result, a method or means that contains, has, includes or accommodates one or more steps or elements, has this one or more steps or elements, but is not limited to having only this one or more steps or elements. Similarly, a method step or tool element that contains, has, includes, or accommodates one or more features, has those one or more features, but is not limited to having only one or more features. In addition, a method or structure that is configured in a particular way is at least configured in this way, but can also be configured in ways that are not listed.

As used herein, the terms containing, has, including, containing, and other grammatical variations thereof encompass the terms consisting of and consisting essentially of.

The phrase consisting primarily of or its grammatical variations when used herein should be taken to indicate the claimed features, integers, steps or components, but does not preclude the addition of one or more of their additional features, integers, steps, components or groups, but only if their additional features, integers, stages, components or groups do not significantly change the main and new characteristics of the claimed composition, agent or method.

All publications cited in the present description are incorporated herein by reference as if each individual publication were specifically and individually indicated for inclusion as a reference in the present description, as if it were fully set forth.

The subject matter incorporated by reference is not intended to be an alternative to any of the limitations of the claims, unless otherwise indicated.

Where one or more ranges are referred to in this specification, each range is intended to be a concise presentation of information, where the range is understood to cover each discrete point within the range as if it were fully set forth herein.

While several aspects and embodiments of the present invention have been described and depicted herein, alternative aspects and embodiments may be influenced by those skilled in the art to achieve the same objectives.

Accordingly, the present disclosure and the appended claims are intended to cover all such additional and alternative aspects and embodiments that fall within the true spirit and scope of the invention.

Examples

The following preparative examples are given in order that the present invention may be more fully understood. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

Ways.

HPLC analysis.

Equipment.

A. HPLC analysis was performed using an Agilent 1100/1200 series HPLC system consisting of a pump, ChemStation UV VWD or DAD detector, auto-injector and column heater or equivalent. ChemStation software installed on GX270 or equivalent. The column was HALO C18 150x4.6mm.

B. Column: HALO C18 150x4.6 mm, 2.7 microns or equivalent.

C. Vial autosampler, silicone/teflon septa, 12x32mm.

D. Class A 100 ml volumetric flasks.

E. Weighing funnels.

F. Spatulas.

G. Disposable glass Pasteur pipettes.

H. A balance capable of accurately weighing 0.01 mg.

I. 2x2-l solvent tank.

Reagents.

A. Water, HPLC grade or equivalent.

B. Acetonitrile (ACN), HPLC grade or equivalent.

C. Trifluoroacetic acid (TFA) HPLC grade or equivalent.

D. Intermediate test piece.

E. Intermediate authentic materials or reference material, if available.

- 20 041479

Solvent and thinner.

A. Solvent A: 0.1% TFA in water (i.e. 1 ml in 1 liter of water).

B. Solvent B: 0.1% TFA in acetonitrile (i.e. 1 ml in 1 L of ACN).

C. Thinner: acetonitrile/water.

Column temperature: 40°C.

Time table

Time (minute) % Solvent A % Solvent B 0 85 15 10 5 95 15 5 95

Retention time of selected compounds

Compound The approximate time retention (min) Isooxazole-3-carboxylic acid (1') 1.8 Connection (2') 3, 1 Connection (3') 6, 2 Connection (4') 8, 6 Connection (5') 5, 1 Connection (6') 6, 2 Connection (7') 10.3 Connection (8') 100 Connection (9') 8.8 Connection (10') 7.0 formula! V 9, 3 Compound I 8.9

Nuclear magnetic resonance spectroscopy.

1 H NMR spectra of all compounds were recorded on a BRUKER NMR spectrometer operating at 500 MHz at room temperature. Samples dissolved in CDCl3 were reported relative to the residual solvent peak at 7.27 ppm. Samples dissolved in DMSO-d ₆ were indicated relative to the residual solvent peak at 2.50 ppm.

The resulting FIDs were transferred to a PC and processed using ACD/Labs NMR processing software.

Example 1

i) Coupling compound (1') and N,O-dimethylhydroxylamine to give N-methoxy-Nmethylisoxazole-3-carboxamide (2').

O\_HN(MeO)Me.HCI O\_

OH / ^N ”°\ (1') (2')

Isooxazole-3-carboxylic acid ((1'), 241.6 g, 2137 mmol, 1.0 eq.), toluene (1450 ml) and DMF (7.8 g, 107 mmol, 0.05 eq.) were loaded into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The resulting suspension was heated to 45-50°C. Oxalyl chloride (325 g, 2559 mmol, 1.2 eq.) was then loaded through an addition funnel over 2 h while maintaining the reaction temperature from 45 to 50° C. and vigorous gas evolution was observed. Upon addition, a brown mixture was obtained. The brown mixture was heated to 87-92°C for 1 hour and stirred at 87-92°C for 1 hour. The reaction was complete by HPLC. During heating, the brown mixture turned into a dark solution. The reaction was monitored by quenching part of the reaction mixture in 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 insolubles. The dark filtrate was concentrated under reduced pressure to a volume of 400 ml dark oil.

Potassium carbonate (413 g, 2988 mmol, 1.4 eq.) and water (1000 ml) were charged into 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-dimethylhydroxyamine hydrochloride (229 g, 2348 mmol, 1.1 eq.)

- 21 041479 walking reaction vessel and dissolved in water (1000 ml). Then the solution of Ν,Ο-dimethylhydroxyamine and dichloromethane (2500 ml) were loaded into the potassium carbonate solution.

The above dark oil (400 ml) was then slowly loaded through an addition funnel, maintaining the reaction temperature from -10 to 0°C. The addition was slightly exothermic and a brown mixture was obtained after the addition. The mixture was stirred at 0-5°C for 20 min and then heated to 20-25°C. The lower organic layer was collected and the upper aq. the layer was extracted with dichloromethane (400 ml). The combined organic layers were washed with 15% sodium chloride solution (1200 ml). The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give intermediate (2') as a dark oil (261.9 g, 97 wt.%, 76% yield, 3 wt.% toluene by 1 H-NMR, water content 0.04 wt. % by KF).

1 H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.48 (s, 1H); 6.71 (s, 1H); 3.78 (s, 3H); 3.38 (s, 3H).

ii) Alkylation of compound (2') and ethyl propiolate to give (E)-ethyl 4-(isoxazol-3-yl)-2(methoxy(methyl)amino)-4-oxobut-2-enoate (3').

(2') (3')

Intermediate (2') (72.2 g, 96 wt.%, 444 mmol, 1.0 eq.), ethyl propiolate (65.7 g, 670 mmol, 1.5 eq.) and anhydrous THF (650 ml) loaded into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to -65 to -55°C. Sodium bis(trimethylsilyl)amide in THF (1 M, 650 ml, 650 mmol, 1.46 eq.) was then slowly loaded through an addition funnel, maintaining the reaction temperature from -65 to -55°C. The mixture was stirred at a temperature below -55°C for 10 min after addition was complete. 1N HCl (650 ml, 650 mmol, 1.46 eq.) was then charged to quench the reaction, keeping the reaction temperature below -20° C., followed by immediate 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 layer was concentrated under reduced pressure to give a dark oil.

The dark oil was dissolved in a dichloromethane/ethyl acetate/heptane solution (150/100/100 ml). The solution was applied to a silica gel pad (410 g) and the silica gel pad was eluted with ethyl acetate/heptane (1/1 v/v). The filtrate (~3000 ml) was collected and then concentrated under reduced pressure to a volume of 150 ml to obtain a suspension on standing. Heptane (200 ml) was then added to the suspension, and the suspension was concentrated under reduced pressure to a volume of 150 ml. The resulting suspension was filtered and the filter cake was washed with heptane (150 ml). The filter cake was then air dried overnight to give intermediate (3') as a brown solid (63.4 g, 56% yield, >99% HPLC purity).

1 H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.42 (d, J=1.53 Hz, 1H); 6.76 (d, J=1.53 Hz, 1H); 6.18 (s, 1H); 4.47 (kv, J=7.07 Hz, 2H); 3.75 (s, 3H); 3.21 (s, 3H); 1.41 (t, J=7.17 Hz, 3H).

iii) Cyclization of compound 3' and 2-fluorobenzylhydrazine to give ethyl 1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1H-pyrazole-3-carboxylate (4').

(3') (4')

Intermediate (3') (72.9 g, 287 mmol, 1.0 eq.) and absolute ethanol (730 ml) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was cooled to 0-5°C. 2-fluorobenzylhydrazine (48.2 g, 344 mmol, 1.2 eq.) was then charged into the mixture. The mixture was stirred at 0-10°C for 1 hour and then heated to 20-25°C and stirred at 20-25°C for 16 hours. The reaction was complete by HPLC. Concentrated HCl (33.9 g, 37 wt.%, 344 mmol, 1.2 eq.) Was charged into the reaction mixture for 1 min and the temperature of the mixture was exothermic from 20 to 38°C. Received a suspension. The mixture was cooled to 0-10°C over 1 hour and stirred at 0-10°C for 1 hour. The resulting suspension was filtered and the filter cake was washed with ethanol (200 ml). The filter cake was dried in vacuo at 30-40° C. for 16 h to give intermediate (4') as an off-white solid (81.3 g, 90% yield, >99% HPLC purity).

1I-NMR (500 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=1.68 Hz, 1H); 7.15-7.26 (m, 2H); 6.94-7.08 (m, 2H);

- 22 041479

6.77-6.87 (m, 1H); 6.55 (d, J=1.68 Hz, 1H); 5.95 (s, 2H); 4.43 (kv, J=7.02 Hz, 2 N); 1.41 (t, J=7.17 Hz, 3H).

iv) Amination of compound (4') to give 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide hydrochloride (5'B).

(4') (5B')

Anhydrous ammonium chloride (267 g, 4991 mmol, 5.0 eq.) and toluene (5400 ml) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Trimethylaluminum in toluene (2 M, 2400 ml, 4800 mmol, 4.8 eq.) was slowly loaded through an addition funnel while maintaining the reaction temperature at 20-40° C. (Note: methane gas evolution was observed during the addition). The mixture was then heated to 75-80° C. for 30 min to give a clear white solution. Intermediate (4') (315 g, 999 mmol, 1.0 eq.) was loaded into the reaction mixture in four equal portions over 1 h at 75-90°C. The reaction mixture was stirred at 80-90°C for 30 min and then heated to 100-110°C and stirred at 100-110°C for 3 hours. The reaction was complete according to HPLC. The reaction mixture was cooled to 10-20°C and methanol (461 g, 14.4 mol, 14.4 eq.) Was slowly loaded through an addition funnel, maintaining the reaction temperature at 10-40°C. Note: The quench was very exothermic and a large amount of gas was observed. A thick suspension was obtained. 3 n. HCl (6400 ml, 3N, 19.2 mol, 19.2 eq.) was then slowly loaded through an addition funnel, maintaining the reaction temperature at 20-45°C. The mixture was heated to 80-85°C and stirred at 80-85°C for 10 min to obtain a clear biphasic mixture. The mixture was cooled to 0-5°C over 3 hours and stirred at 0-5°C for 1 hour. The resulting suspension was filtered and the filter cake was washed with water (3000 ml). The filter cake was dried in vacuo at 50-60° C. for 24 h to give intermediate (5'B) as an off-white solid (292 g, 91% yield, >99% HPLC purity).

1 H-NMR (500 MHz, DMSO-d6) δ ppm 9.52 (s, 2H); 9.33 (s, 2H); 9.18 (d, J=1.53 Hz, 1H); 7.88 (s, 1H); 7.29-7.38 (m, 1H); 7.19-7.25 (m, 1H); 7.10-7.16 (m, 1H); 7.03 (d, J=1.53 Hz, 1H); 6.92-6.98 (m, 1H); 5.91 (s, 2 H). M.R. 180-185°C.

v) Cyclization of compound (5'B) and diethyl fluoromalonate to give 5-fluoro-2-(1-(2-fluorobenzyl)5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4, 6-diol (6').

F (5'V) _(6E

Intermediate (5'B) (224.6 g, 698 mmol, 1.0 eq.), methanol (2250 ml) and diethyl fluoromalonate (187 g, 1050 mmol, 1.5 eq.) were charged into a suitable reaction vessel, equipped with mechanical stirrer and digital thermometer. Then sodium methoxide in methanol solution (567 g, 30 wt.%, 3149 mmol, 4.5 eq.) was loaded through an addition funnel, maintaining the reaction temperature from 20 to 35°C. The mixture was stirred at 20-35°C for 30 min and a clear suspension was obtained. The reaction was completed according to HPLC. Solution 1.5 N. HCl (2300 ml, 3450 mmol, 4.9 equiv.) was loaded through an addition funnel for 1 h while maintaining the reaction temperature of 20-30°C. A white suspension was obtained. The pH of the reaction mixture should be ~1 according to the pH of the paper. The suspension was stirred at 20-30°C for 30 min. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of methanol and water (500/500 ml) and then with water (1000 ml). The filter cake was dried in vacuo at 50-60° C. for 16 h to give intermediate (6') as an off-white solid (264 g, 97% yield, >99% HPLC purity).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.82 (br s, 1H); 12.31 (br s, 1H); 9.14 (d, J=1.53 Hz, 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=7.55 Hz, 1H); 5.88 (s, 2H).

- 23 041479 vi) Chlorination of compound (6') to give 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole ( 7').

Intermediate (6') (264 g, 711 mmol, 1.0 eq.), acetonitrile (4000 ml) and

N,N-dimethylaniline (138 g, 1137 mmol, 1.6 eq.) was loaded into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The suspension mixture was heated to 70-80°C. Phosphorus oxychloride (655 g, 4270 mmol, 6.0 eq.) was then charged via an addition funnel over 1 hour while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80° C. for 22 hours to give a brown solution. The reaction was terminated by HPLC. The mixture was then cooled to 0 to 5°C and cottony solids precipitated at 25°C. Water (3000 ml) was slowly loaded through the addition funnel, maintaining the reaction temperature at 0-10°C. The suspension was stirred at 0-10°C for 30 min. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of acetonitrile and water (500/500 ml). The filter cake was dried in vacuo at 35-45° C. for 16 h to give intermediate (7') as an off-white solid (283 g, 98% yield, >99% HPLC purity).

¹ H-NMR (500 MHz, CDCl3) δ ppm 8.48 (d, J=1.68 Hz, 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=1.68 Hz, 1H); 6.03 (s, 2H).

vii) Substitution of compound (7') with methoxide to give 3-(3-(4-chloro-5-fluoro-6methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (8').

Methanol (3400 ml) and sodium methoxide in methanol (154 ml, 5.4 M, 832 mmol, 1.2 eq.) were loaded into 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 eq.) was loaded into the mixture in small portions (5-10 g each portion) for 40 min, maintaining the reaction temperature of 23-27°C. The suspension was stirred at 23-27°C for 30 minutes. The reaction was completed according to HPLC. The resulting suspension was filtered and the filter cake was washed with methanol (850 ml) and then with water (850 ml). The filter cake was dried in vacuo at 50-60° C. for 16 h to give intermediate (8') as an off-white solid (277 g, 99% yield, 97% HPLC purity).

¹ H-NMR (500 MHz, CDCl3) δ ppm 8.47 (d, J=1.83 Hz, 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=1.68 Hz, 1H); 6.00 (s, 2H); 4.21 (s, 3H).

viii) Hydrogenation of compound (8') to give 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (9').

Intermediate (8') (226 g, 560 mmol, 1.0 eq.), palladium (10% on charcoal, nominally 50% water wet, 22.6 g, 0.01 mol, 0.018 eq.), tetrahydrofuran (3400 mL) and triethyl 24041479 min (91 g, 897 mmol, 1.6 eq.) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Nitrogen was bubbled into the reaction mixture through Teflon tubes for 10 min at 20-30°C. The mixture was then heated to 40-50°C and hydrogen gas was bubbled into the reaction mixture through Teflon tubes for 6 hours while maintaining the reaction temperature at 40-50°C. The reaction was completed according to HPLC. Nitrogen was then bubbled into the reaction mixture through Teflon tubes for 10 min at 40-50°C. The reaction mixture was filtered while hot through Hypo Supercel™ and the filter cake was washed with tetrahydrofuran (2000 ml). The filtrate was concentrated under reduced pressure to a volume of ~1300 ml to obtain a suspension. The tetrahydrofuran was then replaced with methanol under reduced pressure by continuously feeding methanol (3000 ml). The final volume after solvent change was 1300 ml. The resulting suspension was filtered and the filter cake was washed with methanol (500 ml). The filter cake was dried in vacuo at 20-25° C. for 16 h to give intermediate (9') as a white solid (192 g, 93% yield, 98% HPLC purity).

¹ H-NMR (500 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=1.68 Hz, 1H); 8.41 (d, J=2.59 Hz, 1H); 7.36 (s, 1H); 7.17-7.24 (m, 1H); 6.95-7.07 (m, 2H); 6.83-6.90 (m, 1H); 6.60 (d, J=1.68 Hz, 1H); 5.99 (s, 2H); 4.19 (s, 3H).

ix) Demethylation of compound (9') to give 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)1 H-pyrazol-3-yl)pyrimidin-4-ol (10 ').

(9') (1θ')

Intermediate (9') (230 g, 623 mmol, 1.0 eq.), MeOH (3450 ml) and conc. HCl (307 g, 37 wt.%, 3117 mmol, 5.0 eq.) Was loaded into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was heated to 60-65° C. and a solution was obtained. The mixture was then stirred at 60-65° C. for 17 hours to give a suspension. The reaction was completed according to HPLC. The suspension was cooled to 20-25°C over 2 hours and stirred at 20-25°C for 30 minutes. The resulting suspension was filtered and the filter cake was washed with methanol (1000 ml). The filter cake was dried in vacuo at 35-45° C. for 16 h to give intermediate (10') as a white solid (214 g, 97% yield, >99% HPLC purity).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.90-13.61 (br s, 1H); 9.11 (d, J=1.68 Hz, 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).

x) Chlorination of compound (10') to give 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (formula IV).

(10') Formula IV

Intermediate (10') (214 g, 602 mmol, 1.0 eq.), acetonitrile (3000 ml) and N,N-dimethylaniline (109 g, 899 mmol, 1.5 eq.) were loaded into a suitable reaction vessel, equipped with mechanical stirrer and digital thermometer. The suspension mixture was heated to 70-80°C. Phosphorus oxychloride (276 g, 1802 mmol, 3.0 eq.) was then charged via an addition funnel over 30 minutes while maintaining the reaction temperature at 70-80°C. The mixture was stirred at 75-80° C. for 2 hours to give a green solution. The reaction was completed according to HPLC. The mixture was then cooled to 0-5°C. Water (1500 ml) was slowly loaded through the addition funnel, maintaining the reaction temperature at 0-10°C. The suspension was stirred at 0-10°C for 30 min. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of acetonitrile and water (500/500 ml) and water and water (500 ml). The filter cake was dried in vacuo at 30-40° C. for 16 h to give the Formula IV intermediate as a white to pink solid (214 g, 95% yield, >99% HPLC purity).

¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 8.65 (s, 1H); 8.48 (d, J=1.68 Hz, 1H); 7.44 (s, 1H); 7.21-7.25 (m, 1H);

- 25 041479

6.97-7.06 (m, 2H); 6.83-6.87 (m, 1H); 6.61 (d, J=1.68 Hz, 1H); 6.03 (s, 2H).

a) Amination of compound 12 to give 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (14).

nh ₄ oh h ₂ nf ₃ c CF ₃

A solution of ammonium hydroxide (29% (as NH ₃ )) in water, 354 ml, 5435 mmol, 9.7 eq) and methyl tert-butyl ether (354 ml) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. (Note: Condenser temperature was set to -20°C and minimized ammonium hydroxide evaporation.) 2,2-Bis(trifluoromethyl)oxirane ((12), 101 g, 561 mmol, 1.0 eq.) funnel for 40 minutes while maintaining the reaction temperature at 20-26°C. The mixture was stirred at 20-26° C. for 3 hours after the addition. The mixture was left to separate and the lower aqueous layer was extracted with methyl tert-butyl ether (2x354 ml). The combined organic layers were concentrated under reduced pressure to bring the volume to 303 ml. Methyl tert-butyl ether (354 ml) was added and the mixture was concentrated under reduced pressure to bring the volume to 303 ml. Heptane (303 ml) was added and the mixture was concentrated under reduced pressure to bring the volume to 303 ml. The suspension was filtered and the filter cake was washed with heptane (100 ml). The solid was dried in a fume hood at 20-25° C. for 2 h until constant weight to give intermediate (14) as a white solid. (79.5 g, 71% yield).

¹ H NMR (500 MHz, MeOD) δ ppm 3.09 (s, 2H).

b) Coupling of a compound of formula IV and compound 14 to give 1,1,1,3,3,3-hexafluoro-2-(((5fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole-3) yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2ol (compound I).

F ₃ C CF ₃

Formula IV

Compound I

Formula IV Intermediate (133 g, 356 mmol, 1.0 eq.), Intermediate (14) in dimethyl sulfoxide solution (352 g, 60 wt.%, 1071 mmol, 3.0 eq.) and dimethyl sulfoxide (1200 ml) 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 according to HPLC. The mixture was then cooled to 20-25°C. Then the reaction mixture was charged with methyl tert-butyl ether (3800 ml) and water (2600 ml). The organic layer was washed with saturated sodium bicarbonate solution (1000 ml) and 1N. HCl solution (1000 ml) and then concentrated under reduced pressure to a volume of 1500 ml. The organic solution was applied to a silica gel pad (800 g) and the silica gel pad was eluted with methyl tert-butyl ether. Pure fractions were 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 loaded through an addition funnel over 30 min, maintaining the reaction temperature from 45 to 55°C to obtain a suspension. The suspension was cooled to 20-25°C and stirred at 20-25°C for 30 min. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of MTBE and heptane (400/600 ml). The filter cake was then dried in vacuo at 45-55° C. for 5 h to give compound I as an off-white solid (130 g, 68% yield, >99% HPLC purity).

1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.11 (d, J=1.96 Hz, 1H); 8.66 (s, 1H); 8.37 (d, J=3.13 Hz, 1H); 8.11 (t, J=5.87 Hz, 1H); 7.48 (s, 1H); 7.30-7.37 (m, 1H); 7.17-7.24 (m, 1H); 7.21 (d, J=1.7 Hz, 1H); 7.06-7.13 (m, 1H); 7.00-7.06 (m, 1H); 5.87 (s, 2H); 4.11 (d, J=5.87 Hz, 2H).

Example 2 Methods on the scale of kilograms.

i) Coupling of compound (1') and N,O-dimethylhydroxylamine to give N-methoxy-Nmethylisoxazole-3-carboxamide (2').

Isooxazole-3-carboxylic acid ((1'), 3.857 kg, 34.1 mol, 1.0 eq.), toluene (19.3 L) and DMF (0.131 L, 1.692 mol, 0.05 eq.) were mixed in a jacketed 30 L reaction vessel equipped with nitrogen inlet/outlet, overhead stirrer, thermocouple and addition funnel. The resulting suspension was heated to 45-55°C. Oxalyl chloride (4.8 kg, 37.8 mol, 1.11 eq.) was then charged via an addition funnel over 4 h 30 min while maintaining the reaction temperature at 45 to 55° C. and vigorous gas evolution was observed. A brown mixture was obtained after the addition. brown mixture you

- 26 041479 kept at 45-55°C for 30 min and then heated to 85-95°C and stirred at 85-95°C for 1 hour During heating, the brown mixture turned into a dark mixture. The dark mixture was slowly cooled to 20-25° C. over 4 h and the reaction was monitored by quenching part of the reaction mixture in piperidine and monitoring the disappearance of the piperidine amide by HPLC until the % area/area (1'): piperidine amide was < 1.9). After completion of the reaction by HPLC, the dark mixture was stream-filtered in a 20 L rotary evaporator flask. Toluene (3.9 L) was used to wash the reactor and was filtered in the flow into a 20 L rotary evaporator flask. The filtered reaction mixture was concentrated under reduced pressure until most of the toluene was distilled off to give 4.4 kg of the acyl chloride as a dark oil.

Separately, potassium carbonate (7.06 kg, 51.1 mol, 1.5 eq.) and water (31 L) were stirred in a 100 L jacketed reactor. The reaction solution was cooled to -10-10°C. X,O-dimethylhydroxylamine hydrochloride (3.93 kg, 40.3 mol, 1.18 eq.) was charged to the reactor followed by the addition of dichloromethane (39 L). The reaction mixture was cooled to -10-0°C. The above intermediate acyl chloride as a dark oil (4.4 kg) was then slowly charged into a 100 L jacketed reactor containing X,O-dimethylhydroxylamine in dichloromethane with vigorous stirring while maintaining the reaction temperature from -10 to 0°C for a period 30 min. The addition was slightly exothermic and a brown mixture was obtained after the addition. The reaction mixture was stirred at -10-0°C for 20 min and then heated to 15-25°C and stirred for 10 min. The layers were separated and the lower organic layer was collected and the upper 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 lower organic layer was collected and the upper 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 charged into this dark oil and concentrated under reduced pressure until most of the tetrahydrofuran was removed to give intermediate (2') as a dark oil (4.6 kg, 86% yield). , water content 0.01 wt%, by KF, 98.9% purity by HPLC).

ii) Alkylation of compound (2') and ethyl propiolate to give (E)-ethyl 4-(isoxazol-3-yl)-2(methoxy(methyl)amino)-4-oxobut-2-enoate (3').

Intermediate (2') (2.99 kg, 19.15 mol, 1.0 eq.), ethyl propiolate (2.08 kg, 21.2 mol, 1.1 eq.) and anhydrous THF (15 L) were mixed in a 50 L round-bottom flask equipped with a mechanical stirrer and a digital thermometer. The reaction solution was cooled to -70 to -60°C. Sodium bis(trimethylsilyl)amide in THF (40 wt.%, 9.52 kg, 21 mol, 1.1 eq.) was then slowly loaded through an addition funnel, maintaining the reaction temperature at -65 to -50°C for 1 h and 30 min. After the addition, the reaction mixture was stirred at below -55° C. for 10 minutes. Then 2 n. HCl (10.7 L, 21.6 mol, 1.14 eq) was charged over 2 min to quench the reaction while maintaining the reaction temperature below 20°C (exotherms from -65°C to 18°C).

Separately, ethyl acetate (39 L) was preloaded into a 100 L jacketed reaction vessel, and the above reaction mixture from a 50 L round bottom flask was quickly transferred to a 100 L jacketed reaction vessel containing ethyl acetate. 20% citric acid (10.5 L, 10.93 mol, 0.57 eq.) was charged to adjust the batch pH to ~4-5 and mixed for 5 minutes. The lower aqueous layer was discarded and the upper ethyl acetate layer was collected and washed twice with 15 wt% sodium chloride solution (9.0 L per wash). The organic layer was stream filtered and concentrated under reduced pressure to a volume of 9.0 L. Ethanol (9.0 L) was charged and concentrated to azeotropically remove water under reduced pressure to a volume of 9.0 L to give 8.1 kg of crude product (3') in ethanol as a dark brown oil (3.59 kg with 1H-NMR analysis, 74% yield.

iii) Cyclization of compound (3') and 2-fluorobenzylhydrazine to give ethyl 1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1 H-pyrazole-3-carboxylate (4').

2-Fluorobenzylhydrazine (3.234 kg, 18.3 mol, 1.3 eq.), water (0.9 L) and absolute 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 eq.) was charged to a suitable reaction vessel and dissolved in water (1.8 L). Then, the potassium carbonate solution was charged into a 100 L jacketed reaction vessel containing the 2-fluorobenzylhydrazine solution at a temperature of 15-25° C., followed by the addition of absolute ethanol (25.2 L). The reaction solution was cooled to 10-20° C. and intermediate (3') (3.59 kg, 14.12 mol, 1.0 eq.) in anhydrous ethanol was charged via an addition funnel for 5 min keeping the temperature below 30° C. This addition was slightly exothermic. After stirring for a minimum of 12 hours at 15-25° C., the reaction was complete according to HPLC (area/area %(3'):(4')=0.7). Conc. HCl (1.53 L, 37 wt.%, 18.4 mol, 1.3 eq.) was loaded into the reaction mixture for 1 min and the temperature of the mixture was exothermic from 20 to 38°C. The mixture was cooled to 0-5°C over 2 hours and stirred at 0-5°C for 1 hour. The resulting suspension was filtered and the filter cake was washed with a mixture of ethanol (11.5 L) and water (2.9 L), then water (28.7 l). The filter cake was dried under high vacuum at 40° C. for 16 h to give intermediate (4') as

- 27 041479 off-white solid (2.538 kg, 57% yield, 98.8% HPLC purity).

iv) Amination of compound (4') to give 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide hydrochloride (5'B).

Anhydrous ammonium chloride (1.39 kg, 26.0 mol, 3.8 eq.) and toluene (34.1 L) were mixed in a 100 L jacketed reaction vessel. Trimethylaluminum in toluene (2 M, 12 L, 24 mol, 3.5 eq.) was slowly loaded through an addition funnel, maintaining the reaction temperature at 20-40° C. for 2 hours (note: methane gas evolution was observed during the addition). The reaction mixture was stirred for a minimum of 30 min at 20-40°C. Intermediate (4') (2.16 kg, 6.85 mol, 1.0 eq.) in toluene (6.5 L) as a suspension was loaded into the reaction mixture in one portion at 20-40°C. The reaction mixture was heated to 70-80°C and kept for 30 min and then heated to 100-110°C for 30 min and kept for 3 h at 100-110°C. The reaction was completed according to 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 eq.) was slowly loaded through the addition funnel, maintaining the reaction temperature at 20-40°C for 1 hour. (Note : a very exothermic cooling and evolution of a large amount of gas was observed.) A very thick slurry was obtained. 3 n. HCl (26.3 L, 78.9 mol, 11.5 eq.) was then slowly added through an addition funnel while maintaining the reaction temperature at 20-45°C. The mixture was heated to 82-85°C and stirred at 82-85°C and held for 10 min to obtain a clear biphasic mixture. The mixture was cooled to 20-25°C over 2 hours and stirred at 20-25°C for 30 minutes. The resulting suspension was filtered and the filter cake was washed with water (10.8 L). The filter cake was dried in vacuo at 60° C. for 16 h to give intermediate (5'B) as an off-white solid (2.015 kg, 91% yield, 96% HPLC purity).

v) Cyclization of compound (5'B) and diethyl fluoromalonate to give 5-fluoro-2-(1-(2-fluorobenzyl)5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4, 6-diol (6').

Intermediate (5'B) (3.34 kg, 10.38 mol, 1.0 eq.), methanol (33.4 L) and diethyl fluoromalonate (2.95 L, 3.33 kg, 18.69 mol , 1.8 eq.) was mixed in a 100 L jacketed reaction vessel. Sodium methoxide in methanol solution (5.4 M solution, 8.75 L, 47.2 mol, 4.5 eq.) was charged over 1 h 30 min through an addition funnel while maintaining the reaction temperature at 20-30°C. The reaction mixture was stirred at 20-30°C for 30 min and a clear suspension was obtained. The reaction was completed according to HPLC (I-5: ND vs I-6). 1.5 n. HCl (34 L, 51 mol, 4.9 eq.) was charged via an addition funnel over 1 h 20 min while maintaining the reaction temperature at 20-30°C. A white suspension was obtained. The pH of the reaction mixture should be ~1 according to the pH of the paper. The suspension was stirred at 20-30°C for 30 min. The resulting suspension was filtered and the filter cake was washed with a premixed solution of methanol and water (8.35/8.35 L) and water (16.7 L) followed by acetonitrile (10 L). The filter cake was dried in vacuo at 60° C. for 16 h to give intermediate (6') as an off-white solid (3.76 kg, 98% yield, >99% HPLC purity).

vi) Chlorination of compound (6') to give 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (7') .

Intermediate (6') (3.6 kg, 9.695 mol, 1.00 eq.), acetonitrile (50.4 L) and N,N-dimethylaniline (1.98 L, 15.6 mol, 1.6 eq. .) was mixed in a 100 L jacketed reaction vessel equipped with nitrogen inlet/outlet, thermocouple, condenser, addition funnel and overhead stirrer. The mixture was then heated to 70-80°C. Phosphoryl chloride (5.44 L, 8.95 kg, 58.37 mol, 6.0 eq.) was charged via an addition funnel over 1 hour 40 minutes while maintaining the reaction temperature at 70-80°C. The reaction mixture was stirred at 75-80° C. for 21 hours to give a brown solution. The reaction was completed according to HPLC (area/area % (6'):(7')). The reaction mixture was cooled to 0-5°C over 40 min with vigorous stirring and precipitation of solids at 28-30°C. Water (39.6 L) was added slowly through the addition funnel over 2 hours 20 minutes while maintaining the reaction temperature from 0 to 10°C. The suspension was stirred at 0-5°C for 30 min. The resulting suspension was filtered through a 45 cm Buchner funnel. A solution of acetonitrile (9 L) and water (9 L) was mixed in the reactor to cool to 10-15° C. and transferred to a filter to wash the precipitate. Water (18 L) was cooled in the reactor to 16° C. and transferred to a filter to wash the precipitate. The wet cake was dried on the filter for 21 h and then the wet cake was dried in vacuo at 50° C. for 50 h to constant weight to give intermediate (7') as an off-white solid (3.755 kg, 95% yield , 99% purity by HPLC).

vii) Substitution of compound (7') with methoxide to give 3-(3-(4-chloro-5-fluoro-6methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole ( 8').

Methanol (45 L) and sodium methoxide in methanol (2.02 L, 5.4 M, 10.91 mol, 1.19 eq.) were mixed in a 100 L reaction vessel with nitrogen inlet jacket, thermocouple, condenser, and top stirrer. The reaction mixture was heated to 23-27°C. Intermediate (7') (3.755 kg, 9.2 mol, 1.0 equiv.) was loaded into the reaction mixture in small portions (40-60 g of each portion) for 1 h 30 min, maintaining the reaction temperature at 23-27° C. The suspension was stirred at 15-27°C for 1 hour. The reaction was complete according to HPLC (area/area % (7'):(8')=1.8). The suspension was filtered through a 45 cm Buchner funnel. Methanol (7.5 L) was charged into the reactor and then

- 28 041479 was transferred to the filter to wash the precipitate. The filter cake was washed with water (11.3 L) and then with methanol (7.5 L). The wet cake was dried on the filter for 1 h and then dried in vacuo at 40° C. for 18 h to constant weight to give intermediate (8') as an off-white solid (3.59 kg, 97% yield, 96.4% HPLC purity).

viii) Hydrogenation of compound (8') to give 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (9').

Intermediate (8') (1.87 kg, 4.63 mol, 1.0 eq.), palladium (10% on charcoal, nominally 50% water wet, 0.188 kg, 87 mmol, 0.02 eq.) , tetrahydrofuran (26.2 L) and triethylamine (1.03 L, 7.39 mol, 1.6 eq.) were mixed in a 30 L reaction vessel with nitrogen inlet jacket, thermocouple, condenser and overhead stirrer. Nitrogen was bubbled into the reaction mixture through Teflon tubes for 24 min at 15-30°C. The mixture was then heated to 40-50°C and hydrogen gas was bubbled into the reaction mixture through Teflon tubes for 3 hours while maintaining the reaction temperature at 40-50°C. The reaction was completed according to HPLC (area/area % (8'):(9')=1.7). Nitrogen was then bubbled into the reaction mixture through Teflon tubes for 25 min at 40-50°C and the mixture was heated to 45-50°C until filtered. The reaction mixture was filtered while hot through Hyflo Supercel. Tetrahydrofuran (11.2 L) was loaded into 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 give a slurry, and then the tetrahydrofuran was replaced with methanol under reduced pressure by continuously feeding methanol (22.5 L). The final volume after solvent change was 11.2 L and the THF content was confirmed to be <1 wt% by 1H-NMR. The resulting suspension was filtered through a 45 cm Buchner funnel and the filter cake washed with methanol (3.7 L). The wet cake was dried on the filter for 25 min and then dried in vacuo at 40° C. for 4 h to constant weight to give intermediate (9') as a white solid (1.54 kg, 90% yield, 98. 4% purity by HPLC).

ix) Demethylation of compound (9') to give 5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)1 H-pyrazol-3-yl)pyrimidin-4-ol (10 ').

Intermediate (9') (4.44 kg, 12.0 mol, 1.0 eq.), methanol (64.4 L) and concentrated hydrochloric acid (4.88 L, 37 wt%, 59.4 mol , 4.95 eq.) was loaded into a jacketed 75 L reaction vessel equipped with nitrogen inlet/outlet, thermocouple, condenser and overhead stirrer. The mixture was heated to 62-65°C and became a solution at 63°C. Then the reaction mixture was stirred at 62-65°C for 20 h and received a suspension. The reaction was completed according to HPLC (area/area %(9'):(10')=0.4). The suspension was cooled to 20-25°C over 50 min and held for 45 min. The resulting suspension was filtered through a 45 cm Buchner funnel. Methanol (13.3 L) was charged into the reactor and then transferred to a filter to wash the filter cake. The wet cake was dried on the filter for 1 h 30 min and then the solid was dried in vacuo at 40° C. for 8 h to constant weight to give intermediate (10') as a white solid (4.11 kg, 96% yield). %, 99.7% HPLC purity).

x) Chlorination of compound (10') to give 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (formula IV).

Intermediate (10') (2.66 kg, 7.48 mol, 1.0 eq.), acetonitrile (37.2 L) and X,X-dimethylaniline (1.41 L, 1.348 kg, 11.12 mol , 1.49 eq.) was mixed in a 100 L reaction vessel with a nitrogen inlet jacket, thermocouple, addition funnel, condenser and overhead stirrer. The suspension was heated to 70-80°C. Phosphoroxychloride (2.1 L, 3.46 kg, 22.5 mol, 3.0 eq.) was charged via an addition funnel over 1 hour 20 minutes while maintaining the reaction temperature at 70 to 80°C. The mixture was stirred at 75-80° C. for 2 hours to give a green solution. The reaction was completed according to HPLC (area/area % (10'): formula IV=0.2). The mixture was then cooled to -5-5°C over 1 hour. Water (18.6 L) was slowly charged over 40 minutes through an addition funnel while maintaining the reaction temperature at -5-5°C. The suspension was stirred at 0-5°C for 30 min, then filtered through a 45 cm Buchner funnel. Acetonitrile (6.6 L) and water (6.6 L) were charged into the reactor and stirred for 3 min, then transferred to the filter to wash the sediment. Water (6.6 L) was cooled in the reactor to 13° C. and transferred to a filter to wash the precipitate. The wet cake was dried on the filter for 2 h and then dried in vacuo at 40° C. for 16 h to give intermediate of formula IV as a white to pink solid (2.67 kg, 96% yield, 99.3 % HPLC purity).

a) Amination of compound (12) to give 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (14).

Ammonium hydroxide (28-30% solution in water, 7.7 L, 57.3 mol, 4.7 eq.) and methyl tert-butyl ether (7.7 L) were charged to a 30 L jacketed reactor equipped with a mechanical stirrer. , digital thermometer, nitrogen inlet/outlet, addition funnel and condenser. (Note: the condenser temperature was set below -10°C and minimized the evaporation of ammonium hydroxide.) The mixture was heated to 23-28°C. 2,2-Bis(trifluoromethyl)oxirane ((12), 2.2 kg, 12.22 mol, 1.0 eq.) was charged via an addition funnel for 1 hour while maintaining the reaction temperature from 20 to 30°C. The reaction mixture was stirred at 20-30° C. for 3 hours after the addition. The layers were allowed to separate for

- 29 041479 min and lower water. the layer was extracted twice with methyl tert-butyl ether (2 x 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. Methyl tert-butyl ether (11 L) was charged continuously and concentrated to a volume of 6.6 L. Dimethyl sulfoxide (2.42 L) was then charged and continued until most of the methyl tert-butyl ether was distilled off to give 4.95 kg of compound 1-13 in a solution of dimethyl sulfoxide which has 1.887 kg (14) based on 1H -NMR analysis (1.887 kg by ¹ H-NMR, 78% yield).

b) Coupling of formula IV and compound 14 to give 1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2fluorobenzyl)-5-(isoxazol-3)yl )-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol (compound I).

Intermediate Formula IV (1.51 kg, 4.04 mol, 1.0 eq), dimethyl sulfoxide (9.6 L), Hunig's base (1.42 L, 8.08 mol, 2.0 eq) and the above intermediate (14) in dimethyl sulfoxide solution (total mass 4.95 kg, 1.887 kg, 9.58 mol, 2.37 eq.) was loaded into a 100 L reactor. The reaction mixture was heated to 125-130° C. and kept for 3.5 hours. The reaction was complete according to HPLC (area/area % formula ^compound I=1.0). Then the reaction mixture was cooled to 15-25°C. Then the reaction mixture was charged with methyl tert-butyl ether (44 L) and water (18 L). The organic layer was washed with 1 N. HCl (10.6 L, 10.6 mol, 2.6 eq.) then water (9.1 L). The organic layer was then concentrated under reduced pressure to a volume of 13.6 L. Methyl tert-butyl ether (7.6 L) was charged and concentrated under reduced pressure to a volume of 13.6 L. The organic layer was then transferred to a 100 L reactor using inline filtration. Methyl tert-butyl ether (4.5 L) was charged to the 100 L reactor via a transfer line to bring the volume to 18.1 L. The MTBE solution was heated to 50-56° C. and heptane (18.1 L) was charged via an addition funnel over 1 hour 30 minutes while maintaining the reaction temperature above 50° C. to obtain a suspension. The resulting suspension was cooled to 15-25°C and stirred at 15-25°C for 30 min. The suspension was filtered through a 45 cm Buchner funnel and the filter cake was washed with a pre-mixed solution of MTBE and heptane (4.5 L/9.0 L). The filter cake was dried on the filter for 1 hour and then dried in vacuo at 40° C. for 4 hours to give Compound I as an off-white solid (1.625 kg, 75% yield).

Example 3A. Alternative route for the synthesis of compound I (small scale).

A) Substitution of (7') with amine (14) to give 2-(((6-chloro-5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3yl)-1H-pyrazole-3 -yl)pyrimidin-4-yl)amino)methyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (formula X).

F

p.j Formula x

Compound (7') (0.2 g, 0.5 mmol, 1.0 eq.), amine (14) (0.25 g, 1.3 mmol, 2.6 eq.) and dimethyl sulfoxide (2 ml) loaded into a reaction vessel 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 complete according to HPLC.

Acetonitrile (4 ml) and then water (3 ml) were added at 57-63°C. The resulting suspension was filtered and dried in vacuo at 35-45° C. for 16 h to give Formula X as an off-white solid (0.2 g, 72% yield, 99% HPLC purity).

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.11 (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).

Example 3B. Alternative route for the synthesis of compound I (large scale).

(A) Substitution of (7') with amine (14) to give 2-(((6-chloro-5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol3-yl)-1H-pyrazol- 3-yl)pyrimidin-4-yl)amino)methyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (formula X).

Compound (7') (22.0 g, 53.9 mmol, 1.0 eq.), amine (14) (24.4 g, 124 mmol, 2.3 eq.) and dimethyl sulfoxide (220 ml) were loaded into reaction vessel with mechanical stirrer and digital thermometer. The reaction mixture was heated to 80-84°C and stirred at 80-84°C for 4 hours. The reaction was complete according to 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 suspension was cooled to 40-50°C over 1 hour and stirred at 40-50°C for 2 hours. The suspension was filtered and the filter cake was washed with acetonitrile/water (110 ml, 1/1 v/v) and dried in vacuo at 35-45° C. for 16 h to give the compound of formula X as an off-white solid (27.9 g, 91% yield, 99% HPLC purity).

¹ H-NMR (500 MHz, DMSO-d6) δ ppm 9.11 (d, J=1.53, 1H); 8.33 (s, 1H); 8.28 (t, J=6.03, 1H); 7.48 (s,

-

Claims (11)

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). Example 4 Alternative Synthesis of Formula IV. 1) monohydroxylation of dichloropyrimidine (7') - 36 041479 sodium hydroxide in a mixture of aprotic and protic solvent in the presence of a phase transfer catalyst to obtain hydroxypyrimidine (8'B) 1) monohydroxylation of dichloropyrimidine (7) sodium hydroxide in a mixture of aprotic and protic solvent in the presence of a phase transfer catalyst to obtain hydroxypyrimidine (8B) 1. Process for the preparation of a compound of formula II where R ¹ is an unsubstituted 5-6 membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O and S; R ² is phenyl substituted with up to three R ⁵ ; and each R ⁵ is independently selected from halogen; wherein said method comprises the steps - 31 041479 i) amidation of the starting material (1) ABOUT R ¹ OH (1) by reacting it with oxalyl chloride in a mixture of water and an aprotic organic solvent in the presence of a catalyst; then with N,O-dimethylhydroxylamine hydrochloride in the presence of a base in a mixture of water and an aprotic solvent to give the amide (2) ABOUT R ¹ N (2) where R ¹ is an unsubstituted 5-6 membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O and S; ii) alkylating the amide intermediate (2) with ethyl propiolate in an aprotic organic solvent in the presence of a base to give β-enaminoketoester (3) iii) condensation of the β-enaminoketoester (3) with a hydrazine of the formula R2-CH2-NH-NH2 or its HCl salt in the presence of a base in a protic solvent to give the pyrazole ester intermediate (4) R ¹ /—R ² st O' (4) _; where R ² is phenyl substituted with up to three R ⁵ , where each R ⁵ is independently halogen; iv) amination of the pyrazole ester intermediate (4) with ammonium chloride in the presence of trimethylaluminum in an aprotic organic solvent to give the amidine (5A) or after treatment with an aqueous mineral acid solution of the amidine salt (5B): v) condensation of an amidine (5A) or an amidine salt (5B) and a fluoromalonate in the presence of a base in a protic solvent to give, after treatment with a mineral acid, a diol (6) - 32 041479 vi) chlorination of diol (6) with phosphoryl chloride in an aprotic organic solvent in the presence of a base to obtain dichloropyrimidine (7) vii) monomethoxylation of dichloropyrimidine (7) with sodium methoxide in a protic solvent to give methoxypyrimidine (8) viii) dechlorination of methoxypyrimidine (8) with hydrogen gas in the presence of a metal catalyst, in the presence of a base in an organic solvent to obtain fluoromethoxypyrimidine (9) ix) demethylation of fluoromethoxypyrimidine (9) by reacting it with an aqueous acid solution in a protic solvent to obtain alcohol (10) x) chlorination of alcohol (10) with phosphoryl chloride and a base in an aprotic organic solvent. 1) Substitution of intermediate (7') with hydroxy to give 6-chloro-5-fluoro-2-(1-(2fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4 -ola (Intermediate 8'B). 2) dechlorination of hydroxypyrimidine (8'B) with hydrogen gas in the presence of a metal catalyst in the presence of a base in an organic solvent to obtain fluorohydroxypyrimidine (10') ; And 2) dechlorination of hydroxypyrimidine (8B) with gaseous hydrogen in the presence of a metal catalyst, in the presence of a base in an organic solvent to obtain fluorohydroxypyrimidine (10) 2. Process for the preparation of a compound of formula II F Formula II where R ¹ is an unsubstituted 5-6 membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O and S; R ² is phenyl optionally substituted with up to three R ⁵ ; and each R ⁵ is independently halogen; wherein said method comprises the steps - 33 041479 2) Hydrogenation of intermediate (8'B) to give 5-fluoro-2-(1-(2-fluorobenzyl)-5(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol . Intermediate (10'). 3) chlorination of alcohol (10') with phosphoryl chloride and a base in an aprotic organic solvent. 3. The method according to claim 1 for obtaining a compound of formula IV including stages i) amidating the starting material (1') by reacting it with oxalyl chloride in an aprotic organic solvent in the presence of a catalyst; then N,O-dimethylhydroxylamine hydrochloride in the presence of a base in a mixture of water and an aprotic organic solvent to give the amide (2') ii) alkylation of the amide intermediate (2') with ethyl propiolate in an aprotic organic solution - 34 041479 nitele in the presence of a base to obtain β-enaminoketoester (3') iii) condensation of the β-enaminoketoester (3') with a hydrazine of the formula NH ₂ NH-CH ₂ -(2-fluorophenyl) or its HCl salt in the presence of a base in a protic solvent to give the pyrazole ester intermediate (4') iv) amination of the pyrazole ester intermediate (4') with ammonium chloride in the presence of trimethylaluminum in an aprotic organic solvent to give the amidine (5'A) or after treatment with an aqueous mineral acid solution of the amidine salt (5'B): v) condensation of an amidine (5'A) or a salt of an amidine (5'B) and a fluoromalonate in the presence of a base, in a protic solvent to give, after treatment with a mineral acid, a diol (6') vi) chlorination of diol (6') with phosphoryl chloride in an aprotic organic solvent in the presence of a base to give dichloropyrimidine (7') - 35 041479 vii) monomethoxylation of dichloropyrimidine (7') with sodium methoxide in a protic solvent to obtain methoxypyrimidine (8') viii) dechlorination of the methoxypyrimidine (8') with hydrogen gas in the presence of a metal catalyst in the presence of a base in an organic solvent to obtain a fluoromethoxypyrimidine (9') ix) demethylation of the fluoromethoxypyrimidine (9') by reacting it with an aqueous acid solution in a protic solvent to give an alcohol (10') x) chlorination of alcohol (10') with phosphoryl chloride and a base in an aprotic organic solvent. 3) chlorination of fluorohydroxypyrimidine alcohol (10) with phosphoryl chloride and a base in an aprotic organic solvent. 4. The method according to claim 2 for obtaining a compound of formula IV including stages 5. Method according to any of pi. 1 and 2, where R ¹ is a 5-membered heteroaryl ring containing up to three heteroatoms independently selected from N, O, and S. 6. The method of claim 5 wherein R ¹ is isoxalyl. 7. The method according to claim 6, where R ¹ represents 3-isoxalyl. (7') (8'B) Intermediate (7') (0.41 g, 1.0 mmol, 1.0 eq.), 1N. NaOH (2.2 ml, 2.2 mmol, 2.2 eq.), tetrabutylammonium hydroxide in water (0.1 g, 40 wt.%, 0.15 mmol, 0.15 eq.) and tetrahydrofuran (4 ml ) was loaded into a reaction vessel 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 complete according to HPLC. Added 1 n. HCl (3 ml) and then methyl tert-butyl ether (4 ml) at 45-60°C. The resulting suspension was cooled to 20-25°C and stirred at 20-25°C for 20 min. The suspension was filtered and dried in vacuo at 35-45° C. for 16 h to give intermediate (8'B) as an off-white solid (0.29 g, 73% yield, 99% HPLC purity). ¹ H-NMR (500 MHz, DMSO-d6) δ ppm 13.68 (br s, 1H); 9.11 (d, J=1.68 Hz, 1H); 7.69 (s, 1H); 7.29-7.39 (m, 1H); 7.17-7.29 (m, 2H); 7.12 (td, J=7.55, 1.07 Hz, 1H); 6.97 (td, J=7.71, 1.53 Hz, 1H); 5.93 (s, 2H). 8. The method according to any one of claims 1, 2 and 5-7, wherein R ² is phenyl substituted with one R ⁵ , where R ⁵ is halogen. (8'B) (!°') Intermediate (8'B) (0.1 g, 0.26 mmol, 1.0 eq.), palladium (10% on charcoal, nominally 50% water wet, 5 mg), triethylamine (0.038 g, 0.0 38 mmol, 1.5 eq.), tetrahydrofuran (2 ml) and methanol (1 ml) were charged into a 25 ml round bottom flask with a magnetic stirrer. The reaction mixture was hydrogenated under a hydrogen balloon at 20–25°C for 16 h. HPLC showed that intermediate (10') was formed in 73% purity in the crude reaction mixture. CLAIM 9. The method according to claim 8, where R ⁵ represents fluorine. 10. The method according to any one of claims 1, 2 and 5-7, wherein R ² is phenyl substituted with two R ⁵ , where each R ⁵ is independently halogen. 11. The method according to claim 10, where each R ⁵ represents fluorine. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2