EA040047B1 - NEW METHODS FOR OBTAINING SOLUBLE GUANYLATE CYCLASE STIMULANTS - Google Patents

Description

The present invention relates to novel methods for the preparation of compounds useful as soluble guanylate cyclase (sGC) promoters. These processes are amenable to large scale preparation and give stable 3-(2-pyrimidinyl)pyrazoles of formula I in high purity and yields. 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.

F

Formula I

In one aspect, the compounds of formula I and their pharmaceutically acceptable salts are sGC stimulants useful in the treatment of diseases or disorders that benefit from stimulation of sGC or from increased concentrations of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP). In another aspect, compounds of formula I are useful intermediates in the preparation of other sGC stimulants, including other compounds of formula I.

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 second messenger cGMP. 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 have shown 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 stimulants. There is also a need to develop efficient methods suitable for large-scale production for the synthesis of these new sGC promoters, and in particular for compounds of formula I. 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

New processes for the preparation of compounds of formula I are described herein.

- 1 040047

Certain compounds of formula I and their pharmaceutically acceptable salts are sGC stimulants which are useful in the treatment of diseases or disorders that benefit from stimulation of sGC or from an increase in NO and/or cGMP. Other compounds of formula I are useful as intermediates in the synthesis of other sGC stimulants, including other compounds of formula I.

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

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

R ² is phenyl or 6-membered heteroaryl, both optionally substituted with up to three R ⁵ , wherein said 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms;

R ⁴ is halogen or -NR6R ⁷ ;

each R ⁵ is independently selected from C ₁ _ ₆ αkyl, C ₁ _ ₆ αlkoxy, or halogen;

R ⁶ is hydrogen or C ₁ _ ₆ alkyl substituted with 0-3 R ⁸ ;

R ⁷ is hydrogen or C ₁ _ ₆ alkyl substituted with 0-3 R ⁸ ; and each R ⁸ is independently selected from -OH, C ₁ _ ₃ haloalkyl, halogen, or -C(O)NH ₂ .

New intermediates useful in the preparation of compounds of formula I 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 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. 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 Ed. 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, 5 ^th Ed., Smith, MB 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 chemically reactive conditions, for at least a week. A chemically feasible compound is a compound that can be prepared by a person skilled in the art at

- 2 040047 on the basis of the information disclosed here, supplemented, if necessary, by relevant knowledge in this field.

A compound, such as compounds of formula I or other compounds described herein, may be present in its free form (eg, amorphous form, or crystalline form, or polymorph form). Under certain conditions, compounds can also form coforms. As used herein, the term coform is synonymous with the term multicomponent crystalline form. When one of the components in a coform explicitly donates or loses a proton, the resulting coform is called a salt. Salt formation is determined by how big the difference in pKa is between the partners that form the mixture.

In all cases described herein, the term compound also includes a pharmaceutically acceptable salt of the compound, whether or not the phrase pharmaceutically acceptable salt is actually used. The phrase pharmaceutically acceptable salt as used herein refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.

Pharmaceutically acceptable salts of the compounds described in the present description are used in medicine. Salts that are not pharmaceutically acceptable may, however, be useful in the preparation of the compound described herein or other pharmaceutically acceptable salts. A pharmaceutically acceptable salt includes the inclusion of another atom or molecule that acts as a counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Where multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. In some cases, the counterions may be the same. In other cases, they may be different for each charged atom. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

Pharmaceutically acceptable salts of the compounds described herein include salts obtained by reacting the compounds described herein with inorganic or organic bases. In some embodiments, the salts may be generated in situ during the final isolation and purification of the compounds. In other embodiments, salts may be obtained from the free form of a compound described herein in a separate synthetic step.

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., Pharmaceutical Salts, J. Pharm. Sci., 1977:66:1-19, incorporated herein by reference in its entirety.

In the event that only one isomer is depicted and appropriately specified, structures referred to herein are also meant to include all stereoisomeric (e.g., enantiomers, diastereomers, atropisomers, and cis-trans isomers) forms of the structure, e.g., the R and S configurations for each asymmetric center, Ra- and Sa-configuration for each asymmetric axis, (Z)- and ^-configuration of the double bond and cis- and trans-conformational isomers. Therefore, individual stereochemical isomers as well as racemates and mixtures of enantiomers, diastereomers and cistrans 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:

σννχη

OR where R can be hydrogen will include both compounds shown below:

- 3 040047

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, ⁿ 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 substrate receptor occupancy. The isotopically labeled compounds of the present invention can be prepared by the methods below, analogously to those described in the Schemes and/or Examples below in this specification, 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.

The term alkyl (as in an alkyl chain or alkyl group) as used herein refers to a straight or branched saturated monovalent hydrocarbon radical. C _x alkyl is an alkyl chain containing x carbon atoms, where x is an integer other than 0. _{C x} - _y alkyl, where x and y are two different integers both different from 0, is an alkyl chain , containing from x to y number of carbon atoms, inclusive. For example, _C1 . ₆ alkyl is alkyl, as defined above, containing any number from 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (C1 alkyl), ethyl (C2 alkyl), n-propyl (C3 alkyl), isopropyl C3 alkyl), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl , hexyl, heptyl, octyl and the like.

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 (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1 ,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2 ,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl.

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 particular 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 substituted 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 haloalkyl means alkyl substituted with one or more halogen atoms. For example, _C1 . ₃ haloalkyl may be represented by -CFHCH ₂ CHF ₂ . The term fluoroalkyl means alkyl substituted with one or more fluorine atoms. This term includes perfluorinated alkyl groups such as -CF3 and -CF2CF3.

As used herein, the term alkoxy refers to an alkyl group, as defined above, attached to a molecule or other chain or ring through an oxygen atom. Alkoxy can be described as -O-Cx.y alkyl or C _x _ _y alkoxy.

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 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 interchangeably.

Some common characteristics of protic solvents are the ability to exhibit hydrogen bonds having acidic hydrogens (although these can be very weakly 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. 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 mentioned both by its chemical structure and by its

- 5 040047 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 that definition throughout the specification and in all independent claims.

Embodiments

New processes for the preparation of compounds of formula I are described herein.

F

Formula I

Certain compounds of formula I and their pharmaceutically acceptable salts are sGC stimulants which are useful in the treatment of diseases or disorders that benefit from stimulation of sGC or from an increase in NO and/or cGMP. Other compounds of formula I are useful as intermediates in the synthesis of other sGC stimulants, including other compounds of formula I.

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

R ¹ is unsubstituted phenyl or a 5-6 membered heteroaryl ring containing up to 3 ring heteroatoms independently selected from N, O or S;

R ² is phenyl or 6-membered heteroaryl, both optionally substituted with up to three R ⁵ ; where the specified 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms;

R ⁴ is halogen or -NR6R ⁷ ;

each R ⁵ is independently selected from C ₁ _ ₆ alkyl, C ₁ _ ₆ αlkoxy, or halogen;

R ⁶ is hydrogen or C ₁ _ ₆ alkyl substituted with 0-3 R ⁸ ;

R ⁷ is hydrogen or C ₁ _ ₆ alkyl substituted with 0-3 R ⁸ ; and each R ⁸ is independently selected from -OH, C ₁ _ ₃ haloalkyl, halogen, or -C(O)NH ₂ .

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

i) amidating the starting material (1) by reacting it with a suitable amount of oxalyl chloride or an equivalent reagent in a suitable aprotic organic solvent at a suitable temperature, in the presence of an appropriate amount of a suitable catalyst; then with an appropriate amount of N,O-dimethylhydroxylamine hydrochloride in the presence of an appropriate excess of a suitable base at a suitable temperature in a suitable mixture of water and an aprotic solvent under anhydrous or aqueous conditions to give an amide (2);

(1) (2) where R ¹ is an unsubstituted phenyl or a 5-6 membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S;

ii) alkylating the amide intermediate (2) with an appropriate amount of ethyl propiolate in an appropriate aprotic organic solvent, at an appropriate temperature in the presence of an appropriate amount of an appropriate base, to give β-enaminoketoester (3);

O O ^R1 \ / °

N-0 (3) iii) condensation of β-enaminoketoester (3) with an appropriate amount of hydrazine of the formula R ² CH ₂ -NH-NH ₂ or its HCl salt, optionally in the presence of an appropriate amount of a suitable

- 6,040,047 bases (in order to neutralize the acid from hydrazine hydrochloride when the hydrochloride form of hydrazine is used) in a suitable protic solvent at a suitable temperature to give the pyrazole ester intermediate (4); where R ² is phenyl or 6-membered heteroaryl, both optionally substituted with up to three R ⁵ ; where the 6-membered heteroaryl ring contains up to 2 ring nitrogen atoms;

(4) .

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

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

vi) chlorination of diol (6) with an appropriate amount of phosphoryl chloride, at an appropriate temperature, in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base, to give dichloropyrimidine (7);

vii) monomethoxylation of dichloropyrimidine (7) with a suitable amount of sodium methoxide, at a suitable temperature in a suitable protic solvent, to obtain methoxypyrimidine (8);

- 7 040047

(8) viii) dechlorination of the methoxypyrimidine (8) with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at an appropriate temperature in a suitable organic solvent, to obtain a fluoromethoxypyrimidine (9);

F(9) .

D ix) demethylation of the fluoromethoxypyrimidine (9) by reacting it with an appropriate amount of aqueous acid in an appropriate protic solvent at an appropriate temperature to give an alcohol (10);

F (Yu); And

x) chlorinating the alcohol (10) with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base, at a suitable temperature in a suitable aprotic organic solvent, to give a chloropyrimidine of formula II.

F

Formula II

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

1) monohydroxylation of dichloropyrimidine (7) with an appropriate amount of sodium hydroxide at an appropriate temperature, in an appropriate mixture of aprotic and protic solvent, in the presence of an appropriate amount of an appropriate phase transfer catalyst, to give hydroxypyrimidine (8B);

- 8 040047

2) dechlorination of hydroxypyrimidine (8B) with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at an appropriate temperature in a suitable organic solvent, to obtain a fluorohydroxypyrimidine (10);

3) chlorination of the alcohol (10) with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base, at a suitable temperature in a suitable aprotic organic solvent, to give a chloropyrimidine of formula II.

^R1 ^ ^R2

Cl

Formula II

Compounds of formula 8B are useful as intermediates in the preparation of compounds of formula II.

In another aspect, this document describes an alternative one-step method for the synthesis of a compound of formula II, comprising direct selective dechlorination of dichloropyrimidine (7) with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in an appropriate suitable organic solvent to give the monochloropyrimidine of formula II.

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 an unsubstituted 5-membered heteroaryl ring containing up to 3 heteroatoms independently selected from N , O, or S. In further embodiments, 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 an unsubstituted phenyl or a 6-membered heteroaryl ring containing up to 3 ring nitrogen atoms. In some embodiments, R ¹ is pyridine or pyrimidine. In other embodiments, R ¹ is phenyl.

In some embodiments of the above methods for preparing a compound of formula II, for compounds of formula II, intermediates (4)-(10) and (8B), and hydrazine of formula R ² CH ₂ -NH-NH ₂ or its corresponding hydrochloride, R ² is is a 6-membered heteroaryl optionally substituted with 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

- 9 040047 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 fluoro.

In another aspect, this document describes a one-step method for obtaining the compounds of formula III.

^R1 /

^R®n'r

^FR7

Formula W

A one-step process for preparing a compound of formula III comprises coupling an appropriate amount of amine (13) with a chloropyrimidine of formula II in a suitable aprotic organic solvent, optionally in the presence of an appropriate amount of a suitable base, at a suitable temperature, to give a compound of formula III.

,R ^e (13)

In another aspect, this document describes an alternative method for obtaining the compounds of formula III, including stages.

A) Coupling an appropriate amount of amine (13) with dichloropyrimidine (7) in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base at an appropriate temperature, to give an intermediate of formula VII.

Formula VII; And

B) Dechlorination of an intermediate of formula VII with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in a suitable organic solvent, to give a compound of formula III.

In some embodiments of the above methods for preparing a compound of formula III, for compounds of formula III and for intermediates of formula II and formula VII, R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O, or S. In additional embodiments, 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 III, for compounds of formula III, and for an intermediate of formula II and formula VII, R ¹ is unsubstituted phenyl or 6-membered heteroaryl containing up to three ring nitrogen atoms. In other embodiments, R ¹ is pyrimidine or pyridine. In yet other embodiments, R ¹ is pyridine. In yet other embodiments, R ¹ is phenyl.

In some embodiments of the above methods for preparing a compound of formula III, for compounds of formula III and an intermediate of formula II and formula VII, R ² is a 6-membered heteroaryl optionally substituted with up to three R ⁵ . In other variants

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 fluoro. 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 some embodiments of the above methods for preparing compounds of formula III, R ⁶ is hydrogen, methyl, or ethyl in intermediate (13), in a compound of formula III, and in an intermediate of formula VII. In some embodiments of the process for preparing compounds of formula III, R ⁶ is hydrogen in intermediate (13), in a compound of formula III, and in an intermediate of formula VII.

In some embodiments of the above methods for preparing compounds of formula III, R ⁷ is C1.6αkyl in said intermediate 13 and said compound of formula III and intermediate of formula VII; where the specified C1.6alkyl is substituted to 3 R ⁸ . In other embodiments, R ⁷ is C1. ₂ alkyl; where specified C ₁ . ₂ αkyl is substituted to 3 R ⁸ . In other embodiments, R ⁷ is ethyl substituted with 3 R ⁸ .

In some embodiments of the above methods for preparing compounds of formula III, for said compounds of formula III and said intermediate 13 or intermediate of formula VII, one example of R ⁸ is -OH. In other embodiments, one example of R ⁸ is -OH and one example is C ₁ . ₃ haloalkyl. In other embodiments, one example of R ⁸ is -OH and one example is trifluoromethyl.

In some embodiments of the above methods for preparing compounds of formula III, R ⁷ is ethyl in said intermediate 13 and in said compound of formula III and intermediate of formula VII; where said ethyl is substituted with 3 R ⁸ groups; where one of the three R ⁸ represents -OH. In other embodiments, R ⁷ is ethyl substituted with 3 R ⁸ ; where one of said R ⁸ is -OH and the other R ⁸ is C1. 3 haloalkyl. In some embodiments, one example of R ⁸ is -OH and the other R ⁸ is trifluoromethyl. In other embodiments, R ⁷ is ethyl substituted with three R ⁸ ; where one example of R ⁸ is -OH, one example of R ⁸ is trifluoromethyl and the third R ⁸ is -C(O)NH2.

In another aspect, the present document describes a process for preparing a compound of formula IV, comprising the steps of:

i) amidating the starting material (1') by reacting it with a suitable amount of oxalyl chloride or an equivalent reagent, in a suitable aprotic organic solvent at a suitable temperature, in the presence of an appropriate amount of a suitable catalyst; then with an appropriate amount of N,O-dimethylhydroxylamine hydrochloride in the presence of an appropriate excess of a suitable base, at a suitable temperature, in a suitable mixture of water and an aprotic solvent under anhydrous or aqueous conditions, to give the amide (2');

(D) (2') ii) alkylating the amide intermediate (2') with an appropriate amount of ethyl propiolate in an appropriate aprotic organic solvent, at an appropriate temperature in the presence of an appropriate amount of an appropriate base, to give the β-enaminoketoester (3');

N-O / \ (3') .

D iii) condensation of the β-enaminoketoester (3') with an appropriate amount of hydrazine of the formula NH ₂ NH-CH ₂ -(2-fluorophenyl) or its HCl salt, optionally in the presence of an appropriate amount of a suitable base (in order to neutralize the acid from hydrazine hydrochloride , When

- 11 040047 using the hydrochloride form of hydrazine) in a suitable protic solvent at a suitable temperature to give the pyrazole ester intermediate (4');

(4') iv) amination of the pyrazole ester intermediate (4') with an appropriate amount of ammonium chloride in the presence of an appropriate amount of trimethylaluminum, in an appropriate aprotic organic solvent at an appropriate temperature, to give amidine (5'A) or, after treatment with an appropriate aqueous solution of mineral acids, amidine salts (5'B);

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

vi) chlorination of diol (6') with an appropriate amount of phosphoryl chloride, at an appropriate temperature, in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base, to give dichloropyrimidine (V);

vii) monomethoxylation of dichloropyrimidine (7') with a suitable amount of sodium methoxide, at a suitable temperature in a suitable protic solvent, to obtain methoxypyrimidine (8');

- 12 040047

viii) dechlorination of the methoxypyrimidine (8') with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at an appropriate temperature in a suitable organic solvent, to give a fluoromethoxypyrimidine (9');

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

x) chlorinating the alcohol (10') with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base, at a suitable temperature in a suitable aprotic organic solvent, to give a chloropyrimidine of formula IV.

F

Formula IV

In another aspect, this document describes an alternative method for synthesizing the compound

- 13 040047 formula IV, comprising the steps:

1) monohydroxylation of dichloropyrimidine (7') with an appropriate amount of sodium hydroxide at an appropriate temperature, in an appropriate mixture of aprotic and protic solvent, in the presence of an appropriate amount of an appropriate phase transfer catalyst, to give hydroxypyrimidine (8'B);

N

Ϊ if

ΟΙ^ΎόΗ

F(8'B) .

r

2) dechlorination of hydroxypyrimidine (8'B) with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at an appropriate temperature in a suitable organic solvent, to give a fluorohydroxypyrimidine (10');

F (yu ) 'g I

3) chlorination of the alcohol (10') with an appropriate amount of phosphoryl chloride and optionally an appropriate amount of a suitable base, at a suitable temperature in a suitable aprotic organic solvent, to give a chloropyrimidine of formula IV.

F

Formula IV

In another aspect, this document describes an alternative one-step method for the synthesis of a compound of formula IV, comprising direct selective dechlorination of dichloropyrimidine (7') with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in in a suitable organic solvent to give the monochloropyrimidine of formula IV.

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

- 14 040047 to approximately 3 equivalents. In other embodiments, the appropriate amount is from about 1 to about 2 equivalents. In yet 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 yet 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 corresponding amount of DMF is a catalytic amount, ie less than one equivalent of DMF for each equivalent of feed (1) or feed (1'). In some embodiments.

An 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 still 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 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 still 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 organic solvent mixture is, for example, dichloromethane (DCM). Other suitable solvents are, for example, ethyl acetate,

- 15 040047 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 still 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 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 (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 yet 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 from 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.

- 16 040047

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 yet 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 about 4 equivalents. In other embodiments, the corresponding amount is about 3.5 equivalents.

A suitable aprotic organic solvent is, for example, toluene. Another suitable solvent is, 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, H ₂ SO 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 from about 1.7 to 1.9 equivalents.

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

An 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 still other embodiments, the implementation 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 yet 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.

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 still other embodiments, the appropriate amount is about 6 equivalents of POCl3 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 is 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 suitable metal catalyst is a catalytic amount, i.e. less than one equivalent of Pd per equivalent of intermediate

- 18 040047 ( 8) or intermediate (8'). In some embodiments, the 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, the 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, the 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 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 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.

A suitable amount of suitable base is from about 0.2 to about

- 19 040047 positively 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 500°C to about 65°C. In other embodiments, it is from about 55°C to about 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, ie 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 organic 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 is 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 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 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 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 POCl3 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 POCl ₃ for each equivalent

- 20 040047 tapes of intermediate connection (10) or intermediate connection (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 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 (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. HCOOH is 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, eg 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 (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 (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.

In another aspect, this document describes a one-step process for preparing a compound of formula V comprising coupling an appropriate amount of an amine (13) with a chloropyrimidine of formula IV, optionally in the presence of an appropriate amount of a suitable base, in a suitable aprotic organic solvent, at a suitable temperature, to obtain a compound of formula V .

Formula V

In another aspect, this document describes an alternative method for obtaining compounds of formula V, including the following stages.

- 21 040047

A) Coupling an appropriate amount of amine (13) with dichloropyrimidine (7') in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base at an appropriate temperature, to give an intermediate of formula VIII.

Formula VIII.

B) Dechlorination of an intermediate of formula VIII with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature in a suitable organic solvent, to give a compound of formula V.

In some embodiments of the above methods for preparing compounds of formula V, R ⁶ is hydrogen, methyl, or ethyl in intermediate (13), compound of formula V, and intermediate of formula VIII. In some embodiments of the process for preparing compounds of formula V, R ⁶ is hydrogen in intermediate (13), compound of formula V, and intermediate of formula VIII.

In some embodiments of the above methods for preparing compounds of formula V, R ⁷ is C1-6αalkyl in intermediate 13, intermediate of formula VIII, and compound of formula V; where the specified C1-6alkyl substituted to 3 R ⁸ . In other embodiments, R ⁷ is C1-2 alkyl; where the specified C _1-2 alkyl substituted to 3 R ⁸ . In other embodiments, R ⁷ is ethyl substituted with 3 R ⁸ .

In some embodiments of the above methods for preparing compounds of formula V, for compounds of formula V, intermediate of formula VIII, and intermediate 13, one example of R ⁸ is OH. In other embodiments, one example of R ⁸ is OH and one example is C _1-3 haloalkyl. In other embodiments, one example of R ⁸ is OH and one example is trifluoromethyl.

In some embodiments of the above methods for preparing compounds of formula V, R ⁷ is ethyl in said intermediate 13, intermediate of formula VIII, and compound of formula V; where said ethyl is substituted with 3 R ⁸ groups; where one of the three R ⁸ represents OH. In other embodiments, R ⁷ is ethyl; where said ethyl is substituted with 3 R ⁸ groups; where one of these R ⁸ represents -OH and the other R ⁸ represents C _1-3 haloalkyl. In some embodiments, one example of R ⁸ is OH and the other R ⁸ is trifluoromethyl. In other embodiments, R ⁷ is ethyl substituted with three R ⁸ ; where one example of R ⁸ is OH, one example of R ⁸ is trifluoromethyl and the third R ⁸ is -C(O)NH2.

In another aspect, this document describes a one-step method for obtaining the compounds of formula VI.

_NH2

Formula VI

A one-step process for preparing a compound of formula VI comprises combining an appropriate amount of amine (14) with a chloropyrimidine of formula II, optionally in the presence of an appropriate amount of a suitable base, in a suitable aprotic organic solvent, at a suitable temperature, to form an intermediate compound of formula VI.

- 22 040047

(14)

In another aspect, this document describes an alternative method for obtaining compounds of formula VI, including the following stages.

A) Coupling an appropriate amount of amine (14) with dichloropyrimidine (7) in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base at an appropriate temperature, to give an intermediate of formula IX.

Formula IX; And

B) Dechlorination of an intermediate of formula IX with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at an appropriate temperature, in a suitable organic solvent, to give a compound of formula VI.

In another aspect, a process for preparing a compound of formula VI comprises the steps of:

a) treating intermediate bromine 15 with an appropriate amount of trimethylsilanecarbonitrile, KCN or NaCN in the presence of an appropriate amount of a suitable organic amine, optionally in the presence of water as a solvent, at a suitable temperature, to obtain intermediate 16;

b) treating intermediate 16 with an appropriate amount of strong aqueous mineral acid, at the appropriate temperature, to give intermediate 17;

c) treating intermediate 17 with an appropriate amount of ammonia, in an appropriate protic solvent at an appropriate temperature, to give amine 14.

In some embodiments of the above methods for preparing a compound of formula VI, for compounds of formula VI, and for intermediates of formula II, and intermediates of formula IX, R ¹ is an unsubstituted 5-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S. In additional embodiments, 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 VI, for compounds of formula VI, and for intermediates of formula II and intermediates of formula IX, R ¹ is an unsubstituted phenyl or a 6-membered heteroaryl ring containing up to three ring nitrogen atoms. In other embodiments, R ¹ is phenyl.

In some embodiments of the above methods for preparing a compound of formula VI, for compounds of formula VI and intermediates of formula II, and intermediates of formula IX, R ² is a 6-membered heteroaryl optionally substituted with 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 others

- 23 040047 embodiments R ² is phenyl substituted with two R ⁵ and each R ⁵ is halogen. In still other embodiments, R ² is phenyl substituted with two R ⁵ , and each R ⁵ is fluoro.

In another aspect, this document describes a one-step method for obtaining a compound.

In another aspect, this document describes a one-step method for the preparation of compound I. Compound I is 3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazole- 3yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide and has the structure shown below. Compound I is an sGC stimulant that has been shown to be effective in the treatment of a number of NO related disorders in preclinical models.

Compound I

A one-step process for preparing compound I involves combining an appropriate amount of amine (14) with a chloropyrimidine of formula IV, optionally in the presence of an appropriate amount of a suitable base, in a suitable aprotic organic solvent, at a suitable temperature, to obtain compound I.

Oh (14)

For the above one-step processes for preparing a compound of formula III, a compound of formula V, a compound of formula VI, or a compound I by reacting a formula II intermediate or a formula IV intermediate with an amine (13), or alternatively a formula II intermediate or a formula IV intermediate with an amine (14 ).

The corresponding amount of amine (13) or amine (14) is at least one equivalent of amine (13) or amine (14) for each equivalent of a compound of formula II or a compound of formula IV. In some embodiments, an excess of amine (13) or amine (14) may be used. In some embodiments, an amount of from about 1 to about 5 equivalents of amine (13) or amine (14) can be used. In other embodiments, the appropriate amount is from about 1 to about 4 equivalents. In other embodiments, it is from about 1 to about 3 equivalents.

A suitable optional base is, for example, the Hunig base. Other suitable optional bases are, for example, Et ₃ N, NaHCO ₃ and KHCO 3 . Amine (13) or amine (14) by itself can also be used as a base.

An appropriate amount of a suitable base is at least one equivalent of an optional base for each equivalent of an intermediate of formula II or an intermediate of formula IV. In some embodiments, the corresponding amount is about 2 equivalents.

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

A suitable temperature is from about 100°C to about 135°C. In some embodiments, a suitable temperature is from about 120°C to about 130°C. In other embodiments, a suitable temperature is from about 125°C to about 130°C.

In another aspect, this document describes an alternative method for obtaining compounds I, including the following stages.

A) Coupling an appropriate amount of amine (14) with dichloropyrimidine (7'), in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base, at an appropriate temperature, to give an intermediate of formula X.

- 24 040047

Formula X ; And

B) Dechlorination of an intermediate of formula X with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in a suitable organic solvent, to give Compound I.

In another aspect, this document describes another method for preparing Compound I.

This process for the preparation of compound I comprises the following steps:

a) treating intermediate bromine (15) with an appropriate amount of trimethylsilanecarbonitrile, KCN or NaCN in the presence of an appropriate amount of a suitable organic amine, optionally in the presence of water as a solvent, at a suitable temperature, to obtain intermediate (16);

b) treating intermediate (16) with an appropriate amount of a suitable strong aqueous mineral acid, at a suitable temperature, to give intermediate (17);

c) treating intermediate (17) with an appropriate amount of ammonia, in a suitable protic solvent at an appropriate temperature, to give amine (14).

For step a) in the above processes for the preparation of a compound of formula VI or compound I

The corresponding amount of trimethylsilanecarbonitrile (TMSCN), KCN or NaCN is slightly deficient in relation to the amount of intermediate bromine (15), i.e. slightly less than 1 equivalent of TMSCN, NaCN or KCN for each equivalent of intermediate bromine (15). In some embodiments, the appropriate amount of TMSCN, KCN, or NaCN is from about 0.9 to about 1.1 equivalents of TMSCN, NaCN, or KCN for each equivalent of intermediate bromine (15). In other embodiments, the appropriate amount is from about 0.95 to about 1 equivalent.

A suitable organic amine is, for example, triethylamine (Et ₃ N). Another suitable amine is, for example, Hunig's base.

An appropriate amount of a suitable organic amine is a catalytic amount. In some embodiments, the catalytic amount is from about 0.01 equivalents to about 0.1 equivalents of amine for each equivalent of intermediate bromine (15). In other embodiments, it is from about 0.01 equivalents to about 0.05 equivalents. In other embodiments, it is from about 0.01 to about 0.03 equivalents.

A suitable temperature is from about 0°C to about 25°C. In some embodiments, a suitable temperature is from about 5°C to about 25°C. In other embodiments, the implementation is from about 10°C to about 20°C.

For step b) in the above processes for the preparation of a compound of formula VI or compound I

A suitable strong aqueous mineral acid is, for example, concentrated sulfuric acid (H ₂ SO ₄ ). Other aqueous mineral acids that can be used are, for example, concentrated HCl.

The corresponding amount of strong aqueous mineral acid is an excess of acid, that is, more than one equivalent of mineral acid for each equivalent of intermediate 16. In some embodiments, the corresponding amount is more than 2 equivalents. In other embodiments, the implementation is more than 3 equivalents. In yet other embodiments, it is about 4 equivalents. In other embodiments, the appropriate amount is from about 3 to about 8 equivalents.

A suitable temperature is from about 50°C to about 90°C. In some embodiments, a suitable temperature is from about 50°C to about 75°C. In other embodiments, a suitable temperature is from about 65°C to about 75°C. In still other embodiments, a suitable temperature

- 25 040047 is from about 60°C to about 80°C. In some embodiments, a suitable temperature is from about 60°C to about 75°C. In yet other embodiments, the implementation is a temperature below about 75°C.

For step c) in the above methods for preparing a compound of formula VI or compound I:

The corresponding amount of ammonia is a large excess: that is, a large excess relative to the number of equivalents of intermediate (17). In some embodiments, the implementation of a large excess is more than 5 equivalents. In other embodiments, it is from about 5 to about 12 equivalents. In other embodiments, it is about 10 equivalents or more.

A suitable protic solvent is, for example, MeOH. Other protic solvents that can be used are, for example, EtOH, iPrOH and water.

A suitable temperature is from about 18°C to about 30°C. In other embodiments, it is from about 18°C to about 25°C. In still other embodiments, it is from about 20°C to about 28°C. In yet other embodiments, it is from about 20°C to about 25°C.

In another aspect, this document describes a one-step method for the synthesis of compound IA. Compound IA is (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3yl)-1H-pyrazole-3- yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide and has the structure shown below. Compound I is an sGC stimulant that has been shown to be effective in the treatment of a number of NO related disorders in preclinical models.

Connection IA

A one-step process for preparing compound IA involves coupling an appropriate amount of amine (14A) with a chloropyrimidine of formula IV in a suitable aprotic organic solvent, optionally in the presence of an appropriate amount of a suitable base, at a suitable temperature, to give compound IA.

H ₂ N I nh ₂

F3C OH (14A)

In another aspect, this document describes an alternative method for obtaining compounds IA, including the following stages.

A) Coupling an appropriate amount of amine (14A) with dichloropyrimidine (7') in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base, at an appropriate temperature, to give an intermediate of formula XA.

XA formula

B) Dechlorination of an intermediate compound of formula XA with hydrogen gas or reagent

- 26 040047 with a transfer hydrogenation agent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at an appropriate temperature, in a suitable organic solvent, to give compound IA.

In another aspect, this document describes another method for obtaining compound IA, including the steps:

a) treating intermediate bromine (15) with an appropriate amount of trimethylsilanecarbonitrile, KCN or NaCN in the presence of an appropriate amount of a suitable organic amine, optionally in the presence of water as a solvent, at a suitable temperature, to obtain intermediate (16);

b) treating intermediate (16) with an appropriate amount of a suitable strong aqueous mineral acid, at a suitable temperature, to give intermediate (17);

c) treating intermediate (17) with an appropriate amount of ammonia, in a suitable protic solvent at a suitable temperature, to give amine (14);

d) reacting the amine intermediate (14) with an appropriate amount of (D)-malic acid in a suitable aprotic organic solvent, at a suitable temperature, to give a 1-1 salt of the chiral intermediate (18A) and (D)-malic acid; followed by crystallization to separate this salt from the unreacted enantiomeric amine (14B);

e) heating the malic acid salt (D) obtained in step d) at a suitable temperature, in a suitable solvent, to release intermediate (14A) into solution with loss of acetone, and reacting the resulting solution with a fluorochloropyrimidine intermediate of formula IV, in a suitable solvent, at a suitable temperature, optionally in the presence of an appropriate amount of a suitable organic amine, to give compound IA.

ABOUT

HN N NH ₂

D-0 ^CF 3

NO (18A) O

OH OH (D) - malic acid

In another aspect, this document describes a one-step method for the synthesis of compound IB. Compound IB is (S)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3yl)-1H-pyrazole-3- yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide and has the structure shown below. Compound IB is an sGC stimulant that has been shown to be effective in treating a number of NO related disorders in preclinical models.

_CF3

IB connection

A one-step process for preparing compound IB comprises combining an appropriate amount of amine (14B) with a chloropyrimidine of formula IV in an appropriate polar aprotic solvent, optionally in the presence of an appropriate amount of an appropriate base, at an appropriate temperature, to form compound IB.

h ₂ n X NH ₂

NO CF ₃ (14V)

- 27 040047

In another aspect, this document describes an alternative method for obtaining compounds IB, including the following stages.

A) Coupling an appropriate amount of amine (14B) with dichloropyrimidine (7') in an appropriate aprotic organic solvent, optionally in the presence of an appropriate amount of an appropriate base, at an appropriate temperature, to give an intermediate of formula XB.

_CF3

XB formula; And

B) Dechlorination of an intermediate of formula XB with hydrogen gas or a transfer hydrogenation reagent and optionally an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in a suitable organic solvent, to give compound IB.

In another aspect, this document describes another way to obtain the connection IB.

This method for preparing compound IB includes the steps:

a) treating intermediate bromine (15) with an appropriate amount of trimethylsilanecarbonitrile, KCN or NaCN in the presence of an appropriate amount of a suitable organic amine, optionally in the presence of water as a solvent, at a suitable temperature, to obtain intermediate (16);

b) treating intermediate (16) with an appropriate amount of a suitable strong aqueous mineral acid, at a suitable temperature, to give intermediate (17);

c) treating intermediate (17) with an appropriate amount of ammonia, in a suitable protic solvent at a suitable temperature, to give amine (14);

d) reacting the amine intermediate (14) with an appropriate amount of (L)-malic acid in a suitable aprotic polar solvent, at the appropriate temperature, to give the 11 salt of the chiral intermediate (18B) and (L)-malic acid; followed by crystallization to separate this salt from the unreacted enantiomeric amine (14A);

e) heating the malic acid salt (L) obtained in step d) at a suitable temperature, in a suitable solvent, to release intermediate (14B) into solution with loss of acetone, and reacting the resulting solution with a fluorochloropyrimidine intermediate of formula IV, in a suitable solvent, at a suitable temperature, optionally in the presence of an appropriate amount of a suitable organic amine, to give compound IB.

ABOUT

HN K NH ₂ λ-O CF3

NO (18V) O

He

O OH (|_)-Malic acid

For step a) in the above methods for preparing the compound compound IA or compound IB

The corresponding amount of trimethylsilanecarbonitrile (TMSCN), KCN or NaCN is slightly deficient in relation to the amount of intermediate bromine (15), i.e. slightly less than 1 equivalent of TMSCN, NaCN or KCN for each equivalent of intermediate bromine (15). In some embodiments, the appropriate amount of TMSCN, KCN, or NaCN is from about 0.9 to about 1.1 equivalents of TMSCN, NaCN, or KCN for each equivalent of intermediate bromine (15). In other embodiments, the appropriate amount is from about 0.95 to about 1 equivalent.

- 28 040047

A suitable organic amine is, for example, triethylamine (Et ₃ N). Another suitable amine is, for example, Hunig's base.

An appropriate amount of a suitable organic amine is a catalytic amount. In some embodiments, the catalytic amount is from about 0.01 equivalents to about 0.1 equivalents of amine for each equivalent of intermediate bromine (15). In other embodiments, it is from about 0.01 equivalents to about 0.05 equivalents. In other embodiments, it is from about 0.01 to about 0.03 equivalents.

A suitable temperature is from about 0°C to about 25°C. In some embodiments, a suitable temperature is from about 5°C to about 25°C. In other embodiments, it is from about 10°C to about 20°C.

For step b) in the above methods for obtaining compound IA or compound IB

A suitable strong aqueous mineral acid is, for example, concentrated sulfuric acid (H ₂ SO ₄ ). Other aqueous mineral acids that can be used are, for example, concentrated HCl.

The corresponding amount of strong aqueous mineral acid is an excess of acid, i.e. more than one equivalent of mineral acid for each equivalent of intermediate (16). In some embodiments, the corresponding amount is more than 2 equivalents. In other embodiments, the implementation is more than 3 equivalents. In yet other embodiments, it is about 4 equivalents. In other embodiments, the appropriate amount is from about 3 to about 8 equivalents.

A suitable temperature is from about 50°C to about 90°C. In some embodiments, a suitable temperature is from about 50°C to about 75°C. In other embodiments, a suitable temperature is from about 50°C to about 75°C. In yet other embodiments, this temperature is below about 75°C.

For step c) in the above methods for preparing compound IA or compound IB

The corresponding amount of ammonia is a large excess, ie a large excess relative to the amount of equivalents of intermediate (17). In some embodiments, the implementation of a large excess is more than 5 equivalents. In other embodiments, it is from about 5 to about 12 equivalents. In other embodiments, it is about 10 equivalents or more.

A suitable protic solvent is, for example, MeOH. Other protic solvents that can be used are, for example, EtOH, iPrOH and water.

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

For step d) in the above methods for preparing compound IA or compound IB

A suitable amount of (L)-malic acid or (D) malic acid is 1 equivalent of (L) or (D) malic acid per equivalent of amine (14).

A suitable aprotic polar solvent is acetone.

A suitable temperature is from about 15°C to about 55°C. In some embodiments, a suitable temperature is from about 20°C to about 55°C. In other embodiments, a suitable temperature is from about 20°C to about 40°C. In still other embodiments, a suitable temperature is from about 20°C to about 32°C. In yet other embodiments, a suitable temperature is from about 28°C to about 32°C. In other embodiments, a suitable temperature is from about 20°C to about 25°C.

For step e) in the above methods for preparing compound IA or compound IB

A suitable solvent for heating 1:1 malic acid salts of intermediates (18A) or (18B) obtained in step d) to release the amine (14A) or amine (14B) into solution is water. Another suitable solvent is a mixture of water and DMSO.

A suitable temperature for heating 1:1 malic acid salts of intermediates (18A) or (18B) obtained in step d) to release the amine (14A) or amine (14B) into solution is 10 to 40°C. In some embodiments, the implementation it is from 10 to 50°C. In other embodiments, it is approximately 40°C.

A suitable amount of intermediate amine (14A) or amine (14B) released into solution to react with intermediate of formula IV is at least one equivalent of amine (14A) or amine (14B) for each equivalent of intermediate of formula IV. In other embodiments, the amount of amine is at least two equivalents. In other embodiments, it is about 2.5 equivalents. In other embodiments, it is from about 1 equivalent to about 1.5 equivalents.

A suitable solvent for the reaction of an intermediate amine (14A) or amine (14B) with an intermediate of formula IV is dimethyl sulfoxide (DMSO). In other embodiments, it is a mixture of DMSO and water. In other embodiments, a suitable solvent that can be used is DMF or acetonitrile.

A suitable temperature is from about 80°C to about 100°C. In other embodiments, a suitable temperature is from about 85°C to about 95°C. In other embodiments, it is approximately 90°C.

A suitable optional organic amine is Hunig's base. Another suitable organic amine is, for example, Et ₃ N.

The appropriate amount of a suitable organic amine is at least one equivalent of amine for each equivalent of intermediate amine 14A or amine 14B released in the previous step. In some embodiments, a suitable amount of amine is from about 1 to about 5 equivalents of the formula IV intermediate. In other embodiments, it is from about 2 to about 4 equivalents. In yet other embodiments, it is from about 2.5 to about 3 equivalents.

For the above one-step processes for preparing compound IA or compound IB by reacting an intermediate of formula IV with an amine (14A) or an amine (14B).

The corresponding amount of amine (14A) or amine (14B) is at least one equivalent of amine (14A) or amine (14B) for each equivalent of the compound of formula IV. In some embodiments, an excess of amine (14A) or amine (14B) can be used. In some embodiments, an amount of from about 1 to about 5 equivalents of amine (14A) or amine (14B) can be used. In other embodiments, the appropriate amount is from about 1 to about 4 equivalents. In other embodiments, the implementation is from about 1 to about 3 equivalents.

A suitable optional base is, for example, the Hunig base. Other suitable optional bases are, for example, Et ₃ N, NaHCO ₃ and KHCO 3 . The intermediate amines (14A) and amine (14B), when used in excess, can also be used as the base.

An appropriate amount of a suitable optional base is at least one equivalent of an optional base for each equivalent of an intermediate of formula IV. In some embodiments, the corresponding amount is about 2 equivalents. In other embodiments, the appropriate amount is from about 0 to about 2 equivalents.

A suitable aprotic organic solvent is dimethyl sulfoxide (DMSO). Other suitable aprotic organic solvents are, for example, DMF, DMA or tert-BuOH.

A suitable temperature is from about 100°C to about 135°C. In some embodiments, a suitable temperature is from about 125°C to about 130°C.

For step A) in the above methods for preparing a compound of formula III, a compound of formula V, a compound of formula VI, a compound I, a compound IA or a compound IB

The corresponding amount of amine (13), amine (14), amine (14A) or amine (14B) is at least one equivalent of amine (13), amine (14), amine (14A) or amine (14B) for each equivalent of intermediate compound (7) or intermediate compound (7'). In some embodiments, an excess of amine (13) or amine (14) may be used. In some embodiments, an amount of from about 1 to about 3 equivalents of amine (13) or amine (14) can be used. In other embodiments, the appropriate amount is from about 1 to about 2.9 equivalents. In other embodiments, it is from about 1 to about 2.7 equivalents. In other embodiments, it is about 2.6 equivalents.

A suitable optional base is, for example, the Hunig base. Other suitable optional bases are, for example, Et3N, NaHCO3 and KHCO3. The amine (13), amine (14), amine (14A) or amine (14B) alone can also be used as the base if used in excess.

An appropriate amount of a suitable base is at least one equivalent of an optional base for each equivalent of intermediate (7) or intermediate (7'). In some embodiments, the corresponding amount is approximately 2 equivalents.

A suitable aprotic organic solvent is dimethyl sulfoxide (DMSO).

- 30 040047

Other suitable aprotic organic solvents are, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) and t-butanol (t-BuOH).

A suitable temperature is from about 50°C to about 65°C. In some embodiments, a suitable temperature is from about 55°C to about 65°C. In other embodiments, a suitable temperature is from about 57°C to about 63°C.

For step B) in the above processes for preparing a compound of formula III, a compound of formula V, a compound of formula VI, a compound I, a compound IA or a compound IB

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

An appropriate amount of a suitable metal catalyst is a catalytic amount, ie less than one equivalent of Pd per equivalent of an intermediate of Formula VII, Formula VIII, Formula IX, Formula X, Formula XA, or Formula XB. In some embodiments, an appropriate amount of a suitable metal catalyst is from 0.01 to 0.02 equivalents of Pd per equivalent of an intermediate of Formula VII, Formula VIII, Formula IX, Formula X, Formula XA, or Formula XB.

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 an intermediate of formula VII, formula VIII, formula IX, formula X, formula XA, or formula XB. 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.

The advantage of the methods described herein is that they allow the preparation of sGC promoters and formula I intermediates in high yield and purity. The present invention has the added benefit of simple reaction conditions that are easily scaled up for large scale preparation.

In one embodiment of the above methods, the compound of formula I is a compound of formula II. In other embodiments, the compound of formula I is a compound of formula III. In another embodiment, the compound of formula I is a compound of formula IV. In another embodiment, this is a compound of formula V. In yet other embodiments, this is a compound of formula VI. In yet other embodiments, the compound of formula I is compound I 3)yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)propan-2-ol). In still other embodiments, the compound of formula I is a compound of formula IA or formula IB. In still other embodiments, the implementation is a compound of formula IA. In yet other embodiments, the implementation is a compound of formula IB.

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.

Scheme 1

(4')

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

- 31 040047

NH ₂ NH-CH ₂ -(2-fluorophenyl).

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

Scheme 2

(4·)

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.

In publications US 8748442 B2, 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, via the formation of an intermediate compound (10') as illustrated for the final compound of formula IV below.

- 32 040047

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 alternative methods. They are exemplified for the final compound of formula IV in Scheme 4 below.

Scheme 4

ROS1 ₃

stage

The preparation of compounds of formula II or formula IV according to Scheme 4 has been found to offer several advantages over their preparation according to Scheme 3. Although

- 33 040047 the process shown in Scheme 3 is very short and not as scalable for large scale production as Scheme 4. Use of unsymmetrical reagents (25) and (26) or similar reagents to prepare intermediates (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.

This document also describes a new method for the preparation of compounds of formula III, formula V, formula VI or compound I using intermediate (7) or intermediate (7'), which are themselves formed from intermediates (6) and (6'). The method is summarized in Scheme 5 below. The process is exemplified for the preparation of a compound of formula V below. Similar methods will be used to prepare compounds of formula III and VI, as well as compound I.

Scheme 5

This method has an advantage over alternative methods for obtaining compounds

- 34 040047 formula III, formula V, formula VI and compound I, since it uses a symmetrical intermediate compound (7) or (7') as a starting material. From this symmetrical intermediate, prepared from symmetrical intermediates (6) and (6'), as noted above, results in overall high yields and purity of subsequent steps. Two high-yield steps give the final amine of formula V. The general process is scalable for large scale production.

Several methods for the preparation of compounds of formula VI, compound I, compound IA and compound IB were previously described in WO 2014144100. In this publication, enantiomerically pure compound IA and compound IB were obtained after chiral separation of the corresponding racemic mixture of compound I using chiral liquid chromatography. Compounds of formula VI and compound I can be prepared by reacting an intermediate of formula II or an intermediate of formula IV with the appropriate racemic amine (14). Racemic amine (14) was prepared according to Scheme 6 below from compound (17), which is commercially available, by forming an epoxide intermediate which was isolated but not purified before the next amination step.

Scheme 6

Several new alternative routes are described here for the preparation of compounds of formula VI, compounds I, compounds IA and compounds IB from intermediates of formula IV or (7'). They are shown in Scheme 7 below as an example for Compound IA. These pathways offer several advantages over those previously described.

The epoxy intermediate of Scheme 5 is a known genotoxic impurity which therefore requires special handling by the Food and Drug Administration (FDA) and potentially other regulatory authorities. Therefore, a method avoiding the use of this intermediate is desirable if the final product (eg Compound I or Compound IA) is to be used in human clinical trials.

The processes summarized in Scheme 6 avoid the formation of such an intermediate by obtaining the amine (14) directly from the intermediate (17) in one step. Intermediate (17) is produced on a large scale from readily available starting material (15) using known techniques.

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Scheme 7

The processes summarized in Scheme 7 use a chiral amine to couple to formula IV or (7') intermediates rather than a racemic mixture (14). This eliminates the need for a chiral separation of the two enantiomers of compound I or formula VI, which would be formed using racemic amine (14). It also makes the process much more efficient, in particular when only one of the two enantiomers is desired, as this minimizes waste of formula IV or (7') intermediates, which are costly and time consuming to produce on a large scale.

Surprisingly, it was found that the reaction of racemic amine (14) with (D)-malic acid in acetone leads to the formation of a previously unknown 1:1 diastereomeric salt of (18A) and (D)malic acid. This salt precipitates out of solution, leaving the unwanted amine enantiomer (14B) dissolved, providing an easy means to separate the two amine enantiomers before they are reacted with the expensive Formula IV or (7') intermediate. Similarly, when racemic amine (14) was reacted with (L)-malic acid in ketone, only the previously unknown 1:1 diastereomeric salt of new intermediate (18B) and (L)-malic acid precipitated out of solution, leaving the undesired enantiomer amine (14A) in solution. The chiral salts (18A) or (18B) thus obtained can then be heated in solution, releasing the desired chiral amines with loss of acetone, before being used in the subsequent coupling step.

This document describes the chiral preparation of Compound IA and Compound IB using the respective enantiomerically pure amines (14A) and (14B), which are chirally separated before they are reacted with intermediates.

Also disclosed are new intermediates that are useful in the methods described herein.

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. It will be further understood that the terms contain (and any of its forms, such as contains and containing), have (and any of its forms, such as has or having), 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 µm 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.

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I. 2x 2-liter solvent reservoir.

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. 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 IN 0 85 15 10 5 95 15 5 95

Retention time of selected compounds

Compound Approximate retention (min) time Isooxazole acid (1' 3-carbon 18 Compound (2') 3, 1 Compound ABOUT') 6, 2 Compound (4') 8, b Compound (5') 5, 1 Compound (b') 6, 2 Compound (7') 10, 3 Compound (8') 100 Compound (9') 8, 8 Compound (10') 7.0 Formula IV 9, 3 Compound I 8, 9

Nuclear magnetic resonance spectroscopy.

Ή NMR spectra of all compounds were recorded on a BRUKER NMR spectrometer operating at 500 MHz at room temperature. Samples dissolved in CDCI3 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 of compound (D) and N,O-dimethylhydroxylamine to give N-mctokch-N-methylisoxazole-3-carboxamide (2')

HN(MeO)Me.HCI (G)

(2')

Isooxazole-3-carboxylic acid ((G), 241.6 g, 2137 mmol, 1.0 eq.), toluene (1450 ml) and DMF (7.8 g,

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107 mmol, 0.05 eq.) was 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 charged via 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 8792° C. for 1 hour. The reaction was terminated 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)-(-5)°C. N,O-dimethylhydroxyamine hydrochloride (229 g, 2348 mmol, 1.1 eq.) was charged to a suitable reaction vessel and dissolved in water (1000 ml). The N,Odimethylhydroxyamine solution and dichloromethane (2500 ml) were then charged into the potassium carbonate solution.

The above dark oil (400 ml) was then slowly loaded through the addition funnel, maintaining the reaction temperature -10-0°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, CDCl3) 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').

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)-(-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 completed. 1 N 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 ml/100 ml/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)-1 H-pyrazole-3-carboxylate (4').

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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 loaded into the mixture. The mixture was stirred at 0-10°C for 1 hour and then heated to 20-25°C and stirred at 2025°C for 16 hours. The reaction was complete according to HPLC. Concentrated HCl (33.9 g, 37 wt.%, 344 mmol, 1.2 eq.) was loaded into the reaction mixture for 1 min and the temperature of the mixture was exothermic from 20°C to 38°C. Received a suspension. The mixture was cooled to 0-10°C for 1 h and stirred at 0-10°C for 1 h. 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). ¹ H-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); 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, 2H); 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').

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, 3 N, 19.2 mol, 19.2 eq.) was then slowly loaded through the addition funnel while maintaining the reaction temperature at 20-45°C. The mixture was heated to 80-85°C and stirred at 80-85°C for 10 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 40-50° C. for 24 h to give intermediate (5') as an off-white solid (292 g, 91% yield, >99% HPLC purity). ¹ H-NMR (500 MHz, DMSO-d ₆ ) 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, 2H). M.R. 180-185°C.

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

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Intermediate (5') (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 of 20-35°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 ml/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 d6) 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); 7.187.25 (m, 1H); 7.10-7.15 (m, 2H); 6.97-7.02 (t, J=7.55 Hz, 1H); 5.88 (s, 2H).

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

(6') (7')

Intermediate (6') (264 g, 711 mmol, 1.0 eq.), acetonitrile (4000 ml) and N,Ndimethylaniline (138 g, 1137 mmol, 1.6 eq.) were loaded into a suitable reaction vessel equipped with a mechanical stirrer and 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 completed according to 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 ml/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, CDCl ₃ ) 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').

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(7') (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 35-45° 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, CDCl ₃ ) 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').

(8') (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 triethylamine (91 g, 897 mmol, 1.6 eq.) were loaded 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 ').

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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, DMSOd 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); 7.177.28 (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).

(YU')

Formula IV

Intermediate (10') (214 g, 602 mmol, 1.0 eq.), acetonitrile (3000 ml) and N,Ndimethylaniline (109 g, 899 mmol, 1.5 eq.) were loaded into a suitable reaction vessel equipped with a 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 ml/500 ml) 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). 1H NMR (500 MHz, CDC^) δ ppm 8.65 (s, 1H); 8.48 (d, J=1.68 Hz, 1H); 7.44 (s, 1H); 7.21-7.25 (m, 1H); 6.97-7.06 (m, 2H); 6.83-6.87 (m, 1H); 6.61 (d, J=1.68 Hz, 1H); 6.03 (s, 2H).

a) Cyanation of intermediate (15) to give 2-(bromomethyl)-3,3,3-trifluoro-2((trimethylsilyl)oxy)propanenitrile (16).

Trimethylsilanecarbonitrile (153 g, 1.54 mol, 0.97 eq.) and triethylamine (4.44 ml, 3.22 g, 0.032 mol, 0.02 eq.) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. . The mixture was cooled to 5°C. 3-Bromo-1,1,1-trifluoropropan-2-one ((15), 304 g, 1.59 mol,

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1.0 equiv.) was loaded through an addition funnel for 35 min, maintaining the reaction temperature from 10 to 20°C. The mixture was stirred at 20-30° C. for 3 hours after addition to give intermediate (16) as a thick oil, which was used directly in the next step.

¹ H-NMR (500 MHz, CDC13) δ ppm 3.68 (d, J=11.14 Hz, 1H); 3.57 (d, J=11.14 Hz, 1H), 0.34-0.37 (m, 9H).

b) Conversion of the nitrile of compound (16) to an amide to give 2-(bromomethyl)-3,3,3-trifluoro-2hydroxypropanamide (17).

(17) (16)

Concentrated sulfuric acid (339 ml, 6.37 mol, 4.0 eq.) was stirred in a suitable reaction vessel equipped with a mechanical stirrer, digital thermometer and addition funnel.

Sulfuric acid was heated to 45°C. The above intermediate (16) was added via an addition funnel over 50 minutes keeping the temperature below 75°C. The reaction mixture was stirred at 75°C for 2 h and then allowed to cool to room temperature. 1H-NMR showed that the reaction was complete. The reaction mixture was cooled to -15°C and diluted with ethyl acetate (1824 ml) via an addition funnel over 45 min (very exoteric), maintaining the temperature from -15 to 5°C. Water (1520 ml) was slowly added via an addition funnel over 1 h 20 min (very exoteric) from -10 to 0°C. The layers were separated and the organic layer was washed with 15% aqueous sodium chloride solution (1520 ml), 25% aqueous sodium carbonate solution (911 ml) and then with 15% aqueous sodium chloride solution (911 ml). The organic layer was filtered and concentrated under reduced pressure to give 348 g of intermediate (17) as a light yellow oil. This oil was dissolved in methanol (1200 ml) and concentrated to give 380 g of intermediate (17). (296 g adjusted weight, 79% yield). 1H-NMR (500 MHz, CDC13) δ 6.61-6.94 (m, 1H); 5.92-6.26 (m, 1H); 3.93-4.00 (m, 1H); 3.68 (d, J=11.14 Hz, 1H).

c) N-alkylation of the hydroxypropanamide compound (14).

(17) to give 2-(aminomethyl)-3,3,3-trifluoro-2-

_NH3

Meon

(17) (14) A solution of ammonia in methanol (600 ml, 4.28 mol, 10 eq.) was charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to 0-5°C. Intermediate (17) (102 g, 0.432 mol, 1 eq.) was then added via addition funnel over 30 min at 0-5°C. The reaction mixture was heated to 20-25° C. for 1 hour and kept for 72 hours. The reaction was complete according to HPLC. The reaction mixture was cooled to 0-5°C and sodium methoxide (78 ml, 5.4 M, 0.421 mol, 0.97 eq) was added over 2 minutes. The reaction mixture was then concentrated under reduced pressure to a volume of 300 ml. 2 L of ethyl acetate was added and concentration was continued under reduced pressure to a volume of 700 ml to obtain a suspension. 700 ml of ethyl acetate was added to the suspension to bring the final volume to 1400 ml. 102 ml of water was added and stirred for 2 minutes to give a biphasic solution. The layers were separated. The ethyl acetate layer was concentrated under reduced pressure to a volume of 600 ml. Then the ethyl acetate layer was heated to >60°C and slowly added heptane (600 ml) from 55 to 60°C. The mixture was cooled to 15-20°C to obtain a suspension. The suspension was stirred at 15-20°C for 2 h and filtered. The solids were dried in vacuo at 25° C. for 16 h to give the amine (14) as a white solid (48 g, 64% yield). 1H-NMR (500 MHz, MeOH-d4) δ ppm 2.94 (d, J=13.73 Hz, 1H); 3.24 (d, J=13.58 Hz, 1H).

d) Chiral resolution of amine (14) as 1:1 salt of (R)-2,2-dimethyl-5-(trifluoromethyl)oxazolidine 5-carboxamide (R)-2-hydroxysuccinate (18A) and salt of (D)-malic acid .

- 44 040047

Amine (14) (105 g, 0.608 mol, 1.0 eq.), (D)-malic acid (82 g, 0.608 mol, 1.0 eq.) and acetone (1571 ml) were charged into a suitable reaction vessel equipped with mechanical stirrer and digital thermometer. The reaction mixture was stirred at 20-25° C. for 16 hours. The resulting suspension was filtered and the wet cake was washed with acetone (300 ml). The wet cake was loaded back into the reaction vessel and loaded with acetone (625 ml). The slurry was heated to 53° C. and held for 6 hours. The slurry was cooled to 20-25° C. and kept at this temperature for 16 hours. The slurry was filtered and the wet cake was washed with acetone (200 ml). The wet cake was dried in vacuo at 40° C. for 4 hours to give 82.4 g of the salt (18A) and (D)-malic acid 1:1 as a white solid (82.4 g, 39% yield, 97 % ee). ¹ H-NMR (500 MHz, D2O) δ ppm 4.33 (br s, 1H); 3.61 (brd, J=13.58 Hz, 1H); 3.40-3.47 (m, 1H); 2.76 (brd, J=15.87 Hz, 1H); 2.53-2.63 (m, 1H); 2.16 (br s, 4H).

e) 1:1 coupling of the (D)-malic acid salt of intermediate (18A) and formula IV to give (R)-3,3,3-trifluoro-2-(((5-fluoro-2-( 1 -( 2-fluorobenzyl)-5-(isoxazol-3-yl)-1 H-pyrazol-3-yl)pyrimidin4-yl)amino)methyl)-2-hydroxypropanamide (compound IA).

1:1 salt of intermediate (18A) and (D)-malic acid (74.1 g, 0.214 mol, 2.5 eq.) and water (44.8 ml) were charged into a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 70°C and stirred for 20 min. The acetone formed during the reaction was removed by purging with nitrogen. The reaction mixture was cooled to 3040°C and loaded with the compound of formula IV (32 g, 0.086 mol, 1.0 eq.), DMSO (448 ml) and Hunig's base (44.7 ml, 0.257 mol, 3.0 eq.). The reaction mixture was heated to 90°C and stirred at 90°C for 17 hours the Reaction was completed using HPLC. The mixture was then cooled to 60°C. Another portion of Hunig's base (104 ml, 0.599 mol, 7.0 eq.) was loaded followed by water (224 ml) at 55-62°C. The reaction mixture was stirred for 15 min at 55-60°C to form a seed layer. Water (320 ml) was added via an addition funnel at 55-62°C over 30 minutes and the resulting suspension was stirred for 1 hour at 55-60°C. The resulting suspension was filtered and the filter cake was washed with a pre-mixed solution of methanol and water (320 ml/320 ml), then with water (640 ml). The filter cake was then dried in vacuo at 40° C. for 16 h to give compound IA as an off-white solid (40 g, 92% yield, 99% HPLC purity, 98% ee). ¹ H-NMR (500 MHz,

DMSO-d6) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, br, 1H); 7.90 (s, 1H); 7.78 (s, br, 1H); 7.69 (s, br, 1H); 7.52 (s, 1H); 7.33 (kv, J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1H); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

Example 2: methods on the scale of kilograms.

i) Coupling of compound (1') and N,O-dimethylhydroxylamine to give N-methoxy-N-methylisoxazole-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 a 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 observed

- 45 040047 vigorous outgassing. A brown mixture was obtained after the addition. The brown mixture was held at 45-55°C for 30 minutes 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 into 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. N,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 N,Odimethylhydroxylamine in dichloromethane, with vigorous stirring, maintaining the reaction temperature from -10 to 0°C over a period of 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)-(-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 a temperature below -55°C for 10 minutes. Then 2N 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 by ¹ H-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°C 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 in high vacuum at 40° C. for 16 h to give intermediate (4') as an off-white solid (2.538 kg, 57% yield, 98.8% HPLC purity) .

iv) Amination of compound (4') to give 1-(2-fluorobenzyl)-5-(uzoksαzol-3-yl)-1H-nyrαzol-3carboximidamide 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 charged over 2 h through an addition funnel while maintaining the reaction temperature at 20-40° C. (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 I-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. Then the mixture was 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 2040°C and methanol (2.94 L, 72.6 mol, 10.6 eq.) was charged over 1 hour via an addition funnel while maintaining the reaction temperature at 20-40°C. (Note: very exothermic cooling and large amounts of gas were observed). A thick suspension was obtained. 3 N HCl (26.3 L, 78.9 mol, 11.5 eq.) was charged through an addition funnel while maintaining the reaction temperature at 20-45°C. The mixture was heated to 82-85°C and stirred for 10 min to obtain a clear biphasic mixture. The mixture was cooled to 20-25°C over 2 hours and stirred 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 constant weight to give intermediate (5'B) as an off-white solid (2.015 kg, 91% yield, 96% HPLC purity). ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ ppm 9.52 (s, 2H); 9.33 (s, 2H); 9.18 (d, J=1.53 Hz, 1H); 7.88 (s, 1 H); 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, 2H). M.R. 180-185°C.

v) Cyclization of compound (5') 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') (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 hour 30 minutes 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 washed with a premixed solution of methanol and water (8.35 L/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,Ndimethylaniline (1.98 L, 15.6 mol, 1.6 eq.) was mixed in a 100 L jacketed reaction vessel equipped with a nitrogen inlet/outlet, a thermocouple, a condenser, an addition funnel and an 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 7080°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')=0.4). 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 on 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 hours and then the wet cake was dried in vacuo at 50° C. for 50 hours 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 eq.) was loaded into the reaction mixture in small portions (40-60 g each portion) over 1 h

- 47 040047 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 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 suspension, 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 content of tetrahydrofuran was confirmed to be <1 wt% by ¹ H-NMR. The resulting suspension was filtered on 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, yielding intermediate (9') as a white solid (1.54 kg, 90% yield, 98 .4% HPLC purity).

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 terminated by 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, yield 96%, 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 N,Ndimethylaniline (1.41 L, 1.348 kg, 11.12 mol, 1 49 eq) was mixed in a 100 L jacketed reaction vessel with nitrogen inlet, 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 by 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 added slowly over 40 minutes. through an addition funnel, 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) Cyanation of intermediate (15) to give 2-(bromomethyl)-3,3,3-trifluoro-2((trimethylsilyl)oxy)propanenitrile (16).

Trimethylsilanecarbonitrile (2.52 kg, 25.4 mmol, 0.97 eq.) and triethylamine (0.073 L, 0.053 kg, 0.52 mol, 0.02 eq.) were mixed in a 12 L round bottom flask equipped with a mechanical stirrer, dropping funnel and digital thermometer. The mixture was cooled to 10-15°C. 3-Bromo-1,1,1-trifluoropropan2-one ((15), 5.0 kg, 26.2 mol, 1.0 eq.) was loaded through an addition funnel for 40 min, maintaining

- 48 040047 reaction temperature from 0 to 15°C. The reaction mixture was then stirred at 20-25°C for 1 hour.

1H-NMR of the reaction sample showed that the reaction was complete (area:area % (15): (16) < 1%)) and intermediate (16) was obtained as a thick oil. This intermediate (16) was used directly in the next step without further purification. ¹ H-NMR (500 MHz,

CDCl·,) δ ppm 3.68 (d, J=11.14 Hz, 1H); 3.57 (d, J=11.14 Hz, 1H), 0.34-0.37 (m, 9H).

b) Conversion of the nitrile intermediate (16) to 2-(bromomethyl)-3,3,3-trifluoro-2hydroxypropanamide (17).

Concentrated sulfuric acid (7.5 L, 136 mol, 5.2 eq.) was stirred in a 75 L jacketed reactor. Sulfuric acid was heated at 40-45°C, then the intermediate compound (16) obtained above was added through an addition funnel for 1 hour, maintaining the temperature below 75°C. The reaction mixture was stirred at 65-75°C for 2 h and then left to cool to 20-25°C and kept at this temperature for 17 h. The reaction mixture was cooled to (-15)-(-5)°C and diluted ethyl acetate (35 L) via an addition funnel for 2 h (very exoteric), maintaining the temperature at -15 to -5°C. Water (25 L) was added via an addition funnel over 1 h 30 min (very exoteric) maintaining the temperature at -15 to -5°C. The reaction mixture was heated to and kept at 0-5°C. The layers were separated and 15% aqueous sodium chloride solution (13.5 L) was added to the organic layer, followed by addition of 20% aqueous sodium bicarbonate solution (13 L) over 5 minutes while maintaining the temperature at 5 to 20°C. The mixture was stirred for 10 min and the layers were separated. The organic layer was washed with 15% aqueous sodium chloride solution (13.5 L). The organic layer was transferred through a pre-column filter through a gas dispersion tube (large frit) to a 20 L rotary evaporator and concentrated under reduced pressure until no more distillate was observed to give 8.38 kg of crude intermediate (17) as light yellow oil, which contained 72 wt.% intermediate compound (17) according to the analysis of 1H-NMR. This oil was dissolved in methanol (10 L) and concentrated again to give 8.47 kg of crude intermediate (17). (6.04 kg corrected weight, 98% yield). 1H-NMR (500 MHz, CDCI3) δ 6.61-6.94 (m, 1H); 5.92-6.26 (m, 1H); 3.93-4.00 (m, 1H); 3.68 (d, J=11.14 Hz, 1H).

c) N-alkylation of compound (17) to give 2-(aminomethyl)-3,3,3-trifluoro-2hydroxypropanamide (14).

n ammonia in methanol (41.5 L, 291 mol, 11.4 eq.) was stirred in a 75 L reactor. The solution was cooled to -10-10°C. The above crude intermediate (17) (6.04 kg, 25.6 mol, 1.0 eq) was then added via an addition funnel over 3 minutes. The reaction mixture was heated to 20-30°C for 1 h and kept at this temperature for 16 h. The reaction mixture was cooled to 010°C and sodium methoxide (4.53 L, 5.4 M, 24.5 mol, 0 .96 eq.) was added over 2 minutes. Then the reaction mixture was divided into 4 equal parts and processed. Each batch was concentrated under reduced pressure to a volume of 6.0 L and ethyl acetate (15.1 L) was continuously charged under distillation to azeotropically remove methanol to a volume of 6.0 L as a slurry. This process was repeated for the remaining three parts. All 4 parts ethyl acetate slurries were transferred to a 75 L jacketed reactor and more ethyl acetate was added to bring the volume to 65 L. Water (6.0 L) was added and the reaction mixture was vigorously stirred for 20-30 minutes and then allowed to separate for at least 12 hours.

The ethyl acetate layer was then divided into 4 equal parts and processed. Each portion was concentrated under reduced pressure to a volume of 6.0 L. This process was repeated for the remaining three parts. All 4 portions were transferred to a 75 L jacketed reactor and ethyl acetate was added to bring the volume to 36.2 L. The reaction mixture was heated to 55-60°C and heptane (36.2 L) was added over 30 minutes maintaining the temperature above 50°C. The resulting suspension was cooled to 20-25°C over 30 min, maintained at 20-25°C for 1 h, and filtered through a 45 cm Buchner funnel. Ethyl acetate (6.0 L) and heptane (12.1 L) were charged into the reactor, the mixture was stirred for 2 min 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 2530° C. for 36 h to give the amine (14) at constant weight as an off-white solid (2.52 kg, 57% yield). 1 H-NMR (500 MHz, MeOH-d4) 5 ppm 2.94 (d, J=13.73 Hz, 1H); 3.24 (d, J=13.58 Hz, 1H).

d) Chiral resolution of amine (14) as 1:1 (R)-2,2-dimethyl-5-(trifluoromethyl)oxazolidine-5carboxamide (R)-2-hydroxysuccinate (18A): (D)-malic acid salt.

Amine (14) (2.0 kg, 11.6 mol, 1.0 eq.) and acetone (10.0 L) were mixed in a 22 L round bottom flask equipped with a mechanical stirrer, addition funnel and digital thermometer. The reaction mixture was stirred at low speed at 20-25°C until a solution was obtained.

Separately, D-(+)-malic acid (1.56 kg, 11.6 mol, 1.0 eq.) and acetone (30 L) were stirred in a 100 L jacketed reactor. The reaction solution was heated to 33-38°C. Then, 20% of the above amine (14) in acetone was charged to a 100 L jacketed reactor in one portion, followed by a 1:1 suspension of the salt of intermediate (18A) and (D)-malic acid (0.52 g) in acetone (20 ml ) as a seed. The remaining 80% amine (14) in acetone was then loaded into a 100 L jacketed reactor for a minimum of 1 hour while maintaining the reaction temperature from 33 to 38°C. The reaction mixture was cooled

- 49 040047 to 28-32°C evenly over a minimum of 2 hours and stirred at 28-32°C for a minimum of 12 hours.

The resulting suspension was filtered at 28-32° C. and the filter cake washed with acetone (16.0 L). (Note: care was taken to ensure that the filter cake did not dry out at the beginning of the filtration.) The filter cake was then dried in vacuo at 30°C for 8 h to constant weight to give a 1:1 salt of intermediate (18A) and (D)-malic acid as an off-white solid (1.53 kg, 38% yield, RR:SR=97:3 by chiral GC). ¹ H-NMR (500 MHz, D2O) δ ppm 4.33 (br s, 1H); 3.61 (brd, J=13.58 Hz, 1H); 3.40-3.47 (m, 1H); 2.76 (brd, J=15.87 Hz, 1H); 2.532.63 (m, 1H); 2.16 (br s, 4H).

e) Coupling of formula IV and a 1:1 salt of intermediate (18A) and (D)-malic acid to give (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1- (2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (compound IA).

A 1:1 salt of intermediate (18A) and (D)-malic acid (0.81 kg, 2.34 mol, 1.25 eq.) and water (0.98 L) were charged to a 30 L jacketed reaction vessel. The reaction mixture was stirred at low speed and the jacket was heated to 65-70°C and maintained at this temperature for 30 minutes. The acetone formed during the reaction was removed using a slight vacuum. The reaction mixture was cooled to 20-40°C and loaded with the compound of formula IV (0.70 kg, 1.87 mol, 1.0 eq.), DMSO (9.8 L) and Hunig's base (0.82 L, 4. 71 mol, 2.5 eq.). The reaction mixture was heated to 88-93° C. for 2 hours and kept at 88-93° C. for 20 hours. The reaction was complete according to HPLC (area/area % formula IV:compound IA=0.5). The mixture was then cooled to 50-60°C. The mixture was then cooled to 60°C. Another portion of Hunig's base (1.96 L, 11.3 mol, 6.0 eq.) was charged followed by water (4.9 L) for 15 min at 50-60°C. The reaction mixture was stirred for 15 min at 50-60°C to form a seed layer. Water (7.0 L) was added via an addition funnel at 50-60°C over 30 minutes and the mixture was held at 50-60°C for 30 minutes. The resulting suspension was filtered at 50 to 60° C. and the filter cake was washed with a premixed solution of methanol and water (3.5 L/3.5 L). The filter cake was then dried in vacuo at 50° C. for 16 h to constant weight to give the crude compound IA as an off-white solid (0.83 kg, 87% yield). ¹ H-NMR (500 MHz, DMSO-d6) δ ppm 9.10 (s, 1H); 8.33 (d, J=2.90 Hz, 1H); 7.93 (s, br, 1H); 7.90 (s, 1H); 7.78 (s, br, 1H); 7.69 (s, br, 1H); 7.52 (s, 1H); 7.33 (kv, J=7.02 Hz, 1H); 7.17-7.25 (m, 1H); 7.17-7.25 (m, 1H); 7.10 (t, J=7.48 Hz, 1H); 6.98 (t, J=7.55 Hz, 1H); 5.90 (s, 2H); 3.92-4.05 (m, 2H).

Claims (10)

Claim 1. The method of obtaining compound I, including: a) amine condensation (14) with dichloropyrimidine (7') - 50 040047 in an aprotic organic solvent, in the presence of a base, to give an intermediate compound of formula X nh ₂ formula X ; And b) dechlorination of an intermediate of formula X with hydrogen gas in the presence of a metal catalyst, in the presence of a base, in an organic solvent. 2. The method of claim 1, further comprising: a) processing of the bromo intermediate (15) CF ₃ (15) with trimethylsilanecarbonitrile, KCN or NaCN, in the presence of an organic amine, in the presence of water as a solvent, to give intermediate (16); b) processing of the intermediate connection (16) an aqueous solution of a strong mineral acid, to obtain an intermediate compound (17) O Br nh ₂ '3 (17) ; And c) treating intermediate (17) with ammonia, in a suitable protic solvent, to give amine (14). 3. Method for preparing compound IA - 51 040047 H comprising the condensation of an amine (14A) (14A) with a fluorochloropyrimidine of formula IV formula IV in an aprotic organic solvent, in the presence of a base, where the amine (14A) is obtained by: i) reacting the amine intermediate (14) with D-malic acid in an aprotic organic solvent to give a 1:1 salt of the chiral intermediate (18A) and (D)malic acid ABOUT HN NH ₂ V-O ^CF 3 NO (18A) O HE OH (D) - malic acid followed by crystallization to isolate the indicated salt form from the unreacted enantiomeric amine (14B) ii) heating the (D)-malic acid salt obtained in step d) in a solvent to release intermediate (14A) - 52 040047 including a) amine condensation (14A) into solution with loss of acetone. 4. Method for the preparation of compound IA with dichloropyrimidine (7') in an aprotic organic solvent, in the presence of a base, to obtain an intermediate compound of formula XA F _CF3 Formula XA; And b) dechlorination of an intermediate of formula XA with hydrogen gas in the presence of a metal catalyst in an organic solvent. 5. Method for preparing compound IA - 53 040047 including a) treatment of the bromo intermediate (15) with trimethylsilanecarbonitrile, KCN or NaCN, in the presence of an organic amine, in the presence of water as a solvent, to obtain an intermediate compound (16) b) treating intermediate (16) with an aqueous solution of a strong mineral acid to give intermediate (17) c) treating intermediate (17) with ammonia, in a protic solvent, to give amine (14) F ₃ C O (14) d) reacting the amine intermediate (14) with (D)-malic acid in an aprotic organic solvent to give a 1:1 salt of the chiral intermediate (18A) and (D)-malic acid About /hyazh ΗΝ Λ ΝΗ ₂ α-ό ^CF3 NO (18A) O HE OH(D)-malic acid followed by crystallization to separate said salt from the unreacted enantiomeric amine (14B) - 54 040047 h ₂ n >< nh ₂ ^but CF ₃ e) heating the (D)-malic acid salt obtained in step d) in a solvent to release intermediate (14A) (14B) η ₂ ν zf νη ₂ F ₃ C OH (14A) into a solution with the loss of acetone and the interaction of the resulting solution with an intermediate fluorochloropyrimidine of the formula IV F formula IV in a solvent, in the presence of an organic amine. 6. Method for preparing compound IB comprising the condensation of an amine (14B) with a chloropyrimidine of formula IV - 55 040047 formula IV in a polar aprotic solvent, in the presence of a base, where the amine (14B) is obtained by: i) interactions of intermediate (14) (14) with (L)-malic acid in an aprotic organic solvent to give a 1:1 salt of chiral intermediate (18B) and (L)-malic acid ABOUT (18V) O O OH ([_)- malic acid followed by crystallization to separate this salt from the unreacted enantiomeric amine (14A) ii) heating the (L)-malic acid salt obtained in step i) in a solvent to release intermediate (14B) O NH ₂ HO CF ₃ (14V) into solution with loss of acetone. 7. Method for preparing compound IB - 56 040047 with dichloropyrimidine (7') comprising: a) amine condensation (14B) in an aprotic organic solvent, in the presence of a base, to give an intermediate compound of formula XB XV formula b) dechlorination of an intermediate of formula XB with hydrogen gas in the presence of a metal catalyst, in the presence of a base, in an organic solvent. 8. Method for preparing compound IB - 57 040047 including: a) treatment of intermediate bromine (15) with trimethylsilanecarbonitrile, KCN or NaCN, in the presence of an organic amine, in the presence of water as solvent, to obtain intermediate (16); b) processing of the intermediate connection (16) with an aqueous solution of a strong mineral acid, to obtain intermediate compound (17) c) treating intermediate (17) with ammonia, in a protic solvent, to give amine (14) d) reacting the amine intermediate (14) with (L)-malic acid in an aprotic polar solvent to give a 1:1 salt of the chiral intermediate (18B) and (L)-malic acid O /HHH ΗΝ νη ₂ D-0 ^CF 3 NO (18V) O ABOUT HE OH ([_)- malic acid followed by crystallization to separate this salt from the unreacted enantiomeric amine (14A) - 58 040047 e) heating the (L)-malic acid salt obtained in step d) in a solvent to release intermediate (14B) into a solution with the loss of acetone and the interaction of the resulting solution with an intermediate fluorochloropyrimidine of the formula IV formula IV in a solvent, in the presence of an organic amine. 9. Connection selected from 1:1 salt of compound (18A) with (D)-malic acid CF ₃ formula X 10. Connection selected from - 59 040047 (18A) (D)- malic acid 1:1 salt of compound (18B) with (b)-malic acid