NZ614173B2 - Synthesis of 2-carboxamide cycloamino urea derivatives - Google Patents

Abstract

Provided herein are processes and intermediate compounds useful for the preparation of (1,3-Thiazol-2-yl)Pyrrolidine-1,2-Dicarboxamide Derivatives derivatives of formula (X), and useful intermediates (such as compounds of formula (V)) therefore. in particular synthetic methods for the preparation of (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (i.e., the compound of formula (10), alpelisib or BYL-719). also disclosed is compound (1) (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (i.e., the compound of formula (10), alpelisib or BYL-719). also disclosed is compound (1)

Description

SYNTHESIS OF 2-CARBOXAMIDE CYCLOAMINO UREA DERIVATIVES FIELD OF INVENTION The present invention is directed to processes for preparing oxamide cycloamino urea derivatives, and useful intermediates therefore.

BACKGROUND The processes of the present invention are useful for the preparation of alpha-selective phosphatidylinositol (PI) 3-kinase inhibitor nds according to formula (X), and intermediates therefore. Phosphatidylinositol 3-kinases (P13Ks) comprise a family of lipid kinases that catalyze the transfer ofphosphate to the D-3' position of inositol lipids to produce phosphoinositolphosphate (PIP), phosphoinositol-3,4—diphosphate (PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3), which, in turn, act as second gers in signaling cascades by docking proteins containing pleckstrin—homology, FYVE, Phox and other olipid-binding domains into a variety of signaling complexes often at the plasma membrane.

PCT Publication No. discloses PI3K inhibitors. The compounds sed therein include (S)-pyrrolidine-1,2-dicarboxylic acid 2-amide l-( {4-methy1—5—[2- (2,2,2-trifluoro-1,1-dimethyl—ethyl)-pyridinyl]-thiazolyl}-amide) (i.e., the compound of a (10)). The present invention is directed to improved ses for preparing compounds of the formula (X), specifically the compound of formula (10), as well as useful intermediates such as nds of the formula (I), specifically the compound of formula (1): N N HN—\< NH2 NH2 N, O o N, o 0 \ s 3 R2 \ H30 CH3 CH3 N/ / CF3 CF3 R1 N/ R1 N/ H30 CH3 H30 CH3 (X) (10) (l) (1) SUMMARY OF THE INVENTION Provided herein are processes for the preparation of compounds of formula (X). Also provided herein are intermediate compounds, as well as methods of making those intermediates, that are useful for the preparation of compounds of formula (X). The compounds of formulas ) and the compounds of formulas (1) to (8) and (10) refer to the compounds as defined in the description herein.

In one aspect of the present invention, there is provided a process for making a compound of formula (X): N/ O 0 N R1 comprising the following steps: Step A: contacting a compound of formula (I) with a solvent ydrofuran and a base lithium diisopropylamide, and contacting the resulting mixture with a compound of formula (II) at an internal ature of less than about -5°C to about -15°C, such that a compound of formula (III) is produced: (followed by page 2a) CH3 R2 \ 0 \ / )L ,OCH3 l R2 '1‘ / N R1 N R1 0) (II) (III) Step B: contacting a compound of formula (III) with thiourea, in a reaction mixture comprising a solvent selected from toluene, ethanol or a combination thereof and an oxidizing agent N—bromosuccinimide, such that a nd of a (V) is produced: Step C: contacting a compound of formula (V) with a compound of formula (VII), in a reaction mixture comprising a solvent tetrahydrofuran and a base amine, such that a compound of formula (VIII) is produced: N/ O O \ (VII) (VIII) Step D: contacting a compound of formula (VIII) with the compound of a (IX), (followed by page 2b) 0 H (IX) in a reaction mixture comprising a solvent selected from tetrahydrofuran, water or a combination thereof, such that a compound of formula (X) is produced wherein R1 is a branched or linear C1-C7 alkyl, which may be optionally substituted one or more times With deuterium, halogen, or C3-C5 cycloalkyl, R2, is methyl R3 is halogen, R4 is C6-C14 aryloxy and X is a halide.

In a further aspect of the present invention, there is provided a s for making the compound of formula (10): N/ cF3 H3C CH3 (10) comprising the following steps: M: contacting the nd of formula (1) with a solvent tetrahydrofuran and a base lithium diisopropylamide, and contacting the resulting mixture with the compound of formula (2) at an internal temperature of less than about -5°C to about -15°C, such that the compound of a (3) is ed: (followed by page 20) CH3 H30 \ 0 \ 'N/ CF3 HstLlfl’OCHs’ 'N/ CF3 H3C CH3 CH3 H30 CH3 (1) (2) (3) ; Step B: contacting the compound of formula (3) with thiourea, in a reaction mixture comprising a solvent ed from toluene, l or a combination thereof and an oxidizing agent N-bromosuccinimide, such that the compound of formula (5) is produced: Step C: contacting the compound of formula (5) with the nd of formula (7), in a reaction mixture comprising a solvent tetrahydrofiiran and a base amine, such that the compound of formula (8) is produced: N/ 0 <1 ° '\ OACI N/ CF3 H30 CH3 (7) (3) ;and Step D: contacting the compound of formula (8) with the compound of formula (IX) (followed by page 2d) 0 H (IX) in a reaction mixture comprising a solvent selected from tetrahydrofuran, water or a combination f, such that the compound of formula (10) is produced.

Also described herein is a process for making a compound of a (V) - HX N R1 comprising contacting a nd of formula (I) with a solvent and a base and contacting the resulting mixture with a compound of formula (11), such that a compound of a (III) is produced (STEP A). The compound of formula (III) is then contacted with thiourea, in a reaction mixture comprising a solvent and an oxidizing agent, such that a compound of formula (V) is produced (STEP B). (followed by page 3) Also described herein is a process for making a nd of formula (X) N/ O 0 N R1 comprising contacting a nd of formula (V) with a compound of formula (VII), in a reaction mixture comprising a solvent and a base, such that a compound of a (VIII) is produced (STEP C). The compound of formula (VIII) is then contacted with the compound of formula (IX) in a reaction mixture comprising a solvent, such that a compound of formula (X) is produced (STEP D).

In still another aspect, provided herein is a process for making a compound of formula (X), comprising contacting a compound of formula (I) with a solvent and a base, and ting the resulting mixture with a compound of formula (11), such that a compound of formula (III) is produced (STEP A); contacting a compound of formula (III) with thiourea, in a reaction mixture comprising a solvent and an oxidizing agent, such that a compound of formula (V) is produced (STEP B); contacting a compound of formula (V) with a compound of formula (VII), in a reaction e comprising a solvent and a base, such that a compound of formula (VIII) is produced (STEP C); and contacting a compound of formula (VIII) with the nd of formula (IX) in a reaction mixture comprising a solvent, such that a compound of formula (X) is produced (STEP D).

In accordance with the t invention, the solvent of Step A comprises one or more ts selected from aromatic solvents, aliphatic solvents, halogenated solvents, polar aprotic ts and ethereal solvents.

In accordance with the present invention, the solvent of Steps B, C and D independently comprises one or more solvents selected from aromatic solvents, aliphatic solvents, halogenated solvents, ethereal solvents, polar aprotic solvents, water and alcohol solvents.

Also described herein is a process for making the compound of formula (10), comprising contacting the compound of formula (1) with a solvent and a base, and contacting the resulting mixture with a compound of formula (2), such that the compound of a (3) is produced (STEP A). The compound of formula (3) is then contacted with thiourea, in a reaction mixture comprising a t and an ing agent, such that the nd of formula (5) is produced (STEP B). The compound of formula (5) is next contacted with the compound of formula (7), in a reaction mixture comprising a t and a base, such that the nd of formula (8) is produced (STEP C). Finally, the compound of formula (8) is contacted with the compound of formula (IX), in a reaction mixture comprising a solvent, such that the compound of formula (10) is produced (STEP D).

In one embodiment of the synthesis of the compound of formula (10), the solvent of Step A comprises ydrofuran, the base of Step A is lithium diisopropylamide, the solvent of Step B comprises toluene and ethanol, the oxidizing agent of Step B is N-bromosuccinimide, the solvent of Step C comprises tetrahydrofuran, the base of Step C is pyridine and the solvent of Step D comprises tetrahydrofuran and water.

In a r aspect of the t invention, there is provided a compound according to a (1).

DETAILED DESCRIPTION Provided herein are processes and intermediate compounds useful for the preparation of PI3K inhibitors. These processes are advantageous over previously—known processes (see, e.g., PCT Publication No. ) in several ways. For e, the instant processes do not employ transition metal-catalyzed reactions, and therefore do not require steps to remove transition metal byproducts, es and impurities. Additionally, the instant processes do not require reactions to be performed at very low temperatures (e.g., —78 °C). 2012/053559 In one aspect of the present invention, ed herein is a process for making a compound of formula (V), sing the following steps: Step A: contacting a compound of formula (I) with a solvent and a base, and contacting the resulting mixture with a compound of a (11), such that a compound of formula (III) is produced: CH3 1. Base R2 \ \ I, 2. O I/ N R1 )L ,OCH3 N R2 r}: CH3 ; then H30+ (I) (II) (III) ; and Step B: contacting a compound of formula (III) with thiourea, in a reaction mixture comprising a solvent and an oxidizing agent [X+], such that a compound of formula (V) is produced: o N:( s \ 3 R2 JL R2 H2N NH2 \ \ I I N/ R1 N’ R [x+] 1 (III) (V) wherein R1 is a cyclic or acyclic, branched or linear C1-C7 alkyl, which may be optionally substituted one or more times with deuterium, halogen, or C3-C5 cycloalkyl; wherein R2 is selected from (1) hydrogen, (2) fluoro, chloro, (3) optionally substituted methyl, wherein said substituents are independently selected from one or more, preferably one to three of the following moieties: ium, fluoro, chloro, dimethylamino; and wherein X is selected from the group consisting of halide, carboxylate and sulfonate.

In another aspect, provided herein is a process for making a compound of formula (X), comprising the following steps: Step C: contacting a compound of formula (V) with a compound of formula (VII), in a reaction mixture sing a solvent and a base, such that a compound of formula (VIII) is produced: NH?- R3 N..— O R2 \ 3 . HX R2 I O \ / I N R1 R3JLR4 / N R1 Step D: contacting a compound of a (VIII) with the compound of formula (IX), in a reaction mixture comprising a solvent, such that a nd of foxmula (X) is produced: M") (X) wherein R1 is a cyclic or acyclic, branched or linear C1-C7 alkyl, which may be optionally substituted one or more times with deuterium, halogen, or C3-C5 cycloalkyl; and wherein R2 is selected from (1) hydrogen, (2) fluoro, chloro, (3) ally tuted methyl, wherein said substituents are independently selected from one or W0 2012/117071 more, preferably one to three of the following moieties: deuterium, fluoro, chloro, dimethylamino; and wherein X is selected from the group ting of halide, carboxylate and sulfonate; and wherein R3 and R4 are ndently selected from the group consisting of halogen, heteroaryl, alkoxy and aryloxy; and wherein the heteroaryl, alkoxy and y moieties of R3 and R4 are optionally, ndently substituted one or more times with alkyl, alkoxy, halogen and nitro.

In still another aspect, provided herein is a process for making a compound of formula (X), comprising the following steps:M3 contacting a compound of formula (I) with a solvent and a base, and contacting the ing mixture with a compound of formula (II), such that a compound of formula (III) is produced;M: contacting a nd of formula (III) with thiourea, in a reaction mixture comprising a solvent and an oxidizing agent, such that a compound of formula (V) is produced;M: contacting a compound of formula (V) with a compound of formula (VII), in a on mixture comprising a solvent and a base, such that a nd of formula (VIII) is produced; and M: contacting a compound of formula (VIII) with the compound of formula (IX), in a reaction mixture comprising a solvent, such that a compound of formula (X) is produced; wherein R1, R2, R3, R4 and X are as defined above.

In accordance with the present invention, the solvent of Step A comprises one or more solvents selected from aromatic ts, aliphatic solvents, halogenated solvents, polar aprotic solvents and ethereal solvents. Numerous examples ofthese solvents known to those with skill in the art. Non-limiting examples of aromatic solvents include benzene, toluene, xylenes, nitrobenzene, anisole, ethylbenzene, and pyridine. Non- ng examples of tic solvents include petroleum ether, ligroin, n-hexane, cyclohexane and heptane. Non-limiting examples of halogenated solvents include chloroform, chlorobenzene and perfluorohexane. Non-limiting examples of polar aprotic solvents include dimethylsulfoxide, dimethylformamide and N-methyl idone. Non- limiting examples of ethereal solvents include l ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-methyl ydrofuran and oxyethane. In certain embodiments, 2012/053559 the solvent of Step A is an c, organic solvent. In preferred embodiments, the t of Step A comprises tetrahydrofuran.

In accordance with the present invention, the solvent of Steps B, C and D independently comprises one or more solvents selected from ic solvents, aliphatic solvents, halogenated solvents, ethereal solvents, polar aprotic solvents, water and alcohol solvents. miting examples ofalcohol solvents include ethanol, tertiary- l and ethylene glycol. Other alcohol solvents are known to those skilled in the art.

In certain embodiments, the solvent of Step B comprises an aromatic solvent and an alcohol solvent. In a preferred embodiment, the solvent of Step B comprises toluene and ethanol. In n embodiments, the solvent of Step C comprises an ethereal solvent. In a preferred embodiment, the solvent of Step C comprises tetrahydrofuran. In certain embodiments, the solvent of Step D comprises and al solvent and water. In a preferred embodiment, the solvent of Step D comprises tetrahydrofuran and water.

In accordance with the present invention, the base of Step A is a strong base.

Strong bases include the conjugate bases ocarbons, ammonia, amines and dihydrogen. Non-limiting examples of strong bases include n-butyllithium, n- hexyllithium, sodium hydride and lithium diisopropylamide. Other strong bases are known to those skilled in the art. In certain ments, the base of Step A is lithium diisopropylamide. Methods ofpreparing lithium diisopropylamide are known to those of skill in the art (see, e.g., Smith, A. P.; Lamba, J. J. 8.; Fraser, C. L., Org. Syn. Col.

Vol. : 107, (2004)). In one embodiment, the lithium diisopropylamide is prepared by the deprotonation of isopropylamine with an alkyllithium base such as llithium, n- hexyllithium or n-octyllithium. Safety and economic considerations may influence the selection of reagents used for the preparation of lithium diisopropylamide (see, e. g., Chapter 3: t Selection, in "Practical Process Research and Development", ic Press, 2000). In one embodiment, the lithium diisopropylamide is prepared by the deprotonation ofdiisopropylamine with n-hexyllithium. One of skill in the art would understand that solutions of lithium diisopropylamide in certain solvents, such as THF, should be maintained at temperatures equal to or below 0 °C.

W0 2012/117071 2012/053559 In one embodiment ofthe above processes, the base of Step C is an amine. Non- limiting examples of amine bases include tertiary-butylamine, piperidine, triethylamine, 1,8-Diazabicyclo[5.4.0]undecene and pyridine. Other amine bases are known to those skilled in the art. In n embodiments, the base of Step C is pyridine.

In accordance with the t invention, the oxidizing agent of Step B is an electrophilic halogen reagent. Numerous ophilic halogen reagents are known to the skilled practitioner, including dibromine, diiodine, dichlorine, sulfuryl chloride, N- bromosuccinimide, succinimide, N-chlorosuccinimide and l,3-dibromo—5,S- dimethylhydantoin. In certain embodiments, the oxidizing agent of Step B is N- bromosuccinimide.

In one embodiment ofthe present invention, the oxidizing agent of Step B is N- bromosuccinimide, and the subsequent mixture is diluted with an olvent agent. In a preferred ment, the anti-solvent is pyl acetate.

In accordance with the the present invention, X is selected from the group consisting of halide, carboxylate, and sulfonate. In certain embodiments, X is a halide.

In a red embodiment, X is bromine.

In a preferred embodiment ofthe above processes, the solvent of Step A comprises tetrahydrofuran, the base of Step A is lithium diisopropylarnide, the solvent of Step B comprises toluene and ethanol, the oxidizing agent of Step B is N- bromosuccinimide, the solvent of Step C comprises tetrahydrofiiran, the base of Step C is pyridine and the solvent of Step D comprises tetrahydrofuran and water.

In various embodiments ofthe above processes, R; is a cyclic or acyclic, branched or linear C1-C7 alkyl, all of which may be optionally substituted one or more times with deuterium, halogen, or C3-C5 cycloalkyl. In other embodiments, R1 is a branched or linear C1-C7 alkyl that is optionally substituted one or more times with mCF3 halogen. In a red embodiment, R1 is H3O In s embodiments ofthe above processes, R2 represents (1) hydrogen, (2) fluoro, chloro, (3) optionally substituted methyl, wherein said substituents are independently selected from one or more, preferably one to three of the following es: deuterium, fluoro, chloro, dimethylamino. In certain ments, R2 is selected from hydrogen, cyclic or acyclic, branched or linear C1-C7 alkyl, and halogen wherein the alkyl is optiOnally substituted one or more times with deuterium, fluorine, chlorine and dimethylamino. In other embodiments, R2 is a branched or linear C1-C7 alkyl. In a preferred embodiment, R2 is methyl.

In various embodiments, R3 and R4 are independently ed from the group consisting of halogen, heteroaryl, alkoxy and aryloxy; wherein the heteroaryl, alkoxy and aryloxy moieties ofR3 and R4 are ally, independently substituted one or more times with alkyl, alkoxy, halogen and nitro. In certain embodiments, R3 is aryloxy and R4 are both heteroaryl. In other embodiments, R3 is aryloxy and R4 is halogen.

. In a preferred embodiment, R3 is phenoxy and R4 is chlorine. \93KCF3 In a preferred embodiment of the above. . CH3 processes, R1 is H3O , R2 15 methyl, R3 is phenoxy, R4 is chlorine and X is bromine.

In one embodiment ofthe present invention, the nd of formula (I) is first contacted with the compound of a (II) in a reaction mixture comprising a base and t, and second optionally contacted with a reaction mixture sing an aqueous acid or base resulting in the pH of the aqueous phase to be within the range 2 < pH < 4, preferably pH 3. Preferably, the base is lithium diisopropylamide and the first solvent is THF, wherein the reaction mixture is maintained such that the internal ature remains less than -5°C, preferably at -15°C. ably, the pH of the aqueous phase is adjusted to pH 3 with a reaction mixture comprising sulfuric acid, water and toluene.

In one embodiment ofthe present invention, the compound of formula (VIII) is contacted with the compound of formula (IX) in a reaction mixture comprising a first solvent, such that the compound of a (X) is formed. An aromatic solvent is then added to the mixture, followed by removal of the first solvent by distillation, resulting in the precipitation of the compound of formula (X). Preferably, the aromatic solvent is toluene.

In another aspect of the present invention, provided herein is a process for making the compound of formula (10), sing the following steps: Step A: contacting the compound offormula (1) with a solvent and a base, and . contacting the resulting mixture with the compound of formula (2), such that the compound of formula (3) is produced: CH3‘ 1. Base H3O l \ / CF3 2- 0 l N JK / CF3 CH3 ,OCH3 N H30 H30 '3 H3C CH3 CH3 ; then H3O+ (1) (2) (3) Step B: contacting the nd of formula (3) with thiourea, in a reaction mixture comprising a solvent and an oxidizing agent [Br+], such that the compound of formula (5) is produced: 0 N=( H30 \ 3 JL H30 _ HBr \ HZN NH2 l \ / CF3 l N CFa H30 CH3 “3”] H30 CH3 (3) (5) Step C: contacting the compound of formula (5) with the compound of formula (7), in a on mixture comprising a solvent and a base, such that the compound of formula (8) is produced: ‘HBr H3C l \ CF3 (Z) N/ . l N/ CF3 H30 CH3 H3O CH3 (5) (8) ;and Step D: contacting the compound offormula (8) with the compound of formula (IX), in a reaction mixture sing a solvent, such that the compound of formula (10) is produced: HN—<°@ 0 I'd HN—< ”“2 s 2 \ s H3C \ (IX) I \ -———~ I N/ CF3 N/ CF3 H3C CH3 H30 CH3 (8) (10) .In accordance with this aspect of the present invention, the t of Step A comprises one or more solvents selected from ic solvents, aliphatic solvents, halogenated solvents, polar aprotic solVents and ethereal solvents. us examples of these solvents are known to those with skill in the art. Non-limiting examples of aromatic solvents include benzene, toluene, xylenes, nitrobenzene, anisole, ethylbenzene, and pyridine. Non- ng examples of aliphatic ts include petroleum ether, ligroin, n—hexane, cyclohexane and heptane. Non-limiting examples of halogenated solvents include chloroform, chlorobenzene and perfluorohexane. miting examples ofpolar aprotic solvents include dimethylsulfoxide, dimethylformamide and N-methyl pyrrolidone. Non- limiting examples of ethereal ts include diethyl ether, methyl tertiary-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran and dimethoxyethane. In certain embodiments, W0 2012/117071 2012/053559 the solvent of Step A is an aprotic, organic solvent.

In preferred embodiments, the t of Step A comprises tetrahydrofuran.

In accordance with this aspect ofthe present invention, the solvent of Steps B, C and D independently comprises one or more solvents selected from aromatic solvents, aliphatic solvents, halogenated solvents, ethereal solvents, polar aprotic solvents, water and alcohol ts. Non-limiting examples of alcohol solvents include ethanol, tertiary-butanol and ne glycol. Other alcohol solvents are known to those skilled in the art. In certain embodiments, the solvent of Step B comprises an aromatic t and an alcohol solvent. In a preferred embodiment, the solvent of Step B comprises toluene and ethanol. In certain embodiments, the solvent of Step C comprises an ethereal solvent.

In a preferred embodiment, the solvent of Step C comprises ydrofuran. In certain embodiments, the solvent of Step D comprises and ethereal solvent and water. In a preferred embodiment, the solvent of Step D comprises tetrahydrofuran and water.

In accordance with this aspect of the present invention, the base of Step A is a strong base. Strong bases include the conjugate bases of hydrocarbons, ammonia, amines and dihydrogen. Non-limiting examples of strong bases include n-butyllithium, n- hexyllithium, sodium hydride and m diisopropylamide. Other strong bases are known to those skilled in the art. In n embodiments, the base of Step A is m diisopropylamide. Methods ofpreparing lithium diisopropylamide are known to those of skill in the art (see, e.g., Smith, A. P.; Lamba, J. J. 8.; Fraser, C. L., Org. Syn. Col. Vol. : 107, ). In one ment, the lithium diisopropylamide is prepared by the deprotonation of isopropylamine with an alkyllithium base such as llithium, n— hexyllithium or n-octyllithium. Safety and economic considerations may influence the selection of reagents used for the preparation of lithium diisopropylamide (see, e.g., Chapter 3: Reagent Selection, in "Practical Process Research and Development", Academic Press, 2000). In one embodiment, the lithium diisopropylamide is prepared by the deprotonation ofdiisopropylamine with n-hexyllithium.

One of skill in the art would understand that solutions of lithium diisopropylamide in certain ts, such as THF, should be maintained at temperatures equal to or below 0 °C.

In a further embodiment ofthe above processes of the present invention, the base of Step C is an amine. Non-limiting examples of amine bases e ry-butylamine, piperidine, triethylamine, 1,8-Diazabicyclo[5.4.0]undecene and pyridine. Other amine bases are known to those skilled in the art. In certain embodiments, the base of Step C is In one embodiment ofthe above processes of the present invention, the oxidizing agent of Step B is an electrophilic halogen reagent. Numerous ophilic halogen reagents are known to the skilled practitioner, including dibromine, diiodine, rine, sulfuryl chloride, N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide and bromo-5,S-dimethylhydantoin. In certain embodiments, the oxidizing agent of Step B is N-bromosuccinimide.

In one embodiment ofthe present invention, the oxidizing agent of Step B is N— bromosuccinimide, and the subsequent mixture is diluted with an anti-solvent agent. In a red ment, the anti-solvent is isopropyl acetate.

In a preferred embodiment of the synthesis of the compound of formula (10), the t of Step A comprises tetrahydrofuran, the base of Step A is lithium diisopropylamide, the solvent of Step B comprises toluene and ethanol, the oxidizing agent of Step B is N—bromosuccinimide, the solvent of Step C comprises tetrahydrofuran, the base of Step C is pyridine and the solvent of Step D ses tetrahydrofuran and water.

In one embodiment ofthe present invention, the compound of formula (1) is first contacted with the compound of formula (2) in a reaction e comprising a base and solvent, and second optionally contacted with a reaction mixture comprising an aqueous acid or base ing in the pH of the s phase to be within the range 2 < pH < 4, preferably pH 3. Preferably, the base is lithium diisopropylamide and the first solvent is THF, wherein the reaction mixture is maintained such that the internal temperature remains less than -5°C, preferably at -15°C. Preferably, the pH of the aqueous phase is adjusted to pH 3 with a reaction mixture comprising sulfuric acid, water and toluene.

In one embodiment ofthe present invention, the compound of formula (5) is contacted with the compound of formula (7) in a reaction mixture comprising the solvent W0 2012/117071 THF and the base pyridine, and then the base pyridine is removed by addition saturated saline or aqueous salt (preferably sodium chloride) solution. In one embodiment ofthe t invention, the compound of formula (8) is contacted with the compound of formula (IX) in a reaction mixture sing a first t, such that the nd of formula (10) is formed. An aromatic solvent is then added to the mixture, followed by removal of the first t by distillation, resulting in the precipitation of the compound of formula (10). Preferably, the ic solvent is toluene.

In another aspect of the invention, provided herein is a compound according to formula (1): N/ CF3 H3C CH3 The compound of a (1) is particularly useful as a starting material, or an intermediate, in the preparation of the compound of formula (10), as well as chemical analogues of the compound of formula (10). The compound of formula (1) can be synthesized in accordance with the preparation methods set forth in Scheme 4 or Scheme herein.

The skilled practitioner will recognize several parameters of the foregoing processes that may be varied advantageously in order to obtain a desirable outcome.

These ters include, for example, the methods and means ofpurification of on components and solvents; the order of addition of said reaction components and solvents to the reaction mixture; the duration of reaction of said reaction components and solvents; and the temperature and rate of stirring, mixing or agitation of the on components and solvents during said reaction.

Definitions W0 2012/117071 As used herein, the term “lower” or “Cl-C7” denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple ing.

As used herein, the term ” refers to a straight-chain or ed-chain alkyl group, preferably represents a straight-chain or branched-chain €1-12alkyl, particularly ably represents a straight-chain or branched-chain kyl; for example, methyl, ethyl, n- or opyl, n-, iso-, sec- or tert—butyl, n-pentyl, n-hexyl, n—heptyl, n-octyl, nnonyl , n-decyl, n-undecyl, n-dodecyl, with particular ence given to methyl, ethyl, n- propyl, iso-propyl and n-butyl and iso-butyl. Alkyl may be unsubstituted or substituted.

Exemplary substituents include, but are not d to deuterium, hydroxy, alkoxy, halo and amino. An example of a substituted alkyl is trifluoromethyl. Cycloalkyl may also be a substituent to alkyl. An example of such a case is the moiety (alkyl)-cyclopropyl or alkandiyl-cycloproyl, e.g. —CH2-cyclopropyl. C1-C7-alkyl is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert—butyl, propyl, such as n-propyl or isopropyl, ethyl or preferably methyl.

Each alkyl part of other groups like “alkoxy”, “alkoxyalkyl”, “alkoxycarbonyl”, “alkoxy-carbonylalkyl”, “alkylsulfonyl”, “alkylsulfoxyl”, “alkylamino”, “haloalkyl” shall have the same meaning as described in the above-mentioned definition of “alkyl” As used herein, the term “alkandiyl” refers to a straight-chain or branched-chain alkandiyl group bound by two different Carbon atoms to the moiety, it preferably represents a straight-chain or branched-chain C 1.12 alkandiyl, particularly ably ents a straight-chain or branched-chain CM, alkandiyl; for example, methandiyl;(- CH2-), 1,2-ethanediyl (-CHz-CH2-), 1,1-ethanediyl ((-CH(CH3)-), 1,1-, l,2~, 1,3- propanediyl and 1,1-, 1,2—, 1,3-, 1,4-butanediyl, with particular preference given to methandiyl, 1,1-ethanediyl, 1,2—ethanediyl, opanediyl, 1,4-butanediyl.

As used herein, the term “cycloalkyl” refers to a saturated or partially saturated, monocyclic, fused polycyclic, or Spiro polycyclic, carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative es of cycloalkyl groups include the following es: cyclopropyl, cyclobutyl, cyclpentyl and hexyl. Cycloalkyl may be unsubstituted or substituted; exemplary substituents are provided in the definition for alkyl and also include alkyl itself (e.g. ). A moiety like —(CH3)cyclopropyl is considered substituted cycloalkyl.

As used herein, the term “aryl” refers to an ic homocyclic ring system (lie. only Carbon as ring forming atoms) with 6 or more carbon atoms; aryl is preferably an aromatic moiety with 6 to 14 ring carbon atoms, more preferably with 6 to 10 ring carbon atoms, such as phenyl or naphthyl, preferably phenyl. Aryl may be unsubstituted or substituted by one or more, preferably up to three, more preferably up to two substituents independently selected from the group ting of unsubstituted or substituted heterocyclyl as described below, especially pyrrolidinyl, such as pyrrolidino, oxopyrrolidinyl, such as oxopyrrolidino, C1-C7-alkyl-pyrrolidinyl, "2,5-di-(C1- C7alkyl)pyrrolidinyl, such as 2,5-di-(C1-C7alkyl)-pyrrolidino, tetrahydrofuranyl, thio- phenyl, C1-C7-alkylpyrazolidinyl, pyridinyl, C1-C7-alkylpiperidinyl, piperidino, piperidino substituted by amino or N—mono— or -[lower alkyl, phenyl, C1-C7- alkanoyl and/or phenyl-lower alkyl)-amino, unsubstituted or r alkyl tuted piperidinyl bound Via a ring carbon atom, zino, lower alkylpiperazino, morpholino, thiomorpholino, S-oxo—thiomorpholino or S,S-dioxothiomorpholino; C1-C7-alkyl, amino- C1—C7-alkyl, N—Cl-C7-alkanoylamino-C1-C7-alkyl, N-C1-C7-alkanesulfonyl-amino-C1-C7- alkyl, carbamoyl-Cl-Cralkyl, [N-mono- or N,N-di—(C1-C7—alkyl)-carbamoyl]-C1-C7-alkyl, C1-C7-alkanesulfinyl-C1-C7—alkyl, C1-C7-alkanesulfonyl-C1-C7-alkyl, phenyl, naphthyl, mono- to tri-[Cl-C7-alkyl, halo and/or cyano]-phenyl or mono- to tri-[Cl-C7-alkyl, halo and/or cyano]-naphthyl; C3-Cg-cycloalkyl, mono- to tri-[C1-C7-alkyl and/or hydroxy]-C3- Cg-cycloalkyl; halo, hydroxy, lower alkoxy, lower-alkoxy-lower alkoxy, (lower-alkoxy)- lower alkoxy-lower alkoxy, halo-Cl-C7-alkoxy, phenoxy, yloxy, phenyl- or naphthyl-lower alkoxy; amino-CI-C7-alkoxy, lower-alkanoyloxy, benzoyloxy, naphthoyloxy, formyl (CHO), amino, N-mono- or -(C1-C7-a1kyl)-amino, C1-C7- alkanoylamino, 01-C7-alkanesulfonylarnino, carboxy, lower alkoxy yl, e.g.; phenyl- or naphthyl-lower alkoxycarbonyl, such as benzyloxycarbonyl; alkanoyl, such as acetyl, benzoyl, naphthoyl, carbamoyl, N-mono- or substituted carbamoyl, such as N-mono— or N,N-di-substituted carbamoyl wherein the substitutents are selected from lower alkyl, (lower-alkoxy)-lower alkyl and hydroxy-lower alkyl; amidino, guanidi- no, ureido, mercapto, lower alkylthio, phenyl— or naphthylthio, phenyl- or naphthyl-lower alkylthio, lower phenylthio, lower alkyl-naphthylthio, halo-lower alkylmercapto, sulfo (-SO3H), lower alkanesulfonyl, phenyl- or naphthyl-sulfonyl, - or naphthyl- lower alkylsulfonyl, alkylphenylsulfonyl, halo-lower alkylsulfonyl, such as trifluorome- thanesulfonyl; amido, benzosulfonamido, azido, azido-Cl-C7-alkyl, especially azidomethyl, alkanesulfonyl, sulfamoyl, N-mono- or N,N-di-(C1—C7-alkyl)- sulfamoyl, morpholinosulfonyl, thiomorpholinosulfonyl, cyano and nitro; where each phenyl or naphthyl (also in phenoxy or oxy) mentioned above as substituent or part of a substituent of substituted alkyl (or also of substituted aryl, cyclyl etc. mentioned herein) is itself unsubstituted or substituted by one or more, e. g. up to three, preferably 1 or 2, substituents independently selected fi'om halo, halo-lower alkyl, such as trifluoromethyl, hydroxy, lower alkoxy, azido, amino, - or —(lower alkyl and/or C1-C7-alkanoyl)-amino, nitro, carboxy, lower-alkoxycarbonyl, carbamoyl, cyano and/or sulfamoyl.

The term “aryloxy” refers to a moiety comprising an oxygen atom that is substituted with an aryl group, as defined above.

The term “heteroaryl,” as used herein, represents a stable monocyclic or bicyclic ring ofup to 7 atoms in each ring, wherein at least one ring is ic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope ofthis definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, fixranyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, yl, tetrahydroquinoline. As with the definition of heterocycle below, “heteroaryl” is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the ic ring or via the heteroatom containing ring, respectively.

As used herein, the term “heterocycle” or ocyclyl” refers to a heterocyclic radical that is unsaturated (= ng the highest possible number of conjugated double bonds in the ring(s)), saturated or partially saturated and is preferably a monocyclic or in a broader aspect of the invention bicyclic, tricyclic or spirocyclic ring; and has 3 to 24, more ably 4 to 16, most preferably 5 to 10 and most preferably 5 or 6 ring atoms; wherein one or more, preferably one to four, especially one or two ring atoms are a heteroatom (the remaining ring atoms therefore being carbon). The g ring (1'. e. the ring connecting to the molecule) ably has 4 to 12, especially 5 to 7 ring atoms. The term heterocyclyl also includes heteroaryl. The heterocyclic radical (heterocyclyl) may be unsubstituted or substituted by one or more, especially 1 to 3, substituents independently selected from the group consisting of the substituents defined above for tuted alkyl and / or from one or more of the following substituents: oxo (=0), thiocarbonyl (=S), imino(=NI-I), imino—lower alkyl. Further, heterocyclyl is especially a heterocyclyl radical selected from the group consisting of oxiranyl, azirinyl, aziridinyl, 1,2-oxathiolanyl, thienyl (= thiophenyl), furanyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrro- lidinyl, imidazolyl, olidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, lidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, (S-oxo or S,S- dioxo)—thiomorpholinyl, indolizinyl, azepanyl, diazepanyl, ally azepanyl, isoindolyl, 3H—indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, yl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, droisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, yridinyl, alyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthri- dinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, hiazinyl, azinyl, chromenyl, isochromanyl, chromanyl, benzo[l,3]dioxolyl and 2,3- dihydro-benzo[l ,4]dioxinyI, each ofthese ls being unsubstituted or substituted by one or more, preferably up to three, substituents ed from those mentioned above for substituted aryl and/or from one or more of the following substituents: oxo (=0), thiocarbonyl (=S), imino(=NH), imino-lower alkyl.

The term “heteroatoms” are atoms other than Carbon and Hydrogen, preferably nitrogen (N), oxygen (0) or sulfur (S), in particular nitrogen. 2012/053559 Moreover, the alkyl, alkoxy, aryl, aryloxy and heteroaryl groups described above can be “unsubstituted” or “substituted.” The term “substituted” is intended to describe moieties having substituents replacing a hydrogen on one or more atoms, e. g. C, O or N, of a molecule. Such substituents can independently include, for example, one or more of the following: ht or branched alkyl (preferably C1-C5), cycloalkyl (preferably C3-C3), alkoxy (preferably C1-C6), thioalkyl (preferably C1-C6), alkenyl rably C2-C6), alkynyl (preferably C2-C6), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g, phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group, (CR’R”)o.3NR’R” (e.g., -NH2), (CR’R”)0_3CN (e.g., —CN), —NOz, halogen (e.g., -F, -Cl, -Br, or -I), (CR’R”)0-3C(halogen)3 _ (e.g., -CF3), (CR’R”)0-3CH(halogen)2, (CR’R”)0_3CH2(halogen), (CR’R”)0_3CONR’R”, (CR’R”)O-3(CNH)NR,R”2 (CR’R”)o—3$(0)1.2NR’R”, (CR’R”)o-3CH0, (CR’R”)0.30(CR’R”)0.3H, (CR’R”)0-3S(O)0.3R’ (e.g., ~SO3H, -OSO3H), )¢30(CR’R”)0.3H (e.g., -CH20CH3 and -OCH3), )0_3S(CR’R”)0_3H (e.g., -SH and -SCH3), (CR’R”)o-3OH (e.g., —OH), (CR’R”)MCOR’, (CR’R”)0-3(substituted or unsubstituted phenyl), (CR,R”)0_3(C3-Cs cycloalkyl), (CR’R”)0_3C02R’ (e.g., -C02H), or (CR’R”)0_3OR’ group, or the side chain ofany lly occurring amino acid; wherein R’ and R” are each independently hydrogen, a C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, or aryl group.

As used herein, the term “halogen” or “halo” refers to fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine. Halogen—substituted groups and es, such as alkyl substituted by halogen (haloalkyl) can be mono-, poly- or per-halogenated.

The term “amine” or “amino” should be understood as being broadly d to both a molecule, or a moiety or functional group, as lly understood in the art, and may be primary, secondary, or tertiary. The term “amine” or ” includes compounds where a nitrogen atom is covalently bonded to at least one carbon, hydrogen or atom. The terms include, for example, but are not limited to, “alkyl amino,” “arylamino,” “diarylamino,” “alkylarylamino,” “alkylaminoaryl,” “arylaminoalkyl,” “alkaminoalkyl,” “amide,” ,” and “aminocarbony .” The term “alkyl amino” comprises groups and compounds wherein the nitrogen is bound to at least one additional W0 2012/117071 alkyl group. The term “dialkyl amino” includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term “arylamino” and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term “alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.

The term “alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.

Examples Abbreviations - The following abbreviations are used in the figures and text: THF (tetrahydrofuran); RT (room temperature); iPerH (diisopropylamine); iPerLi (lithium diisopropylamide); LDA (lithium diisopropylamide); H2804 ric acid); H20 (water); IPA opyl acetate); NaCl (sodium chloride); MsCl nesulfonyl chloride); NaH m hydride); n-BuLi (n-butyllithium); SF4 (sulfur uoride); HCl (hydrochloric acid); HF (hydrofluoric acid).

Synthesis Procedures Scheme 1 LPqNH n-hexyllithium (in n—hexane) 1. Me THF l Me‘o--L'I / CF I n ~15°c N 3 Me»: 0 Me Me Me Me (1 ) i-Pl'zNLi \ 15Maq. H2304 \ (in THF/n—hexane) I 2. O N/ CF3 luene N/ CF3 MeJL'flDMe Me Me 0°C Me Me (2) (3) To a solution of 1.5 equiv. of lithium diisopropylamide in THF at ~15 °C, freshly prepared from n-hexyllithium and diisopropylamine, was added a solution of 1.0 equiv. of building block (1) in THF over 30 min. The resulting deep brown-red W0 2012/117071 solution was then d at ~15 °C for 30 min. Subsequently, a solution of 1.15 equiv. of Weinreb amide (2) in THF was added over 30 min, and the reaction stirred at —15 °C for 1 h before being transferred onto a mixture of 1.5 molar aqueous sulfuric acid and toluene at 10 °C. The biphasic mixture was vigorously stirred at room temperature for min. Care was taken that the aqueous layer stayed at 2 < pH < 4, preferably pH 3.

After phase tion, the organic layer was washed with water, then concentrated at 50 °C under vacuum to ca. 15-20% of its original volume to provide a solution of crude ketone (3) in e.

Scheme 2 s 'HBr abs. Ethanol, 40 °C \ + A / 01:3 HzN NHz l N CF3 2.|PA,0°C N Me Me Me Me (3) (5) A solution of 1.0 equivalents of crude (3) in toluene is diluted with te ethanol at room temperature, then 1.10 equivalents ofthiourea was added. The yellow suspension is heated to 40 °C, and imately 1.01 equivalents of solid N— bromosuccinimide was added in portions over 30 min. After complete addition, the resulting red, clear solution was stirred at 40 °C for l h. The reaction e was diluted with isopropyl acetate (IPA), and the fine, yellow—orange suspension was cooled to 0 °C over 1.5 h. Filtration over a sintered glass filter and subsequent washing provided the wet reaction product (5), which was finally dried at 50 °C under vacuum.

WO 17071 Scheme3 NH2 NH2 1 ' 0 N- N— . I I \ S \ s Clio Me Me ‘HBr Pyridine. _ (7) \ \ THF. 40 no r I ._____, I N/ CF3 THF! RT N/ CF3 2. wash with saturated Me Me Me Me aqueous NaCl (5) (6) O N N— o—Q 1.411336% (IX) N- _<\o o \ 3 H 0 Me \ 3 \ THF/H20. 60 °C \ I _. I N’ CF3 2. add toluene. N’ CF3 Me Me distill Off THF, Me Me then add water (8) (10) To a yellow suspension of 1.0 lents of compound (5) in THF at room temperature was added 2.0 equivalents ofpyridine. The reaction mixture was heated to 40 °C, then a solution of 1.0 lents ofphenyl chloroformate (7) in THF was added over 30 min. After stirring at 40 °C for 1 h, the reaction was cooled to RT, then saturated aqueous NaCl solution was added, and the biphasic e was stirred at RT for 10 min before phase separation. The organic layer was heated to 60 °C, then a solution of 1.0 equivalents of L-prolinamide (IX) in water was added over 30 min. The reaction was stirred at 60 °C fer 2 h, then the reaction mixture was cooled to 50 °C, then toluene was added, followed by removal of THF via distillation under vacuum. The resulting suspension was treated with water, and the reaction mixture was stirred at 50 °C for 30 min, before being cooled to 10 °C over 2 h. After stirring at 10 °C for another 30 min, the off-whitesuspension was filtered, and the filter cake washed with toluene, then dried at 50 °C under vacuum to give (10).

Scheme 4 TMSCF3 \ NaOAc l K2C03 N/ Me DMSO OTMS MeOH. RT RTto 45°C 0 NeM CF3 NMe CF3 Me Me MSCI, NaH \ AIM63 \ I I THF. / OMs / CF N cyclohexane, RT a RT“ 4° C Me CFa Me Me (d) (1) 4-Meth l 2 2 uoro—1-meth I-l-trimeth lsilan lox ridine (b). To a fine, white sion of sodium acetate (96.0 g, 117 mmol, 1.0 equiv.) in 1 L DMSO was added yl-4—methylpyridine (158 g, 117 mmol, 1.0 equiv.). After dilution with another 0.5 L DMSO, trimethyl—trifluoromethylsilane (375 g, 264 mmol, 2.2 equiv.) was added over 75 minutes. During the addition, the reaction vessel was placed in a cooling bath at 10 °C to keep the internal ature between 20-25°. The resulting dark suspension was stirred at room temperature over night, then quenched carefully by addition of 1.5 L water over 20' minutes. During the on of water, the reaction vessel was placed in a cooling bath at -5 °C to keep the internal temperature between 10-25 °C.

After stirring at room temperature for 45 minutes, the mixture was d with 3 L ethyl acetate and stirred for another 15 minutes. The phases were separated, and the water layer was extracted with 2L ethyl acetate. The combined organic phases were washed with 3 L saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to give 346 g (106%, 88.6 area°o by HPLC) oftrifluoromethyl compound (b) as a brown, intensively smelling oil. 1,1,1-Trifluoro§4-methylpyridinyl[propan-Z-ol (c). To a solution of 4-methyl (2,2,2-trifluoromethyltrimethylsilanyloxy-ethyl)pyridine (b) (346 g, 125 mmol, 1.0 equiv.) in 1.5 L MeOH at room temperature was added solid K2CO3 (344 g, 249 mmol, 2.0 ). The resulting beige suspension was stirred at room temperature for 1 hour, then filtered over filter paper. The filtrate was concentrated in vacuo to give a solid, intensively smelling residue. The residue was dissolved in 1 L ethyl acetate and washed with water (2 x 1 L). After drying over MgSO4 and ion, tration in vacuo provided 252 g (98%) of alcohol (c) as an oil. 1,1,1-Trifluorog4-methylpgidin-2—yl)propan-Z-yl methanesulfonate (d). To a suspension ofNaH (60% in l oil, 23.4 g, 585 mmol, 1.5 equiv.) in l L THF at 0 °C was added a solution of 1,1,l~trifluor02-(4-methylpyridinyl)propanol (c) (80 g, 390 mmol, 1.0 equiv.) in 200 m1 THF dropwise over 34 minutes. Gas evolution occurred, and the reaction mixture turned brownish. The reaction was warmed to 40 °C and stirred at 40 °C for 45 s, when gas evolution had ceased. After cooling to room temperature, a solution of methanesulfonyl chloride (45.6 ml, 585 mmol, 1.5 equiv.) in 50 ml THF was added dropwise over 30 minutes. The internal temperature rose to 36 °C, and the reaction mixture turned into a light brown suspension. The reaction mixture was warmed to 40 °C and stirred at this temperature for 15 minutes, then cooled to room temperature and further stirred over night. The reaction'was carefully quenched by addition of 750 ml water with cooling in an ice bath. The resulting brown biphasic mixture was stirred at room temperature for 30 s, then the phases were separated. The aqueous layer was extracted with 750 ml ethyl acetate, and the combined c phases were washed with saturated aqueous NaHCO3. Drying over MgSO4, filtration and concentration in vacuo provided a beige solid. The residue was redissolved in 300 ml ethyl e to give a turbid solution, then filtered over a plug of silica gel (120 g) and eluted with 600 ml ethyl acetate. Concentration in vacuo provided a beige solid which was redissolved in 400 ml heptane and 150 ml ethyl acetate at reflux. After hot filtration over a fritted funnel, the product llized at 0 °C. The crystals were collected by ion, washed with cold heptane/ ethyl acetate 8:3 (2 x 80 ml) and dried (50 °C, 10 mbar) over night to give 94.0 g (85%) of mesylate (d) as white crystals. yl1l,1,1-trifluoromethylpropan—2—ylzpyridine (1). To a sion of 1,1,1- trifluoro(4-methylpyridinyl)propan-2—y1methanesulfonate (d) (5,68 g, 20.1 mmol, 1.0 equiv.) in 60 ml cyclohexane at 10 °C was added AlMe3 in hexane (2.0 M, 15.0 ml, mmol, 23.0 equiv.) dropwise over 15 minutes. The reaction was warmed at room temperature and stirred at room temperature for 3 hours. The mixture was quenched by l addition to 100 ml water at 0 °C and stirred at room temperature for 15 minutes.

Afier filtration over a plug of ck and elution with ethyl acetate, the phases were separated. The aqueous layer was ted with ethyl acetate, and the combined c phases were washed with water and saturated aqueous NaCl. After drying over Na2S04, filtration and concentration in vacuo provided a slightly brownish oil, which was purified by chromatography on siliga gel (hexane/ TBME 9: 1) to provide 1.15 g (28%) of the desired compound (1) as a colorless oil.

Schemes Me Me Me \ n-BuLi, Mel; \ NaOH \ l ———>| _.l N/ diethylcarbonate N/ (30215t N/ 002Na Me Me Me Me (6) (r) (9') SF4, HF \ / CF3 Me Me To a solution of n-butyllithium (2.04 equiv.) in 2-methyltetrahydrofuran at maximum —40 °C was added a solution of2,4-dimethylpyridine (e) (2.02 equiv.) in 2- methyltetrahydrofuran over 60 min, keeping the temperature below —30 °C. The reaction e was stirred for 30 min at maximum —30 °C. A on of diethyl carbonate (1.00 equiv.) in 2-methyltetrahydrofuran was added over 60 min, keeping the temperature below —30 °C. The reaction was warmed to room temperature, and then d at this temperature for 5 h. After cooling to 0 °C, methyl iodide (2.15 equiv.) was charged over 40 min, keeping the temperature below 25 °C. The reaction was further d at room temperature for 1 h, then 1 M HCl was added, and the pH was adjusted to a value ofpH 8-9. After stirring for 15 min, the phases were separated, and the organic phase was washed with water. Distillation at 35 °C under vacuum then provided crude dimethylated ester (1‘). Ester (1’) was subsequently added to a solution of sodium hydroxide (1.05 equiv.) in ethanol at 78 °C over 2 h. More ethanol was added, and the reaction was stirred at 78 °C for 10 h. The volume was reduced to approximately 50% by distillation under normal pressure. After cooling to room temperature, tert-butyl methyl ether was added, and the reaction mixture was stirred at this temperature for 30 min. Filtration was med after cooling to 5-10 °C, and the filter cake was washed with dichloromethane.

The wet t was dried at 60-70 °C under vacuum to give sodium carboxylate (g').

Compound (g') was reacted with sulfur tetrafluoride and hydrofluoric acid to afford compound (1).

Claims (16)

1. A process for making a compound of formula (X): comprising the following steps: M: contacting a compound of formula (I) with a t tetrahydrofuran and a base lithium ropylamide, and contacting the resulting mixture with a compound of formula (II) at an internal temperature of less than about -5°C to about -15°C, such that a compound of formula (III) is ed: CH3 R2 \ 0 \ / )L ,OCHs ' N R1 R2 'fl N R1 (I) (II) (”I) Step B: contacting a compound of formula (III) with thiourea, in a reaction mixture comprising a solvent selected from toluene, l solvent, ethanol or a combination thereof and an oxidizing agent N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin, such that a compound of formula (V) is produced: - HX N R1 Step C: contacting a compound of formula (V) with a compound of a (VII), in a reaction mixture comprising a solvent tetrahydrofuran and a base amine, such that a compound of formula (VIII) is produced: N/ O O \ A ' R3 R4 N R1 (VII) (VIII) Step D: contacting a compound of formula (VIII) with the compound of formula (IX), 0 H (IX) in a reaction e comprising a solvent selected from tetrahydrofuran, water or a combination thereof, such that a nd of formula (X) is produced wherein R1 is a branched or linear C1-C7 alkyl, which may be optionally substituted one or more times with ium, n, or C3-C5 cycloalkyl, R2, is methyl R3 is halogen or heteroaryl, R4 is C6-C14 aryloxy or heteroaryl and X is a halide.

2. The process of claim 1, wherein the resulting mixture of a compound of formula (I) and a solvent tetrahydrofuran and a base lithium diisopropylamide of Step A is contacted with a compound of formula (II) at an internal temperature of about -15°C.

3. The process of claim 1, wherein the t of Step B comprises toluene and ethanol.

4. The process of claim 1, wherein the t of Step D comprises tetrahydrofuran and water.

5. The process of claim 1, wherein the base of Step C is pyridine.

6. The process of any one of claims 1 to 5, wherein the solvent of Step B ses toluene and ethanoland the solvent of Step D comprises tetrahydrofuran and water. ‘f CF3 7<CH3

7. The process of any one of claims 1 to 6, wherein R1 is H30 , R2 is methyl, R4 is phenoxy, R3 is chlorine and X is bromine.

8. A process for making the compound of formula (10): HN grim N:( o O N/ CF15 H30 CH3 (10) comprising the ing steps: m: contacting the compound of formula (1) with a solvent tetrahydrofiiran and a base lithium ropylamide, and contacting the resulting mixture with the compound of formula (2) at an internal temperature of less than about -5°C to about -15°C, such that the compound of formula (3) is produced: CH3 H3C \ 0 N/ CF3 HacJLNpcm l N/ CF3 H3C CH3 CH3 - H3C CH3 (1) (2) (3) ; Step B: contacting the compound of formula (3) with ea, in a reaction mixture comprising a solvent selected from toluene, ethanol or a combination thereof and an oxidizing agent N-bromosuccinimide, such that the compound of formula (5) is produced: Step C: contacting the compound of formula (5) with the compound of a (7), in a reaction mixture comprising a solvent tetrahydrofuran and a base amine, such that the compound of formula (8) is produced: N/ 0 <1 ° '\ O/U\Cl N/ CF" H30 CH3 (7) (3) ;and Step D: contacting the compound of formula (8) with the compound of formula (IX) o H (IX) in a reaction mixture comprising a solvent selected from tetrahydrofuran, water or a combination thereof, such that the compound of formula (10) is produced.

9. The process of claim 8, wherein the resulting mixture of a compound of formula (1) and a solvent tetrahydrofuran and a base lithium diisopropylamide of Step A is contacted with a compound of formula (2) at an internal temperature of about -15°C.

10. The compound according to formula (1): N/ CF3 H30 CH3

11. The process of claim 1, substantially as herein described with reference to any one of the Examples thereof.

12. The process of any one of claims 1 to 7, substantially as herein bed.

13. The s of claim 8, substantially as herein bed with reference to any one of the Examples thereof.

14. The process of claim 8 or 9, substantially as herein described.

15. The compound of claim 10, substantially as herein described with reference to any one of the Examples thereof.

16. The nd of claim 10, substantially as herein described.