ZA200604198B - Processes for the preparation of pyrazolo[1,5-a]-1,3,5-triazines and intermediates thereof - Google Patents

Description

PROCESSES FOR THE PREPARATION OF

PYRAZOLO[1,5-a]-1,3,5-TRIAZINES AND

INTERMEDIATES THEREOF

CROSS -REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application Serial No. , filed November 10, 2004, which claims priority to U.S. Provisional Application Serial

No. 60/ 525,050, filed November 25, 2003, the disclosures of which are incorporated herein b y reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel processes amenable= to large scale preparation of pyrazolo[1,5-a]-1,3,5-triazines. . BACKGROUND OF THE INVENTION

[0003] Corticotropin releasing factor (CRF), synonymous witka corticotropin releasing hormone (CRH), is a 41 amino acid peptide that coordina—tes the overall respons e of the body to stress. As an agonist of CRF receptors (e.g., CRF, and CRF),

CRF is well known as the primary physiological secretagogue controllings hypothalamic- pituitary-adrenal (HPA) axis activity which mediates the endocrine stress response. CRF also plays a central role in the autonomic and behavioral responses to stress. Variation in physiological levels of CRF has been correlated with various disomders including depression and anxiety.

[0004] Antagonists of CRF receptors have been shown to effecti_vely ameliorate behavioral stress responses in animal models. It is well established that systemic administration of CRF) receptor antagonists leads to anxiolytic and antidezpressant effects in rodents. Animal model evidence also shows that CRF; antagonists camn help alleviate the symptoms of drug withdrawal, stress-induced seizures, and certain in#flammations. A role fox CRF has also been postulated in the etiology and pathophysiology of Alzheimer’s diseases, Parkinson's disease, Huntington’s disease, progressive supranu=clear palsy, and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF~ neurons in the central nervous system. Eating disorders, such as anorexia nervosa, have also been linked to elev ated levels of CRF.

[0005] Though widely dispersed throughout the centwral nervous system, CRF receptors are also found in peripheral systems includling glandular, vascular, gastrointestinal, and immune system tissues. Accordingly, CRRF antagonists are believed to have potential in treating numerous other disorders outside the central nervous system.

Some CRF-related disorders of peripheral systems include, for example, hypertension, tachycardia, congestive heart failure, stroke, irritable bowel syndrome, post-operative ileus, and colonic hypersensitivity. Studies have indicated tthat CRF; antagonists may also be useful as hair growth stimulators.

[0006] Pyrazolo[1,5-a]}-1,3,5-triazine derivatives have been identified as potent

CRF, antagonists and are currently being studied as therapeutic agents for treatment of various CRF-related disorders, including many of those mentioned above. Numerous pyrazolotriazine CRF; antagonists have been reported in, for example, U.S. Pat. Nos. . 6,124,289; 6,191,131; 6,313,124; 6,060,478; 6,136,809; and 6,358,950, as well as WO 02/72202 and WO 98/08847. [00071 Preparation of pyrazolo[1,5-a]-1,3,5-triazine cormpounds typically involves a multi-step procedure including two ring-forming reactions tc» produce the bicyclic core.

Syntheses of various pyrazolo[1,5-a]-1,3,5-triazine compound s are reported in the above references as well as in WO 01/23388; U.S. Pat. Nos. 4,824, 834, 3,910,907, 5,137,887, 4,892,576, and 5,484,760; EP 594149; He et al., J. Med. Cheran., 2000, 43, 449; Senga, et al., J Med Chem., 1982, 25, 243; Bruni, et al, J. Heterocyscl. Chem., 1995, 32, 291;

Kobe, et al., J Het Chem., 1974, 991; Kobe, et al., J. Het. C_hem. 1974, 199; Novinson, et al, J Het Chem., 1974, 691; and Albert, et al., J. Het. Chem. 1973, 885. Ring- forming and other reactions are reported in Beyer, et al., Ber. 1960, 93, 2209 and

Cusmano, et al., Gazz. Chim. Ital., 1952, 82, 373.

[0008] Numerous active pyrazolo[1,5-a]-1,3,5-triazimne compounds include a multi-substituted aryl or heteroaryl group attached to the 8-pcsition of the bicyclic core.

Introduction of the 8-subsituent often involves the use of an ar-yl or heteroaryl acetonitrile derivative. Methods for preparing aryl or heteroaryl acetoritrile derivatives from the corresponding halomethyl compound and cyanide are reported in JP 2001302658; CN 1088574; and Nishida, et al., Technol. Rep. Yamaguchi Uni-v., 1988, 4(2), 145. Other references reporting reactions that can be used in the preparation of aryl or heteroaryl acetonitrile derivatives include, for example, Nagel, ef al., J. Org. Chem., 1977, 42, 3626 and Stogryn, J. Org. Chem., 1972, 37, 673 (n-BuLi metallaation of aryl bromides and

W/O 2005/051954 PCT/US2004/039046 condensation with DMF to form aldehydes); Li, et al., Tetrahedron Lett. 2001, 1175 (sodium borohydride reduction of benzyl aldehydes to benzyl alcohols); J. Org. Chem., 12970, 35,3195, J. Org. Chem., 1971, 36, 3044, Tetrahedron 19°71, 27, 5979 (chlorination of benzyl alcohol with mesyl chloride and base); J. 4m. Chem_ Soc., 1951, 73, 2239, J.

Am. Chem. Soc., 1953, 75, 2053 (conversion of benzyl chloricle to cyanide derivative); amd Repic, Principles of Process Research and Chemiceaal Development in the

Pharmaceutical Industry, Wiley, 1998, p. 38. [C009] In view of the importance of pyrazolo[1,5-a]-1,33,5-triazine derivatives in the treatment of CRF-related disorders such as anxiety and depre=ssion, improved methods for their synthesis are needed. Such improvements can includ-e, for example, enhanced emantiomeric and/or diastereomeric selectivity in individual -reaction steps, enhanced chemical purity, increased yields, employment of lower cost starting materials, . eamployment of less toxic starting materials, lowered energy con_sumption (e.g., avoidance o f reactions conducted at very high or low temperatures or preessures), reduction in the number of synthetic steps, and improved scale-up conditions. The processes and intermediates discussed herein help fulfill these and other needs.

SUMMARY OF THE INVENTION

[66010] The present invention provides, inter alia, processses and intermediates for preparing pyrazolo[1,5-a]-1,3,5-triazines of Formula I below which are CRF receptor amtagonists useful for treating CRF-related disorders including a—nxiety and depression. [©0011] The present invention further provides processses and intermediates for preparing aryl and heteroaryl acetonitrile compounds useful as ®ntermediates in preparing pyrazolo[1,5-a]-1,3,5-triazines of Formula I.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[€0012]) The present invention provides, inter alia, processes for preparing pryrazolo[1,5-a]-1,3,5-triazines of Formula I:

R'. N° R2

NA NN 28

RA A N BNE

Ar

I wherein:

Ar is phenyl or pyridyl substituted with 0 to 5 R?; each R! and R? is, independently, H, (Ci-Cg)alkyl, or (C1-Cs)alkoxyalkyl; each R? is, independently, H, halo, CN, mitro, (C1-Cylalkyl, (C;-Cgalkoxy, (Ci-

Ca)haloalkyl, or (C;-Cs)haloalkoxy; and each R” and R® is, independently, (C;-C4)aalkyl. In some embodiments, either or

A both R* and R® are methyl. In further embodiments, Ar can be 2-methyl-4- methoxyphenyl, 2-chloro-5-fluoro-4-methoxyphemyl, or 2-methyl-6-methoxypyrid-3-yl.

In yet further embodiments, both R' and R? can be methoxyethyl, or R!is H and R? is pent-3-yl, or R! is H and R? is but-2-yl.

[0013] According to the present invention the processes of preparing compounds of Formula I can comprise the steps: (a) contacting a compound of F ormula ITI:

OH

NAN Nore

RA A N A

Ar

Im with POX; in the presence of an amine, prefemrably a sterically encumbered amine, selected from diisopropylethylamine, diethylphenylamine, diisopropylaniline, diethylaniline, diisopropylisobutylamine, tribenzylamine, triphenylamine, tricyclohexylamine, diethylisopropylamine wheresin X is halo, for a time and under conditions sufficient to provide a compound of Formula II:

X

NPN 8

NON

Ar

I and; (b) contacting the compound of Formula II with NHR'R? for a time and under conditions sufficient to provide the compound of Feormula IL.

[0014] The reaction of step (a) involves th-e replacement of a hydroxyl moiety in the intermediate of Formula III with a halogen mmoiety derived from the reagent POXj.

Example POX; reagents include POF;, POCls, POBr;, and the like. In some embodiments, X is Cl. The amine step (a) cam serve as catalyst for halogenation. . Suitable amines are typically bulky tertiary aamines selected from, for example, diisopropylethylamine, diethylphenylamine, diisopropylaniline, diethylaniline, diisopropylisobutylamine, tribenzylamine, toriphenylamine, tricyclohexylamine, diethylisopropylamine. In some embodiments, diiseopropylethylamine is used as the amine catalyst. The molar ratio of amine catalyst to POX = can he ahout 1:1.

[0015] In some embodiments, the contacting of step (a) is carried out in the } presence of an ammonium salt which can act as a phase transfer agent. Any ammonium salt is suitable. Some example ammonium s alts include benzyltriethylammonium chloride, benzyltributylammonium chloride=, Adogens® (methyltrialkyl(Cs-

Cio)ammonium chloride). In some embodiments, the ammonium salt is benzyltriethylammonium chloride. The ammonivum salt can be provided in a catalytic amount. Example amounts of ammonium salt are Jess than 1 eq (versus the compound of

Formula IIT).

[0016] The contacting of step (a) can be acarried out in any solvent that is non- reactive under the reaction conditions. Preferred solvents for this transformation are methyl t-butyl ether, acetonitrile, isopropylacetate., toluene and 1-chlorobutane. Suitable reaction conditions can include ambient pressure and temperatures of about 50 to about 110 °C, preferably about 50 to about 70 °C .

[0017] The reaction of step (b) involves tne replacement of a halogen moiety in intermediates of Formula II with an amine moietsy. Any primary or secondary amine is suitable, such as an amine having the formula NHR'R?. Amine can be provided in an excess amount relative to the compound of Formula II (or Formula III). Some amines of formula NHR'R? can include, for example,

CHy ONC, nm, JN

H R , OT s .

[0018] Any suitable solverat can be used to carry out the reaction of step (b).

According to some embodiments, the reaction of step (b) is carried out in organic solvent.

Some example organic solvents include methyl t-butyl ether, acetonitrile, isopropyl acetate, toluene, and l-chlorobutane. In some embodiments, the organic solvent comprises either or both acetonitrile and methyl t-butyl ether, such as a mixture of acetonitrile and methyl #-butyl etimer. An example acetonitrile:methyl #-butyl ether v/v ratio can be about 1:4. The reaction of step (b) can be carried out under ambient pressure ’ and temperature. An example temperature can be from about 0 to about 50 °C.

[0019] In some embodimemts, the intermediate of Formula II can be reacted in situ and is not isolated prior to carrying out the reaction of step (b).

[0020] The present invention further provides processes for a first ring closure wherein a compound of Formula IL] is prepared by (c) contacting a compound of Formula

IV: 0)

H,N A NN, <8 nC : Ar wv with (R*)C(OR?), wherein R* is (C 1-CJ)alkyl, for a time and under conditions sufficient to provide the compound of Formula III. A suitable amount of (R*)C(OR?) can be about 1 equivalent or more (versus the compound of Formula IV).

[0021] The above first rings closure process can be carried out in the presence or absence of catalytic acid or base. The reaction is typically carried out in an organic solvent.’ Some suitable solvents include acetonitrile, 1-methyl-2-pyrrolidinone or tetrahydrofuran. In the absence of acid or base, suitable temperatures for carrying out the first ring closure reaction are typically elevated (e.g., greater than room T, such as greater than about 25 °C). Example elevated temperatures can range from about 30 to about 100 °C, or 50 to about 100 °C, or about “75 to about 100 °C.

[0022] An acid may be swmitable for catalyzing the first ring closure reaction.

Example acids include p-toluensulf<onic acid (pTSA), methanesulfonic acid, sulfuric acid, and acetic acid. In some embod&ments, pTSA is used as an acid catalyst. Suitable temperatures for carrying out the ac-id catalyzed reaction can range from about 40 to about 100, about 40 to about 70, or about 40 to about 60 °C.

[0023] According to some embodiments, the first ring closure reaction is carried out in a mixture of l-methyl-2-pwrrolidinone and pTSA. In other embodiments, the : reaction can be carried out in acetoritrile.

[0024] In further embodirnents, the reagent (R*)C(OR*) can be trimethyl orthoacetate (where both R* and R* are methyl) or triethyl orthoacetate. ’ [0025] The present invention further provides processes for a second ring closure wherein a compound of Formula I'V is prepared by (d) contacting a compound of Formula

Vv: }

NH,

Hy Ao op :

Ar

Vv with base for a time and under con.ditions sufficient to provide the compound of Formula

IV. The base can be provided in. any suitable amount, such as one equivalent or less (versus the compound of Formula W).

[0026] Any base can be sui table for carrying out the above processes for a second ring closure reaction. Preferrecl example bases include hydroxides, amines, 1,5- diazabicyclo[4.3.0]-non-5-ene and imidazole. Less preferred examples include alkoxides.

In some embodiments, the base is 1 ,8-diazabicyclo[5.4.0Jundec-7-ene (DBU).

[0027] The above second ring closure reaction can be carried out in organic solvent. Suitable organic solwents include acetonitrile, 1-methyl-2-pyrrolidinone, tetrahydrofuran, aqueous isopropy-1 alcohol or mixtures thereof. In some embodiments, the solvent includes 1-methyl-2-pyrrolidinone or acetonitrile.

[0028) Suitable temperatures for carrying out the second ring closure reactions can include lowered temperatures, such as temperature below room T (e.g., below 25 °C), as well as temperatures ranging from about 0 to about 30 °C. Example temperatures can range from about —20 to about 20, about —10 to about 10, about 0 to about 10, about 10 to about 20, about 20 to about 30, or about 30 to about 35 °C. Ambient pressure is also suitable.

[6029] The present invention further provides semicarbazone-forming processes wherein a compound of Formula V is prepared by (e) contacting a compound of Formula

VI: : oy

NC va Re

Ar

VI wherein Y is an alkali metal or Z'Z2, wherein Z' is halo and Z’ is an alkaline earth metal, with semicarbazide, or acid addition salt thereof, for a time and under conditions sufficient to provide said compound of Formula VI. In some embodiments, the semicarbazide is provided as semicarbazide hydrochloride. The semicarbazide can be provided in an amount greater than about one equivalent (versus the compound of

Formula VI or VII).

[0030] According to some embodiments of the above semicarbazone-forming processes, Y is an alkali metal such as K. In other embodiments, Y is Z'72 such as, for example, MgBr.

[0031] In further embodiments, the above semicarbazone-forming processes are carried out at a pH of from about 1 to about 6, and more preferably from about 3 to about 5. Accordingly, the contacting of step (e) can be carried out in the presence of acid such as acetic acid, hydrochloric acid, sulfuric acid, propionic acid, or butyric acid. In some embodiments, the acid is acetic acid.

[0032] In yet further embodiments, the above semicarbazone-forming processes can be carried out in aqueous solvent. Additionally, the aqueous solvent can include alcohol such as, for example, isopropyl alcohol, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol, ethylene glycol or propylene glycol. In some embodiments, the aqueous solvent contains isopropyl alcohol.

[0033] Suitable reaction conditions for the above semicarbazone-forming proce=sses further include ambient pressure and temperature. E=xample temperatures can range from about 20 to about 40 °C.

[0034] The present invention further provides aryl addition processes wherein a compound of Formula VI is prepared by (f) contacting a compound of Formula VII:

NC ar

VII with an addition reagent having the formula: 0 : R® Hore wher-ein; ’ each R® and RC is, independently, (C;-Ca)alkyl; in the presences of (-BuQ)Y for a time and —under conditions sufficient to provide the compound of Formula VI. In some embodiments, Y is an alkali metal such as K. In other embodimmaents, Y is Z'Z?, such as, for e=tample, MgBr.

[00355] In some embodiments, the reagent (-BuO)Y can be in excess of the addit ion reagent. For example, a suitable amount of (#~-BuO)Y can be about 1 to about 2 eq relative to the amount of compound of Formula VII. [003a5] According to some embodiments, the addition reagent can be ethyl acetate (e.g., RE is methyl and RE is ethyl).

[00377] The aryl addition processes above can be carried ©ut at ambient or elevated temp eratures, such as temperatures above 25 °C. Example elevated temperatures can ranges from about 25 to about 60 or about 30 to about 50 °C. Ambient pressure is suitable.

[00338] The present invention further provides compound s of Formula II or III:

RAN RAN

Ar Mr

II oI wherein:

Ar is 2-methyl-4-methoxyphenyl, 2-chloro-5-fluoro-4—~methoxyphenyl, or 2- methyl-6-methoxypyrid-3-yl;

Xis Cl; and each R* and R® is methyl.

[0039] The present invention further provides compounds of Formula IV, V, or

VI:

NH, 0 So

WL -N B Ny oe % B

I~ R NC < R NC Va R

HN

Ar Ar Ar

Iv A V1 wherein:

Y is an alkali metal or Z!Z?, wherein:

Z! is halo; and 72 is an alkaline earth metal;

Ar is phenyl or pyridyl substituted with 0 to 5 R3; each R® is, independently, H, halo, CN, nitro, (C1-Cqlal kyl, (C,-Cy)alkoxy, (Ci-

Cyhaloalkyl, or (C;-Cs)haloalkoxy; and each R* and R® is methyl. In some embodiments, the compounds of Formulas TV,

V, and VI are substituted wherein Ar is 2-methyl-4-methoxyphemnyl, 2-chloro-5-fluoro-4- methoxyphenyl, or 2-methyl-6-methoxypyrid-3-yl. In further emnbodiments, compounds of Formula VI are provided wherein Y is K.

[0040] Scheme I provides an example of a process of preparing pyrazolo[1,5-a]- 1,3,5-triazines according to the present invention.

Scheme I

RF X

PS _N NHR'R? AN

RA AN = step 6 RA SN

Ar Ar

I 1 §

POX; ] step 5 amine 0] RA OH

A rio" or? PN N

HNT ON a h NZ ONT a

R OR PR R

= —_ NS = w= RA A= ] Ar step 4 Ar wv m step 3 base oY

NH, semicarbazide, RB }

A or acid additiom NC Y/

HN (o] salt thereof

S -— Ar

De step 2 o V1

NC

RE ore step 1 v t-BuOY* " )

Ar vii

[0041] The present invention further provides methods for preparing aryl or heteroaryl acetonitrile derivatives (e.g., compounds of Formula VII) as intermediates in the processes for preparing the CRF antagonist compounds of Formula I. Accordingly, the present invention encompasses processes for preparing compounds of Formula VIII:

CN

AS Al

At A=

A3 vil wherein each A', A%, A, AY, and A’ is, independently, F, Cl, Br, (C;-Ca)alkyl, (C1-Co)haloalkyl, (Cy-Cy)alkoxy, or (C;-Cs)haloalkoxxy; comprising: (a) contacting a compound of Formula IX:

Br

AS A

. AY A=

AS

IX with cyanide in the presence of acid for a tirme and under conditions sufficient to provide the compound of Formula VIII. In some ermbodiments, Alis ql, A? is H, A% is methoxy, A%isT, and A’ isH.

[0042] According to some embodiments of the processes for preparing compounds of Formula VIII, the contacting of step a) can be carried out in the presence of an ammonium salt. Example ammonium salts iraclude benzyltrialkylammonium salts such as benzyltributylammonium chlorides, benzyltrialkylammonium, or tetraalkylammonium salts. Ammonium salt can be provided in an amount of about less than 1 eq, or less than 0.1 eq (versus the compound oef Formula IX).

[0043] In further embodiments of the proacesses for preparing compounds of

Formula VIII, the cyanide in the contacting of step (a) can be provided as a cyanide salt such as sodium or potassium cyanide. Acetone cyaraohydrin may also be used. Cyanide can be provided in an amount of about 1 equivalen=t or greater (versus the compound of

Formula IX). In some embodiments, about 3 to 4 equaivalents of cyanide is provided.

[0044] In even further embodiments of the processes for preparing compounds of

Formula VIII, prior to said contacting of step (a), ghe compound of Formula IX can be dissolved in organic solvent and the cyanide and ammonium salt can be dissolved in aqueous solvent. Accordingly, contacting can be camried out such that individual reagents are dissolved in non-miscible (or weakly miscible) solvents, creating a two-phase reaction system. Any combination of non-miscibole solvents can be suitable, so long as the reagents are sufficiently soluble. An example of a non-miscible solvent combination that can form a two-phase system is the combimation of organic solvent and water, Example organic solvents that are not miscible im water include, pentane, hexanes, benzene, toluene, diethyl ether, or mixtures thereof. The non-miscible solvent combination in the presence of an ammoniam salt catalyst forsms the basis of phase transfer catalysis (PTC).

PTC is well understood, by those knovwledgeable in the art, to have a significant enhancement in the rate of formation of compounds such as compound of Formula VIIL

In some embodiments, the two-phase system includes toluene and water. For example, the compound of Formula IX can be dissol-ved in toluene and the cyanide and ammonium salt can be dissolved in water. - [0045] In yet further embodiments of the processes for preparing compounds of

Formula VIII, the acid in the contacting of step (a) may be a weak carboxylic acid, such as propionic, butyric, or isobutyric acid. _A preferred example acid is acetic acid. The acid can be provided in an amount of about less than one equivalent (versus the compound of Formula IX). An example amnount is about 0.3 to about 0.4 eq.

[0046] The above processes for pxeparing compounds of Formula VIII can be carried out at ambient or elevated temperatures, such as temperatures above 25 °C.

Example elevated temperatures can range from about 25 to about 40 or about 30 to about 40 °C. Ambient pressure is suitable.

[0047] According to some embodiments, compounds of Formula IX can be prepared by (b) contacting a compound of Formula X:

OH

AS Al

At A?

AS

X with HBr for a time and under conditions sufficient to provide the compound of Formula

IX. A suitable amount of HBr can be greater than one equivalent (relative to the compound of Formula X) greater than 10 equivalents, or between about 10 and 20 equivalents.

[0048] The contacting of step (b) involving compounds of Formula X and HBr can be carried out at any suitable temperatiare and pressure. Initial contacting can be carried out at low temperatures, such as from about 0 to about 20 C or about 0 to about 15

C and then later raised to higher temperaturess such as from about 25 to about 60 °C or about 30 to about 55 °C. Ambient pressure iss suitable. The compound of Formula X can be dissolved in any suitable solvent system. Example solvents include organic solvents, such as those that are not miscible in water.

[0049] In further embodiments, the ceompound of Formula X can be prepared by (c) contacting a compound of Formula XI:

CO,Me

A> A poe pnd

X1 with reducing agent for a time and under conditions sufficient to provide the compound of Formula X. Any suitable recucing agent can be used. The amount of reducing agent can be about one or more reducing equivalents. Example reducing agents include bis(2-methoxyethoxy) aluminum hy=dride (Red-Al), lithium aluminum hydride, lithium borohydride, aluminum borohydride, borane, aluminum hydride, lithium triethyl borohydride, sodium borohydride with agppropriate activating ligands and certain enzymes. In some embodiments, the reducing agent is sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al).

[0050] Suitable solvent systems for the contacting of step (c¢) in preparing compounds of Formula X, can be, for example, organic solvents that are inert to strong reducing agents. Example solvents irclude benzene, toluene, diethyl ether, tetrahydrofuran, pentane, hexanes, mixtures thereof, and the like. In some embodiments, a suitable solvent is toluene.

[0051] The contacting of step (¢), imvolving compounds of Formula XI, can be carried out at any suitable temperature. Some suitable temperatures fall below 25 C, including temperatures ranging from about O® to about 20, about 10 to about 20, or about 14 to about 17 °C. Ambient pressure is suitalible.

[0652] The present invention also pros vides compounds of Formula VIII, IX, or X: 1-4

~N Br OH

AS Al AS Al AS Al

JCC AZ Al A2 AY A2

A? A® A via X X wherein A! is Cl, A%is H, A is methoxy, A*is F, and A® is H.

[0053] An example process of preparing compounds of Formula VIII is provided below in Scheme II.

Scheme II

CN Br 1 5 1 4 2 acid 4 2

A = A step 3 A X A

A A

VILL IX

HBr | step 2

OH

C O,Me

AS Al reducing AS Al agent

A A? step] AS A2

A3 A® b.¢ | X

[0054] The present invention also provides processes for preparing compounds of

Formula XI:

CO,Me

Cl

F

OCH3;

XI comprising (a) contacting a compound of Formula XII:

COCI

Cl

F

XII with methoxide for a time and urader conditions sufficient to provide the compoun«d of

Formula XI. Methoxide can be provided in an amount greater than about 2 eq (versuss the compound of Formula XII). An example amount of methoxide is about 3 eq. Suit-able solvent systems include methanol. Ambient temperature and pressure is also suitable.

[0055] In some embodiments, compounds of Formula XII can be prepared byw (b) contacting a compound of Formula XIII:

CO,H ) Cl ie)

F

Xm with oxaly! chloride or thionyl chloride for a time and under conditions sufficierat to provide the compound of Formuala XII. Oxalyl chloride or thionyl chloride car be provided in an amount of at least about one equivalent (versus the compound of Forrmula

XIII). An example amount of oxallyl chloride or thionyl chloride is about 2 eq.

[0056] In some embodiments, the contacting of step (b) in the preparation of compounds of Formula XII is carrzied out in the presence of DMF. DMF can be prov—ided in an amount that is less than one equivalent (eq) (versus the compound of Formula 3X1).

Example amounts of DMF includes between about 0.3 and about 0.6 eq.

[0057] Additionally, the contacting of step (b) in the preparation of compounds of

Formula XII can be carried out in the presence of organic solvent, sucka as dimethylformamide (DMF), tolue=ne, or mixtures thereof, or any other solvent tha=t are non-reactive with the reagents.

[0058] Suitable temperatur-es for preparing compounds of Formula XII can be= less than about 25 °C. In some embocliments, the initial temperature at which the contacting of step (b) is carried out is below 25 °C and which is then raised to above 25 °C at a later point in time, such to a temperature from about 40 to about 60 °C. Excess oxalyl chloride can be removed by distillation according to known procedures.

[0059] The present invention further provides a compound of Formula XI:

CO;Me

Cl io

OCHgj3

XI.

[0060] Processes for preparing compounds of Formula XI are illustrated] in

Scheme III.

Scheme ITE

CO,Me COC CO,H cl methoxide Cl hionide Ci 3 F step 2 F step'l F

OCH; F F

Xi b.¢ | SE XI

[0061] The p resent invention further provides processes for preparing compo-unds of Formula XIV:

B!

B*~ NB?

Xv wherein each B', B? B*, and B* is, independently, F, Cl, Br, (C;-Coalkyl, (Ci-

Cs)baloalkyl, (Ci-Ca)alkoxy, or (Ci-Cs)haloalkoxy. In some embodiments, B! isH, Bis

H, B® is methoxy, arad B* is methyl.

[0062] The processes of preparing compounds of Formula XIV comprise contacting a compouand of Formula XV:

Bg | Ng?

Xv with cyanide for a time and umder conditions sufficient to provide the compound of

Formula XIV. Any source of cyanide is suitable. In some embodiments, the cyanide is provided as sodium cyanide. The cyanide reagent can also be provided in an amount that is about one or more equivalents relative to the compound of Formula XV. In some embodiments, the about 3 to abouat 4 equivalents of cyanide are provided.

[0063] The contacting of step (a) for preparing compounds of Formula XIV can be optionally carried out in the presence of an iodide salt. Any iodide salt is suitable, including for example, sodium ox potassium salts. Iodide can be provided in a catalytic amount, such as less than one equivalent relative to the compound of Formula XV. In some embodiments, about 0.1 eq of iodide is provided.

[0064] In the preparation of compounds of Formula XIV, the contacting of step (a) can be carried out at any suitable temperature or pressure. In some embodiments, contacting is carried out at ambiemt temperature and pressure.

[0065] In some embodiments, the Formula XV can be prepared by (b) contacting a compound of Formula XVT:

Bg? 4 “N” NB?

XVI with a chlorinating agent for a. time and under conditions sufficient to provide the compound of Formula XV. Any chlorinating agent is suitable. In some embodiments, the chlorinating agent is mesyl chloride or thionyl chloride. Mesyl chloride can be provided in an amount of at least about one equivalent relative to the compound of

Formula XVI. Thionyl chloride can be provided in an amount of at least about 0.5 equivalents relative to the compound of Formula XVI.

[0066] In the preparation of compounds of Formula XV, the contacting of step (b) can be carried out in any suitable solvent. In some embodiments, the solvent includes acetonitrile. Any temperature or pressure can be appropriate. In some embodiments, the contacting is carried out at a temperature of from about 0 to about 10 °C, ox about 0 to about 5 °C.

[0067] According to some embodiments, the compounds of Formula XVI are prepared by cosntacting a compound of Formula XVII:

B!

HD B?

B? | NB?

XVII with a reducing agent for a time and under conditions sufficient to provide thes compound of Formula 3X VI. Any reducing agent of sufficient strength is suitable, and can be provided in am amount of at least about one equivalent relative to the compound of

Formula XVI. In some embodiments, the reducing agent is NaBHs. Na_BH4 can be provided in am aqueous hydroxide solution (e.g., about 10 to about 20 M NaOH).

[0068] In the contacting of step (¢) for preparing compounds of Formula XVI, suitable solverts include those that are inert to the reducing agent. In some ermbodiments, the solvent in cludes alcohol, such as methanol, ethanol, isopropanol, etc., aand mixtures thereof. :

[0069] According to some embodiments, compounds of Formula 3XVII can be prepared by (3) contacting a compound of Formula XVII: g!

BN” B?

Xvil with n-BuLi Followed by a formylating reagent for a time and under conditions sufficient to provide said compound of Formula XVII. The n-BuLi can be provided in an amount of about 1 eq relative to the compound of Formula XVII. Compounds of Feormula XVII may also be prepared by contacting a compound of Formula XVIII with a reamgent capable of metal-halozgen exchange, such as magnesium, lithium, or alkyl lithiums.

[0070] Suitable formylating reagents include dimethylformamide CDMEF), ethyl formate, N-Formylpiperidine, N-methoxy-N-methylformamide. ~Accordimg to some embodiments-, the formylating reagent is DMF. The formylating reagent cara be provided in an ammount of at least about one equivalent (relative to the compound of Formula

XVII). In some embodiments, the formylating reagent is provided in an amount of about wo eq. [0071) Suitable solvents for the contacting of step (d) in prepar-ing compounds of

Formul a XVII are inert to n-BuLi such as, for example, benzene, toluene, hexanes, pentane, and the like. Tetrahydrofuran may also be suitable. Suitables temperatures can range £rom -80 to about 0 °C, such as about —60 °C, for initial coratacting. Ambient temperature and pressure are suitable after initial contacting.

[6072] An example process for the preparation of compounds ©f Formula XIV is provided in Scheme IV.

Scheme IV

B' B'

B? B?

BN” B® stepd pA NT gl

Xv XV step 3 chlorina-ting agent , i. 51 2 reducing B2

B4 NG gd step 2 B4 N~ Be

Xvi XVI n-BuLi step 1 | DME

B' 2 ~

B*” “NB

XVIII

[0073] The present invention further provides processes for preparing compounds of Formula XIX:

“TL

B*~ | N" oB®

XX wherein:

B*is F, Cl, Br, (Ci-Cqalkyl, (Ci-Cs)haloalkyl, (€-Ca)alkoxy, or (Ci-

Cs)haloalkoxy; and

B’ is (C)-Cy)alkyl; comprising: contacting a compound of Formula XX:

B*” “Nr

XX with BO" for a time and under conditions sufficient to -provide the compound of Formula

XIX. According to some embodiments, B> can be methyl or B* can be methyl. In further embodiments BO is provided as an alkali salt such ass a sodium or potassium salt. The reagent BO can be provided in excess, such as for example greater than 1 eq relative to the amount of compound of Formula XX. The contacting of step (a) can be carried out in any suitable solvent. Some suitable solvents include mmethanol, benzene, toluene, and the like. Suitable temperatures at which the contacting of step (a) can be carried out include temperatures between about 0 and 120 °C. For example, the temperature can be from about 60 to about 80 °C or about 65 to about 75 °C. Ambient pressure is suitable.

[0074] In further embodiments, the compound Of Formula XX can be prepared by (b) contacting a compound of Formula XXI:

B* >N” “NH,

Xxa or acid addition salt thereof, with nitrite and Br, in tlme presence of acid for a time and under conditions sufficient to provide the compouvand of Formula XX. In some embodiments, the nitrite can be provided as NaNO; or- HONO. In further embodiments, the acid can be HBr. Each of the nitrite, Br,, and acid can be provided in excess, such as for example, greater than 1 eq relative to the amoumt of compound of Formula XXI. The contacting of step (b) can be carried out at zany suitable temperature. Example temperatures can range from about —10 to about 240, about —5 to about 10, or about 0 to about 5 °C.

[0075] The reaction mixture resulting fromm the contacting of step (b) can be further contacted with base to adjust the pH to a vallue greater than about 7. For example, the hydroxide (such as NaOH, or KOH, etc.) can be added to achieve a solution pH of about 8 to about 14, about 10 to about 14, or about 113.

[0076] In some embodiments, the compound of Formula XXI can be prepared by (¢) contacting a compound of Formula XXII:

JR

BON” NIH,

XX with Br, in the presence of acid for a time and uncer conditions sufficient to provide the compound of Formula XXI. In some embodirments, the acid is acetic acid. The contacting of step (c) can be carried out at any suitable temperature and pressure. Some suitable temperatures can be from about 10 to abowmt 25, about 15 to about 20 or about 18 °C. Acid can be provided in excess relative to thee compound of Formula XXII and can serve as solvent. Bromine (Bry) can be provided im an amount of about 0.5 to about 1.5, about 0.9 to about 1.1 or about 1.0 eq relative to thes compound of Formula XXII. 10077} The present invention further provides compounds of Formula XIV or XV:

B’ B'

BY NT 8° BON el

Xv Xv wherein B' is H, B? is H, B® is methoxy, ancl B* is methyl.

[0078] An example process for the prepara-tion of compounds of Formula XIX is provided in Scheme V.

Scheme V

Br XN BO" Br x

IL 5 Step 3 TL

N oB B N Br

Xx XX nitrite j step 2 | Br, acid

B* N° NH, 2d gt NT NH,

XXII step 1 XXT

[0079] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 'H or °C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.

[0080] The term “contacting” as used herein refers to the bringing together of reagents to within distances sufficient to effect molecular transformation such as bond breakage and formation. The reagents provided for contacting can be in any form, such as gas, liquid, solid, or in solution.

[0081] The reactions of the processes described herein can be carried out in suitable solvents, such as organic or aqueous solvents, which may be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non- reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent's freezing temperature to the solvent's boiling temperature. A given : reaction may be carried out in one solvent or a mixture of more than one solvent.

Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.

[0082] Suitable organic solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform,

bromochloromethane, dibromormethane, butyl chloride, dichloromethare, tetrachloroethylene, trichloroethyle=ne, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1.1- dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o- dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichlorometharne, chlorotrifluoromethane, bromnotrifluoromethane, carbon tetrafluoricie, dichlorofluoromethane, chlor-odifluoromethane, trifluoromethane, 1.2- dichlorotetrafluorethane, hexafluoroethane, 1-chlorobutane, and 1,2-dichloroethane.

[06083] Suitable organic solvents include ethers such as dimethoxymethame, tetrahydrofuran, 1,3-dioxane, 1,4-d ioxane, furan, diethyl ether, ethylene glycol dimetinyl ether, ethylene glycol diethyl ethemr, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimmethyl ether, anisole, t-butyl methyl ether, di-n-burtyl ether, 2-methyltetrahydrofuran, or R,3-dioxolane.

[0084] Suitable protic solv-ents may include, by way of example and without limitation, water, or organic solwents such as methanol, ethanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-triflucroetharol, ethylene glycol, 1l-propanol, 2-propanol, 2- methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyetharnol, diethylene glycol, 1-, 2-, or 3- pemmtanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, ben zy alcohol, phenol, glycerol, or 1-metknoxy-2-propanol.

[0085] Suitable aprotic soE vents may include, by way of example and with out limitation, the organic solvents tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide = (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidineone (DMPU), 1,3-dimethyl-2-imidazclidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, EN-methylformamide, acetonitrile, dimethyl sulfox3de, propionitrile, ethyl formate, metlmyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfoRane, N,N-dimethylpropionamide, tetramethyluwea, nitromethane, nitrobenzene, hex amethylphosphoramide, n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl propionate, 2-pentanone, or methyl iso-butyl ketone.

[0086] Suitable organic solvents include hydrocarbons such as benzene, cyclohexane, pentane, hexane, -toluene, cyclobeptane, methylcyclohexane, heptane, ethylbenzene, m-, 0-, or p-xylene, -octane, indane, nonane, or naphthalene.

[0087] As used herein, sui table acids include, but are not limited to hydrochl oric acid, hydrobromic acid, sulfuric acsid, phosphoric acid, nitric acid, and organic acids.

[0088] Suitable organic acids include formic acid, acetic acid, propiomic acid, butanoic acid, wmethanesulfonic acid, p-toluene sulfonic acid, benzenesulfondic acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and lecanoic acid.

[0089] Ms used herein, suitable bases include, but are not limited to: lithium hydroxide, sodivim hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium hydroxide, calcium hydroxide, calcium cazbonate, sodium bicarbonate and potassium bicarbonate.

[0090] As used herein, suitable strong bases include, but are not limited to, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wwherein; alkoxides inclucle lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides in_clude sodium amide, potassium amide and lithium amide; metal ¥nydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialky~lamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl arad cyclohexyl substituted amides.

[0091] The compounds described herein may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isormers are contemplated ira the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically =active starting materials are known in the art, such as by resolution of racemic forms or by synthesis. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended.

[0092] The present invention includes all isotopes of atoms occurring in the intermediates ox- final compounds. Isotopes include those atoms having the samee atomic number but difFerent mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0093] When any variable occurs more than one time in any constituent ©r in any formula, its definition on each occurrence is independent of its definition at evesry other

Claims (11)

PCT/US2004/039046 CLAIMS:

1. A process of preparing a compound of Formula II: 1 NZ N-N J J) AY = R Ni Ar II wherein: Ar is phenyl or pyridyl substituted -with 0 to 5 R?; X is halo; each R? is, independently, H, halo, CN, nitro, (C;-Cs)alkyl, (C,-C4)alkoxy, (C,- Cs)haloalkyl, or (C;-C4)haloalkoxy; and each R* and RB is, independently, (C,-Cj)alkyl; comprising contacting a compound of Forrnula III: £ \ RB — Ar I with POX; in the presence of an ammonium. halide salt and an amine selected from diisopropylethylamine, diethylphenylamine, diisopropylaniline, diethylaniline, diisopropylisobutylamine, tribenzylamine, teiphenylamine, tricyclohexylamine, or diethylisopropylamine for a time and under conditions sufficient to provide said compound of Formula II.

2. The process of claim 1 wherein X is Cl.

3. The process of claim | wherein said amine is diisopropylethylamine. 46 AMENDED SHEET

/ I } : PCT/US2004/039046 4, The process of claim 1 wherein said amrxaonium halide salt is benzyltriethylammonium chloride, benzyltributy’lammonium chloride, or methyltrialkyl(Cg-Cp)ammonium chloride.

5. The process of claim 1 wherein said ammonium halide salt is benzyltributylammonium chloride

6. The process of claim 1 wherein said contacting is carried out in an organic solvent.

7. The process of claim 6 wherein said organic solvent comprises methyl z-butyl ether, acetonitrile, isopropyl acetate, toluene, or 1-chlorobutane, or mixtures thereof.

8. The process of claim 6 wherein said organic solvent is a mixture of acetonitrile and methyl t-butyl ether.

9. The process of claim 1 wherein said con tacting is carried out at a temperature of about 50 to about 70 °C.

10. The process of claim 1 wherein Ar is 2-rnethyl-4-methoxyphenyl, 2-chloro-5- fluoro-4-methoxyphenyl, or 2-methyl-6-methox ypyrid-3-yl.

11. A process of claim 1, substantially as hesrein described with reference to and as illustrated in any of the examples. 47 AMENDED SHEET