PROCESS FOR PREPARING BICYCLIC PYRAZOLYL AND IMIDAZOLYL COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to a process for preparing bicyclic pyrazolyl and imidazolyl compounds, in particular the preparation of 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-7-(2,2-difluoro-prop yl)-6,7-dihydro- 2H,5H-4-oxa-1 ,2,7-triaza-azulen-8-one, and intermediates useful in the synthesis of such bicyclic compounds. The bicyclic pyrazolyl and imidazolyl compounds prepared by the process described herein have been shown to be CB-1 receptor antagonists.

BACKGROUND

CB-1 antagonists have been shown to useful for the treatment of a variety of diseases, conditions and/or disorders including obesity, alcoholism, smoking cessation, Parkinson's disease, inflammation, sexual dysfunctions, dementia, and so forth. Consequently, there exists a desire to develop compounds that selectively antagonize the CB-1 receptor. US Publication No. 2005/0101592 and PCT Publication No. WO 05/044822 describe a series of bicyclic pyrazolyl and imidazolyl compounds that act as selective CB-1 antagonists. However, there exists a need to produce these compounds, in particular, 3-(4-chloro-phenyl)-2-(2- chloro-phenyl)-7-(2,2-difluoro-propyl)-6,7-dihydro-2H,5H-4-o xa-1,2,7-triaza-azulen-8-one, in a more efficient, environmentally safe, and cost effective manner at larger scales of manufacture.

SUMMARY

The present invention provides an improved process for preparing compounds of Formula (I):

(I) wherein

A is nitrogen and B is carbon, or A is carbon and B is nitrogen;

R ^oa , R ^ob , R ^1a , and R ^1b are each independently halo, (C _r C ₄ )alkoxy, (Ci-C ₄ )alkyl, halo-substituted (C ₁ - C ₄ )alkyl, or cyano (preferably, R ^Oa is chloro, fluoro, or methyl; R ^ob is chloro, fluoro or hydrogen (i.e., m is 0); R ^1a is chloro, fluoro, (CrC ₄ )alkyl, trifluoromethyl, (CrC ₄ )alkoxy, or cyano; and R ^1b is hydrogen (i.e., n is O)); n and m are each independently 0, 1 or 2;

X is O, S, SO, SO ₂ , -N(R ^2a )- or -C(R ^2b )(R ^2c )-, where R ^2a , R ^2b and R ²⁰ are each independently hydrogen, (Ci-C ₄ )alkyl, halo-substituted (CrC ₄ )alkyl or (CrC ₅ )acyl; (preferably, R ^2a is hydrogen, (Ci-C ₄ )alkyl,

or fluoro-substituted (CrC ₄ )alkyl); and at least one of R ^2b and R ^2c is (Ci-C ₄ )alkyl or fluoro-substituted (C ₁ - C ₄ )alkyl, or both R ^2b and R ²⁰ are hydrogen);

R ^3a and R ^3b are each independently hydrogen, (Ci-C ₆ )alkyl, or halo-substituted (CrC ₆ )alkyl (preferably, R ^3a and R ^3b are each independently hydrogen, (C ₁ -C ₄ )alkyl, or fluoro-substituted (Ci-C ₄ )alkyl), or either R ^3a or R ^3b taken together with R ⁴ forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents; and

R ⁴ is a chemical moiety selected from the group consisting of (C ₁ -C ₈ )alkyl, aryl, heteroaryl, aryl(Cr C ₄ )alkyl, a 3- to 8-membered partially or fully saturated carbocyclic ring(s), heteroaryl(C ₁ -C ₃ )alkyl, 5-6 membered lactone, 5- to 6-membered lactam, and a 3- to 8-membered partially or fully saturated heterocycle, where said chemical moiety is optionally substituted with one or more substituents, or R ⁴ taken together with either R ^3a or R ^3b forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where the heterocyclic ring optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur and is optionally substituted with one or more substituents; a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the compound, or the salt.

Preferably, R ⁴ is a chemical moiety selected from the group consisting of (Ci-C ₈ )alkyl, aryl((V C ₄ )alkyl, 3- to 8-membered partially or fully saturated carbocyclic ring(s), and 3- to 8-membered partially or fully saturated heterocycle, where said chemical moiety is optionally substituted with one or more substituents.or R ⁴ taken together with either R ^3a or R ^3b forms a fully or partially saturated 5- to 6-membered heterocyclic ring, where said heterocyclic ring is optionally substituted with one or more substituents. More preferably, R ⁴ is (CrC ₈ )alkyl, halo-substituted (Ci-C ₈ )alkyl (preferably, fluoro-substituted (CrC ₈ )alkyl), cyclopentyl, cyclohexyl, piperidin-1-yl, pyrrolidin-1-yl, or morpholin-1-yl. Most preferably, R ⁴ is 2,2- difluoropropyl.

Preferably A is nitrogen and B is carbon. R ^3a and R ^3b are both preferably hydrogen.

The process for the preparation of the compound of Formula (I) comprises the steps of:

(1 ) cyclizing the compound of Formula (l-a) in the presence of 1 ,1 '-carbonyldiimidazole to produce a compound of Formula (I)

where R is hydrogen and A, B, R -,0 ^υ a ^a , R _O 0 ^U b ^D , o Ri ^η a ^a , R ₃ 1 ¹ b ^D , n, m, X, R ^3a , R ^3b , and R ⁴ are as defined above; and

(2) isolating the compound of Formula (1), a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or the salt.

Alternatively, one may start with the ester where R is an alkyl group. The ester group is hydrolyzed to the corresponding carboxylic acid (i.e., compound of Formula (l-a) where R is hydrogen) followed by the formation of the final product (i.e., the compound of Formula (I)) as described above. Preferably, the compound of Formula (I) is isolated as the compound per se, or a hydrate or solvate thereof. In a preferred embodiment, the compound of Formula (I) is 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-

7-(2,2-difluoro-propyl)-6,7-dihydro-2H,5H-4-oxa-1 ,2,7-thaza-azulen-8-one (i.e., A is nitrogen, B is carbon, n and m are both 0, R ^Oa and R ^1a are both chloro, R ^3a and R ^3b are both hydrogen, and R ⁴ is 2,2-difluoro-π- propyl).

When A is nitrogen, B is carbon, n and m are both 0, R ^Oa and R ^1c are both chloro, R ^3a and R ^3b are both hydrogen, X is oxygen, and R ⁴ is 2,2-difluoro-n-propyl, the compound of Formula (l-a), is preferably prepared by

(i) coupling a compound of Formula (l-2a-1) with a compound of Formula (l-2b-1) to produce a compound of Formula (l-2c-1)

(I-2C-1)

wherein Pgi is an carboxy-protecting group (e.g., ethyl), and Pg ₂ is a amino-protecting group (e.g., -

C(O)OC(CH ₃ ) ₃ ) or BOC); and (ii) removing said amino-protecting group (Pg ₂ ) and said carboxy-protecting group (Pg-,) -to produce said compound of Formula (1-1 a).

In another embodiment of the present invention, a crystalline form of 3-(4-chloro-phenyl)-2-(2-chloro- phenyl)-7-(2,2-difluoro-propyl)-6,7-dihydro-2H,5H-4-oxa-1 ,2,7-triaza-azulen-8-one is provided which was prepared by the process above. In yet another embodiment of the present invention, a substantially pure crystalline form of 3-(4- chloro-phenyl)-2-(2-chloro-phenyl)-7-(2,2-difluoro-propyl)-6 ,7-dihydro-2H,5H-4-oxa-1 ,2,7-triaza-azulen-8-one having a x-ray diffraction pattern illustrated in Figure 1 is provided.

The process described above provides an advantage over the previously described process. For example, the inventive process avoids the use of halogenated solvents, such as 1 ,2-dichloroethane, as compared to the previously disclosed route (see, US Publication No. 2005/0101592 or PCT Publication No.

WO 05/044822). In addition, the product may be isolated directly from the reaction mixture via precipitation, thus resulting in the elimination of extra isolation steps and less impurities.

Definitions

As used herein, the term "alkyl" refers to a hydrocarbon radical of the general formula C _n H _2n+I . The alkane radical may be straight or branched. For example, the term "(CrC ₆ )alkyl" refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, π-propyl, /-propyl, n- butyl, /-butyl, s-butyl, f-butyl, n-pentyl, 1-methylbutyl, 2-methyl butyl, 3-methylbutyl, neopentyl, 3,3- dimethylpropyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, and alkylthio group have the same definition as above. When indicated as being "optionally substituted", the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three substituents except in the case of halogen substituents such as perchloro or perfluoroalkyls) independently selected from the group of substituents

listed below in the definition for "substituted." "Halo-substituted alkyl" refers to an alkyl group substituted with one or more halogen atoms (e.g., "fluoro-substituted alkyl" refers to fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1 ,1-difluoroethyl, 1 ,2-difluoroethyl, 2,2-difluoroethyl, 1 ,1 ,1- trifluoroethyl, 2,2,2-trifluoroethyl, 1 ,1 ,2-trifluoroethyl, 1 ,2,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1 ,1 ,2,2- tetrafluoroethyl, 1 ,1 ,1 ,2-tetrafluoroethyl, 1 ,1 ,2,2,2-pentafluoroethyl, 1 ,1 ,1 ,2,2-pentafluoroethyl, perfluoroethyl, etc.). Preferred halo-substituted alkyls are the chloro- and fluoro-substituted alkyls, more preferably, fluoro- substituted alkyls. When substituted, the alkane radicals or alkyl moieties are preferably fluoro substituents (as described above), or 1 or 2 substituents independently selected from (CrC ₃ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₂ - C ₃ )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro, cyano, hydroxy, (CrC ₃ )alkoxy, aryloxy, amino, (CrC ₆ )alkyl amino, di-(C _r C ₄ )alkyl amino, aminocarboxylate (i.e., (C _r C ₃ )alkyl-O-C(O)-NH-), hydroxy(C ₂ -C ₃ )alkylamino, or keto (oxo), and more preferably, 1 to 3 fluoro groups, or 1 substituent selected from (CrC ₃ )a\k)f\, (C ₃ -C ₆ )cycloalkyl, (CβJaryl, 6-membered-heteroaryl, 3- to 6-membered heterocycle, (C ₁ - C ₃ )alkoxy, (CrC ₄ )alkyl amino or di-(d-C ₂ )alkyl amino.

The terms "partially or fully saturated carbocyclic ring" (also referred to as "partially or fully saturated cycloalkyl") refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the carbocyclic ring is generally a 3- to 8-membered ring. For example, partially or fully saturated carbocyclic rings (or cycloalkyl) include groups such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclpentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, norbornyl (bicyclo[2.2.1]heptyl), norbornenyl, bicyclo[2.2.2]octyl, and the like. When designated as being "optionally substituted", the partially saturated or fully saturated cycloalkyl group may be unsubstituted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted." A substituted carbocyclic ring also includes groups wherein the carbocyclic ring is fused to a phenyl ring (e.g., indanyl). The carbocyclic group may be attached to the chemical entity or moiety by any one of the carbon atoms within the carbocyclic ring system. When substituted, the carbocyclic group is preferably substituted with 1 or 2 substituents independently selected from (CrC ₃ )alkyl, (C ₂ -C ₃ )alkenyl, (C ₁ - C ₆ )alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro, fluoro, cyano, hydroxy, (C ₁ -C ₃ JaIkOXy, aryloxy, amino, (CrCβJalkyl amino, di-(C ₁ -C ₄ )alkyl amino, aminocarboxylate (i.e., (CrC^alkyl-O-C^-NH-), hydroxy(C ₂ -C ₃ )alkylamino, or keto (oxo), and more preferably 1 or 2 from substituents independently selected from (C-i-C^alkyl, 3- to 6-membered heterocycle, fluoro, (C-ι-C ₃ )alkoxy, (Ci-C ₄ )alkyl amino or di-(Cr C ₂ )alkyl amino. Similarly, any cycloalkyl portion of a group (e.g., cycloalkylalkyl, cycloalkylamino, etc.) has the same definition as above.

The term "partially saturated or fully saturated heterocyclic ring" (also referred to as "partially saturated or fully saturated heterocycle") refers to nonaromatic rings that are either partially or fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified otherwise, the heterocyclic ring is generally a 3- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2

heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Partially saturated or fully saturated heterocyclic rings include groups such as epoxy, aziridinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl, piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl, oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl, tetrahydrothienyl 1 ,1 -dioxide, and the like. When indicated as being "optionally substituted", the partially saturated or fully saturated heterocycle group may be unsubstiuted or substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted." A substituted heterocyclic ring includes groups wherein the heterocyclic ring is fused to an aryl or heteroaryl ring (e.g., 2,3-dihydrobenzofuranyl, 2,3-dihydroindolyl, 2,3- dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, etc.). When substituted, the heterocycle group is preferably substituted with 1 or 2 substituents independently selected from (Ci-C ₃ )alkyl, (C ₃ -C ₆ )cycloalkyl, (C ₂ -C ₄ )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, chloro, fluoro, cyano, hydroxy, (CrC ₃ )alkoxy, aryloxy, amino, (CrC ₆ )alkyl amino, di-(Ci-C ₃ )alkyl amino, aminocarboxylate (i.e., (CrC ₃ )alkyl-O-C(O)-NH-), or keto (oxo), and more preferably with 1 or 2 substituents independently selected from (Ci-C ₃ )alkyl, (C ₃ - C ₆ )cycloalkyl, (C ₆ )aryl, 6-membered-heteroaryl, 3- to 6-membered heterocycle, or fluoro. The heterocyclic group may be attached to the chemical entity or moiety by any one of the ring atoms within the heterocyclic ring system. Similarly, any heterocycle portion of a group (e.g., heterocycle-substituted alkyl, heterocycle carbonyl, etc.) has the same definition as above.

The term "aryl" or "aromatic carbocyclic ring" refers to aromatic moieties having a single (e.g., phenyl) or a fused ring system (e.g., naphthalene, anthracene, phenanthrene, etc.). A typical aryl group is a 6- to 10-membered aromatic carbocyclic ring(s). When indicated as being "optionally substituted", the aryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted." Substituted aryl groups include a chain of aromatic moieties (e.g., biphenyl, terphenyl, phenylnaphthalyl, etc.). When substituted, the aromatic moieties are preferably substituted with 1 or 2 substituents independently selected from (Ci-C ₄ )alkyl, (C ₂ -C ₃ )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (CrC ₄ )alkoxy, aryloxy, amino, (CrC ₆ )alkyl amino, di-(C-|-C ₃ )alkyl amino, or aminocarboxylate (i.e., (Ci-C ₃ )alkyl-O-C(O)-NH-), and more preferably, 1 or 2 substituents independently selected from (Ci-C ₄ )alkyl, chloro, fluoro, cyano, hydroxy, or (Ci-C ₄ )alkoxy. The aryl group may be attached to the chemical entity or moiety by any one of the carbon atoms within the aromatic ring system. Similarly, the aryl portion (i.e., aromatic moiety) of an aroyl or aroyloxy (i.e., (aryl)- C(O)-O-) has the same definition as above.

The term "heteroaryl" or "heteroaromatic ring" refers to aromatic moieties containing at least one heteratom (e.g., oxygen, sulfur, nitrogen or combinations thereof) within a 5- to 10-membered aromatic ring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl, thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl, triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl, quinolinyl, isoquinolinyl,

benzothiophenyl, benzoxazolyl, etc.). The heteroaromatic moiety may consist of a single or fused ring system. A typical single heteroaryl ring is a 5- to 6-membered ring containing one to three heteroatoms independently selected from oxygen, sulfur and nitrogen and a typical fused heteroaryl ring system is a 9- to 10-membered ring system containing one to four heteroatoms independently selected from oxygen, sulfur and nitrogen. When indicated as being "optionally substituted", the heteroaryl groups may be unsubstituted or substituted with one or more substituents (preferably no more than three substituents) independently selected from the group of substituents listed below in the definition for "substituted." When substituted, the heteroaromatic moieties are preferably substituted with 1 or 2 substituents independently selected from (C ₁ - C ₄ )alkyl, (C ₂ -C ₃ )alkenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (Ci-C ₄ )alkoxy, aryloxy, amino, (Ci-C ₆ )alkyl amino, di-(Ci-C ₃ )alkyl amino, or aminocarboxylate (i.e., (C ₁ -C ₃ )alkyl-O-C(O)-NH-), and more preferably, 1 or 2 substituents independently selected from (CrC ₄ )alkyl, chloro, fluoro, cyano, hydroxy, (Ci-C ₄ )alkoxy, (CrC ₄ )alkyl amino or di-(Ci-C ₂ )alkyl amino. The heteroaryl group may be attached to the chemical entity or moiety by any one of the atoms within the aromatic ring system (e.g., imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrid-5- yl, or pyrid-6-yl). Similarly, the heteroaryl portion (i.e., heteroaromatic moiety) of a heteroaroyl or heteroaroyloxy (i.e., (heteroaryl)-C(O)-O-) has the same definition as above.

The term "acyl" refers to hydrogen, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups. For example, acyl includes groups such as (Ci-C ₆ )alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, f-butylacetyl, etc.), (C ₃ -C ₆ )cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl (e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl, furanyl-3-carbonyl, 1H- pyrroyl-2-carbonyl, ^" IH-pyrroyl-3-carbonyl, benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions above. When indicated as being "optionally substituted", the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted" or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively.

The term "substituted" specifically envisions and allows for one or more substitutions that are common in the art. However, it is generally understood by those skilled in the art that the substituents should be selected so as to not adversely affect the pharmacological characteristics of the compound or adversely interfere with the use of the medicament. Suitable substituents for any of the groups defined above include (C _r C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, (C ₂ -C ₆ )alkenyl, (CrC^alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (Ci-C ₆ )alkoxy, aryloxy, sulfhydryl

(mercapto), (Ci-C ₆ )alkylthio, arylthio, amino, mono- or di-(Ci-C ₆ )alkyl amino, quaternary ammonium salts, amino(CrC ₆ )alkoxy, aminocarboxylate (i.e., (CrC^alkyl-O-C^-NH-), hydroxy(C ₂ -C ₆ )alkylamino, amino^- C _e )alkylthio, cyanoamino, nitro, (C ₁ -C ₆ )carbamyl, keto (oxo), acyl, (Ci-C ₆ )alkyl-CO ₂ -, glycolyl, glycyl, hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thio(C ₁ -C ₆ )alkyl-C(O)-, thio(Ci-C ₆ )alkyl-CO ₂ -, and combinations thereof. In the case of substituted combinations, such as "substituted 8IyI(C ₁ -C ₆ )alkyl", either the aryl or the alkyl group may be substituted, or both the aryl and the alkyl groups may be substituted with one or more substituents (typically, one to three substituents except in the case of perhalo substitutions). An aryl or heteroaryl substituted carbocyclic or heterocyclic group may be a fused ring (e.g., indanyl, dihydrobenzofuranyl, dihydroindolyl, etc.). The term "solvate" refers to a molecular complex of a compound represented by Formula (I) and pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water. The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

The term "substantially pure" refers to a compound purity of greater than or equal to 99.0% (preferably, greater than or equal to 99.2%, more preferably greater than or equal to 99.5%, most preferably greater than or equal to 99.7%). BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 illustrates the powder X-ray diffraction of_3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-7-(2,2- difluoro-propyl)-6,7-dihydro-2H,5H-4-oxa-1 ,2,7-triaza-azulen-8-one (IA-1) that was synthesized using the process described herein.

DETAILED DESCRIPTION The starting materials used in the processes described herein are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1 -19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

Scheme I below summarizes the process of the present invention as well as the key intermediate. For a more detailed description of the individual reaction steps, see the Examples section below.

Scheme I

The starting material (l-a) may be prepared using procedures described in US Patent Publication No. 2005/010592, incorporated herein by reference. When beginning with a compound of Formula (l-a) where R is alkyl (or a carboxy-protecting group), the ester is first hydrolyzed to the corresponding carboxylic acid using conventional hydrolysis procedures well-know to those skilled in the art. For example, the carboxy- protecting group may be removed by treating the ester with a strong base (e.g., an alkali metal hydroxide, such as potassium hydroxide) in a protic solvent (e.g., ethanol). A solution of 1,1'-carbonyldiimidazole is then dissolved in an appropriate solvent (e.g., acetone, tetrahydrofuran, acetonitrile, dichloromethane or ethyl acetate) at or near room temperature. This solution is then added to a suspension of the carboxylic acid intermediate (j^a, where R is H) in an appropriate solvent at or near room temperature. Water is added to quench the reaction. When water miscible solvents are used (e.g., acetone, tetrahydrofuran and acetonitrile), the salts dissolve in the aqueous solution and the product precipitates directly from the reaction mixture. When water immiscible solvents are used (e.g., ethyl acetate or dichloromethane), the product generally does not precipitate directly from the reaction mixture but remains dissolved in the organic solvent, thus requiring concentration of the solvent to precipitate the product. Therefore, water miscible solvents are preferred.

When X is oxygen, the starting compound having Formula (l-a) may be prepared as described in Scheme Il below. Compounds of Formula (l-a) where X is sulfur or a nitrogen having attached thereto an electron-withdrawing group (e.g., acyl group) may also be prepared using this procedure.

ppgi

(1-20-1) Scheme Il

The starting materials (l-2a) and (l-2b) may be prepared using procedures described in US Patent Publication No. 2005/010592, incorporated herein by reference. See also the Example section below for representative examples of such preparations. Generally, the compound of Formula (l-2a) may be coupled with the compound of Formula (l-2b) using Mitsunobu reaction conditions. For example, the amino-protected compound of Formula (l-2b-1) is added to a solution of the carboxy-protected compound of Formula (l-2a-1) in the presence of triphenylphosphine dissolved in a non-polar solvent (e.g., tetrahydrofuran, diethyl ether, methylene chloride, or toluene) at about room temperature. Diisopropyl azodicarboxylate is then added to the mixture which has been cooled to about 0 ⁰ C followed by slowly warming to about room temperature to complete the reaction. For a more detailed description, see the Example section below. The protecting groups may then be removed using standard conditions typical for removal of the particular protecting group used.

Conventional methods and/or techniques of separation and purification known to one of ordinary skill in the art can be used to isolate the compounds of the present invention, as well as the various intermediates related thereto. Such techniques are well-known to one of ordinary skill in the art and may include, for example, all types of chromatography (high pressure liquid chromatography (HPLC), column chromatography using common adsorbents such as silica gel, and thin-layer chromatography), recrystallization, and differential (i.e., liquid-liquid) extraction techniques. The compounds may be isolated and used per se or in the form of its pharmaceutically acceptable salt, solvate and/or hydrate. In some instances, the free base is preferred. As used herein the term "free base" refers to an amino group having a lone pair of electrons. The term "salts" refers to inorganic and organic salts of a compound which may be incorporated into the molecule via an ionic bond or as a complex. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate,

benzoate, lactate, phosphate, hexafluorophosphate, benzene sulfonate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts, and the like. Preferred salts include hydrochloride, mesylate and besylate salts. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, e.g., Berge, et al., J. Pharm. Sc/., 66, 1-19 (1977).

The compounds (including intermediates) may contain asymmetric or chiral centers; therefore, the compounds and intermediates may exist in different stereoisomeric forms (e.g., enantiomers and diasteroisomers). It is intended that all stereoisomeric forms of the intermediates and compounds as well as mixtures thereof, including racemic mixtures, form a part of the present invention.

The compounds prepared by the inventive process may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms of the compounds. A list of pharmaceutically acceptable solvents are available from the Center for Drug Evaluation and Research (CDER) of the United States Federal Drug Administration (FDA), Washington DC.

It is also possible that the intermediates and compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. The present invention also embraces the use of isotopically-labeled compounds (including intermediates) which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the intermediates or compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ 0, ¹⁷ 0, ¹⁸ 0, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ 1, ¹²⁵ I and ³⁶ CI, respectively.

Certain isotopically-labeled compounds (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be

preferred in some circumstances. Positron emitting isotopes such as ¹⁵ 0, ¹³ N, ¹¹ C, and ¹⁸ F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy, lsotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Compounds made by the process of the present invention are useful for treating diseases, conditions and disorders modulated by cannabinoid receptor antagonists.

Preliminary investigations have indicated that the following diseases, conditions, and/or disorders are modulated by cannabinoid receptor antagonists: eating disorders (e.g., binge eating disorder, anorexia, and bulimia), weight loss or control (e.g., reduction in calorie or food intake, and/or appetite suppression), obesity, depression, atypical depression, bipolar disorders, psychoses, schizophrenia, behavioral addictions, suppression of reward-related behaviors (e.g., conditioned place avoidance, such as suppression of cocaine- and morphine-induced conditioned place preference), substance abuse, addictive disorders, impulsivity, alcoholism (e.g., alcohol abuse, addiction and/or dependence including treatment for abstinence, craving reduction and relapse prevention of alcohol intake), tobacco abuse (e.g., smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking), dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder), sexual dysfunction in males (e.g., erectile difficulty), seizure disorders, epilepsy, inflammation, gastrointestinal disorders (e.g., dysfunction of gastrointestinal motility or intestinal propulsion), attention deficit disorder (ADD including attention deficit hyperactivity disorder (ADHD)), Parkinson's disease, and type Il diabetes.

Embodiments of the present invention are illustrated by the following Example. It is to be understood, however, that the embodiments of the invention are not limited to the specific details of this Example, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art. In particular, other compounds of Formula (I) may be prepared from starting materials described in US Publication No. 2005/0101592 or PCT Publication No. WO 05/044822, incorporated herein by reference.

EXAMPLES

Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wl), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England).

General Experimental Procedures

NMR spectra were recorded on a Varian Unity™ 400 or 500 (available from Varian Inc., Palo Alto, CA) at room temperature at 400 and 500 MHz ¹ H, respectively. Chemical shifts are expressed in parts per million (δ) relative to residual solvent as an internal reference. The peak shapes are denoted as follows: s, singlet; d,

doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet; v br s, very broad singlet; br m, broad multiplet; 2s, two singlets. In some cases only representative ¹ H NMR peaks are given.

Mass spectra were recorded by direct flow analysis using positive and negative atmospheric pressure chemical ionization (APcI) scan modes. A Waters APcl/MS model ZMD mass spectrometer equipped with Gilson 215 liquid handling system was used to carry out the experiments.

Mass spectrometry analysis was also obtained by RP-HPLC gradient method for chromatographic separation. Molecular weight identification was recorded by positive and negative electrospray ionization (ESI) scan modes. A Waters/Micromass ESI/MS model ZMD or LCZ mass spectrometer equipped with Gilson 215 liquid handling system and HP 1100 DAD was used to carry out the experiments. Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3:1 for ³⁵ CI/ ³⁷ CI-containing ions and 1 :1 for ⁷⁹ Br/ ⁸¹ Br-containing ions) and only the lower mass ion is given. MS peaks are reported for all examples.

Optical rotations were determined on a PerkinElmer™ 241 polarimeter (available from PerkinElmer Inc., Wellesley, MA) using the sodium D line (λ = 589 nm) at the indicated temperature and are reported as follows [α] _D ^temp , concentration (c = g/100 ml), and solvent.

Column chromatography was performed with either Baker™ silica gel (40 μm; JT. Baker, Phillipsburg, NJ) or Silica Gel 50 (EM Sciences™, Gibbstown, NJ) in glass columns or in Biotage™ columns (ISC, Inc., Shelton, CT) under low nitrogen pressure. Radial chromatography was performed using a Chromatotron™ (Harrison Research). Starting Materials/Intermediates

The reagents and various starting materials used in the following preparations may be purchased from commercial vendors, such as Sigma-Aldrich Company (Milwaukee, Wl USA)

Preparation of starting material 2,2-Difluoro-Dropionic acid ethyl ester (l-3a):

(l-3a)

(Diethylamino)sulfur trifluoride (125 g, 780 mmol) was added dropwise to stirred, cooled (O ⁰ C) ethyl pyruvate (71 ml, 650 mmol). The reaction was allowed to warm to ambient temperature overnight, then quenched by slowly pouring over an ice/water mixture and extracted with diethyl ether. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The resulting oil was fractionally distilled at ambient pressure (110-115 ⁰ C) to afford the title compound (l-3a) as a colorless oil, 55.6 gm.

Preparation of Intermediate 2,2-Difluoro-N-(2-hvdroxy-ethyl)-propionamide (l-3b):

(l-3b)

2,2-Difluoro-propionic acid ethyl ester l-3a (10.1 g, 70 mmol) was added dropwise to stirred, cooled (O ⁰ C) ethanolamine (4.4 ml, 70 mmol) and the resulting solution was allowed to stir at ambient temperature for 4 hours. Concentration of the reaction mixture in vacuo afforded the title compound (l-3b) as a solid, 11.2 g-

Preparation of Intermediate 2-(2,2-Difluoro-propylamino)-eihanol (l-3c):

(l-3c)

To a stirred solution of lithium aluminum hydride (5.5 g, 146 mmol) in diethyl ether (85 ml) was added a solution of 2,2-difluoro-N-(2-hydroxy-ethyl)-propionamide (11.2 g, 73 mmol) in diethyl ether (55 ml) dropwise at such a rate to maintain a gentle reflux. After an additional 1.5 hours, the reaction was quenched with sodium sulfate decahydrate, diluted with ethyl acetate and allowed to stir for 18 hours. The mixture was filtered with the aid of diatomaceous earth, washing with ethyl acetate. The filtrate was concentrated in vacuo and fractionally distilled (11 torr, collecting fractions distilling at 75-88 ⁰ C) to afford the title compound (l-3c) as a colorless oil, 4.5 g.

The following illustrates two different ways of making the starting intermediate 5-(4-chlorophenyl)-1- (2-chlorophenyl)-4-hydroxy-1 H-pyrazole-3-carboxylic acid ethyl ester (referred to herein as 1-1 a-4 and 1-1 a- Z).

Preparation of Intermediate 4-Bromo-5-(4-chlorophenyl)-1-(2-chlorophenyl)-1H-pyrazole-3- carboxylic acid ethyl ester (1-1 a-1):

(1-1 a-1 )

Bromine (15 ml, 294 mmol) was added in one portion to a cooled (ice/water bath) stirred solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-1 H-pyrazole-3-carboxylic acid ethyl ester (26.6 g, 73.6 mmol) in acetic acid (300 ml). After 45 minutes, the reaction was concentrated in vacuo, the solids slurried in diethyl ether (100 ml), filtered and dried in vacuo lo afford the title compound (1-1 a-1) as a light-yellow colored solid, 29.6 9-

Preparation of Intermediate 5-(4-Chlorophenyl)-1-(2-chlorophenyl)-4-vinyl-1H-pyrazole-3- carboxylic Acid Ethyl Ester (1-1 a-2):

(1-1 a-2)

A solution of 4-bromo-5-(4-chlorophenyl)-1-(2-chlorophenyl)-1H-pyrazole-3- carboxylic acid ethyl ester 1-1 a-1 (5.2 g, 11.9 mmol), tributylvinyltin (7.0 ml, 23.8 mmol) and tetrakistriphenylphosphine palladium (0.7 g, 0.6 mmoi) in DMF (12 ml) was heated at 11O ⁰ C for 18 hours. The dark solution was cooled, partitioned between ethyl ether/water, the organic layer washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford a semi-solid. This semi-solid was stirred with cyclohexanes (35 ml) and filtered to afford the title compound (1-1 a-2) as a white solid, 3.0 g.

Preparation of Intermediate 5-(4-Chlorophenyl)-1-(2-chlorophenyl)-4-formyl-1H-pyrazole-3 -carboxylic Acid Ethyl Ester (1-1 a-3):

(1-1 a-3) A solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-vinyl-1H-pyrazole-3- carboxylic acid ethyl ester

1-1 a-2 (2.9 g, 7.5 mmol), osmium tetroxide (8 mg, 0.08 mmol) and N-methylmorpholine-N-oxide (1.1 g, 8.2 mmol) in dioxane (24 ml)/water (6 ml) was stirred at ambient temperature for 18 hours, then sodium periodate (16 g, 75 mmol) was added and stirring was continued for 3.5 hours. The thick slurry was diluted with ethyl acetate (100 ml), filtered and solids washed 2x with ethyl acetate. The combined filtrates were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuoϊo afford a solid mass. The solids were slurried in hot hexanes (30 ml), cooled, filtered and dried in vacuo to afford the title compound (1-1 a-3) as a tan solid, 2.2 g.

Preparation of Intermediate 5-(4-Chlorophenyl)-1-(2-chlorophenyl)-4-hvdroxy-1H-pyrazole- 3-carboxylic acid ethyl ester (1-1 a-4):

(1-1 a-4)

To a stirred solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-formyl-1 H-pyrazole-3-carboxylic acid ethyl ester 1-1 a-3 (2.2 g, 5.6 mmol) in dichloromethane (22 ml) was added m-chloroperbenzoic acid (2.9 g (50% purity), 8.4 mmol) and the resulting slurry was stirred for 6 hours. The mixture was diluted into ethyl ether,

washed with half-saturated aqueous sodium bicarbonate, water, brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford a yellow solid, 3.5 g. To a slurry of this material in methanol (20 ml), was added triethylamine (1 ml) to produce a solution. After 45 minutes, the reaction was concentrated in vacuo to afford a yellow solid. This material was purified by silica gel chromatograpy (Combiflash instrument, 120 g silica gel column, 5-25% gradient of ethyl acetate/hexanes to afford the title compound (1-1 a-4) as a yellow solid, 1.5 g.

The following describes an alternative procedure for the preparation of lntermediate_5-(4- Chlorophenyl)-1-(2-chlorophenyl)-4-hydroxy-1 H-pyrazole-3-carboxylic acid ethyl ester (1-1 a-4). Preparation of Intermediate 4-(4-Chlorophenyl)-3-oxo-butyric Acid Ethyl Ester (1-1 a-5):

(1-1 a-5)

Triethylamine (58.7 kg/580 mol) and magnesium dichloride (23.2 kg/244 mol) were added to ethyl potassium malonate(41.5 kg/ 244 mol) in 2-methyltetrahydrofuran (73 gallons). The mixture was heated to 6O ⁰ C. In a separate container, 4-chlorophenylacetic acid (19.8 kg/116 mol) in tetrahydrofuran (21 gallons) was added to a suspension of 1,1'-carbonyldiimidazole (19.8 kg/122 mol) in tetrahydrofuran (37 gallons). This activated acyl imidazole reaction mixture was added to the prepared malonate mixture at 6O ⁰ C and held for two hours. Aqueous citric acid (96 kg/500mol in 90 gallons water) was added to effect decarboxylation after cooling the reaction mixture to ambient temperature. An additional wash with aqueous citric acid and two washes with aqueous sodium bicarbonate removed all salts and unreacted reagents leaving the desired product in the organic layer. The organic layer, a mixture of tetrahydrofuran and 2-methyltetrahydrofuran, was concentrated under vacuum and displaced with 2B ethanol. The title compound (1-1 a-5) was then isolated as a solution in 2B Ethanol (24 gallon).

Preparation of Intermediate 4-(4-Chlorophenyl)-2-F(2-chlorophenyl)-hydrazonoh3-oxobutyri c Acid Ethyl Ester (1-1 a-6):

(1-1 a-6) 2-Chloroaniline (14.1 kg/110 mol) was dissolved in a mixture of water (34 gallons) and 2B Ethanol(41 gallons). The solution was cooled to O ⁰ C before treating with 35% aqueous hydrochloric acid (32.1 kg/307 mol). A solution of aqueous 97% sodium nitrite (7.9 kg/110 mol in 4 gallons water) followed by the addition of aqueous sodium acetate (27.1 kg/331 mol in 21 gallons water) was added cold to the aniline hydrochloride salt mixture forming the diazonium intermediate. Compound 1-1 a-5 (from above) in 2B ethanol was then added and the reaction warmed to ambient temperature, triturated and filtered. The filter cake of the title compound (1-1 a-6) was washed once with water (8 gallons) and four times with 2B ethanol (8 gallons each wash). The ethanol washes removed most of the dark orange color leaving a yellow solid. After drying in a vacuum oven overnight, 40 kg (91% of theory) of the title compound (1-1 a-6) was recovered.

Preparation of intermediate 5-(4-Chlorophenyl)-1-(2-chlorophenyl)-4-hvdroxy-1H-pyrazole- 3-carboxylic acid ethyl ester (1-1 a-7):

(1-1 a-7)

A solution of pyridinium tribromide (18.2 kg/51.2 mol) in tetrahydrofuran (42 gallons) was added at ambient temperature to Intermediate 1-1 a-6 (18 kg/47.5 mol) in tetrahydrofuran (33 gallons). Aqueous sodium bicarbonate (8.8 kg/104mol in 30 gallons water) and aqueous sodium sulfite (6.0 kg/47.5 mol in 18

gallons water) were added. The mixture stirred four hours to complete cyclization to the pyrazole. The aqueous layer was extracted with ethyl acetate (24 gallons) after the initial phase separation. The ethyl acetate and tetrahydrofuran extracts were combined and washed with aqueous citric acid (18.2kg/94.9 mol in 20 gallons water) and aqueous sodium chloride (24 kg/411 mol in 20 gallons water). The organic layer was concentrated under vacuum displacing the mixed solvent completely with 2-propanol. The title compound (Jb 1a-7) was filtered from the mixture as a yellow solid after four hours granulation and washed with 2-propanol (6 gallons). After drying in a vacuum oven 2 days, the yield was 13.6 kg (76% of theory). The title compound (1-1 a-7) was equivalent to compound 1-1 a-4 produced above.

Example

Preparation of Intermediate tert-butyl 2-(3-(ethoxycarbonyl)-1-(2-chlorophenyl)-5-(4-chlorophenyl)- 1H- oyrazol-4-yloxy)ethyl2,2-difluoropropylcarbamate (1-1 a-8):

(1-1 a-8) A solution of di-fert-butyldicarbonate (15.5 kg/ 70.9 mol) in tetrahydrofuran (7 gallons) was added over one hour to a 4O ⁰ C solution of 2-(2,2-difIuoro-propylamino)-ethanol (l-3c: 9.1 kg/64.4 mol) in tetrahydrofuran (7 gallons). After two hours the reaction was cooled and held at 20 ⁰ C. The solution was then allowed to stir overnight. The solution was then added to a mixture of triphenylphosphine (21.3 kg/80.5 mol) and 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-hydroxy-1 H-pyrazole-3-carboxylic acid ethyl ester (1-1 a-7: 24.3 kg/64.4 mol) in tetrahydrofuran (51 gallons). The reaction mixture was cooled and held at O ⁰ C while diisopropyl azodicarboxylate (16.3 kg/80.5 mol) was added over one hour. The reaction was continued for one hour at O ⁰ C, then warmed to 2O ⁰ C over 90 minutes. The mixture was concentrated under vacuum until 30 gallons remained. 2-Propanol (55 gallons) was added and the mixture was concentrated atmospherically to distill the remaining tetrahydrofuran. The reaction mixture was reheated and held at 75 ⁰ C in 2-propanol

(95 gallons) for one hour then cooled and held at 20 ⁰ C. Seeding with crystals from a concentrated sample induced crystallization of the batch. After stirring overnight, the solids were filtered and washed with 2- propanol (16 gallons). After two days drying in a vacuum oven, 29.9 kg of the title compound (1-1 a-8) was recovered (77% yield).

¹ H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (m, 12 H) 1.5 (m, 3 H) 3.4 (m, 2 H) 3.6 (t, J= 13.7, 2 H) 4.0 (m, 2 H) 4.3 (q, J= 7.3, 2 H) 7.2 (m, 2 H) 7.4 (d, J= 8.1 , 2 H) 7.5 (m, 3 H) 7.7 (m,1 H)

Preparation of 4-(2-(2,2-difluoropropylamino)ethoxy)-1-(2-chloroDhenyl)-5-( 4-chlorophenyl)-1H-pyrazole-3- carboxylic acid Hydrochloride salt (1-1 a-9):

(1-1 a-9)

A solution of potassium hydroxide (2.8 kg.50.3 mol) in water (1 gallon) was added over 30 minutes to a solution of 1-1 a-8 (25.1 kg/41.9 mol) in 2B ethanol (17 gallons) and 2-methyltetrahydrofuran (33 gallons) at 2O ⁰ C. An HPLC assay determined hydrolysis was complete within 4 hours. The reaction was neutralized with a solution of concentrated hydrochloric acid (6.4 kg/90.6 mol) in water (46 gallons) added over 30 minutes. The mixture was diluted with 2-methyltetrahydrofuran (17 gallons) and the phases split. The organic layer was washed with brine and concentrated under vacuum to approximately 33 gallons. Concentrated 35% hydrochloric acid (12.8 kg/181.2 mol) was added and the mixture heated to 60 ⁰ C. Within 8 hours at 60 ⁰ C the reaction was determined to be 99.5% complete and was cooled to 2O ⁰ C. The mixture was diluted with 2-methyltetrahydrofuran (100 gallons) and concentrated under vacuum until approximately 66 gallons remained. To remove the remaining water as an azeotrope, the concentrated mixture was heated and concentrated atmospherically until approximately 33 gallons remained. Since no crystals were evident on cooling, the dilution and concentration step was repeated. 2-Methyltetrahydrofuran (95 gallons) was added and the mixture concentrated atmospherically until approximately 33 gallons remained. The desired product crystallized from the mixture on cooling to 2O ⁰ C and was filtered after granulating 2 hours. The solids were washed with 2-methyltetrahydrofuran (13 gallons) and dried in a Hastelloy tray drier at 4O ⁰ C for 15 hours. The title compound (1-1 a-9) was isolated in 90% yield (19.1 kg).

¹ H NMR (400 MHz, DMSO-D6) δ ppm 1.7 (t, J=19.5 Hz, 3 H) 3.3 (t, J=5.2 Hz, 2 H) 3.6 (t, Jt 14.7 Hz ,2 H) 4.3 (t, J=5.2 Hz, 2 H) 7.3 (d, J=8.3 Hz, 2 H) 7.4 (d, J=8.3 Hz, 2 H) 7.5 (m, 3 H) 7.7 (dd, J=7.1 , 2.1 Hz, 1 H)

Preparation of 3-(4-chloro-phenyl)-2-(2-chloro-ohenyl)-7-(2.2-difluoro-DroD Vl)-6J-dihvdro-2H.5H-4-oxa-1,2,7- triaza-azulen-8-one (IA-D from intermediate (1-1 a-9):

(1-1 a-9) (IA-1)

A solution of 1 ,1'-carbonyldiimidazole (10.6 kg/65.3 mol) in acetone (40 gallons) was added over 90 minutes at 20 ⁰ C to a suspension of compound 1-1 a-9 (19.1 kg/37.7 mol) in acetone (25 gallons). After one hour the reaction was approximately 88% complete by HPLC analysis. One hour after this charge, the reaction was greater than 99% complete. Water (110 gallons) was added to the mixture at 2O ⁰ C over a 90 minute period. The resultant slurry was stirred 14 hours at 20 ⁰ C and 90 minutes at 5 ⁰ C. The filtered solids were washed with water (5 gallons) and dried under a stream of nitrogen for only 1 hour to yield 20.7 kg of wet solids. The wet cake from above was used directly in the recrystallization without storage. A 100% yield was assumed for the calculations. A solution of IA-1 (assumed 17.1 kg/37.7 mol) in acetone (27 gallons) was filtered through a 0.05-micron filter. Over 30 minutes filtered water (54 gallons) was added to the acetone solution at 20 ⁰ C. The resultant slurry was stirred 17 hours at 2O ⁰ C. The mixture was cooled to 5 ⁰ C over one hour and held at that temperature an additional 3 hours. The mixture was filtered and washed with filtered water (3.0 gallons). The isolated solids were dried for 2.5 days at 4O ⁰ C to yield 15.3 kg of IA-1 (90% yield). The product was found to be 99.7% pure.

The isolated compound was determined to be fully crystalline by both powder X-ray diffraction (PXRD: Bruker D5000) and polarized light microscopy (PLM) analysis. Using differential scanning colorimetry (DSC; Mettler-Toledo 822e) at a starting temperature of 30.00 ⁰ C and ending temperature of 300.00 ⁰ C, the melting onset temperature was detected at approximately 156°C.

The PXRD pattern shown in Figure 1 was generated using a Bruker D500 X-ray powder diffractometer under the following conditions.

Start: 3

Stop: 40

Step Size: 0.04

Time/step: 1.0 seconds

Scan Mode: Continuous

Generator: 40 kV, 30 mA

Radiation: Copper K ₀ , (fine focus x-ray tube)

Divergence slit: 1 mm

Scattering slit: 1 mm

Receiving slit: 0.6 mm

Detector: Kevex PSI