WO2000001691A1

WO2000001691A1 - Process for making farnesyl-protein transferase inhibitors

Info

Publication number: WO2000001691A1
Application number: PCT/US1999/014726
Authority: WO
Inventors: David Askin; Jennifer A. Cowen; Peter E. Maligres; J. Christopher Mcwilliams; James A. Mccauley
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1998-07-01
Filing date: 1999-06-29
Publication date: 2000-01-13
Anticipated expiration: 2001-01-01
Also published as: AU5086499A

Abstract

The present invention is directed to the improved synthesis of compounds of formula (I): which may be useful as farnesyl-protein transferase inhibitors. The present invention is also directed to the crystal forms of the monohydrate and mon-hydrochloride salt of 1-(3-Chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone.

Description

TITLE OF THE INVENTION

PROCESS FOR MAKING FARNESYL-PROTEIN TRANSFERASE

INHIBITORS

BACKGROUND OF THE INVENTION

The Ras proteins are a family of guanine nucleotide binding GTPases that play a pivotal role in mediating cell growth, differentiation and development. (Barbacid, Annual Review of Biochemistry , Vol. 56, p. 779 (1987)). In mammalian cells, there are three ras genes that encode four Ras proteins, H, N, KA and KB-Ras. (E.C. Lerner et al., Anti- Cancer Drug Design, Vol. 12, pp. 229-238 (1997)). Mutations in Ha-rαs, Ki-ras and N-røs, and the overexpression of Ras has been observed in approximately 30% of all human cancer tissues. (Lerner et al., S.L. Graham, Exp. Opin. Ther. Patents, Vol. 5, no. 12, pp. 1269-1285 (1995); T. Hiwasa, Oncology Reports, Vol. 3, pp. 7-14 (1996); S.L. Graham and T.M. Williams, Exp. Opin. Ther. Patents, Vol. 6, no. 12, pp. 1295-1304 (1996)). Although several steps are involved in modifying Ras proteins, farnesylation is the only step which is required and sufficient for Ras transforming activity. (E.C. Lerner et al.) Therefore, farnesyltrans- ferase (FTase) serves as an attractive target for the development of a potential new class of anti-cancer agents. (E.C. Lerner et al.) It has been noted that routes to inhibitors of Ras farnesylation are apparent from an examination of the substrate specificities of the enzyme. Once can design analogs either of the lipid, or of the peptide sequence to which the lipid is transferred. Such compounds must be stable, and readily cross the cell membrane to gain access to the cytosolic transferase. (J. E. Buss and J.C. Marsters, Jr., Chemistry and Biology, Vol. 2, pp. 787-791 (1995)).

Compounds that incorporate substituted 5-imidazolyl- methyl-2-piperazinone moieties have been observed to be farnesyl- transferase inhibitors. (WO 96/30343 published on October 30, 1996). It is therefore desirable to discover a process for making substituted 5- imidazolyl-methyl-2-piperazinones that is efficient, economical and safe. Prior methods for synthesizing substituted 5-imidazolyl-methyl-2- piperazinone utilized reductive alkylation of a piperazinone compound with an imidazole aldehyde. This procedure was problematic since oxidation of the imidazole alcohol was required, which was difficult to effect and required the use of undesirable reagents such as Sθ3^βpyridine/DMSO. Furthermore, the resulting reductive alkylation of the piperazinone compound with the imidazole aldehyde required the use of NaBH(OAc)3, which is expensive and dangerous due to the production of hydrogen gas as a by-product of the reaction. In previous methods, the end-product was isolated as the bis-HCl salt in the form of an amorphous solid. It is therefore an object of this invention to provide a process for the synthesis of substituted 5-imidazolyl-methyl-2-piperazinones that is more efficient and does not depend on the use of reagents such as SO3»pyridine/DMSO.

It is a further object of this invention to provide a process for the synthesis of substituted 5-imidazolyl-methyl-2-piperazinones that is less expensive and safer by eliminating the use of NaBH(OAc)3.

SUMMARY OF THE INVENTION

The present invention is directed to the improved synthesis of compounds of formula I, which may be useful as farnesyl-protein transferase inhibitors:

I

The instant invention is a novel synthesis for substituted 5- imidazolyl-methyl-2-piperazinones which is more efficient, economical and safer than syntheses previously described. DESCRIPTION OF THE FIGURES FIG. 1

DSC Curve (open cup) for Form I of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone • H2O .

FIG. 2

X-ray powder diffraction pattern for Form I of l-(3-Chlorophenyl)- 4- [ l-(4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone • H2O .

FIG. 3

DSC Curve (open cup) for Form II of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone»HCl.

FIG. 4 DSC Curve (closed cup) for Form II of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone • HC

FIG. 5

X-ray powder diffraction pattern for Form II of l-(3- Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone • HC1.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the synthesis of compounds as illustrated by formula I:

I

wherein Ra is selected from a) H, b) CN, c) -C(0)Rb, d) -C(0)N(Rb)₂, e) unsubstituted or substituted C1-C6 alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl;

Rb is selected from a) H, b) OH, c) unsubstituted or substituted C1-C6 alkyl, d) unsubstituted or substituted Ci-Cβ alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

Rl is selected from a) H, b) unsubstituted or substituted C1-C6 alkyl, c) unsubstituted or substituted aryl, or d) unsubstituted or substituted heteroaryl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted Oχ- CQ alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted Ci-Cβ alkoxy, h) C1-C6 alkynyl; i) CF3, and j) OCF3;

RlO is independently selected from a) unsubstituted or substituted C1-C6 alkyl, b) unsubstituted or substituted aryl, or c) unsubstituted or substituted aralkyl;

Xl, X and X3 are independently selected from

H, halo, unsubstituted or substituted Ci-Cβ alkyl, unsubstituted or substituted Ci-Cβ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR1 , -SO2R10, (Ci-Cβ alkyl)SOi-2(Co-C6 alkyl)-, HC(O)(Cθ-C₆ alkyl)-, (Ci-Cβ alkyl)C(O)(Co-C6 alkyl)-, -N(R10)2, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2R¹⁰, and -N(RlO)SO2RlO;

Xl and X2 or X2 and X3, when located on adjacent carbon atoms, may be joined in a ring;

which comprises the step of: mixing a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A

(where R^a, Xl, X^ and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where R¹, R3, R4, R5 and Z are as defined above and R2 is H) in the presence of a base compound.

In a specific embodiment of the instant invention, the process for preparing the compound of formula IA

IA comprises the step of: mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride in the presence of diisopropylethylamine .

In a second embodiment of the present invention, the process for preparing compounds as illustrated by formula I:

wherein

Ra is selected from a) H, b) CN, c) -C(0)Rb, d) -C(O)N(Rb) , e) unsubstituted or substituted Ci-Cβ alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl;

Rb is selected from a) H, b) OH, c) unsubstituted or substituted Cl-C6 alkyl, d) unsubstituted or substituted Ci-Cβ alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

Rl is selected from a) H, b) unsubstituted or substituted Cl-Cβ alkyl, c) unsubstituted or substituted aryl, or d) unsubstituted or substituted heteroaryl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted O - Cg alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted CI-CQ alkoxy, h) Cl-Cβ alkynyl; i) CF3, and j) OCF₃;

Rl is independently selected from a) unsubstituted or substituted C1-C6 alkyl, b) unsubstituted or substituted aryl, or c) unsubstituted or substituted aralkyl;

Xl, X2 and X3 are independently selected from H, halo, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Cl-Cβ alkyl)SOi-2(Co-C6 alkyl)-, HC(O)(C()-C6 alkyl)-, (Cl-Cβ alkyl)C(O)(Co-C6 alkyl)-, -N(RlO)2, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2RI⁰, and -N(RlO)SO2RlO;

which comprises the steps of: a) mixing a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A

A

(where R^a, χl, χ2 and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4, R5 and Z are as defined above and R is H); b) adding a base compound; and c) isolating the free base form of a compound of formula I.

IA

comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; and c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone.

In third embodiment of the instant invention, the process for synthesizing compounds of formula I

wherein

Ra is selected from a) H, b) CN, c) -C(O)Rb d) -C(0)N(Rb)₂, e) unsubstituted or substituted Ci-Cg alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl;

Rb is selected from a) H, b) OH, c) unsubstituted or substituted Ci-Cg alkyl, d) unsubstituted or substituted Ci-Cg alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

Rl is selected from a) H, b) unsubstituted or substituted Cχ-Cg alkyl, c) unsubstituted or substituted aryl, or d) unsubstituted or substituted heteroaryl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted Oχ- Cg alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted Oχ- Cg alkoxy, h) Cl-Cβ alkynyl; i) CF3, and j) OCF3;

RlO is independently selected from a) unsubstituted or substituted Ci-Cg alkyl, b) unsubstituted or substituted aryl, or c) unsubstituted or substituted aralkyl;

Xl, X2 and X3 are independently selected from H, halo, unsubstituted or substituted Ci-Cβ alkyl, unsubstituted or substituted Ci-Cβ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Ci-Cβ alkyl)SOi-2(Co-Cβ alkyl)-, HC(O)(Co-Cβ alkyl)-, (Ci-Cβ alkyl)C(O)(Co-Cβ alkyl)-,

-N(R10)2, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2RIO, and -N(RlO)SO2Rl ;

Xl and χ2 or X2 and X3, when located on adjacent carbon atoms, may be joined in a ring;

comprises the steps of: a) mixing a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A

(where R^a, Xl, χ2 and X are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4, R5 and Z are as defined above and R2 is H); b) adding a base compound; c) isolating the free base form of a compound of formula I; d) combining the free base form of a compound of formula I in a solvent with HC1; and e) isolating a salt of a compound of formula I in crystalline form.

In further embodiment of the instant invention, the process for synthesizing a salt of the compound of formula IA

IA

comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) combining the free base form in a solvent with HC1; and e) isolating a salt of compound of formula IA in crystalline form.

A further embodiment of the instant invention is the process hereinabove where, in step d), the free base form of a compound of formula I in a mixture of IP A toluene is combined with HC1.

In a specific embodiment of the instant invention, the process for synthesizing a salt of the compound of formula IA

IA

comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) combining the free base form l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylm ethyl] -2-piperazinone in a mixture of

IPA/toluene with HC1; and e) isolating l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylm ethyl] -2-piperazinone *HC1 in crystalline form. In fourth embodiment of the instant invention, the process for synthesizing compounds of formula I

wherein

Ra is selected from a) H, b) CN, c) -C(0)Rb d) -C(0)N(Rb)₂, e) unsubstituted or substituted Cl-Cβ alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl;

Rb is selected from a) H, b) OH, c) unsubstituted or substituted Cl-Cβ alkyl, d) unsubstituted or substituted Cl-Cβ alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl; Rl is selected from a) H, b) unsubstituted or substituted Cl-Cβ alkyl, c) unsubstituted or substituted aryl, or d) unsubstituted or substituted heteroaryl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted Ci- Cβ alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted Cj- Cβ alkoxy, h) Cl-Cβ alkynyl; i) CF3, and j) OCF3;

RlO is independently selected from a) unsubstituted or substituted Cl-Cβ alkyl, b) unsubstituted or substituted aryl, or c) unsubstituted or substituted aralkyl;

Xl, X2 and X are independently selected from H, halo, unsubstituted or substituted Cl-Cβ alkyl, unsubstituted or substituted Ci-Cβ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Ci-Cβ alkyl)SOi-2(Co-Cβ alkyl)-, HC(O)(Co-Cβ alkyl)-, (Ci-Cg alkyl)C(O)(C₀-Cg alkyl)-,

-N(R10)2, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2RIO, and -N(R10)SO2R10; Xl and X2 or X and X3, when located on adjacent carbon atoms, may be joined in a ring;

(where R^a, χl, χ and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4, R5 and Z are as defined above and R2 is H); b) adding a base compound; c) isolating the free base form of a compound of formula I; d) combining the free base form of a compound of formula I with a solution of HC1 in a solvent; and e) isolating a salt of the compound of formula I in crystalline form.

In a further embodiment of the instant invention, the process for synthesizing a salt of the compound of formula IA

IA

comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) combining the free base form with a solution of HC1 in a solvent; and e) isolating a salt of the compound of formula IA in crystalline form.

In a fifth embodiment of the instant invention, the process for synthesizing compounds of formula I

I wherein

Ra is selected from a) H, b) CN, c) -C(0)Rb, d) -C(0)N(Rb)_2> e) unsubstituted or substituted Ci-Cg alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl;

Rb is selected from a) H, b) OH, c) unsubstituted or substituted Cl-Cg alkyl, d) unsubstituted or substituted Cl-Cg alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted C - Cβ alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted Ci- Cβ alkoxy, h) Cl-Cβ alkynyl; i) CF3, and j) OCF3;

Xl, X2 and X are independently selected from

H, halo, unsubstituted or substituted Cl-Cg alkyl, unsubstituted or substituted Cl-Cg alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Ci-Cg alkyl)SOi-2(Co-Cg alkyl)-, HC(O)(Co-Cg alkyl)-, (Cl-Cg alkyl)C(O)(Co-Cg alkyl)-, -N(RlO)₂, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl ,

-NHSO2RIO, and -N(R10)SO2R10;

(where Ra, χl, χ2 and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where Rl, R3, R ₅ R5 and Z are as defined above and R2 is H); b) adding a base compound; c) isolating the free base form of a compound of formula I; d) adding a solution of HC1 in a solvent to the free base form of a compound of Formula I in a solvent; e) isolating a salt of the compound of formula I in crystalline form. A further embodiment of the instant invention is the process hereinabove where an anti-solvent is added before isolating the salt of the compound of formula I in step e).

IA

comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) adding a solution of HCl in a solvent to the free base form in a solvent; e) adding an anti-solvent; and f isolating a salt of the compound of formula IA in crystalline form.

A further embodiment of the instant invention is the process hereinabove where the solution of HCl in step d) comprises HCl in ethanol.

IA

comprises the steps of:

a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) adding a solution of HCl in ethanol to the free base form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone in ethanol; e) adding EtOAc; and f) isolating l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl in crystalline form.

In another embodiment of the instant invention, a process of preparing a purified crystalline form of the free base of the compound of formula I comprises the steps of: a) adding a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A to a mixture of a substituted piperazinone salt of formula B and organic base in a solvent; b) adding activated carbon; and c) crystallizing a purified form of the free base of the compound of formula I.

In a further embodiment of the instant invention, the process of preparing a purified crystalline form of the free base of the compound of formula IA comprises the steps of: a) adding 4-cyanobenzyl-chloromethylimidazole hydrochloride to a mixture of l-(3-chlorophenyl)-2-piperazinone hydrochloride and diisopropylethylamine in ACN; b) adding Darco G-60; and c) crystallizing a purified form of the free base of l-(3-

Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone.

In another embodiment of the instant invention, the process of preparing a purified, crystalline form of the salt of the compound of formula I comprises the steps of: a) dissolving the free base form of the salt of the compound of formula I in a solvent mixture to produce a resulting solution; b) heating the resulting solution and adding activated carbon; c) adding an acid solution; and d) crystallizing a purified form of the salt of the compound of formula I.

In a further embodiment of the instant invention, the process of preparing a purified, crystalline form of the salt of the compound of formula IA comprises the steps of: a) dissolving the free base form of l-(3-Chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl]-2~piperazinone in a mixture of IPA and toluene to produce a solution; b) heating the solution and adding Darco G-60; c) adding a solution of HCl in IP A/toluene; and d) crystallizing a purified form of l-(3-Chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone^#HCl.

In another embodiment of the instant invention, the process of preparing a purified, crystalline form of the salt of the compound of formula I comprises the steps of: a) dissolving the free base form of the salt of the compound of formula I in an acid solution to produce a resulting solution; b) adding activated carbon; c) crystallizing a purified form of the salt of the compound of formula I.

In a further embodiment of the instant invention, the process of preparing a purified, crystalline form of the salt of the compound of formula IA comprises the steps of: a) dissolving the free base form of l-(3-Chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone in an HCl solution to produce a resulting solution; b) adding Darco G-60; c) crystallizing a purified form of l-(3-Chlorophenyl)-4-

[ l-(4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone • HCl.

In another embodiment of the instant invention, the process of purifying the crystalline form of the salt of the compound of formula I comprises the steps of: a) dissolving the crystalline form of the salt of the compound of formula I in a solvent mixture to produce a solution; b) adding activated carbon; and c) crystallizing a purified form of the salt of the compound of formula I.

In a further embodiment of the instant invention, the process of purifying the crystalline form of the salt of the compound of formula I comprises the steps of: a) dissolving l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolyl ethyl] -2-piperazinone* HCl in a mixture of water and IPA to produce a solution; b) adding Darco G-60 to the solution; and c) crystallizing a purified form of l-(3-Chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone*HCl. Another embodiment of the instant invention is crystal Form I of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone • H2O .

Another embodiment of the instant invention is crystal Form II of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]- 2-piperazinone • HCl.

Compounds prepared using the process of the instant invention have been observed to be useful as farnesyl protein transferase inhibitors, such as those described in WO 96/30343 which was published on October 3, 1996 and U.S. Patent Number 5,856,326, which issued on January 5, 1999, and are herein incorporated by reference. Examples of compounds which can be made using the process of the instant invention include, but are not limited to,

5(S)-n-Butyl-l-(2,3-dimethylphenyl)-4-(4-imidazolylmethyl)-piperazin-2- one

5(S)-n-Butyl-4-[l-(4-cyanobenzyl)imidazol-5-ylmethyl]-l-(2,3- dimethylphenyl)piperazin-2-one

4-[l-(4-Cyanobenzyl)imidazol-5-ylmethyl]-l-(2,3-dimethylphenyl)-5(S)-(2- methoxyethyl)piperazin-2-one

(S)-l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2- (methanesulfonyl)ethyl]-2-piperazinone

(S)-l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2- (ethanesulfonyl)ethyl]-2-piperazinone

(S)-l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2- (ethanesulfonyl)methyl]-2-piperazinone (S)-l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[N- ethyl-2-acetamido]-2-piperazinone

(±)-5-(2-Butynyl)-l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylm ethyl] -2-piperazinone

l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone

5(S)-Butyl-4-[l-(4-cyanobenzyl-2-methyl)-5-imidazolylmethyl]-l-(2,3- dimethylphenyl)-piperazin-2-one

5(S)-n-Butyl-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-l-(2- methylphenyl)piperazin-2-one

4-[l-(4-Cyanobenzyl)-5-imidazolylmethyl]-5(S)-(2-fluoroethyl)-l-(3- chlorophenyl)piperazin-2-one

4-[5-(4-Cyanobenzyl)-l-imidazolylethyl]-l-(3-chlorophenyl)piperazin- 2-one;

or the pharmaceutically acceptable salts, thereof.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms, unless otherwise indicated; "alkoxy" represents an alkyl group having 1 to 6 carbon atoms, unless otherwise specified, attached through an oxygen bridge. "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, the term "halide" means chloride, bromide, iodide and fluoride. The term "sulfate" is intended to include, but is not limited to, a substituted or unsubstituted alkyl or aryl sulfate such as methylsulfate, ethylsulfate, propylsulfate, chloromethylsulfate, trichloromethylsulfate, trifluoromethylsulfate, trifluoroethylsulfate, phenylsulfate, tolylsulfate, nitrophenylsulfate, chlorophenylsulfate, bromophenylsulfate and the like. The term "sulfonate" is intended to include, but is not limited to, a substituted or unsubstituted alkyl or aryl sulfonate, such as methanesulfonate, ethanesulfonate, propanesulfonate, chloromethanesulfonate, trichloromethanesulfonate, trifluoromethanesulfonate, trifluoroethanesulfonate, benzenesulfonate, toluenesulfonate, nitrobenzenesulfonate, chlorobenzenesulfonate, bromobenzenesulfonate, and the like. The term "phosphate" is intended to include, but is not limited to, a substituted or unsubstituted alkyl or aryl phosphate, such as methylphosphate, ethylphosphate, propylphosphate , chloromethylphosphate , trichlorom ethyl phosphate , trifluoromethylphosphate, trifluoroethylphosphate, phenylphosphate, tolylphosphate, nitrophenylphosphate, chlorophenylphosphate, bromophenylphosphate, and the like.

As used herein, "aryl", and the "aryl" part of aryloxy, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of monocyclic and bicyclic aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2- oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, and thienyl. As used herein, "aralkyl" is intended to mean an aryl moiety, as defined above, attached through a Ci-Cβ alkyl linker, where alkyl is defined above. Examples of aralkyls inlcude, but are not limited to, benzyl, naphthylmethyl and phenylpropyl. As used herein, "heteroaralkyl" is intended to mean a heteroalkyl moiety, as defined above, attached through a C -C alkyl linker, where alkyl is defined above. Examples of heteroaralkyls include, but are not limited to, 2-pyridylmethyl, 2-imidazolylethyl, 2- quinolinylmethyl, 2-imidazolylmethyl and the like. As used herein, the terms "substituted Cl- Cβ alkyl" and

"substituted Cl- C alkoxy" are intended to include the branch or straight- chain alkyl group of the specified number of carbon atoms, wherein the carbon atoms may be substituted with F, Cl, Br, CF3, N3, NO₂, NH₂, oxo, -OH, -O(Ci- C₆ alkyl), S(O)_0-2, (Cl- C₆ alkyl)S(O)₀-2-, (Cl- C₆ alkyl)S(O)o-2(Ci- C₆ alkyl)-, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NH, (Cl- C₆ alkyl)C(O)NH-, H2N-C(NH)-, (Cl- C₆ alkyl)C(O)-, -O(Cι-C₆ alkyl)CF₃, (Cl- C₆ alkyl)OC(O)-, (Ci- C₆ alkyl)O(Ci- Cg alkyl)-, (Cl- C₆ alkyl)C(O)₂(Cι- C₆ alkyl)-, (Cl- C₆ alkyl)OC(O)NH-, aryl, benzyl, heteroaryl, halo-aryl, halo-benzyl, halo- heteroaryl, cyano-aryl, cyano-benzyl and cyano-heteroaryl. As used herein, the terms "substituted aryl", "substituted aryloxy", "substituted heteroaryl", "substituted aralkyl" and "substituted heteroaralkyl" are intended to include the cyclic group containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound. Such substitutents are preferably selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Ci-Cβ alkyl)2, NO2, CN, N3, C1-C20 alkyl, Cl- C₆ alkoxy, -OH, -O(Ci-C₆ alkyl), S(O)₀.₂, (Cl- C₆ alkyl)S(O)₀-2-, (Cl- C₆ alkyl)S(O)o-2(Ci- C₆ alkyl)-, (Ci-Cβ alkyl)C(O)NH-, H₂N- C(NH)-, (Ci-Cβ alkyl)C(O)-, (Ci-Cβ alkyl)OC(O)-, (Ci-Cβ alkyl)O(Cι-Cβ alkyl)-, (Cl-Cβ alkyl)C(O)2(Ci-Cβ alkyl)-, (Cl-Cβ alkyl)OC(O)NH-, aryl, aralkyl, heteroaryl, heteroaralkyl, halo-aryl, halo-aralkyl, halo- heteroaryl, halo-heteroaralkyl, cyano-aryl, cyano-aralkyl, cyano- heteroaryl and cyano-heteroaralkyl. Preferably, in Formulae I and A, Xl and X3 are independently selected from H, halo, unsubstituted or substituted Cl-Cβ alkoxy, unsubstituted or substituted Cl-Cβ alkyl, NO2, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, (Cl-Cβ alkyl)SOi-2(Co-Cβ alkyl)- or (Cl-Cβ alkyl)C(O)(Co-Cβ alkyl)-. More preferably, Xl and X3 are independently selected from H, halo, unsubstituted or substituted Cl-Cβ alkoxy, unsubstituted or substituted Cl-Cβ alkyl. Most preferably, Xl and X3 are hydrogen.

Preferably, in Formulae I and A, X2 is selected from H, halo, unsubstituted or substituted Ci-Cβ alkyl, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, CF3, OCF3, (Ci-Cβ alkyl)SOi-2(Co-Cβ alkyl)- or (Cl-Cβ alkyl)C(O)(Co-Cβ alkyl)-. More preferably, X2 is selected from H, halo, unsubstituted or substituted Cl-Cβ alkyl, CN, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl. Still more preferably, X is CN, halo, or unsubstituted or substituted Cl-Cβ alkyl.

Most preferably, X2 is p-CN.

Preferably, in Formulae I and A, R^a is selected from H, unsubstituted or substituted Cl-Cβ alkyl, or unsubstituted or substituted aryl. Most preferably, Ra is H.

Preferably, in Formula A, Z is selected from halides, sulfonates and phosphates. More preferably, Z is a halide. Most preferably, Z is Cl.

Preferably, in Formulae I and B, Rl is selected from an unsubstituted or substituted aryl. More preferably Rl is aryl substituted with F, Cl, Br, CF3, NO2, Ci-Cβ alkyl, Ci-Cβ alkoxy, aryl and aralkyl.

Most preferably Rl is 3-chlorophenyl.

Preferably, in Formulae I and B, R3, R4 and R5 of formula I are independently selected from H, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted Ci- Cβ alkyl and Cl-Cβ aikynyl. More preferably, R3, R4 and R5 are independently selected from H or unsubstituted or substituted Cl-Cβ alkyl. Most preferably, R3, R4 and R5 are hydrogen. Abbreviations used throughout the specification include:

ACN acetonitrile

Ac2θ acetic anhydride

Boc t-Butoxycarbonyl

CBz carbobenzyloxy

DBU l,8-diazabicyclo[5.4.0]undec-7-ene

DEAD diethylazodicarboxylate

DEM diethoxymethane

DIAD diisopropylazodicarboxylate

DIEA diisopropylethylamine

DPAD dipiperidineazodicarbonyl

DMA dimethyl acetamide

DMAP 4-Dimethylaminopyridine

DME 1,2-Dimethoxyethane

DMF Dimethylformamide

DMPU 1 ,3-Dimethyl-3 ,4,5 ,6-tetrahydro-2( IH )-pyrimidinone

DMSO dimethyl sulfoxide

EDC l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide- hydrochloride

Et3N triethylamine

EtOAc ethyl acetate

FAB Fast atom bombardment

HMTA hexamethylenetetramine

HOBT 1-Hydroxybenzotriazole hydrate

HOOBT 3-Hydroxy- 1 ,2 ,2-benzotriazin-4( 3H)-one

HPLC High-performance liquid chromatography

IPA isopropanol or 2-propanol

MCPBA m-Chloroperoxybenzoic acid

MEK methyl ethyl ketone

MIBK methyl isobutyl ketone

MsCl methanesulfonyl chloride

MsOH methanesulfonic acid

MTBE methyl-t-butyl-ether

NaHMDS sodium bis(trimethylsilyl)amide NMP l-Methyl-2-pyrrolidinone

ODCB ortho-dichlorobenzene

Py pyridine

TFA trifluoroacetic acid

THF tetrahydrofuran

TsOH toluene sulfonic acid

The compounds synthesized by the invention are prepared by employing reactions as shown in Schemes 1-5. These reactions may be employed in a linear sequence to provide the compounds of the formula I or they may be used to synthesize fragments which are subsequently joined by the reductive alkylation or acylation reactions described in the Schemes.

SCHEME 1

SCHEME 2

SCHEME 2 (CONTINUED)

,

SCHEME 3

SCHEME 4

Solvent

SCHEME 4A

Solvent

SCHEME 5

In the above Schemes, it is understood that

R is independently selected from unsubstituted or substituted Ci- Cβ alkyl, unsubstituted or substituted aryl, or unsubstituted or substituted aralkyl;

R6 independently represents OEt, O-i-Pr, O-t-Bu, pyrrolidine, piperidine, or dialkylamino;

R7 represents Ci- Cβ alkyl or phenyl;

Al is selected from halo, OH or unsubstituted or substituted Ci-Cβ alkoxy; A2 is selected from halo or unsubstituted or substituted sulfonate;

Y is independently selected from a halide, a sulfonate, a phosphate or a sulfate; and

Z independently represents a halide, a sulfate, a sulfonate or a phosphate.

DHA represents dihydroxacetone in equilibrium with its dimer, as shown by the following scheme:

The present invention relates to an improved synthesis for substituted 5-imidazolyl-methyl-2-piperazinones. Types of solvents that may be used in the process for preparing the compounds of formula I include, but are not limited to, water, alcohols, unchlorinated or chlorinated hydrocarbons, nitriles, ketones, ethers, esters, polar aprotic solvents or mixtures thereof. Types of alcohols that can be used include, but are not limited to, methanol, ethanol, n-propanol, i-propanol, butanol or an alkoxy ethanol. Types of unchlorinated hydrocarbons include, but are not limited to, toluene or xylene. Types of chlorinated hydrocarbons include, but are not limited to, dichloromethane, chloroform, chlorobenzene or ODCB. Types of nitriles include, but are limited to, acetonitrile, propionitrile, benzonitrile or tolunitrile. Types of ketones include, but are not limited to, acetone, MEK, MIBK and cyclohexanone. Types of ethers include, but are not limited to, diethyl ether, MTBE, THF, DME and DEM. Types of polar aprotic solvents include, but are not limited to, formamide, DMF, DMA, NMP, DMPU, DMSO, and sulfolane. Preferably, the water soluble organic solvents are selected from nitriles, ethers, and polar aprotic solvents. Most preferably, a mixture of water and THF, DMF, ACN or DMSO is used. In an embodiment of the instant invention, the process for synthesizing compounds as illustrated by formula I comprises the step of mixing a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A

(where Ra, Xl, X2, χ3 and Z are as defined above) with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4, R5 and Z are as defined above and R2 is H), in the presence of a base compound.

Types of base compounds that may be used include, but are not limited to, Et3N, DIPEA, n-Bu3N, Imidazole, N-Me-imidazole,

Pyridine, 2,6-Lutidine, 2,4,6-Collidine, 2,6-tBu2-pyridine, 2,6-t-Bu2-4-Me- pyridine, DMAP, DBU, DBN, DABCO, N-Me-morpholine, N-Et- morpholine, l,2,2,6,6-Me5-piperidine, Mβ4-guanidine, Proton Sponge, N,N-Me2-aniline, N,N-Et2-aniline, Quinoline, i-P^NH , Cyclohex2NH, Cyclohex, iPrNH, Pyrrolidine, Piperidine, 2,2,6,6-Me4-piperidine, TMS₂NH (HMDS), LiNH₂, NaNH₂, KNH₂, LHMDS, NaHMDS, KHMDS, BnNMe3OMe, NaOEt, TlOEt, LiOt-Bu, NaOt-Bu, KOt-Bu, LiOt-A , NaOt-Am, KOt-Am, KH, KOTMS, NaOH, KOH , n-Bu NOH, Triton-B, Ca(OH)₂, CaO, BaO, Na₂SO₃ Li₂CO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃ , NH4OH, (NH₄)₂CO3 , Guanidine carbonate, CaCO₃, NaHCO₃, KHCO3, or K3PO4. Preferably, the base compound is selected from Et3N, DIPEA, n-Bu3N, Imidazole, N-Me-imidazole, Pyridine, 2,6-Lutidine, 2,4,6- Collidine, 2,6-t-Bu2-pyridine, 2,6-t-Bu2-4-Me-pyridine, 1,2,2,6,6-Me5- piperidine, and Me4-guanidine. Most preferably, the base compound is DIPEA. Preferably, the coupling of the 1-substituted benzyl-5-substituted imidazolyl salt of formula A and the substituted piperazinone salt of formula B is conducted at a temperature between about -10 °C and about 50 °C. Most preferably, the temperature is between about 0 °C and about 30 °C.

In second embodiment of the instant invention, the first step in the process requires mixing a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A

A

(where R^a, Xl, X , χ3 and Z are as defined above) with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4, R5 and Z are as defined above and R2 is H).

A base compound is then added to produce a free base form of a compound of formula I. Preferably, the base compound is selected from Et3N, DIPEA, n-Bu3N, Imidazole, N-Me-imidazole, Pyridine, 2,6- Lutidine, 2,4,6-Collidine, 2,6-t-Bu2-pyridine, 2,6-t-Bu2-4-Me-pyridine, l,2,2,6,6-Me5-piperidine, and Me4-guanidine. Most preferably, the base compound is DIPEA. Preferably, the coupling of the 1-substituted benzyl-5-substituted imidazolyl salt of formula A and the substituted piperazinone salt of formula B is conducted at a temperature between about -10 °C and about 50 °C. Most preferably, the temperature is between about 0 °C and about 30 °C. The free base form of a compound of formula I may then be isolated.

In third embodiment of the instant invention, the free base form of a compound of formula I, as previously described, in a solvent, is combined with HCl and the salt form of a compound of formula I is isolated. Types of solvents which may be utilized include the solvents previously described. Preferably, THF, IPA, n-PrOH, EtOH, EtOAc, toluene, water or a mixture thereof is utilized. More preferably, IPA, EtOAc, water, toluene, EtOH, n-PrOH or a mixture thereof. Most preferably, a mixture of IP A/toluene, IP A/water or EtOAc/EtOH is used. The HCl may be added as an aqueous solution, as a gas or as an organic solvent. The solution may then be seeded.

Isolation of the salt can be done using standard methods known in the literature. The isolation can be conducted at a temperature between about -10 °C to about 50 °C. Preferably, prior to the isolation step, the mixture containing the salt is heated to about 25 °C to about 50 °C. The isolation is done by cooling the solution to a temperature between about -40 °C and about 10 °C. Most preferably, the solution is cooled to a temperature between about -10 °C and about 0 °C. In a fourth embodiment, the free base form, as previously described, is combined with a solution of HCl in a solvent and the salt of a compound of formula I is isolated. The solvents previously described may be used here as well. Preferably, the free base form of a compound of formula I is mixed with a solution of HCl in ethanol. In a fifth embodiment, an anti-solvent may then be added and the mixture is stirred until dissolution is complete. Types of anti-solvents include, but are not limited to, esters, THF, MTBE, toluene, acetonitrile, DMF, alcohols, or carboxylic acids. Preferably, the anti-solvent is an ester, which may include, but is not limited to, EtOAc, IP Ac or BuOAc. Most preferably, EtOAc is used. Next, the mixture may be seeded with authentic material. As stated previously, isolation of the salt of a compound of formula I can be done using standard methods in the literature. Preferably, filtration is used to obtain the salt. Preferably, the salt formation is conducted at a temperature between about -30 °C and about 100 °C. Most preferably, the temperature is between about 0 °C and about 75 °C.

In another embodiment of the instant invention, a purified crystalline form of the free base of the compound of formula I is prepared. First, a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A, as defined above, is added to a mixture of a substituted piperazinone salt of formula B, as defined above, and an organic base in a solvent. Preferably, the l-(substituted benzyl)-5-substituted imidazolyl salt of formula A is 4-cyanobenzyl-chloromethylimidazole hydrochloride and the substituted piperazinone salt of formula B is l-(3-chlorophenyl)- 2-piperazinone hydrochloride. Types of organic bases that may be used include, but are not limited to, triethylamine, diisopropylethylamine, tributylamine and the like. Most preferably, diisopropylethylamine in acetonitrile is used. Next, activated carbon is added and the mixture was aged for about 8 to about 72 hours at a temperature of about -10 °C to about 40 °C. Most preferably, the mixture is aged for about 20 to about 45 hours at a temperature of about 0 °C to about 10 °C. Types of activated carbon include, but are not limited to, Darco, Darco G-60, Darco KB, Norit SA3, Norit RO, Norit RB 1, Norit A (alkaline), Norit and the like. Then, a mixture of solvents, preferably water and an organic base such as diisopropylethylamine, is added. This is followed by filtration and washing with a nitrile/water solution to produce a resulting solution. Seed crystals were added to the resulting solution and the resultant mixture aged and cooled prior to filtering off the purified crystals. Most preferably, the purified crystalline form of the free base of l-(3-

Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone is recovered.

In another embodiment of the instant invention, a purified crystalline form of the salt of the compound of formula I is prepared by first dissolving the free base form of a compound of formula I, as previously described, in a solvent mixture to produce a resulting solution. Preferably, the free base form of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone is used. Preferably, the solvent mixture contains an alcohol, as described previously, and an unchlorinated hydrocarbon, as previously described. Most preferably, a mixture of isopropanol and toluene is used. Next, activated carbon, as described above, is added and the mixture is heated to about 30 °C to about reflux, for about 0 to about 72 hours. More preferably, the mixture is heated to about 40 °C to about 55 °C for about 2 to about 12 hours. The mixture is then cooled to about 25 °C to about 40 °C and then aged for about another 0 to about 48 hours. More preferably, the mixture is cooled to about 30 °C to about 40 °C and then aged for about another 12 to about

26 hours. The mixture is then filtered and the filtrate is then treated with an acid solution. The acid solution comprises an acid, as previously described, and a solvent or mixture of solvents, as previously described. Most preferably, a solution of HCl in IPA/toluene is used. Optionally, seed is then added and the mixture is aged. Additional acid solution is added and the solution is aged and cooled again, followed by filtration and isolation of the purified crystals. Most preferably, the purified crystalline form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylm ethyl] -2-piperazinone* HCl is isolated.

In another embodiment of the instant invention, the crystalline form of the salt of the compound of formula I is purified by dissolving the free base form of a compound of formula I in an acid solution to produce a resulting solution. Preferably, the free base form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone and an HCl solution are used. Next, activated carbon, as described above, is added to the resulting solution, which is immediately heated to about 30 °C to about reflux and aged for about 0 to about 72 hours. More preferably, the solution is heated to about 40 °C to about 55 °C for about 2 to about 12 hours. The solution is allowed to cool to a temperature of about 5 °C to about 40 °C over about 1 to about 10 hours, and then aged for about 0 to about 72 hours. More preferably, the mixture is cooled to about 20 °C to about 40 °C for about 2 to about 8 hours and then aged for about 2 to about 24 hours. The activated carbon is then filtered and the filtrate is washed with an alcohol/water mixture, preferably IPA and water, and distilled. Optionally, the solution may be heated and aged. Next, the mixture is cooled to about -10 to about 25 °C, which is followed by recovery of the purified crystals. Most preferably, the purified crystalline form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl is recovered.

In another embodiment of the instant invention, the crystalline form of the salt of the compound of formula I is purified by dissolving the salt in a solvent mixture, as previously described, to produce a solution. Preferably, l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)- 5-imidazolylmethyl] -2-piperazinone* HCl is dissolved in the solvent mixture. Preferably, the solvent mixture comprises a mixture of water and an alcohol. Most preferably, the solvent mixture comprises IPA and water. Next, activated carbon, as described above, is added, followed by immediate heating of the solution to about 30 °C to about reflux and aged for about 0 to about 72 hours. More preferably, the solution is heated to about 40 °C to about 55 °C for about 2 to about 12 hours. The solution is allowed to cool to about 5 °C to about 40 °C over about 1 to about 10 hours and then aged for about 0 to about 72 hours. More preferably, the mixture is cooled to about 20 °C to about 40 °C for about 2 to about 8 hours and then aged for about 2 to about 24 hours. The activated carbon is then filtered and the filtrate is washed with an alcohol/water mixture, preferably IPA and water, and distilled. Optionally, the solution may be heated and aged. Next, the mixture is cooled to about -10 to about 25 °C, which is followed by recovery of the purified crystals. Most preferably, the purified crystalline form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl is recovered.

EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limitative of the reasonable scope thereof.

EXAMPLE 1

Synthesis of the Amide Alcohol (1)

(1 )

At 22 °C, 3-chloroaniline (50.0 g) was combined with 460 ml isopropyl acetate and 20% aqueous potassium bicarbonate (72.5 g dissolved in 290 ml water). The biphasic mixture was cooled to 5 °C and chloroacetyl chloride (42 ml) was added dropwise over 30 minutes, keeping the internal temperature below 10 °C. The reaction mixture was warmed to 22 °C over 30 min. The aqueous layer was removed at 22°C and ethanolamine (92 ml) was added rapidly. The reaction mixture was warmed to 55°C over 30 minutes and aged for 1 hour. At 55 °C, 140 ml water was added with 30 ml isopropyl acetate to the reaction mixture. The biphasic reaction mixture was agitated for 15 minutes at 55°C. The layers were allowed to settle and the aqueous layer was removed. The organic layer was cooled to 45 °C and seed was added. The mixture was cooled to 0 °C over 1 hour and aged for 1 hour. The solids were filtered and washed with chilled isopropyl acetate (2 x 75 ml). The solids were dried in vacuo at 40 °C for 18 hours to provide the amide alcohol (1).

¹H NMR (300 MHz; DMSO-dβ) δ 7.85 (t, IH 2.0 Hz), 7.52 (m, IH), 7.32 (t, IH, 8.0 Hz), 4.5-4.8 (br s, IH), 3.47 (t, IH, 5.5 Hz), 3.30 (s, IH), 2.60 (t, IH 5.0 Hz).

¹³C NMR (75.4 MHz; DMSO-dβ) δ_c 170.9, 140.1, 133.0, 130.3, 122.8 118.5, 117.5, 60.3, 52.7, 51.5.

EXAMPLE 2

Synthesis of l-(3-Chlorophenyl)-2-Piperazinone Hydrochloride with DPAD

An amide alcohol, as described above in Example 1, was slurried with THF (37 ml) at 22 °C, followed by the addition of tributyl phosphine (8.7 ml). The mixture was cooled to 0 °C and the DPAD was added in portions over 15 min. The slurry was aged at 0-5 °C for 30 minutes, warmed to 25 °C and aged for 18 hours. The reaction mixture was filtered and the cake was washed with THF (2 x 25 ml). The filtrate was concentrated in vacuo at < 35 °C and combined with 50 ml of 2- propanol. The solution was cooled to 5°C, seeded with authentic material and treated with ethanol HCl (2.6 ml; 8.4M solution) dropwise over 20 min. The resulting slurry was recooled to 10 °C and aged for 1 hour. The solids were isolated and the cake and flask rinsed with chilled 2-propanol (2 x 10 ml). The product was dried in vacuo at 40 °C for 18 hours to provide the above-titled compound.

1H NMR (300 MHz; DMSO-d₆) δ 10.24 (br s, 2H), 7.50 - 7.30 (m, 4H), 3.92 (t, 2H, 5.5 Hz), 3.84 (s, 2H), 3.51 (t, 5.5 Hz); ¹³C NMR (75.4 MHz; DMSO-d δ_c 162.1, 142.6, 132.9, 130.7, 127.0, 126.1, 124.54, 46.1, 44.9, 39.8.

EXAMPLE 3

Synthesis of l-(3-Chlorophenyl)-2-Piperazinone Hydrochloride with DIAD

58 mL of EtOAc was charged to an N₂-purged flask. Tributylphosphine (28.3 mL, 113.8 mmol) was added, via syringe, and the solution was cooled to about -10°C. DIAD (22.4 mL, 113.8 mmol) was added dropwise over 30 minutes, maintaining the temperature at < 0 °C. The above mixture was cannulated into a slurry of an amide alcohol (20.0 g, 87.5 mmol), as described above in Example 1, in 117 mL EtOAc over 20 minutes, maintaining the temperature at < 0 °C. The reaction was warmed to room temperature over 25 minutes. 99% conversion was observed by LC assay. Water (0.55 mL) was then added, and the reaction was warmed to 40 °C. The solution was seeded with 200 mg of authentic material, and 1.0 eq. HCl (4.0 N in abs. EtOH) was added dropwise over 2 hours. The slurry was cooled to 0 °C over 2 hours and aged at 0 °C for 1 hour. The mixture was filtered, and the cake was washed with chilled EtOAc (3x16 mL). The cake was dried in vacuo overnight at 40 °C to afford the above-titled compound. EXAMPLE 4

Preparation of p-Cyanobenzylamine * H3PO4 salt

A slurry of HMTA in 2.5 L EtOH was added gradually over about 30 min to about 60 min to a stirred slurry of cyanobenzyl-bromide in 3.5 L EtOH and maintained at about 48-53 °C with heating & cooling in a 22L neck flask (small exotherm). Then the transfer of HMTA to the reaction mixture was completed with the use of 1.0 L EtOH. The reaction mixture was heated to about 68-73 °C and aged at about 68-73 °C for about 90 min. The reaction mixture was a slurry containing a granular precipitate which quickly settled when stirring stopped.

The mixture was cooled to a temperature of about 50 °C to about 55 °C. Propionic acid was added to the mixture and the mixture was heated and maintained at a temperature of about 50 °C to about 55 °C. Phosphoric acid was gradually added over about 5 min to about 10 min, maintaining the reaction mixture below about 65 °C to form a precipitate-containing mixture. Then the mixture was gradually warmed to about 65 °C to about 70 °C over about 30 min and aged at about 65 °C to about 70 °C for about 30 min. The mixture was then gradually cooled to about 20-25 °C over about 1 hour and aged at about 20-25 °C for about 1 hour.

The reaction slurry was then filtered. The filter cake was washed four times with EtOH, using the following sequence, 2.5 L each time. The filter cake was then washed with water five times, using 300 mL each time. Finally, the filter cake was washed twice with MeCN (1.0 L each time) and the above identified compound was obtained. EXAMPLE 5

Preparation of 4-Cyanobenzylamine Hydrochloride via Hexamethylene- tetrammonium salt

NH₂ ^»HCI

CN

A 72 liter vessel was charged with 190 proof ethanol (14.4 L) followed by the addition of 4-cyanobenzylbromide (2.98 kg) and HMTA (2.18 kg) at ambient temperature. The mixture was heated to about 72-75 °C over about 60 min. On warming, the solution thickens and additional ethanol (1.0 liter) was added to facilitate stirring. The batch was aged at about 72-75 °C for about 30 min.

The mixture was allowed to cool to about 20 °C over about 60 min, and HCl gas (2.20 kg) was sparged into the slurry over about 4 hours during which time the temperature rose to about 65 °C. The mixture was heated to about 70-72 °C and aged for about 1 hour. The slurry was cooled to about 30 °C and ethyl acetate (22.3 L) added over about 30 min. The slurry was cooled to about -5 °C over about 40 min and aged at about -3 to about -5 °C for about 30 min. The mixture was filtered and the crystalline solid was washed with chilled ethyl acetate (3 x 3 L). The solid was dried under a N2 stream for about 1 hour before charging to a 50 liter vessel containing water (5.5 L). The pH was adjusted to about 10-10.5 with 50% NaOH (4.0 kg) maintaining the internal temperature below about 30°C. At about 25 °C, methylene chloride (2.8 L) was added and stirring continued for about 15 min. The layers were allowed to settle and the lower organic layer was removed. The aqueous layer was extracted with methylene chloride (2 x 2.2 L). The combined organic layers were dried over potassium carbonate (650 g). The carbonate was removed via filtration and the filtrate concentrated in vacuo at about 25 °C to give a free base as a yellow oil. The oil was transferred to a 50 liter vessel with the aid of ethanol (1.8 L). Ethyl acetate (4.1 L) was added at about 25 °C. The solution was cooled to about 15 °C and HCl gas (600 g) was sparged in over about 3 hours, while keeping batch temperature below about 40 °C. At about 20-25 °C, ethyl acetate (5.8 L) was added to the slurry, followed by cooling to about -5 °C over about 1 hour. The slurry was aged at about -5 °C for about 1 hour and the solids isolated via filtration. The cake was washed with a chilled mixture of EtOAc/EtOH (9:1 v/v) (1 x 3.8 L), then the cake was washed with chilled EtOAc (2 x 3.8 L). The solids were dried in vacuo at about 25 °C to provide the above-titled compound.

NMR (250 MHz, CDCI3) δ 7.83-7.79 (d, 2H), 7.60-7.57 (d, 2H), 4.79 (s, 2H), 4.25 (s, 2H); 1³C NMR (62.9 MHz, CDCI3) δ 149.9, 139.8, 134.2, 131.2, 119.7, 113.4, 49.9, 49.5, 49.2, 48.8, 48.5, 48.2, 43.8.

EXAMPLE 6

Preparation of l-(4-Cyanobenzyl)-2-Mercapto-5-Hvdroxymethylimidazole

7% water in acetonitrile (50 mL) was added to a 250 mL roundbottom flask. Next, an amine phosphate salt (12.49 g), as described in Example 5, was added to the flask. Next potassium thiocyanate (6.04 g) and dihydroxyacetone (5.61 g) was added. Lastly, propionic acid (10.0 mL) was added. Acetonitrile/water 93:7 (25 mL) was used to rinse down the sides of the flask. This mixture was then heated to 60 °C, aged for about 30 minutes and seeded with 1% thioimidazole. The mixture was then aged for about 1.5 to about 2 hours at 60 °C. Next, the mixture was heated to 70 °C, and aged for 2 hours. The temperature of the mixture was then cooled to room temperature and was aged overnight. The thioimidazole product was obtained by vacuum filtration. The filter cake was washed four times acetonitrile (25 mL each time) until the filtrates became nearly colorless. Then the filter cake was washed three times with water (approximately 25-50 mL each time) and dried in vacuo to obtain the above-identified compound.

EXAMPLE 7

Preparation of l-(4-Cyanobenzyl)-5-Hvdroxymethylimidazole

A 1L flask with cooling/heating jacket and glass stirrer (Lab-Max) was charged with water (200 mL) at 25 °C. The thioimidazole (90.27 g), as described in Example 6, was added, followed by acetic acid (120 mL) and water (50 mL) to form a pale pink slurry. The reaction was warmed to 40 °C over 10 minutes. Hydrogen peroxide (90.0 g) was added slowly over 2 hours by automatic pump maintaining a temperature of 35- 45 °C. The temperature was lowered to 25 °C and the solution aged for 1 hour. The solution was cooled to 20 °C and quenched by slowly adding 20% aqueous Na2SO3 (25 mL) maintaining the temperature at less than 25 °C. The solution was filtered through a bed of DARCO G-60 (9.0 g) over a bed of SolkaFlok (1.9 g) in a sintered glass funnel. The bed was washed with 25 mL of 10% acetic acid in water. The combined filtrates were cooled to 15 °C and a 25% aqueous ammonia was added over a 30 minute period, maintaining the temperature below 25 °C, to a pH of 9.3. The yellowish slurry was aged overnight at 23 °C (room temperature). The solids were isolated via vacuum filtration. The cake (100 mL wet volume) was washed with 2 x 250 mL 5% ammonia (25%) in water, followed by 100 mL of ethyl acetate. The wet cake was dried with vacuum/N2 flow and the above-titled compound was obtained.

^!H NMR (250 MHz, CDCI3): δ 7.84-7.72 (d, 2H), 7.31-7.28 (d, 2H), 6.85 (s,

IH), 5.34 (s, 2H), 5.14-5.11 (t, IH), 4.30-4.28 (d, 2H), 3.35 (s, IH).

EXAMPLE 8

Preparation of l-(4-cyanobenzyl)-5-chloromethyl imidazole HCl salt

l-(4-Cyanobenzyl)-5-hydroxymethylimidazole (1.0 kg), as described in above in Example 7, was slurried with DMF (4.8 L) at 22 °C and then cooled to -5 °C. Thionyl chloride (390 mL) was added dropwise over 60 min during which time the reaction temperature rose to a maximum of 9 °C. The solution became nearly homogeneous before the product began to precipitate from solution. The slurry was warmed to 26 °C and aged for 1 h.

The slurry was then cooled to 5 °C and 2-propanol (120 mL) was added dropwise, followed by the addition of ethyl acetate (4.8 L). The slurry was aged at 5 °C for 1 h before the solids were isolated and washed with chilled ethyl acetate (3 x 1 L). The product was dried in vacuo at 40 °C overnight to provide the above-titled compound. ^XH NMR (250 MHz DMSO-dβ): δ 9.44 (s, IH), 7.89 (d, 2H, 8.3 Hz), 7.89 (s,

IH), 7.55 (d, 2H, 8.3 Hz), 5.70 (s, 2H), 4.93 (s, 2H). ¹³C NMR (75.5 MHz DMSO-dβ): δ_c 139.7, 137.7, 132.7, 130.1, 128.8, 120.7, 118.4, 111.2, 48.9, 33.1.

EXAMPLE 9

Preparation of l-(4-Cyanobenzyl)-5-Chloromethyl Imidazole HCl salt via addition of Hydroxymethylimidazole to Vilsmeier Reagent

To an ice cold solution of dry acetonitrile (3.2 L, 15 L/Kg hydroxymethylimidazole) was added 99% oxalyl chloride (101 mL, 1.15 mol, 1.15 equiv.), followed by dry DMF (178 mL, 2.30 mol, 2.30 equiv.), at which time vigorous evolution of gas was observed. After stirring for about 5 to 10 min following the addition of DMF, solid hydroxymethylimidazole (213 g, 1.00 mol), as described above in Example 7, was added gradually. After the addition, the internal temperature was allowed to warm to a temperature of about 23 °C to about 25 °C and stirred for about 1 to 3 hours. The mixture was filtered, then washed with dry acetonitrile (400 mL displacement wash, 550 mL slurry wash, and a 400 mL displacement wash). The solid was maintained under a N2 atmosphere during the filtration and washing to prevent hydrolysis of the chloride by adventitious H2O. This yielded the crystalline form of the chloromethylimidazole hydrochloride.

_ NMR (250 MHz DMSO-dβ): δ 9.44 (s, IH), 7.89 (d, 2H, 8.3 Hz), 7.89 (s,

IH), 7.55 (d, 2H, 8.3 Hz), 5.70 (s, 2H), 4.93 (s, 2H). ¹³C NMR (75.5 MHz DMSO-dβ): δ_c 139.7, 137.7, 132.7, 130.1, 128.8, 120.7, 118.4, 111.2, 48.9, 33.1. EXAMPLE 10

Preparation of l-(4-Cyanobenzyl)-5-Chloromethyl Imidazole HCl salt via addition of Vilsmeier Reagent to Hydroxymethylimidazole

To an ice cold solution of dry DMF (178 mL, 2.30 mol, 2.30 equiv.) in dry acetonitrile (2.56 L, 12 L/Kg Hydroxymethylimidazole) was added oxalyl chloride (101 mL, 1.15 mol, 1.15 equiv). The heterogeneous mixture in the reagent vessel was then transferred to a mixture of hydroxymethylimidazole (213 g, 1.00 mol), as described above in Example 7, in dry acetonitrile (1.7 L, 8 L/Kg hydroxymethylimidazole). Additional dry acetonitrile (1.1 - 2.3 L, 5 - 11 L/Kg hydroxymethylimidazole) was added to the remaining solid Vilsmeier reagent in the reagent vessel. This, now nearly homogenous, solution was transferred to the reaction vessel at Ti < +6 °C. The reaction vessel temperature was warmed to a temperature of about 23 °C to about 25 °C and stirred for about 1 to 3 hours. The mixture was then cooled to 0 °C and aged 1 h. The solid was filtered and washed with dry, ice cold acetonitrile (400 mL displacement wash, 550 mL slurry wash, and a 400 mL displacement wash). The solid was maintained under a N2 atmosphere during the filtration and washing to prevent hydrolysis of the chloride by adventitious H2O. This yielded the crystalline form of the chloromethylimidazole hydrochloride.

EXAMPLE 11

Preparation of l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone *H9θ (Crystal Form I)

A 50 L four-neck flask, equipped with a mechanical stirrer, cooling bath, teflon-coated thermocouple, and nitrogen inlet was charged with 4.0 L of acetonitrile. Then 4-cyanobenzyl-5- chloromethylimidazole hydrochloride, as described in Examples 8, 9 or 10, (958 g, 3.36 mol), l-(3-chlorophenyl)-2-piperazinone hydrochloride, as described in Examples 2 or 3, (883 g, 3.54 mol), and the remaining 1.25 L of acetonitrile were added to the flask at room temperature. Diisopropylethylamine (1.99 L, 11.4 mol) was added to the mixture. The bulk of the solid dissolved immediately upon addition of diisopropylethylamine, leaving a slightly turbid solution.

After stirring 30 min, the solution was cooled to 0 °C over 60 min. The solution was stirred 26 h at 0 °C, then warmed to 20 °C over 20 min. Water (2 L) was added to the slightly turbid solution over 20 min. Authentic seed was added to 8 L of water, which was subsequently added to the solution over 70 min. Additional water (17 L) was added over 90 min, and the mixture was aged 60 min thereafter. The temperature throughout the addition and aging was from about 20°C to about 22 °C. The mixture was filtered through a polypropylene filter pot. The crystals were washed with 1:5 acetonitrile/water. The crystalline solid was dried by passage of nitrogen through the filter cake (36 h) to provide the above- titled compound.

!3C NMR (62.9 MHz, CDC1₃): δ 165.2, 142.7, 142.1, 139.4, 134.8, 133.0, 131.0, 130.2, 127.3, 127.1, 126.3, 126.0, 123.9, 118.1, 112.0, 57.7, 50.6, 49.9, 148.8, 148.3.

Solid state x-ray powder diffraction (XRPD) pattern obtained with CuK x-ray radiation using a Phillips Diffractometer APD3720 gave the following d-spacings of 8.29, 6.76, 6.07, 5.31, 5.07, 4.86, 4.71, 4.23, 4.13, 4.06, 3.96, 3.91, 3.82, 3.73, 3.51, 3.45 and 2.91 A. The differential scanning calorimetry (DSC) curve, at a heating rate of 10 °C/min under nitrogen and in an open cup, is characterized by a relatively broad water loss endotherm that normally appears with two peaks at approximately 80 °C and 100 °C. This is followed by a relatively sharp melting-decomposition endotherm at a peak temperature of 151 °C and an extrapolation onset temperature of 148 °C with an associated heat of 76 Joules/gram.

EXAMPLE 12

Preparation of l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethvn -2-piperazinone* HCi

An IP A/toluene mixture (7 L) is made up as a 69:31 wt% ratio by mixing IPA (3.90 Kg, 4.97 L) and toluene(1.76 Kg, 2.03 L).

A pre-weighed 1 L graduated cylinder was charged with IPA (500 mL, 392 g). The cylinder was cooled to 0 °C. Gaseous HCl was bubbled into the IPA until a volume change of roughly +80 mL was observed. The new weight of the cylinder and its contents indicated that 140 g HCl (3.84 moles) had been charged, making up a 6.62 M solution (or 7.22 olal solution). An aliquot (500 mL, 458 g) was transferred to a 5 L flask. To this solution was added toluene (192 mL, 166 g) and the 69:31 IPA/toluene mixture (2.07 Liters, 1.7 Kg). A 22 L flask was charged with the free base form of l-(3- chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, as described above in Example 11. The 69:31 IPA/toluene mixture (11.0 L) was added to this flask, which resulted in dissolution of the solid. The solution was heated to 40 °C. The hot solution was filtered through an in-line filter into a pre-heated (40 °C) 22 L flask. The dissolution flask was further washed with the 69:31 IPA/toluene solution (0.5 L), which was transferred to the crystallization flask through the in-line filter. The in-line filter was replaced with a 4 L addition funnel.

The 1.21 M HCl solution (1.93 L, 1.63 Kg, 2.34 moles, 0.99 equiv.) was charged to the addition funnel. A fraction of the HCl solution (0.19 Liters, 0.23 moles, 0.10 equiv.) was added to the solution of free base over 10 min, whereupon the solution was seeded. After aging the thin slurry for 10-15 min, the remaining HCl solution was added over 2 h. The thick mixture was cooled to -10 °C over 2 h, aged for 30 min, then filtered. The crystals were washed with ice-cold 69:31

IPA/toluene and was then washed three times with ice-cold IPA. The crystals were dried under vacuum with a nitrogen stream and the above-titled compound was obtained.

EXAMPLE 13

Preparation of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyll -2-piperazinone* HCl (Crystal Form II)

A solution of HCl in ethanol was prepared by passing HCl gas (118 g, 3.24 mol) via a Teflon tube into ethanol (385 mL) contained in a 500 mL graduated cylinder cooled in an ice bath. The volume of the solution increased to 447 mL after addition of the correct weight of HCl, making a 7.25 M solution. A one-neck, 22 L flask, fitted with a heating mantle and nitrogen inlet, was charged with l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone *H2θ, as described in

Example 11, (1.14 kg, 2.69 mol) and ethanol (1.36 L). The mixture was heated to 60 °C, whereupon EtOAc (1.7 L) was added. The mixture was stirred at 60 °C until dissolution was complete. A separate one-neck, 5 L flask, fitted with a heating mantle and nitrogen inlet, was charged with EtOAc (2.4 L) and heated to 70 °C.

A solkafloc pad (100 g) in a 2 L sintered-glass funnel equipped with an electrically heated jacket was washed with hot EtOH (1 L), followed by hot 1:1 EtOH/EtOAc (1 L). The funnel containing the washed solkafloc fitted to a 50 L four-neck flask, which was equipped with a water bath, mechanical stirrer, Teflon-coated thermocouple, and three-way stopcock. The three-way stopcock was connected to a nitrogen inlet and to a house vacuum. The hot solution of l-(3-Chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone *H2θ in

EtOAc/EtOH was filtered into the 50 L flask through the heated (70 °C) solkafloc pad under static vacuum. The hot EtOAc (2.4 L) was then used to wash the solkafloc pad. The solution of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylm ethyl] -2-piperazinone *H2θ was maintained at 55-60 °C while the 7.25 M solution of HCl in EtOH (386 mL, 2.80 mol) was added over 30 min.

The solution was seeded with authentic material (1 g total) at about 5 min, and then at about 10 min, after the addition of the HCl had begun. Crystallization ensued after the second seeding when 120 mL of HCl in EtOH had been added. The slurry was aged at 55-60 °C for 20 min, whereupon EtOAc (9.65 L) was added at a constant rate over 3 h. The slurry was cooled from 55 °C to 0 °C over 95 min and aged at 0 °C for 20 min. The slurry were filtered on a polypropylene filter pot. The crystals were washed four times with approximately 5 to about 7L of 9:1 EtOAc/EtOH solution. The filter cake was partly dried under a stream of nitrogen through the filter pot for 2 h. The crystals were transferred to Pyrex trays and dried in a vacuum oven (27" vacuum, 20-25 °C, 18 h) yielding the above-titled compound.

13c NMR (62.9 MHz, D₂O): δ_c 169.4, 142.3, 141.8, 138.0, 135.0, 133.7, 131.7, 130.6, 128.9, 128.0, 126.9, 125.3, 121.0, 119.8, 111.5, 55.9, 51.0, 50.3, 49.1, 48.6

Solid state x-ray powder diffraction (XRPD) pattern obtained with CuKα x-ray radiation using a Phillips Diffractometer APD3720 gave the following d-spacings: 21.6, 8.4, 7.3, 6.1, 5.7, 5.6, 5.4, 5.3, 5.0, 4.9, 4.5, 4.2, 3.9, 3.8, 3.7, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.5, 2.4, and 2.3

A.

The DSC curve at a heating rate of 10°C/min in an open cup and under a nitrogen atmosphere is characterized by a single melting- decomposition endotherm with a peak temperature of 211 °C, an extrapolated onset temperature of 203 °C and an associated heat of 106 Joules/gm.

The DSC curve at a heating rate of 10°C/min in a closed cup and under a nitrogen atmosphere is characterized by a single melting- decomposition endotherm with a peak temperature of 222 °C, an extrapolated onset temperature of 220 °C and an associated heat of 101 Joules/gm.

EXAMPLE 14

Preparation of a purified form of l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)- δ-imidazolylmethyll -2-piperazinone * H )

To an ice-cold mixture of l-(3-chlorophenyl)-2-piperazinone hydrochloride (13.2 g, 99wt% purity, 52.9 mmol) and diisopropylethylamine (29.8 mL, 99%, 169 mmol) in ACN (86 mL) was added l-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride (16.0 g, 93wt% purity, 55.5 mmol). Upon complete dissolution of the solids, Darco G-60 (4.0 g) was added. The mixture was aged at 0 - 4 °C for 2 days. To the cold mixture was added H₂O (32 mL) and diisopropylethylamine (1.9 mL, 11 mmol). After aging 30 min at 0 °C , the mixture was warmed to 23 °C, then filtered through solka floe, washing with ACN (64 mL). The resulting solution was further filtered through a 0.45 μm polypropylene filter into a crystallization flask. The solution was heated to 35 °C, whereupon H₂O (251 mL) was added over 15-20 min. Authentic l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl]-2-piperazinone»H₂O was added for seed, and the resultant mixture aged 1 h at 35 °C. Additional H₂O (212 mL) was added dropwise. After aging 15 min further at 35 °C, the mixture was allowed to cool to 23 °C, then further cooled to 0 °C. After aging at 0 °C for 1 h, the crystals were filtered off, washing with ice-cold 1:5 ACN/H₂O (80 mL), then twice with ice-cold 1:9 ACN/H₂O (96 mL and 80 mL). The crystals were dried under vacuum with a nitrogen sweep to produce the above titled compound.

EXAMPLE 15

Preparation of a purified form of l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-

5-imidazolylmethyπ-2-piperazinone*HCl

To a solution of 69:31 (weight/weight) IPA/toluene (120 mL) was added l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone*H₂O, as described in Example 11, (10.0 g, 23.6 mmol) at rt. The turbid solution was heated to 50 °C, whereupon Darco G-60 (2.5 g) was added to the warm solution. The mixture was aged for 2 h at 50 °C , then cooled to 40 °C and aged 24 h further. The mixture was filtered through a bed of solka floe (7.3 g, pre-washed with 69:31 IPA/toluene), washing with 69:31 IPA/toluene (40 mL). The combined filtrate was filtered through a 0.45 μm polypropylene filter into a flask which was subsequently placed in a bath at 50 °C. A 1.20 M solution of HCl in 69:31 IPA/toluene (5.0 mL, 6 mmol) was added dropwise. The now turbid solution was seeded with l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl]-2-piperazinone*HCl (20 mg). After aging the mixture for 45 min at 50 °C, additional 1.20 M HCl in 69:31 IPA/toluene (13.7 mL, 16.4 mmol) was added over 30 min. The mixture was aged 30 min at 50 ° C, then allowed to cool gradually to 23 °C. The mixture was then cooled further to 0 °C and aged 30 min. The crystals were filtered, washing with ice-cold IPA (2 x 20 mL). The crystals were dried under vacuum with a nitrogen sweep to produce a purified form of l-(3-chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone*HCl.

EXAMPLE 16

Preparation of a purified form of l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-

5-imidazolylm ethyll -2-piperazinone* HCl

Charged H₂O (2.5 L) and 12.1 N HCl (256 mL) were added to a 5L flask, to provide a 1.13 M HCl solution. Isopropanol (14.4 L), followed by the solution of 1.13 M HCl (2.45 L), was charged to a 50 Liter flask equipped with a thermocouple, a mechanical stirrer, a condenser, and a nitrogen inlet.

Next, l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl]-2-piperazinone*H₂O, as described in Example 11, was added to the HCl solution over 2 min. Additional 1.13 M HCl (50 mL, 5.6xl0^"2 moles) was then added.

Darco G-60 (0.300 Kg) was added to the solution, and the resultant mixture was immediately heated to 50 °C. The mixture was aged for 2 hours, whereupon heating was discontinued. The mixture was allowed to cool gradually overnight, with a total age time of 17 hours and 40 min after heating had been discontinued.

A 6 L scintered glass funnel was charged with solka floe (828 g, 2.9 L dry volume). The solka floe was slurry washed with 86:14 IPA/H₂O (5 L), then packed by vacuum removal of the wash. The mixture was transfered from the 50 L flask onto the filter containing solka floe. Once filtered, the flask was washed with 86:14 IPA/H₂O (2 x 2 L), which was subsequently filtered through the solka floe. The carbon cake was further washed with 86:14 IPA H₂O (2 L displacement wash). The filtrate was transferred through a Whatman Polycap 75

TF, PTFE/polypropylene 0.45 μm filter into a 72 L round bottom flask equipped with a thermocouple, a mechanical stirrer, and a bump trap leading to a batch concentrator. The carboys containing the filtrate were washed with IPA (2 L). The IPA wash was then transfered to the 72 L flask through the Whatman Polycap 75 TF, PTFE/polypropylene 0.45 μm filter. Vacuum was applied to the system, while continuously heating with steam. After 9.5 - 10 L of distillate had been collected, a continuous addition of IPA through the Whatman Polycap 75 TF, PTFE/polypropylene 0.45 μm filter was initiated. After another 10 L of distillate had collected, crystals were observed in the solution. Vacuum was discontinued, and the mixture heated to +30 °C under a nitrogen atmosphere. Additional IPA (4 L) was added to the distilling flask via the Whatman Polycap 75 TF, PTFE/polypropylene 0.45 μm filter, along with seed (1.0 g). The mixture was aged at 30 °C for 30 min. After the 30 min age, distillation was resumed, while continuously adding IPA (22 L) through the Whatman Polycap 75 TF, PTFE/polypropylene 0.45 μm filter. The batch volume was reduced to 8 L, whereupon distillation was discontinued, and the system was placed under a nitrogen atmosphere. Additional pre-filtered IPA (2 L) was used to wash down the side of the flask.

An ice bath was placed around the flask, and the mixture aged for 90 min at 0 - 2 °C. The resultant mixture was slowly transferred to a filter funnel. The flask was washed with pre-filtered, ice-cold IPA (5 L), which was used as a displacement wash of the crystal cake. The crystals were dried overnight in the filter pot under vacuum with a nitrogen sweep.

The crystals were then transferred to glass trays and dried further in a vacuum oven with a nitrogen bleed, to provide a purified form of l-(3-chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone • HCl .

EXAMPLE 17

Purification of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl (Crystal Form II)

Crystalline l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl]-2-piperazinone*HCl, as described in Example 12 or

13, was added to a 72 Liter flask fitted with a thermocouple, a mechanical stirrer, a condenser, and a nitrogen inlet. Water (5 L) and

IPA (30 L) were added to the flask sequentially. Stirring was continued until dissolution was complete.

Darco G-60 (0.625 Kg) was added to the solution, and the resultant mixture was immediately heated to T_; = 50 °C. The mixture was aged 2 h, whereupon heating was discontinued. The mixture was allowed to cool gradually overnight, with a total age time of 21 h after heating had been discontinued.

A 46 cm diameter filter funnel was filled with solka floe to a height of 6 cm (10 L). The solka floe was slurry washed with 86:14 IPA/H₂O (8 L), then packed by vacuum removal of the wash. The mixture was pumped from the 72 Liter flask onto the filter containing solka floe. Once filtered, the flask was washed with 86:14 IPA/H₂O (4 L), which was subsequently filtered through the solka floe. The carbon cake was further washed with 86:14 IPA/H₂O (a 4 L displacement wash and a 3 L displacement wash).

The filtrate was transferred through a Whatman Polycap 75 TF, polypropylene 0.45 μm filter into a 100 L round bottom flask equipped with a thermocouple, a mechanical stirrer, and a bump trap leading to a batch concentrator. When the volume of the flask had reached 30 - 35 L, vacuum distillation was initiated.

A solution of IPA (18 L) was filtered through a Whatman Polycap 75 TF, polypropylene 0.45 μm filter into a 22 L round bottom flask fitted with a nitrogen bubbler and a feed tube. Seed (9 g) was added to the solution, whereupon vigorous bubbling of nitrogen was applied. The mixture containing seed was gradually added to the main batch by vacuum transfer at a rate such that the volume of the batch remained at 30 - 35 L. Additional IPA (18 L) was filtered, to which was added seed (10 g). The resultant mixture was transferred to the main batch as above until a seed bed developed. Once a seed bed formed, batch concentration was discontinued and the mixture was heated to T, = 50 °C under a nitrogen atmosphere.

After aging the mixture at 50 °C for 40 min, batch concentration was resumed. The remaining IPA containing seed was added gradually as distillation proceeded. Additional filtered IPA (25 L) was added gradually. Once the addition was complete, the volume of the batch was reduced to <15 L.

The mixture was cooled to 0 °C with an ice/MeOH bath, and aged for 30 min. Filtered, ice-cold IPA (4 L) was used to wash down the sides of the flask. The resultant mixture was slowly transferred to a filter funnel. The flask was washed with filtered, ice-cold IPA (4 L), which was used as a displacement wash of the crystal cake. The crystals were dried overnight in the filter pot under vacuum with a nitrogen sweep.

The crystals were then transferred to glass trays and dried further in a vacuum oven with a nitrogen bleed. Drying was discontinued when analysis by GC indicated <0.13wt% IPA, and the absolute weight was constant.

Claims

WHAT IS CLAIMED IS:

A process for synthesizing compounds as illustrated by formula I:

wherein

Ra is selected from a) H, b) CN, c) -C(O)Rb, d) -C(O)N(Rb)₂, e) unsubstituted or substituted Ci-Cβ alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl;

Rb is selected from a) H b) OH, c) unsubstituted or substituted Cl-Cβ alkyl, d) unsubstituted or substituted Cl-Cβ alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted Ci- C alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted C -Cβ alkoxy, h) Cl-Cβ alkynyl; i) CF3, and j) OCF₃;

Xl, X2 and X3 are independently selected from

H, halo, unsubstituted or substituted Cl-Cβ alkyl, unsubstituted or substituted Cl-Cβ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl,

CF3, OCF3, -SOR10, -SO2R10, (Cl-Cβ alkyl)SOi-2(Cθ-Cβ alkyl)-, HC(O)(Co-Cβ alkyl)-, (Cl-Cβ alkyl)C(O)(Co-Cβ alkyl)-, -N(R10)₂, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2RI⁰, and -N(RlO)SO2RlO; Xl and X2 or X2 and X , when located on adjacent carbon atoms, may be joined in a ring;

(where R^a, χl, χ2 and X are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4_; R5 and Z are as defined above and R2 is H) in the presence of a base compound.

2. The process, according to Claim 1, for preparing the compound of formula IA

IA

which comprises the step of: mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride in the presence of diisopropylethylamine.

3. A process for synthesizing compounds as illustrated by formula I:

wherein

Ra is selected from a) H, b) CN, c) -C(O)Rb d) -C(O)N(Rb)₂, e) unsubstituted or substituted Cl-Cβ alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl; Rb is selected from a) H, b) OH, c) unsubstituted or substituted Cl-Cβ alkyl, d) unsubstituted or substituted Ci-Cβ alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

Rl is selected from a) H, b) unsubstituted or substituted Ci-Cβ alkyl, c) unsubstituted or substituted aryl, or d) unsubstituted or substituted heteroaryl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted Ci- C alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted Ci- Cβ alkoxy, h) Ci-Cβ alkynyl; i) CF3, and j) OCF₃;

RlO is independently selected from a) unsubstituted or substituted Cl-Cβ alkyl, b) unsubstituted or substituted aryl, or c) unsubstituted or substituted aralkyl; Xl, X2 and X3 are independently selected from

H, halo, unsubstituted or substituted Cl-Cβ alkyl, unsubstituted or substituted Ci-Cβ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Ci-Cβ alkyl)SOi-2(Co-Cβ alkyl)-, HC(O)(Co-C₆ alkyl)-, (Cι-C₆ alkyl)C(O)(Co-C₆ alkyl)-, -N(R10)₂, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2RIO, and -N(R10)SO2R10;

Xl and X or X2 and X3, when located on adjacent carbon atoms, may be joined in a ring;

(where R^a, Xl, χ2 and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

4. The process according to Claim 3, wherein Xl and X3 are hydrogen and X2 is CN, halo, or unsubstituted or substituted Cl-Cβ alkyl.

5. The process according to Claim 3, wherein R^a is H.

6. The process according to Claim 3, wherein Z of Formula A is selected from a halide, a sulfonate or a phosphate.

7. The process according to Claim 6, wherein Z is Cl.

8. The process according to Claim 3, wherein R3, R4 and R5 are independently selected from H or unsubstituted or substituted Ci-Cβ alkyl.

9. The process according to Claim 3, wherein the base compound comprises Et3N, DIPEA, n-Bu3N, Imidazole, N-Me- imidazole, Pyridine, 2,6-Lutidine, 2,4,6-Collidine, 2,6-t-Bu2-pyridine, 2,6- t-Bu2-4-Me-pyridine, l,2,2,6,6-Me5-piperidine, or Me4-guanidine.

10. The process according to Claim 9, wherein the base compound is DIPEA.

11. The process according to Claim 3, for synthesizing a compound of formula IA

IA

which comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; and c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone .

12. The process according to Claim 3 for synthesizing a salt of the compound of formula I:

wherein

Ra is selected from a) H, b) CN, c) -C(O)Rb d) -C(O)N(Rb)₂, e) unsubstituted or substituted Cl-Cβ alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl;

Rb is selected from a) H, b) OH, c) unsubstituted or substituted Cl-Cβ alkyl, d) unsubstituted or substituted Ci-Cβ alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted C - C alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted Ci- Cβ alkoxy, h) Cl-Cβ alkynyl; i) CF3, and j) OCF3;

Xl, X2 and X are independently selected from H, halo, unsubstituted or substituted Ci-Cβ alkyl, unsubstituted or substituted Ci-Cβ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Ci-Cβ alkyl)SOi-2(Co-Cβ alkyl)-, HC(O)(Co-C₆ alkyl)-, (Ci-Cβ alkyl)C(O)(Co-Cβ alkyl)-,

-N(R10)₂, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2RIO, and -N(R10)SO2R1 ;

which comprises the steps of: a) mixing a l-( substituted benzyl)-5-substituted imidazolyl salt of formula A

(where R^a, Xl, X2 and X are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4_; R5 and Z are as defined above and R is H); b) adding a base compound; c) isolating the free base form of a compound of formula I; d) combining the free base form of a compound of formula I in a solvent with HCl; and e) isolating a salt of compound of formula I in crystalline form.

13. The process according to Claim 12, wherein the base compound comprises Et3N, DIPEA, n-Bu3N, Imidazole, N-Me- imidazole, Pyridine, 2,6-Lutidine, 2,4,6-Collidine, 2,6-t-Bu2-pyridine, 2,6- t-Bu2-4-Me-pyridine, 1,2,2,6,6-Me5~piperidine, or Me4-guanidine.

14. The process according to Claim 13, wherein the base compound is DIPEA.

15. The process according to Claim 12 for synthesizing a salt of the compound of formula IA

IA

which comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) combining the free base form in a solvent with HCl; and e) isolating a salt of compound of formula IA in crystalline form.

16. The process according to Claim 12, wherein the solvent comprises water, alcohols, unchlorinated or chlorinated hydrocarbons, nitriles, ketones, ethers, polar aprotic solvents or mixtures thereof.

17. The process according to Claim 16, wherein, in step d), the free base form of a compound of formula I in a mixture of IPA/toluene is combined with HCl.

18. The process according to Claim 15 for synthesizing a salt of the compound of formula IA

IA which comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) combining the free base form l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone in a mixture of IPA/toluene with HCl; and e) isolating l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl in crystalline form.

19. A process for synthesizing a salt of a compound of formula I

wherein

Ra is selected from a) H b) CN, c) -C(O)Rb, d) -C(O)N(Rb)₂, e) unsubstituted or substituted Cl-Cβ alkyl, f) unsubstituted or substituted aryl, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or j) unsubstituted or substituted heteroaralkyl; Rb is selected from a) H, b) OH, c) unsubstituted or substituted Cl-Cβ alkyl, d) unsubstituted or substituted Cl-Cβ alkoxy, e) unsubstituted or substituted aryl, f) unsubstituted or substituted aryloxy, g) unsubstituted or substituted heteroaryl, h) unsubstituted or substituted aralkyl, or i) unsubstituted or substituted heteroaralkyl;

R3, R4 and R5 are independently selected from: a) H, b) unsubstituted or substituted C - C alkyl; c) unsubstituted or substituted aryl, d) unsubstituted or substituted heteroaryl, e) unsubstituted or substituted aralkyl, f) unsubstituted or substituted heteroaralkyl, g) unsubstituted or substituted C ~ Cβ alkoxy, h) Cl-Cβ alkynyl; i) CF3, and j) OCF₃;

H, halo, unsubstituted or substituted Cl-Cβ alkyl, unsubstituted or substituted Ci-Cβ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Cl-Cβ alkyl)SOi-2(Cθ-Cβ alkyl)-, HC(O)(C₀-Cβ alkyl)-, (Cι-C₆ alkyl)C(O)(Co-Cβ alkyl)-, -N(R10)₂, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0,

-NHSO2RI⁰, and -N(Rl0)SO2Rl0;

Xl and X or X and X3, when located on adjacent carbon atoms, may be joined in a ring;

(where Ra, Xl, χ2 and X are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate)

with a substituted piperazinone salt of formula B

B

(where R , R3, R4, R5 _anα z are as defined above and is H); b) adding a base compound; c) isolating the free base form of a compound of formula I; d) combining the free base form of a compound of formula I with a solution of HCl in a solvent; and e) isolating a salt of the compound of formula I in crystalline form.

20. The process according to Claim 19, wherein the base compound comprises Et3N, DIPEA, n-Bu3N, Imidazole, N-Me- imidazole, Pyridine, 2,6-Lutidine, 2,4,6-Collidine, 2,6-t-Bu2-pyridine, 2,6- t-Bu2-4-Me-pyridine, l,2,2,6,6-Me5-piperidine, or Me4-guanidine.

21. The process according to Claim 20, wherein the base compound is DIPEA.

22. The process according to Claim 19 for synthesizing a salt of the compound of formula IA

IA

comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone; d) combining the free base form with a solution HCl in a solvent; and e) isolating a salt of the compound of formula IA in crystalline form.

23. A process according to Claim 19 for synthesizing a salt of a compound of formula I which comprises the steps of: a) mixing a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A

with a substituted piperazinone salt of formula B

B

(where Rl, R3, R4, R5 and Z are as defined above and R2 is H); b) adding a base compound; c) isolating the free base form of a compound of formula I; d) adding a solution of HCl in a solvent to the free base form of a compound of Formula I in a solvent; and e) isolating a salt of the compound of formula I in crystalline form.

24. The process according to Claim 23, wherein an anti- solvent is added before the salt of the compound of formula I is isolated in step e).

25. The process according to Claim 24, wherein the anti- solvent comprises esters, THF, MTBE, toluene, acetonitrile, DMF, alcohols, or carboxylic acids.

26. The process according to Claim 25, wherein the anti- solvent is EtOAc.

27. The process according to Claim 24, wherein the base compound comprises Et3N, DIPEA, n-Bu3N, Imidazole, N-Me- imidazole, Pyridine, 2,6-Lutidine, 2,4,6-Collidine, 2,6-t-Bu2-pyridine, 2,6- t-Bu2-4-Me-pyridine, l,2,2,6,6-Me5-piperidine, or Me4-guanidine.

28. The process according to Claim 27, wherein the base compound is DIPEA.

29. The process, according to Claim 24, for synthesizing a salt of the compound of formula IA

IA

which comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l- (4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) adding a solution of HCl in a solvent to the free base form in a solvent; e) adding an anti-solvent; and f) isolating a salt of the compound of formula IA in crystalline form.

30. The process according to Claim 23, wherein the solution of HCl in step d) comprises HCl in ethanol.

31. The process according to Claim 24 for synthesizing a salt of the compound of formula IA

IA which comprises the steps of: a) mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride; b) adding diisopropylethylamine; c) isolating the free base form of l-(3-chlorophenyl)-4-[l-

(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone; d) adding a solution of HCl in ethanol to the free base form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone in ethanol; e) adding EtOAc; and f) isolating l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl in crystalline form.

32. Crystal Form I of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylm ethyl] -2-piperazinone *H2θ which is characterized by a solid state x-ray powder diffraction (XRPD) pattern having the following angles, expressed as degree 2Θ: 10.7, 13.1, 14.6, 16.7, 17.5, 18.2, 18.8, 21.0, 21.5, 21.9, 22.4, 22.7, 23.3, 23.8, 25.4, 25.8 and 30.7, which correspond to the following d-spacings: 8.29, 6.76, 6.07, 5.31, 5.07, 4.86, 4.71, 4.23, 4.13, 4.06, 3.96, 3.91, 3.82, 3.73, 3.51, 3.45 and 2.91 angstroms.

33. Crystal Form I of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone • H2O according to Claim 32 which is further characterized by a relatively broad water loss endotherm that normally appears with two peaks at approximately 80 °C and 100 °C, followed by a relatively sharp melting-decomposition endotherm at a peak temperature of 151 °C and an extrapolation onset temperature of 148 °C with an associated heat of 76 Joules/gram.

34. Crystal Form II of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone* HCl which is characterized by a solid state x-ray powder diffraction (XRPD) pattern having the following d-spacings: 21.6, 8.4, 7.3, 6.1, 5.7, 5.6, 5.4, 5.3, 5.0,

4.9, 4.5, 4.2, 3.9, 3.8, 3.7, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.5, 2.4, and 2.3 A.

35. Crystal Form II of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylm ethyl] -2-piperazinone* HCl according to Claim 34 which is further characterized by a single melting- decomposition endotherm with a peak temperature of 211 °C, an extrapolated onset temperature of 203 °C and an associated heat of 106 Joules/gm.

36. A process for preparing a purified crystalline form of the free base of the compound of formula I which comprises the steps of: a) adding a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A to a mixture of a substituted piperazinone salt of formula B and organic base in a solvent; b) adding activated carbon; and c) crystallizing a purified form of the free base of the compound of formula I.

37. The process of Claim 36 which comprises the steps of: a) adding 4-cyanobenzyl-chloromethylimidazole hydrochloride to a mixture of l-(3-chlorophenyl)-2-piperazinone hydrochloride and diisopropylethylamine in ACN; b) adding Darco G-60; and c) crystallizing a purified form of the free base of l-(3-

Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone.

38. A process for preparing a purified, crystalline form of the salt of the compound of formula I which comprises the steps of: a) dissolving the free base form of the salt of the compound of formula I in a solvent mixture to produce a resulting solution; b) heating the resulting solution and adding activated carbon; c) adding an acid solution; and d) crystallizing a purified form of the salt of the compound of formula I.

39. The process of Claim 38 which comprises the steps of: a) dissolving the free base form of l-(3-Chlorophenyl)-4-

[l-(4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone in a mixture of IPA and toluene to produce a solution; b) heating the solution and adding Darco G-60; c) adding a solution of HCl in IPA/toluene; and d) crystallizing a purified form of l-(3-Chlorophenyl)-4-

[l-(4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone* HCl.

40. A process for preparing a purified, crystalline form of the salt of the compound of formula I which comprises the steps of: a) dissolving the free base form of the salt of the compound of formula I in an acid solution to produce a resulting solution; b) adding activated carbon; c) crystallizing a purified form of the salt of the compound of formula I.

41. The process of Claim 40 which comprises the steps of: a) dissolving the free base form of l-(3-Chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone in an HCl solution to produce a resulting solution; b) adding Darco G-60; c) crystallizing a purified form of l-(3-Chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone* HCl.

42. A process for purifying the crystalline form of the salt of the compound of formula I which comprises the steps of: a) dissolving the crystalline form of the salt of the compound of formula I in a solvent mixture to produce a solution; b) adding activated carbon; and c) crystallizing a purified form of the salt of the compound of formula I.

43. The process of Claim 42 which comprises the steps of: a) dissolving l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl in a mixture of water and IPA to produce a solution; b) adding Darco G-60 to the solution; and c) crystallizing a purified form of l-(3-Chlorophenyl)-4- [l-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone*HCl.