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WO2000001691A1 - Procede de production d'inhibiteurs de farnesyl-proteine transferase - Google Patents

Procede de production d'inhibiteurs de farnesyl-proteine transferase Download PDF

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Publication number
WO2000001691A1
WO2000001691A1 PCT/US1999/014726 US9914726W WO0001691A1 WO 2000001691 A1 WO2000001691 A1 WO 2000001691A1 US 9914726 W US9914726 W US 9914726W WO 0001691 A1 WO0001691 A1 WO 0001691A1
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unsubstituted
substituted
formula
alkyl
compound
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Inventor
David Askin
Jennifer A. Cowen
Peter E. Maligres
J. Christopher Mcwilliams
James A. Mccauley
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Merck and Co Inc
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Merck and Co Inc
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Priority to AU50864/99A priority Critical patent/AU5086499A/en
Publication of WO2000001691A1 publication Critical patent/WO2000001691A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • 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-r ⁇ s, Ki-ras and N-r ⁇ s, and the overexpression of Ras has been observed in approximately 30% of all human cancer tissues. (Lerner et al., S.L. Graham, Exp. Opin.
  • the present invention is directed to the improved synthesis of compounds of formula I, which may be useful as farnesyl-protein transferase inhibitors:
  • 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
  • FIG. 4 DSC Curve (closed cup) for Form II of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl] -2-piperazinone • HC
  • the present invention is directed to the synthesis of compounds as illustrated by formula I:
  • 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-C ⁇ 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 O ⁇ - 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-C ⁇ 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
  • Ci-C ⁇ alkyl unsubstituted or substituted Ci-C ⁇ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR1 , -SO2R10, (Ci-C ⁇ alkyl)SOi-2(Co-C6 alkyl)-, HC(O)(C ⁇ -C 6 alkyl)-, (Ci-C ⁇ alkyl)C(O)(Co-C6 alkyl)-, -N(R10)2, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2R 10 , and -N(RlO)SO2RlO;
  • Xl and X2 or X2 and X3, when located on adjacent carbon atoms, may be joined in a ring;
  • 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
  • IA comprises the step of: mixing 4-cyanobenzyl-chloromethylimidazole hydrochloride with l-(3-chlorophenyl)-2-piperazinone hydrochloride in the presence of diisopropylethylamine .
  • Ra is selected from a) H, b) CN, c) -C(0)Rb, d) -C(O)N(Rb) , e) unsubstituted or substituted Ci-C ⁇ 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-C ⁇ 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-C ⁇ 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-C ⁇ alkynyl; i) CF3, and j) OCF 3 ;
  • 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-C ⁇ alkyl)SOi-2(Co-C6 alkyl)-, HC(O)(C()-C6 alkyl)-, (Cl-C ⁇ alkyl)C(O)(Co-C6 alkyl)-, -N(RlO)2, -NHR10, -NHC(O)Rl0, -N(Rl0)C(O)Rl0, -NHSO2RI 0 , and -N(RlO)SO2R
  • Xl and X2 or X2 and X3, when located on adjacent carbon atoms, may be joined in a ring;
  • R a , ⁇ l, ⁇ 2 and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate
  • 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 C ⁇ -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 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 O ⁇ - Cg alkoxy, h) Cl-C ⁇ 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-C ⁇ alkyl, unsubstituted or substituted Ci-C ⁇ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Ci-C ⁇ alkyl)SOi-2(Co-C ⁇ alkyl)-, HC(O)(Co-C ⁇ alkyl)-, (Ci-C ⁇ alkyl)C(O)(Co-C ⁇ alkyl)-,
  • Xl and ⁇ 2 or X2 and X3, when located on adjacent carbon atoms, may be joined in a ring;
  • R a , Xl, ⁇ 2 and X are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate
  • 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.
  • 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.
  • Ra is selected from a) H, b) CN, c) -C(0)Rb d) -C(0)N(Rb) 2 , e) unsubstituted or substituted Cl-C ⁇ 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-C ⁇ alkyl, d) unsubstituted or substituted Cl-C ⁇ 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-C ⁇ 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 Cj- C ⁇ alkoxy, h) Cl-C ⁇ alkynyl; i) CF3, and j) OCF3;
  • RlO is independently selected from a) unsubstituted or substituted Cl-C ⁇ 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-C ⁇ alkyl, unsubstituted or substituted Ci-C ⁇ alkoxy, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted aryloxy, unsubstituted or substituted heteroaryl, CF3, OCF3, -SOR10, -SO2RIO, (Ci-C ⁇ alkyl)SOi-2(Co-C ⁇ alkyl)-, HC(O)(Co-C ⁇ alkyl)-, (Ci-Cg alkyl)C(O)(C 0 -Cg alkyl)-,
  • Xl and X2 or X and X3, when located on adjacent carbon atoms, may be joined in a ring;
  • R a , ⁇ l, ⁇ and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate
  • 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.
  • 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;
  • Rl is selected from a) H, b) unsubstituted or substituted Cl-C ⁇ 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 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- C ⁇ alkoxy, h) Cl-C ⁇ alkynyl; i) CF3, and j) OCF3;
  • RlO is independently selected from a) unsubstituted or substituted Cl-C ⁇ alkyl, b) unsubstituted or substituted aryl, or c) unsubstituted or substituted aralkyl;
  • Xl, X2 and X are independently selected from
  • Xl and X2 or X2 and X3, when located on adjacent carbon atoms, may be joined in a ring;
  • Ra, ⁇ l, ⁇ 2 and X3 are as defined above and Z is independently selected from a halide, a sulfate, a sulfonate or a phosphate
  • Rl, R3, R 5 R5 and Z are as defined above and R2 is H
  • 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).
  • a further embodiment of the instant invention is the process hereinabove where the solution of HCl in step d) comprises HCl in ethanol.
  • 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.
  • 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-
  • 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.
  • 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.
  • 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.
  • 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-
  • 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.
  • 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.
  • 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.
  • Hydrogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • halide means chloride, bromide, iodide and fluoride.
  • 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.
  • 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.
  • a substituted or unsubstituted alkyl or aryl sulfonate such as methanesulfonate, ethanesulfonate, propanesulfonate, chloromethanesulfonate, trichloromethanesulfonate,
  • 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.
  • a substituted or unsubstituted alkyl or aryl phosphate such as methylphosphate, ethylphosphate, propylphosphate , chloromethylphosphate , trichlorom ethyl phosphate , trifluoromethylphosphate, trifluoroethylphosphate, phenylphosphate, tolylphosphate, nitrophenylphosphate, chloropheny
  • 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.
  • monocyclic and bicyclic aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • 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.
  • 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, piperidy
  • aralkyl is intended to mean an aryl moiety, as defined above, attached through a Ci-C ⁇ alkyl linker, where alkyl is defined above. Examples of aralkyls inlcude, but are not limited to, benzyl, naphthylmethyl and phenylpropyl.
  • 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- C ⁇ 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, NO 2 , NH 2 , oxo, -OH, -O(Ci- C 6 alkyl), S(O) 0-2 , (Cl- C 6 alkyl)S(O) 0 -2-, (Cl- C 6 alkyl)S(O)o-2(Ci- C 6 alkyl)-, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)NH, (Cl- C 6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl- C 6 alkyl)C(O)-, -O(C ⁇ -C 6 alkyl)CF 3 , (Cl- C 6 alky
  • substituted aryl 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-C ⁇ alkyl)2, NO2, CN, N3, C1-C20 alkyl, Cl- C 6 alkoxy, -OH, -O(Ci-C 6 alkyl), S(O) 0 .
  • Xl and X3 are independently selected from H, halo, unsubstituted or substituted Cl-C ⁇ alkoxy, unsubstituted or substituted Cl-C ⁇ alkyl, NO2, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, (Cl-C ⁇ alkyl)SOi-2(Co-C ⁇ alkyl)- or (Cl-C ⁇ alkyl)C(O)(Co-C ⁇ alkyl)-.
  • Xl and X3 are independently selected from H, halo, unsubstituted or substituted Cl-C ⁇ alkoxy, unsubstituted or substituted Cl-C ⁇ alkyl. Most preferably, Xl and X3 are hydrogen.
  • X2 is selected from H, halo, unsubstituted or substituted Ci-C ⁇ alkyl, OH, CN, NO2, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, CF3, OCF3, (Ci-C ⁇ alkyl)SOi-2(Co-C ⁇ alkyl)- or (Cl-C ⁇ alkyl)C(O)(Co-C ⁇ alkyl)-. More preferably, X2 is selected from H, halo, unsubstituted or substituted Cl-C ⁇ alkyl, CN, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl. Still more preferably, X is CN, halo, or unsubstituted or substituted Cl-C ⁇ alkyl.
  • X2 is p-CN.
  • R a is selected from H, unsubstituted or substituted Cl-C ⁇ alkyl, or unsubstituted or substituted aryl. Most preferably, Ra is H.
  • Z is selected from halides, sulfonates and phosphates. More preferably, Z is a halide. Most preferably, Z is Cl.
  • Rl is selected from an unsubstituted or substituted aryl. More preferably Rl is aryl substituted with F, Cl, Br, CF3, NO2, Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, aryl and aralkyl.
  • Rl is 3-chlorophenyl.
  • R3, R4 and R5 of formula I are independently selected from H, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted Ci- C ⁇ alkyl and Cl-C ⁇ aikynyl. More preferably, R3, R4 and R5 are independently selected from H or unsubstituted or substituted Cl-C ⁇ alkyl. Most preferably, R3, R4 and R5 are hydrogen.
  • Abbreviations used throughout the specification include:
  • 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.
  • R is independently selected from unsubstituted or substituted Ci- C ⁇ 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- C ⁇ alkyl or phenyl
  • Al is selected from halo, OH or unsubstituted or substituted Ci-C ⁇ 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;
  • 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.
  • 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.
  • 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
  • Types of base compounds that may be used include, but are not limited to, Et3N, DIPEA, n-Bu3N, Imidazole, N-Me-imidazole,
  • 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.
  • the base compound is DIPEA.
  • 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 first step in the process requires mixing a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A
  • a base compound is then added to produce a free base form of a compound of formula I.
  • 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.
  • the base compound is DIPEA.
  • 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.
  • 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.
  • solvents which may be utilized include the solvents previously described.
  • THF, IPA, n-PrOH, EtOH, EtOAc, toluene, water or a mixture thereof is utilized.
  • 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.
  • 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.
  • the solution is cooled to a temperature between about -10 °C and about 0 °C.
  • 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.
  • the free base form of a compound of formula I is mixed with a solution of HCl in ethanol.
  • 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.
  • the anti-solvent is an ester, which may include, but is not limited to, EtOAc, IP Ac or BuOAc. Most preferably, EtOAc is used.
  • the mixture may be seeded with authentic material.
  • isolation of the salt of a compound of formula I can be done using standard methods in the literature.
  • filtration is used to obtain the salt.
  • 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.
  • a purified crystalline form of the free base of the compound of formula I is prepared.
  • a l-(substituted benzyl)-5-substituted imidazolyl salt of formula A is added to a mixture of a substituted piperazinone salt of formula B, as defined above, and an organic base in a solvent.
  • 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.
  • 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.
  • 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.
  • 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.
  • the free base form of l-(3-Chlorophenyl)-4-[l-(4- cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone is used.
  • 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.
  • 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
  • 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.
  • a solution of HCl in IPA/toluene is used.
  • 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.
  • the purified crystalline form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylm ethyl] -2-piperazinone* HCl is isolated.
  • 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.
  • the free base form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5-imidazolylmethyl]-2- piperazinone and an HCl solution are used.
  • 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.
  • the solution may be heated and aged.
  • 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.
  • 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.
  • a solvent mixture for solving the salt in a solvent mixture, as previously described, to produce a solution.
  • l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)- 5-imidazolylmethyl] -2-piperazinone* HCl is dissolved in the solvent mixture.
  • the solvent mixture comprises a mixture of water and an alcohol.
  • the solvent mixture comprises IPA and water.
  • 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.
  • 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.
  • 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.
  • the solution may be heated and aged.
  • the mixture is cooled to about -10 to about 25 °C, which is followed by recovery of the purified crystals.
  • the purified crystalline form of l-(3-Chlorophenyl)-4-[l-(4-cyanobenzyl)-5- imidazolylmethyl] -2-piperazinone* HCl is recovered.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • the three-way stopcock was connected to a nitrogen inlet and to a house vacuum.
  • 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 *H2 ⁇ 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.
  • Solid state x-ray powder diffraction (XRPD) pattern obtained with CuK ⁇ 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
  • 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.
  • 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 ⁇ m polypropylene filter into a flask which was subsequently placed in a bath at 50 °C.
  • 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.
  • solka floe 828 g, 2.9 L dry volume
  • the solka floe was slurry washed with 86:14 IPA/H 2 O (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/H 2 O (2 x 2 L), which was subsequently filtered through the solka floe.
  • the carbon cake was further washed with 86:14 IPA H 2 O (2 L displacement wash). The filtrate was transferred through a Whatman Polycap 75
  • TF, PTFE/polypropylene 0.45 ⁇ m 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 ⁇ m 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 ⁇ m filter was initiated.
  • 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/H 2 O (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/H 2 O (4 L), which was subsequently filtered through the solka floe.
  • the carbon cake was further washed with 86:14 IPA/H 2 O (a 4 L displacement wash and a 3 L displacement wash).
  • the filtrate was transferred through a Whatman Polycap 75 TF, polypropylene 0.45 ⁇ m 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.
  • 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.

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Abstract

La présente invention concerne la synthèse améliorée de composés de la formule (I) qui peuvent être utiles comme inhibiteurs de farnésyl-protéine transférase. La présente invention concerne également les formes cristallines du sel de monohydrate et de monochlorhydrate de 1-(3-Chlorophényl)-4-[1-(4-cyanobenzyl)-5-imidazolylméthyl]-2-pipérazinone.
PCT/US1999/014726 1998-07-01 1999-06-29 Procede de production d'inhibiteurs de farnesyl-proteine transferase Ceased WO2000001691A1 (fr)

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AU50864/99A AU5086499A (en) 1998-07-01 1999-06-29 Process for making farnesyl-protein transferase inhibitors

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US9136398P 1998-07-01 1998-07-01
US60/091,363 1998-07-01
GB9817175.4 1998-08-06
GBGB9817175.4A GB9817175D0 (en) 1998-08-06 1998-08-06 Process for making farnesyl-protein transferase inhibitors

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US6838467B2 (en) 2000-02-24 2005-01-04 Janssen Pharmaceutica N. V. Dosing regimen
EP2362218A2 (fr) 2004-11-05 2011-08-31 Janssen Pharmaceutica N.V. Methodes de controle de l'efficacite d'inhibiteurs de farnesyltransferase
US8481564B2 (en) 2006-04-20 2013-07-09 Janssen Pharmaceutica, N.V. Inhibitors of c-fms kinase
US8497376B2 (en) 2007-10-17 2013-07-30 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
US8557847B2 (en) 2005-06-10 2013-10-15 Janssen Pharmaceutica, N.V. Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US8859602B2 (en) 2006-04-20 2014-10-14 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9029352B2 (en) 2012-08-07 2015-05-12 Janssen Pharmaceutica Nv Process for the preparation of C-FMS kinase inhibitors
US9303046B2 (en) 2012-08-07 2016-04-05 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives
WO2017031101A1 (fr) 2015-08-17 2017-02-23 Kura Oncology, Inc. Méthodes de traitement de patients cancéreux à l'aide d'inhibiteurs de farnésyltransférases
WO2017184968A1 (fr) 2016-04-22 2017-10-26 Kura Oncology, Inc. Méthodes de sélection de patients atteints de cancer pour le traitement avec des inhibiteurs de farnésyltransférase
US9956215B1 (en) 2017-02-21 2018-05-01 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2018085518A2 (fr) 2016-11-03 2018-05-11 Kura Oncology, Inc. Méthodes de traitement de patients cancéreux par inhibiteurs de farnésyltransférase
WO2018156609A1 (fr) 2017-02-21 2018-08-30 Kura Oncology, Inc. Méthodes de traitement du cancer avec des inhibiteurs de la farnésyltransférase
WO2019113269A1 (fr) 2017-12-08 2019-06-13 Kura Oncology, Inc. Méthodes de traitement de patients cancéreux avec des inhibiteurs de la farnésyltransférase
WO2020092720A2 (fr) 2018-11-01 2020-05-07 Kura Oncology, Inc. Méthodes de traitement du cancer avec des inhibiteurs de la farnésyltransférase
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WO2020180663A1 (fr) 2019-03-01 2020-09-10 Kura Oncology, Inc. Méthodes de traitement du cancer à l'aide d'inhibiteurs de farnésyltransférase
WO2020190604A1 (fr) 2019-03-15 2020-09-24 Kura Oncology, Inc. Méthodes de traitement de patients cancéreux avec des inhibiteurs de la farnésyltransférase
WO2020205387A1 (fr) 2019-04-01 2020-10-08 Kura Oncology, Inc. Méthodes de traitement du cancer à l'aide d'inhibiteurs de la farnésyltransférase
WO2020205486A1 (fr) 2019-03-29 2020-10-08 Kura Oncology, Inc. Procédés de traitement de carcinomes squameux par des inhibiteurs de farnésyltransférase
US10806730B2 (en) 2017-08-07 2020-10-20 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors
WO2020223583A1 (fr) 2019-05-02 2020-11-05 Kura Oncology, Inc. Méthodes de traitement de la leucémie myéloïde aiguë avec des inhibiteurs de la farnésyltransférase
US11291663B2 (en) 2017-08-07 2022-04-05 Kura Oncology, Inc. Methods of treating cancer with farnesyltransferase inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030343A1 (fr) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996030343A1 (fr) * 1995-03-29 1996-10-03 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase

Cited By (50)

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Publication number Priority date Publication date Assignee Title
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US6838467B2 (en) 2000-02-24 2005-01-04 Janssen Pharmaceutica N. V. Dosing regimen
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