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WO2005061485A1 - Procede de fabrication de pyrazoles substitues - Google Patents

Procede de fabrication de pyrazoles substitues Download PDF

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Publication number
WO2005061485A1
WO2005061485A1 PCT/IB2004/004071 IB2004004071W WO2005061485A1 WO 2005061485 A1 WO2005061485 A1 WO 2005061485A1 IB 2004004071 W IB2004004071 W IB 2004004071W WO 2005061485 A1 WO2005061485 A1 WO 2005061485A1
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Prior art keywords
formula
compound
halo
alkyl
alkoxy
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Inventor
Brian P. Chekal
Daniel R. Dukesherer
Michael K. Mao
Win Naing
Shuan R. Selness
John K. Walker
Richard H. Wettach
Gopichand Yalamanchili
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Pharmacia LLC
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Pharmacia LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention is directed to a process for making substituted pyrazoles, including tautomers ofthe substituted pyrazoles, and salts ofthe substituted pyrazoles and tautomers.
  • This invention also is directed to compositions (including methods for making such compositions) comprising compounds that may be used as intermediates in such a process.
  • This invention is additionally directed to pharmaceutical compositions (including methods for making such compositions) comprising substituted pyrazoles, tautomers, 1 and pharmaceutically-acceptable salts prepared by such a process.
  • Mitogen-activated protein kinases is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation.
  • the kinases are activated by a variety of signals, including nutritional and osmotic stress, UV light, growth factors, endotoxin, and inflammatory cytokines.
  • the p38 MAP kinase group is a MAP family of various isoforms, including p38 ⁇ , p38 ⁇ , and p38 ⁇ .
  • kinases are responsible for phosphorylating and activating transcription factors (e.g., ATF2, CHOP, and MEF2C), as well as other kinases (e.g., MAPKAP-2 and MAPKAP-3).
  • the p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress, and pro-inflammatory cytokines, including tumor necrosis factor (“TNF”) and interleukin-1 ("IL-1").
  • TNF tumor necrosis factor
  • IL-1 interleukin-1
  • p38 ⁇ kinase can cause or contribute to the effects of, for example, inflammation generally; arthritis; osteoarthritis; rheumatoid arthritis; neuroinflammation; pain; fever; pulmonary disorders; cardiovascular diseases; cardiomyopathy; stroke; ischemia; reperfusion injury; renal reperfusion injury; brain edema; neurotrauma and brain trauma; neurodegenerative disorders; central nervous system disorders; liver disease and nephritis; gastrointestinal conditions; ulcerative diseases; ophthalmic diseases; ophthalmological conditions; glaucoma; acute injury to the eye tissue and ocular traumas; diabetes; diabetic nephropathy; skin-related conditions; viral and bacterial infections; myalgias due to infection; influenza; endotoxic shock; toxic shock syndrome; autoimmune disease; bone resorption diseases; multiple sclerosis; disorders ofthe female reproductive system; pathological (but non-malignant) conditions, such as hemaginomas, angiofibroma ofthe na
  • TNF, IL-1, and IL-8 affect a wide variety of cells and tissues, and are important inflammatory mediators of a wide variety of conditions.
  • the inhibition of these cytokines by inhibition of the p38 kinase is beneficial in controlling, reducing, and alleviating many of these disease states.
  • TNF is a cytokine produced primarily by activated monocytes and macrophages.
  • TNF can cause or contribute to the effects of inflammation (e.g., rheumatoid arthritis and inflammatory bowel disease), asthma, autoimmune disease, graft rejection, multiple sclerosis, f ⁇ brotic diseases, cancer, fever, psoriasis, cardiovascular diseases (e.g., post-ischemic reperfusion injury and congestive heart failure), pulmonary diseases (e.g., hyperoxic alveolar injury), hemorrhage, coagulation, radiation damage, and acute phase responses like those seen with infections and sepsis and during shock (e.g., septic shock and hemodynamic shock). Chronic release of active TNF can cause cachexia and anorexia. Excessive TNF can be lethal.
  • TNF also has been implicated in infectious diseases. These include, for example, malaria, mycobacterial infection, and meningitis. These also include viral infections, such as
  • herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV),
  • HSV-1 herpes simplex virus type-1
  • HSV-2 herpes simplex virus type-2
  • CMV cytomegalovirus
  • VZV varicella-zoster virus
  • Epstein-Ban * virus human herpesvirus-6 (HHV-6), human hcrpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
  • IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. This cytokine is associated with conditions including inflammation.
  • IL-1 is produced by activated monocytes and macrophages, and is involved in inflammatory responses. IL-1 plays a role in many pathophysiological responses, including rheumatoid arthritis, fever, and reduction of bone resorption.
  • W1PO Int'l Publ. No. WO 00/31063 (PCT Patent Application No. US99/26007 published on June 2, 2000) also reports pyrazoles, compositions containing those pyrazoles, and methods for making pyrazoles.
  • U.S. Patent Application No. 10/254,445 describes a process for making substituted pyrazoles.
  • W1PO Int'l Publ. No. WO 03/026663 PCT Patent Application No. US02/30409 published on April 3, 2003 describes a process for making substituted pyrazoles.
  • No. 60/386,415 describes novel pyrazoles and their use as p38 kinase inhibitors.
  • This invention is directed to a method for making substituted pyrazoles that tend to inhibit p38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity. Briefly, therefore, this invention is directed, in part, to a process for making a substituted pyrazole.
  • the substituted pyrazole corresponds in structure to formula 9:
  • R 3A is halo
  • R 3B , R 3C , R D and R 3E are independently selected from the group consisting of H, halo, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl, wherein: any substitutable carbon of the alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, and cyano;
  • Q is a 6- membered nitrogen-containing heterocycle having at least one carbon atom in its ring; and
  • R is a moiety selected from the group consisting of H, halo, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkyls
  • the process comprises contacting a hydrazorie having the structure of Formula 2:
  • the process comprises treating under de-protecting conditions a protected piperidylpyrazole compound having the structure of Formula 1 , thereby forming an unprotected piperidylpyrazole compound, having the structure of Formula 7:
  • the process comprises contacting an unprotected piperidylpyrazole compound, having the structure of Formula 7, or tautomer or or salt thereof; with a glycolic acid ester having the structure of formula 10:
  • the process comprises contacting an unprotected piperidylpyrazole compound, having the structure of Formula 7, or tautomer or salt thereof; with a acetyl halide compound, having the structure of formula 14:
  • the process comprises treating under de-protection conditions a 2-oxo-2-(4-(3-phenyl-lH-pyrazole-5-yl)piperidin- l -yl)ethyl acetate intermediate compound having the structure of Formula 13, thereby forming the N-(2-hydroxyacetyl)-5-(4-piperidyl)- 3-(phenyl)pyrazole compound having the structure of Formula 9.
  • the process comprises contacting a hydrazone having the structure of formula 2 with an optionally substituted benzoyl halide having the structure of formula 3, thereby forming a protected piperidylpyrazole compound having the structure of formula 1 , wherein the compound having the structure of formula 1 is treated under de- protecting conditions to form a unprotected piperidylpyrazole compound having the structure of formula 7, or tautomer or salt thereof; wherein the compound having the structure of formula 7 is contacted with a glycolic acid ester compound having the structure of formula 10, thereby forming a compound having the structure of formula 9.
  • the process comprises contacting a hydrazone having the structure of formula 2 with an optionally substituted benzoyl halide having the structure of formula 3, thereby forming a protected piperidylpyrazole compound having the structure of formula 1, wherein the compound having the structure of formula 1 is treated under de- protecting conditions to form an unprotected piperidylpyrazole compound having the structure of formula 7, or tautomer or salt thereof; wherein the compound having the structure of formula 7 is contacted with an acctyl halide ester compound having the structure of formula 14, thereby forming a compound having the 2-oxo-2-(4-(3-phenyl-lH-pyrazole-5- yl)pipcridin-l-yl)ethyl acetate intermediate structure of formula 13, wherein the compound having the structure of formula 13 is treated under de-protecting conditions to form a compound having the structure of formula 9.
  • R A is halo
  • R 3B , R C , R 3D and R 3E are independently selected from the group consisting of H, halo, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl, wherein: any substitutable carbon ofthe alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, and cyano; Q is a 6- membered nitrogen-containing heterocycle having at least one carbon atom in its ring; and R 4 is a moiety selected from the group consisting of H, halo, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfony
  • the process comprises contacting a hydrazone having the structure of Formula 2:
  • R B is halo; R >3 J A A i ⁇ s halo; R' is a secondary amino protecting group; and R is an optionally substituted aryl or heteroaryl.
  • Q is selected from the group consisting of pyrimidyl, pyridyl, piperidyl, pyrazyl and piperazyl, in another embodiment Q is pyrimidyl.
  • R 4 is selected from the group consisting of H, alkylthio, cyanocarbocyclyloxy, heterocyclyoxy, carbocyclylamino, dialkylaminoalkoxy and dialkylaminoalkylamino, in another embodiment R 4 is H.
  • Q is selected from the group consisting of pyrimidyl, pyridyl, piperidyl, pyrazyl and piperazyl; and R is selected from the group consisting of H, alkylthio, cyanocarbocyclyloxy, heterocyclyoxy, carbocyclylamino, dialkylaminoalkoxy and dialkylaminoalkylamino.
  • A is pyrimidyl and R 4 is H.
  • R is selected from the group consisting of halo, OH, and a moiety having the structure of Formula 3A:
  • R B is halo.
  • R B is selected from the group consisting of bromo, chloro, fluoro and iodo.
  • R B is chloro.
  • R * , R " , R " , and R are each independently selected from the group consisting of H, halo, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl; and R 3A is halo.
  • R 3A is fluoro
  • R 3B , R 3D , and R 3E are each H
  • R C is chloro.
  • R 3B , R 3D , and R 3E are each H; and R 3A and R 3C are each independently selected from the group consisting of fluoro, chloro, bromo, and iodo. In another embodiment, R 3A is fluoro and R 3C is chloro.
  • R 1 is selected from the group consisting of methyl, tert-butyl, tert-butyloxycarbonyl, benzyl oxymethyl, nitrophenylsulphenyl, toluenesulphonyl, diphenylmethyl, and triphenylmethyl. In another embodiment, R 1 is tert-butyloxycarbonyl.
  • the protected piperidylpyrazole compound corresponds in structure to Formula 4:
  • the process comprises treating under de-protecting conditions a protected piperidylpyrazole compound having the structure of Formula 1, thereby forming an unprotected piperidylpyrazole compound, having the structure of Formula 7:
  • the unprotected piperidylpyrazole compound corresponds in structure to Formula 8:
  • the process comprises contacting an unprotected piperidylpyrazole compound, having the structure of Formula 7,or salt thereof; with a glycolic acid ester having the structure of formula 10:
  • N-(2-hydroxyacetyl)-5-(4-piperidyl)-3-(phenyl)pyrazole compound having the structure of Formula 9, wherein R is selected form the group consisting of methyl, ethyl and butyl. In one embodiment, R is butyl.
  • N-(2-hydroxyacetyl)-5-(4-piperidyl)-3-(phenyl)pyrazole compound corresponds in structure to Formula 11 :
  • the unprotected piperidylpyrazole compound corresponds in structure to Fo ⁇ nula 8, or tautomer or salt thereof; and the glycolic acid ester compound corresponds in structure to formula 12:
  • the process comprises contacting an unprotected piperidylpyrazole compound, having the structure of Formula 7, or salt thereof, with a acetyl halide compound, having the structure of formula 14:
  • X is chloro, fluoro, bromo or iodo. In one embodiment, X is chloro.
  • R D is a C ⁇ -C 6 -alkyl, C 2 - C 6 -alkenyl, C 2 -C 6 -alkynyl, ary or cycloalkyl. In one embodiment, R D is a C ⁇ -C 6 -alkyl. In another embodiment, R D is methyl.
  • the 2-oxo-2-(4-(3-phenyl-lH-pyrazole-5-yl)piperidin l-yl)ethyl acetate intermediate compound corresponds in structure to Formula 16:
  • glycolic acid ester corresponds in structure to Formula 15:
  • the unprotected piperidylpyrazole compound corresponds in structure to Formula 8, or tautomer or salt therof.
  • the process comprises treating under de-protection conditions a 2-oxo-2-(4-(3-phcnyl-lH-pyrazole-5-yl)piperidin-l-yl)ethyl acetate intermediate compound having the structure of Formula 13, thereby forming the N-(2-hydroxyacetyl)-5-(4-piperidyl)- 3-(phenyl)pyrazole compound having the structure of Formula 9.
  • N-(2-hydroxyacetyl)-5-(4-piperidyl)-3-(phenyl)pyrazole compound corresponds in structure to Formula 1 l and the 2-oxo-2-(4-(3-phenyl-lH-pyrazole- 5-yl)piperidin-l-yl)ethyl acetate intermediate compound corresponds in structure to Formula 1 l and the 2-oxo-2-(4-(3-phenyl-lH-pyrazole- 5-yl)piperidin-l-yl)ethyl acetate intermediate compound corresponds in structure to Formula
  • the process comprises contacting a hydrazone having the structure of formula 2 with an optionally substituted benzoyl halide having the structure of formula 3, thereby forming a protected piperidylpyrazole compound having the structure of formula 1, wherein the compound having the structure of formula 1 is treated under de- protecting conditions to form a unprotected piperidylpyrazole compound having the structure of formula 7, or tautomer or salt thereof; wherein the compound having the structure of formula 7 is contacted with a glycolic acid ester compound having the structure of formula 10, thereby forming a compound having the structure of formula 9.
  • the N-(2-hydroxyacetyl)-5-(4-piperidyl)-3(phenyl)pyrazole compound correspond in structure to formula 1 1
  • the hydrazone compound correspond in structure to formula 5
  • the optionally substituted benzoyl halide correspond in structure to formula 6
  • the protected piperidylpyrazole compound correspond in structure to formula 4
  • the unprotected piperidylpyrazole compound correspond in structure to formula 8, or tautomer or salt thereof
  • the glycolic acid ester compound correspond in structure to formula 12.
  • the process comprises contacting a hydrazone having the structure of formula 2 with an optionally substituted benzoyl halide having the structure of formula 3, thereby forming a protected piperidylpyrazole compound having the structure of formula 1 , wherein the compound having the structure of formula 1 is treated under de- protecting conditions to form an unprotected piperidylpyrazole compound having the structure of formula 7, or tautomer or salt thereof; wherein the compound having the structure of formula 7 is contacted with an acetyl halide ester compound having the structure of formula 14, thereby forming a compound having the 2-oxo-2-(4-(3-phenyl-lH-pyrazole-5- yl)piperidin-l-yl)ethyl acetate intermediate structure of formula 13, wherein the compound having the structure of formula 13 is treated under de-protecting conditions to form a compound having the structure of formula 9.
  • the N-(2-hydroxyacetyl)-5-(4-piperidyl)-3(phenyl)pyrazole compound correspond in structure to formula 1 1
  • the hydrazone compound correspond in structure to formula 5
  • the optionally substituted benzoyl halide correspond in structure to formula 6
  • the protected piperidylpyrazole compound correspond in structure to formula 4
  • the unprotected piperidylpyrazole compound correspond in structure to formula 8,or tautomer or salt thereof
  • the acetyl halide compound correspond in structure to formula 15
  • the 2- oxo-2-(4-(3-phenyl-lH-pyrazole-5-yl)piperidin-l -yl)ethyl acetate intermediate corresponds in structure to formula 16.
  • the compounds that can be prepared by the method of this invention include compounds corresponding in structure to Formula 9:
  • R 3A is halo; R 3B , R 3D and R 3E are hydrogen; and R 3C is independently selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl. Any carbon ofthe alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and cyano.
  • the compound corresponds in structure to Formula 9a:
  • R 3A is halo; R C , R D and R 3E are hydrogen; and R 3B is independently selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl. Any carbon ofthe alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and cyano.
  • the compound corresponds in structure to Formula 9b:
  • R 3A is halo; R 3B , R C and R 3E are hydrogen; and R 3D is independently selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl. Any carbon ofthe alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and cyano.
  • the compound corresponds in structure to Formula 9c:
  • R 3A is halo; R 3B , R 3C and R 3D are hydrogen; and R 3E is independently selected from the group consisting of halogen, hydroxy, cyano, amino, alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, and alkoxyalkyl. Any carbon ofthe alkyl, aminoalkyl, monoalkylamino, dialkylamino, alkoxy, or alkoxyalkyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and cyano.
  • the compound corresponds in structure to Formula 9d:
  • R 3A is halo; R B , R C , R 3D and R 3E are hydrogen. In some such embodiments, the compound corresponds in structure to Formula 9e:
  • R 3B , R 3D , and R E are each H; and R 3A and R 3C are each independently selected from the group consisting of fluoro, chloro, bromo, and iodo.
  • R is a moiety selected from the group consisting of H, halo, cyano, hydroxy, thiol, carboxy, nitro, alkyl, carboxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkenyl, carbocyclyloxy, carbocyclylalkoxy, carbocyclyloxyalkyl, carbocyclylthio, carbocyclylsulfinyl, carbocyclylsulfonyl, heterocyclylthio, heterocyclylsulfinyl, heterocyclylsulfonyl, carbocyclylalkoxy, carbocyclylheterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkoxy, amino, aminoalkyl, alkylamino
  • R 4 is hydroxy, alkylthio, cyanocarbocyclyloxy, heterocyclyloxy, carbocyclylamino, dialkylaminoalkoxy, or dialkylaminoalkylamino. [0047] In some embodiments, R 4 is hydrogen.
  • R is halogen, for example chloro.
  • the compound 2 can be charged to a clean dry reactor (which optionally has been purged with nitrogen), along with optionally one or more solvents, at least one base, and compound 3.
  • the amount of solvent can be from about 3:1 to about 5:1 (ml solven grams compound 2 solids), and alternatively about 4:1 (ml solvent:grams compound 2 solids).
  • the solvent can be, for example, ethereal or aromatic, for example, THF or toluene.
  • the amount of base can be from about 1 to about 2 mole equivalents, and alternatively about 1.69 mole equivalents (based on moles of compound 2).
  • the base can be, for example, lithium hexamethyldisilazide, lithium siisopropylamide, potassium tert- butoxide, 4-dimethylaminopyridine or triethylamine, with triethylamine being particularly preferred. Where there are two bases, it can be that one base is 4-dimethylaminopyridine and the other base is triethylamine.
  • an activator of compound 3 can be included in the reaction mixture as well.
  • about 0.1 mole equivalents of 4- dimethylaminopyridine (based on moles of compound 2) may be included, particularly where compound 3 is, for example, 2-fluoro-4-chlorobenzoylchloride.
  • Compound 3 (typically at room temperature) can be, for example, slowly charged to the reactor after compound 2, solvent, base, and any activator have been charged below room temperature. Typically, this addition takes place over a period of at least about 30 minutes, and alternatively at least about 60 minutes.
  • the amount of the compound 3 can be from about 1 to about 2 mole equivalents, and alternatively about 1.2 mole equivalents (based on moles of compound 3).
  • the reaction mixture can be heated.
  • the mixture can be heated to a temperature from about 40°C to about 70°C, alternatively to about 50°C.
  • the heating then can be continued until at least about 98% of compound 2 has been consumed. Typically, the heating can be continued for greater than 30 minutes.
  • the resulting product mixture can be allowed to cool to room temperature.
  • the compound 1 product mixture can be retained for subsequent de-protection.
  • the compound 1 product can be filtered to remove precipitation that may have occurred. Following filtration, the precipitate can be washed, for example, with a solvent. In one embodiment it can be washed with tetrahydrofuran.
  • Both the filtrate and the wash can be returned to a reactor for subsequent de-protection.
  • B-lb Isolation of the Protected Piperidylpyrazole
  • the compound 1 product can be isolated from the product mixture. Such isolation can improve product yield, purity, and reproducibility downstream.
  • the compound 1 product can be isolated as a solid by precipitation from the solvent, for example by crystallization.
  • B-2a Deprotection ofthe Protected Piperidylpyrazole
  • the compound 1 formation reaction product mixture is used directly in the piperidylpyrazole de-protection reaction.
  • compound 1 is isolated as, for example, described in Section B-lb.
  • compound lean be mixed with at least one solvent before the de-protection.
  • the solvent can be an ether, a carboxylic acid ester, an alcohol, a ketone or an aromatc solvent.
  • water, THF, ethyl acetate, ethanol, butanol, isopropyl alcohol, acetone, or toluene can be used.
  • the solvent can be THF or toluene.
  • the amount of solvent can be at least about 1 :1 (ml solvent:grams compound 1), and alternatively from about 1 :1 to about 10:1 (ml solvent:grams compound 1). In some embodiments, for example, the amount of solvent is about 2:1 (ml solven grams compound 1).
  • compound 1 is de-protected using an acid.
  • a solvent can be added to the compound 1 solution.
  • the solvent can be tetrahydrofuran. From about 2 to about 12 mole equivalents, and alternatively about
  • the acid can comprise a mineral acid, such as hydrochloric acid, sulphuric acid, nitric acid or phosphoric acid. If the acid comprises HC1, the solvent can be dioxane or toluene.
  • the de-protection reaction mixture can be maintained at a temperature that is less than 65°C. In some such embodiments, the reaction mixture can be maintained at a temperature of less than about 30°C, and alternatiely at room temperature, for at least about 1 hour. In some other embodiments, the reaction mixture can be maintained at a temperature of from about 25 to about 100°C, alternatively from about 65 °C to about 75°C, and alternatively about 50°C, for from about 10 minutes to about 2 hour, alternatively about
  • the mixture can be cooled to from about 20 °C to about 35°C, and alternatively about 25°C.
  • the resulting mixture can be agitated (e.g., stirred) for from about 1 hour to about 5 hours, and alternatively about 3 hours.
  • the precipitate can be collected using, for example, filtration (with, for example, a 4 micron filter cloth) or centrifugation.
  • the resulting cake can be washed.
  • the resulting cake can be washed with a solvent, for example with tetrahydofuran.
  • the cake can be dried under a stream of nitrogen.
  • compound 7 can be isolated as an aqueous solution for subsequent neutralization by avoiding the filtration step.
  • the de-protected piperidylpyrazole mixture can be cooled to about 20°C to about 30°C, alternatively to about
  • water and solvent can be added, for example toluene, the amount of solvent can be from about 1 :1 (ml water: solvent) to about 1 :5 (ml water: solvent), and alternatively about 1 :2 (ml water: solvent).
  • the resulting solution can be agitated (e.g., stirred) from about 10 minutes to about 1 hour, and alternatively about 30 minutes, and the layers can be allowed to separate upon standing.
  • the organics are then can be removed from the aqueous layer containing the product.
  • the aqueous layer can be washed with a solvent, for example toluene. B-3.
  • compound 7 is neutralized.
  • Compound 7 can be charged with a solvent, the amount of solvent can be from about 1 :1 to about 10:1 (ml solvent: grams compound 7), alternatively about 3:1 (ml solvent: grams compound 7) to form a solution, for example, the solvent can be methanol.
  • Water can be added, for example, in the amount of about 2:1 (ml water: grams compound 7 solution) to the solution to result in an exotherm to about 33°C.
  • a hydroxide base such as NaOH or KOH, from about 1 to about 5 mole equivalents, and alternatively about 2.4 mole equivalents (based on moles of compound 7) can be added.
  • the neutralization can be controlled by pH measurement and additional NaOH can be added to adjust the pH to about 10.5 to about 11.5 if desired.
  • Solids will slowly start to form out ofthe solution.
  • the solution can be heated and maintained at a range from about 30°C to about 60°C, and alternatively about 50°C, for a period of time from about 30 minutes to about 2 hours, alternatively about 30 minutes.
  • the solution can be cooled to below room temperature and the solids can be separated (for example, by filtration or centrifugation) and washed and subsequently dried. B-4.
  • Compound 10 can be a C ⁇ -C 6 -alkyl glycolate (i.e., R »C i • n the above reaction is C ⁇ - C 6 -alkyl), alternatively methyl glycolate, ethyl glycolate or butyl glycolate, and alternatively butyl glycolate.
  • the preference for butyl glycolate stems from, for example, its low cost and the fact that it has a boiling point that is above the preferred temperature for the reaction.
  • the neutralized compound 7 can be charged to a reactor with about 2.0 to about 8.0 mole equivalents, alternatively about 5 mole equivalents of compound 10 in the presence of at least one solvent. Where a solvent is used, it can comprises a polar, aprotic solvent and/or alcohol.
  • the neutralized compound 7 can be reacted with compound 10 in the presence of at least one base.
  • bases for example, lithium hexamethyldisilazide, lithium diisopropylamide, 4-dimethylaminopyridine, triethylamine, sodium ethoxide, sodium methoxide, potassium 2-propoxide, or potassium tert-butoxide can be used.
  • the base can be an alkoxide base such as sodium ethoxide, sodium methoxide, potassium 2-propoxide, or potassium tert-butoxide. Alternatively the base is sodium ethoxide.
  • the base can be added to the solution.
  • the mixture can be heated to about 50°C to about 100°C, alternatively to about 75°C to about 95°C, alternatively to about 85°C to about 90°C for a period of time from about 2 hours to about 10 hours, altematively about 4 hours.
  • the solution can be cooled to about 5°C and the crude product and the corresponding sodium salt can be isolated.
  • the crude solid can be resuspended in ethanol and heated to about 40°C.
  • An acid for example, HCL in an amount from about 1 mole equivalent to about 3 mole equivalents, alternatively about 2.4 mole equivalents, can be added over the time period of about 10 minutes. Water can be added at such a rate to maintain the pot temperature of about 40°C. After water is added, a solution can be obtained.
  • the solvent may be, for example, water, tetrahydrofuran, ethyl acetate, ethanol, butanol, isopropyl alcohol, acetone, or toluene, or any combination thereof, alternatively the solvent is tetrahydrofuran.
  • Compound 7 can be slurried in and subsequently cooled to about room temperature. An amount of at least one base can be added to the mixture.
  • the base can be, for example, lithium hexamethyldisilazide, lithium diisopropylamide, 4-dimethylaminopyridine, triethylamine, sodium ethoxide, sodium methoxide, potassium 2-propoxide, or potassium tert-butoxide, alternatively the base is triethylamine.
  • compound 14 can be added dropwise to the mixture.
  • Compound 14 can be added for the period from about 30 minutes to about 3 hours, alternatively about 1 hour.
  • the mixture can be heated to a temperature in the range of about 30°C to about 70°C, alternatively about 50°C for a time period from about 30 minutes to about 5 hours, alternatively about 30 minutes, and then can be cooled and immediately filtered free ofthe precipitate.
  • the filtrate and the washes can be returned to the reactor and treated with methanol.
  • the mixture can be cooled below room temperature and an amount from about 1 to about 3 mole equivalents of a hydroxide base, such as NaOH or KOH, can be added.
  • a hydroxide base such as NaOH or KOH
  • the present invention can be used to make compounds of Formula 9 having one or more asymmetric carbons as well as achiral compounds. It is known to those skilled in the art that those pyrazoles ofthe present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof. When compounds are made having one or more asymmetric carbons, such compounds, if desired, can be optically resolved using techniques such as crystallization or by chiral chromatographic methods. E. Salts ofthe Compounds Made in this Invention
  • the compounds made in the process of this invention may be used in the form of salts derived from inorganic or organic acids.
  • a salt ofthe compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution ofthe compound.
  • a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context)
  • the salt preferably is pharmaceutically- acceptable.
  • Pharmaceutically-acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.
  • Pharmaceutically-acceptable acid addition salts ofthe compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxyic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohe
  • Pharmaceutically-acceptable base addition salts ofthe compounds of this invention include, for example, metallic salts and organic salts.
  • Preferred metallic salts include alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Preferred organic salts may be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quatemized with agents such as lower alkyl (C ⁇ -C 6 ) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl (C ⁇ -C 6 ) halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates e.g., dimethyl
  • Particularly preferred salts ofthe compounds of this invention include hydrochloric acid (HC1) salts, trifluoroacetate (CF 3 COOH or "TFA”) salts, mesylate salts, and tosylate salts.
  • HC1 hydrochloric acid
  • TFA trifluoroacetate
  • mesylate salts mesylate salts
  • tosylate salts tosylate salts.
  • alkyl alone or in combination with another term(s) means a straight-or branched-chain saturated hydrocarbyl substituent (i.e., a substituent containing only carbon and hydrogen) typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 12 carbon atoms, even more typically from 1 to about 8 carbon atoms, and still even more typically from 1 to about 6 carbon atoms.
  • substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and octyl.
  • alkenyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 12 carbon atoms, even more typically from 2 to about 8 carbon atoms, and still even more typically from 2 to about 6 carbon atoms.
  • substituents include ethenyl (vinyl); 2-propenyl;
  • alkynyl (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 12 carbon atoms, even more typically from 2 to about 8 carbon atoms, and still even more typically from 2 to about 6 carbon atoms.
  • substituents include ethynyl, 1-propynyl,
  • carbocyclyl (alone or in combination with another term(s)) means a saturated cyclic (i.e., “cycloalkyl"), partially saturated cyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., "aryl”) hydrocarbyl substituent containing from 3 to 14 carbon ring atoms ("ring atoms” are the atoms bound together to form the ring or rings of a cyclic substituent).
  • a carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms.
  • carbocyclyls examples include cyclopropanyl, cyclob ⁇ tanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.
  • a carbocyclyl altematively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as "tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as
  • phenalenyl fluoreneyl, decalinyl, and norpinanyl.
  • cycloalkyl (alone or in combination with another term(s)) means a saturated carbocyclyl substituent containing from 3 to about 14 carbon ring atoms, more typically from 3 to about 12 carbon ring atoms, and even more typically from 3 to about 8 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains from
  • single-ring cycloalkyls examples include cyclopropyl (or
  • cyclopropanyl cyclobutyl (or “cyclobutanyl”), cyclopentyl (or “cyclopentanyl”), and cyclohexyl (or “cyclohexanyl”).
  • a cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, for example, decalinyl or norpinanyl.
  • cycloalkylalkyl (alone or in combination with another term(s)) means alkyl substituted with cycloalkyl. Examples of such substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
  • cycloalkenyl (alone or in combination with another term(s)) means a partially unsaturated carbocyclyl substituent. Examples of such substituents include cyclobutenyl, cyclopentenyl, and cyclohexenyl.
  • aryl (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.
  • the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix
  • C x -C y - wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C ⁇ -C 6 -alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C 3 -C 6 -cycloalkyl means a saturated carbocyclyl containing from 3 to 6 carbon ring atoms.
  • arylalkyl (alone or in combination with another term(s)) means alkyl substituted with aryl.
  • benzyl (alone or in combination with another term(s)) means a methyl radical substituted with phenyl, i.e., the following structure:
  • hydrogen (alone or in combination with another term(s)) means a hydrogen radical, and may be depicted as -H.
  • hydroxy or "hydroxyl” (alone or in combination with another term(s)) means -OH.
  • hydroxyalkyl (alone or in combination with another term(s)) means alkyl substituted with one more hydroxy.
  • nitro (alone or in combination with another term(s)) means -NO 2 .
  • cyano (alone or in combination with another term(s)) means -CN, which also may be depicted: N
  • amino (alone or in combination with another term(s)) means -NH .
  • disubstituted amino (alone or in combination with another term(s)) means an amino substituent wherein both ofthe hydrogen atoms are replaced by non-hydrogen substituents, which may be identical or different.
  • halogen means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as -CI), bromine radical (which may be depicted as -Br), or iodine radical (which may be depicted as -I).
  • a fluorine radical or chlorine radical is preferred, with a fluorine radical often being particularly preferred.
  • halo indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals.
  • haloalkyl means an alkyl substituent wherein at least one hydrogen radical is replaced with a halogen radical. Where there are more than one hydrogens replaced with halogens, the halogens may be the identical or different.
  • haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl.
  • haloalkoxy means an alkoxy substituent wherein at least one hydrogen radical is replaced by a halogen radical.
  • haloalkoxy substituents include chloromethoxy, 1 -bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 1,1,1 -trifluoroethoxy. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
  • carbonyl (alone or in combination with another term(s)) means -C(O)-, which also may be depicted as:
  • aminocarbonyl (alone or in combination with another term(s)) means -C(O)-NH 2 , which also may be depicted as:
  • oxy (alone or in combination with another term(s)) means an ether substituent, and may be depicted as -O-.
  • alkoxy (alone or in combination with another term(s)) means an alkylether substituent, i.e., -O-alkyl. Examples of such a substituent include methoxy
  • alkylthio (alone or in combination with another term(s)) means
  • methylthio is -S-CH 3 .
  • alkylthio substituents include ethylthio, propylthio, butylthio, and hexylthio.
  • alkylcarbonyl or “alkanoyl” (alone or in combination with another term(s)) means -C(O)-alkyl.
  • alkylcarbonyl or “alkanoyl” (alone or in combination with another term(s)) means -C(O)-alkyl.
  • ethyl carbonyl may be depicted as:
  • alkylcarbonyl substituents examples include methyl carbonyl, propyl carbonyl, butyl carbonyl, pentyl carbonyl, and hexylcarbonyl.
  • aminoalkylcarbonyl (alone or in combination with another term(s)) means -C(O)-alkyl-NH 2 .
  • aminomethylcarbonyl may be depicted as:
  • alkoxycarbonyl (alone or in combination with another term(s)) means -C(O)-O-alkyl.
  • alkoxycarbonyl substituents include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl.
  • carbocyclylcarbonyl (alone or in combination with another term(s)) means -C(O)-carbocyclyl.
  • phenyl carbonyl may be depicted as:
  • heterocyclylcarbonyl (alone or in combination with another term(s)) means -C(O)-heterocyclyl.
  • heterocyclylalkylcarbonyl (alone or in combination with another term(s)) means -C(O)-alkyl-heterocyclyl.
  • carbocyclyloxycarbonyl (alone or in combination with another term(s)) means -C(O)-O-carbocyclyl.
  • carbocyclylalkoxycarbonyl (alone or in combination with another term(s)) means -C(O)-O-alkyl-carbocyclyl.
  • thio refers to the presence of a sulfur atom with a valence of two.
  • alkylthio means a moiety containing an alkyl radical which is attached to an sulfer atom, such as a methylthio radical. The alkylthio moiety is bonded to the molecule of interest at the sulfer atom ofthe alkylthio.
  • thioalkyl means a moity containing a HS-alkyl radical, such as a thiomethyl radical. The thioalkyl is bonded to the molecule of interest at the alkyl moiety ofthe thioalkyl
  • sulfonyl (alone or in combination with another term(s)) means -S(O) 2 -, which also may be depicted as: V VY
  • alkyl-sulfonyl-alkyl means alkyl-S(O) 2 -alkyl.
  • examples of typically preferred alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
  • alkylsulfinyl or “sulfoxido” (alone or in combination with another term(s)) means -S(O)-.
  • alkylsulfmylalkyl or “alkylsulfoxidoalkyl” means alkyl-S(O)-alkyl.
  • alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.
  • heterocyclyl (alone or in combination with another term(s)) means a saturated (i.e., “heterocycloalkyl"), partially saturated (i.e., “heterocycloalkenyl”), or completely unsaturated (i.e., "heteroaryl”) ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • heteroatom i.e., oxygen, nitrogen, or sulfur
  • a heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms.
  • single-ring heterocyclyls include furanyl, dihydrofurnayl, tetradydrofumayl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, ox
  • oxazinyl including 1 ,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1 ,4-oxazinyl
  • isoxazinyl including o-isoxazinyl or p-isoxazinyl
  • oxazolidinyl isoxazolidinyl
  • oxathiazinyl including
  • a heterocyclyl alternatively may be 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen, or sulfur).
  • substituents include, for example, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.
  • fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as “isobenzazolyl” or “pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”), benzazinyl (including quinolinyl (also known as “1 -benzazinyl”) or isoquinolinyl (also known as "2-benzazinyl”)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as "1,2-benzodiazinyl”) or quinazolinyl
  • isochromanyl isochromanyl
  • benzothiopyranyl also known as “thiochromanyl”
  • benzoxazolyl isochromanyl
  • indoxazinyl also known as “benzisoxazolyl”
  • anthranilyl benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as “coumaronyl"), isobenzofuranyl, benzothienyl
  • isobenzothiofuranyl benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1 -benzoxazinyl, or
  • 2-fused'ring heterocyclyl (alone or in combination with another term(s)) means a saturated, partially saturated, or aryl heterocyclyl containing 2 fused rings.
  • 2-fused-ring heterocyclyls include indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazoly
  • heteroaryl (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents include 6-mcmbered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as
  • tosyl (alone or in combination with another term(s)) means a CH 3 -
  • heterocyclylalkyl (alone or in combination with another term(s)) means alkyl substituted with a heterocyclyl.
  • heterocycloalkyl (alone or in combination with another term(s)) means a fully saturated heterocyclyl.
  • a carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, cyano, nitro, thiol, carboxy, amino, aminocarbonyl, C ⁇ -C 6 -alkyl, amino-C]-C 6 -alkyl, keto, carboxy-C ⁇ -C 6 -alkyl, C]-C 6 -alkylamino, C ⁇ -C 6 -alkylamino-C ⁇ -C 6 -alkyl, amino-C ⁇ -C -alkylamino, C]-C 6 -alkylaminocarbonyl, aminocarbonyl-C ⁇ -C -alkyl, C]-C 6 -alkoxycarbonyl-C]-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C]-C 6 -alkylthio-C
  • a carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as "alkanoyl"), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl.
  • substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as "alkanoyl”), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl
  • a carbocyclyl or heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, d-C 6 -alkyl, C ⁇ -C 6 -alkoxy, d-C 6 -alkoxy-C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkylcarbonyl, aryl, aryl-C ⁇ -C 6 -alkyl, aryl-C ⁇ -C 6 -alkoxy, ary]-C ⁇ -C 6 -alkoxy-C]-C 6 -alkyl, aryl-C ⁇ -C 6 -alkoxycarbonyl, cycloalkyl, cycloalkyl-C ⁇ -C 6 -alkyl, cycloalkyl-C ⁇ -C -alkoxy, cycloalkyl-C ⁇ -C -alkoxy-C]-C 6 -C 6 -alkyl,
  • alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent(s) may further be substituted with one or more halogen.
  • the aryls or cycloalkyls typically have from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms.
  • a carbocyclyl or heterocyclyl optionally is substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkoxy, amino, alkylthio, keto, and alkylamino.
  • a carbocyclyl or heterocyclyl optionally is substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, C t -C 6 -alkyl, C]-C 6 -alkoxy, amino, C ⁇ -C 6 -alkylthio, keto, and C ⁇ -C 6 -alkylamino.
  • a carbocyclyl or heterocyclyl optionally is substituted with up to three substituents independently selected from the group consisting of halogen, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, and amino.
  • a carbocyclyl or heterocyclyl optionally is substituted with up to three substituents independently selected from the group consisting of halogen, nitro, C ⁇ -C 6 -alkyl, halo-C ⁇ -C 6 -alkyl, C ⁇ -C -alkoxy, halo-C ⁇ -C 6 -alkoxy, and amino.
  • a carbocyclyl or heterocyclyl optionally is substituted with up to three substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy.
  • a carbocyclyl or heterocyclyl optionally is substituted with up to three substituents independently selected from the group consisting of halogen, d- -alkyl, halo-C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkoxy, and halo-C ⁇ -C 6 -alkoxy.
  • a substituent is "substitutable” if it comprises at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms.
  • hydrogen, halogen, and cyano do not fall within this definition.
  • a non-hydrogen radical is in the place of a hydrogen radical on a carbon or nitrogen ofthe substituent.
  • a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen radical is in the place of a hydrogen radical on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro radical
  • difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitutions on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).
  • a substituent is described as being “optionally substituted", the substituent may be either (1) not substituted or (2) substituted. If a substituent is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a substituent is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than
  • substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions.
  • tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical.
  • an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.
  • alkylcycloalkyl contains two components: alkyl and cycloalkyl.
  • the C ⁇ -C 6 - prefix on C ⁇ -C 6 -alkylcycloalkyl means that the alkyl component ofthe alkylcycloalkyl contains from 1 to 6 carbon atoms; the C ⁇ -C 6 - prefix does not describe the cycloalkyl component.
  • the prefix "halo" on haloalkoxyalkyl indicates that only the alkoxy component ofthe alkoxyalkyl substituent is substituted with one or more halogen radicals.
  • halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as
  • a "substitutable carbon” is a carbon bonded to at least one H, wherein the H may be replaced with a substituent other than H, as described herein.
  • De-protecting conditions is the removal of a protecting group under conditions appropriate to that particular protecting group. As is well known in the art, some protecting groups are effectively removed with a strong acid, others with a strong base, etc.
  • Unprotected describes a compound that has either had a protecting group removed or a compound that does not contain a protecting group.
  • De-protected describes a compound that has had a protecting group removed.
  • Neutral compound A compound that has neither acid nor basic reaction.
  • boc is tert-butoxy carbonyl.
  • DMAP is dimethylaminopyridine.
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • equiv.” is equivalent. "h” or “hr” is hour or hours. "HC1” is hydrochloric acid. "LDA” is lithium diisopropylamide. “LiHMDS” is lithium hexamethyldisilazide. “mCPBA” is 3-chloroperbenzoic acid, "min” is minute or minutes. “MW” is molecular weight. “NaH” is sodium hydride. “NaOH” is sodium hydroxide.
  • NMP is l-methyl-2-pyrrolidinone (also called, for example, “N-methylpyrrolidinone", “1- methyl-2-pyrrolidone”, “N-methylpyrrolidone”, “N-methyl-2-pyrrolidinone”, “methylpyrrolidinone”, and “N-methyl- ⁇ -pyrrolidone”).
  • N 2 is nitrogen gas.
  • tBuOK is potassium tert-butoxide.
  • TFA is trifluoroacetic acid.
  • THF is tetrahydrofuran.
  • Ts is tosyl.
  • Ethanol 3A is 95% absolute ethanol and 5% methanol (HPLC grade).
  • a 12L round bottom flask was equipped with a large diameter gas outlet tube, 1 L addition funnel, nitrogen sweep, and overhead stirrer.
  • To this vessel was charged 1360 g (7.79 moles, 1 equivalent) of 2-fluoro-4-chlorobenzoic acid. This was followed by addition of 5.0 liters of dry tetrahydrofuran (THF), which readily dissolved the white fluffy solid to give a yellowish clear solution.
  • Oxalyl chloride (1088 g, 8.57 moles, 1.1 equivalent) placed in the addition funnel was added dropwise. As the addition progresses, the batch temperature increased to ca. 38"C.
  • Example 2 [0149] Example 2 can be depicted by the following reaction scheme.
  • a 1 L addition funnel was placed on a 22L round bottom reaction flask fitted with an overhead stirrer.
  • the benzoyl chloride (1 l OOg, 5.70moles, 1.44 equivalent) was transferred into a IL dropping funnel.
  • 6L of dry tetrahydrofuran was charged to the reactor and 49g, (0.40moles, 0.1 equivalent) of 4-dimethylaminopyridine (DMAP) was added to it and stirred until dissolved.
  • the hydrazone (1875g, 3.96 moles, 1 equivalent) was charged to give a thin slurry.
  • To this stirring slurry was added 675g (6.68 moles, 1.69 equivalent) of triethylamine (TEA).
  • the yellow thin slurry was then cooled to under 10°C and the benzoyl chloride was added in a thin stream over an hour. The addition is added at a rate to keep the batch temperature from rising above 10°C. The batch was allowed to warm after the total amount of benzoyl chloride had been added. The batch was then heated carefully to 50°C for 30 minutes to finish the reaction. The reaction was cooled to less than 35°C and filtered to remove triethylamine hydrochloride that had precipitated, usually 700-800g. The filter cake was washed with IL of tetrahydrofuran and the filtrate plus wash was returned to the reactor for subsequent deprotection. The white triethylamine hydrochloride salt was discarded.
  • the product can be utilized without isolation as a solution for the subsequent deprotection reaction to produce the protected piperidylpyrazole.
  • the protected piperidylpyrazole can be isolated as a white solid by crystallization using methanol or toluene solvent.
  • Example 3 can be depicted by the following reaction scheme.
  • a 1 L addition funnel was placed on a 22L round bottom reaction flask fitted with an overhead stirrer.
  • the benzoyl chloride (1 lOOg, 5.70moles, 1.44 equivalent) was transferred into a IL dropping funnel.
  • 6L of dry tetrahydrofuran was charged to the reactor and 49g, (0.40moles, 0.1 equivalent) of 4-dimethylaminopyridine was added to it and stirred until dissolved.
  • the hydrazone (1875g, 3.96 moles, 1 equivalent) was charged to give a thin slurry.
  • To this stirring slurry was added 675g (6.68 moles, 1.69 equivalent) of triethylamine.
  • the yellow thin slurry was then cooled to under 10°C and the benzoyl chloride was added in a thin stream over an hour. The addition was added at a rate to keep the batch temperature from rising above 10°C. The batch was allowed to warm after the total amount of benzoyl chloride had been added. The batch was then heated carefully to 50°C for 30 minutes to finish the reaction. The reaction was cooled to less than 35°C and filtered to remove triethylamine hydrochloride that had precipitated, usually 700-800g. The filter cake was washed with IL of tetrahydrofuran and the filtrate plus wash was returned to the reactor for subsequent deprotection. The white triethylamine hydrochloride salt was discarded.
  • the product can be utilized without isolation as a solution for the subsequent deprotection reaction to produce the unprotected piperidylpyrazole.
  • the protected piperidylpyrazole can be isolated as a white solid by crystallization using methanol or toluene solvent.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte généralement à un procédé de fabrication de pyrazoles substitués. Ces pyrazoles substitués présentent une structure correspondant à la formule 9, dans laquelle Q, R4, R3A, R3B, R3C, R3D, et R3E sont tels que définis dans la description.
PCT/IB2004/004071 2003-12-18 2004-12-08 Procede de fabrication de pyrazoles substitues Ceased WO2005061485A1 (fr)

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US53019303P 2003-12-18 2003-12-18
US60/530,193 2003-12-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109700808A (zh) * 2019-02-19 2019-05-03 北京艾瑟尔生物医学研究有限公司 Sb203580在制备预防和/或治疗急进高原导致的高原病的药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000031063A1 (fr) * 1998-11-20 2000-06-02 G.D. Searle & Co. PYRAZOLES SUBSTITUES UTILISES COMME INHIBITEURS DE LA KINASE p38
WO2003026663A1 (fr) * 2001-09-25 2003-04-03 Pharmacia Corporation Procede de preparation de pyrazoles substitues
WO2004087074A2 (fr) * 2003-04-01 2004-10-14 Pharmacia Corporation Procede de production de pyrazoles substitues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000031063A1 (fr) * 1998-11-20 2000-06-02 G.D. Searle & Co. PYRAZOLES SUBSTITUES UTILISES COMME INHIBITEURS DE LA KINASE p38
WO2003026663A1 (fr) * 2001-09-25 2003-04-03 Pharmacia Corporation Procede de preparation de pyrazoles substitues
WO2004087074A2 (fr) * 2003-04-01 2004-10-14 Pharmacia Corporation Procede de production de pyrazoles substitues

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109700808A (zh) * 2019-02-19 2019-05-03 北京艾瑟尔生物医学研究有限公司 Sb203580在制备预防和/或治疗急进高原导致的高原病的药物中的应用

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