US20090062540A1 - Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds - Google Patents

Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds Download PDF

Info

Publication number
US20090062540A1
US20090062540A1 US12/196,341 US19634108A US2009062540A1 US 20090062540 A1 US20090062540 A1 US 20090062540A1 US 19634108 A US19634108 A US 19634108A US 2009062540 A1 US2009062540 A1 US 2009062540A1
Authority
US
United States
Prior art keywords
alkyl
compound
formula
heterocycle
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/196,341
Other languages
English (en)
Inventor
Mark S. Bednarz
Hugh Alfred Burgoon, JR.
Shinya Iimura
Ramanaiah C. Kanamarlapudi
Qiuling Song
Wenxue Wu
Jie Yan
HaiMing Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lexicon Pharmaceuticals Inc
Original Assignee
Lexicon Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lexicon Pharmaceuticals Inc filed Critical Lexicon Pharmaceuticals Inc
Priority to US12/196,341 priority Critical patent/US20090062540A1/en
Assigned to LEXICON PHARMACEUTICALS, INC. reassignment LEXICON PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BURGOON, HUGH ALFRED, YAN, JIE, BEDNARZ, MARK S., IIMURA, SHINYA, WU, WENXUE, ZHANG, HAIMING, SONG, QIULING, KANAMARLAPUDI, RAMANAIAH C.
Publication of US20090062540A1 publication Critical patent/US20090062540A1/en
Priority to US12/732,311 priority patent/US7968729B2/en
Priority to US13/160,678 priority patent/US8575362B2/en
Assigned to BIOPHARMA CREDIT PLC reassignment BIOPHARMA CREDIT PLC SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEXICON PHARMACEUTICALS, INC.
Assigned to LEXICON PHARMACEUTICALS, INC. reassignment LEXICON PHARMACEUTICALS, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: BIOPHARMA CREDIT PLC
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • This invention relates to methods of making 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds.
  • Certain 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds are inhibitors of the enzyme tryptophan hydroxylase (TPH), which catalyzes the rate limiting step of serotonin's biosynthesis.
  • TPH tryptophan hydroxylase
  • This invention encompasses methods of preparing compounds of formula I:
  • TPH e.g., TPH1
  • preferred compounds of this formula inhibit TPH (e.g., TPH1), and may be useful in the treatment of various diseases and disorders.
  • This invention also encompasses intermediates that are useful in the synthesis of compounds of formula I.
  • FIG. 1 is an X-ray diffraction pattern of a crystalline solid form of (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.
  • the pattern was obtained using a Rigaku MiniFlex diffractometer (Cu (1.54060 ⁇ ) radiation).
  • FIG. 2 is an X-ray diffraction pattern of a crystalline solid form of 1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone.
  • the pattern was obtained using a Rigaku MiniFlex diffractometer (Cu (1.54060 ⁇ ) radiation).
  • FIG. 3 is an X-ray diffraction pattern of a crystalline solid form of 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole. The pattern was obtained using a Rigaku MiniFlex diffractometer (Cu (1.54060 ⁇ ) radiation).
  • This invention is based on the discovery of novel methods of preparing compounds of formula I and intermediates useful therein.
  • preferred compounds of formula I When administered to mammals, preferred compounds of formula I inhibit TPH, and may be used in the treatment of a variety of diseases and disorders. See generally, U.S. patent application Ser. Nos. 11/638,677 and 60/874,596, both filed Dec. 12, 2006.
  • alkenyl means a straight chain, branched and/or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 10 or 2 to 6) carbon atoms, and including at least one carbon-carbon double bond.
  • alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl and 3-decenyl.
  • alkoxy means an —O-alkyl group.
  • alkoxy groups include —OCH 3 , —OCH 2 CH 3 , —O(CH 2 ) 2 CH 3 , —O(CH 2 ) 3 CH 3 , —O(CH 2 ) 4 —CH 3 , —O(cyclopenyl) and —O(CH 2 ) 5 CH 3 .
  • lower alkoxy refers to —O-(lower alkyl).
  • alkyl means a straight chain, branched and/or cyclic (“cycloalkyl”) hydrocarbon having from 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms. Alkyl moieties having from 1 to 4 carbons are referred to as “lower alkyl.” Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.
  • Cycloalkyl moieties may be monocyclic or multicyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Additional examples of alkyl moieties have linear, branched and/or cyclic portions (e.g., 1-ethyl-4-methyl-cyclohexyl).
  • alkyl includes saturated hydrocarbons as well as alkenyl and alkynyl moieties.
  • alkylaryl or “alkyl-aryl” means an alkyl moiety bound to an aryl moiety.
  • alkylheteroaryl or “alkyl-heteroaryl” means an alkyl moiety bound to a heteroaryl moiety.
  • alkylheterocycle or “alkyl-heterocycle” means an alkyl moiety bound to a heterocycle moiety.
  • alkynyl means a straight chain, branched or cyclic hydrocarbon having from 2 to 20 (e.g., 2 to 20 or 2 to 6) carbon atoms, and including at least one carbon-carbon triple bond.
  • alkynyl moieties include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl and 9-decynyl.
  • aryl means an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms.
  • An aryl moiety may comprise multiple rings bound or fused together.
  • aryl moieties include anthracenyl, azulenyl, biphenyl, fluorenyl, indan, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, and tolyl.
  • arylalkyl or “aryl-alkyl” means an aryl moiety bound to an alkyl moiety.
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureido, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
  • biohydrolyzable esters include lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable amides include lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkyl-carbonyl amides.
  • biohydrolyzable carbamates include lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • halogen and “halo” encompass fluorine, chlorine, bromine, and iodine.
  • heteroalkyl refers to an alkyl moiety (e.g., linear, branched or cyclic) in which at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S).
  • heteroaryl means an aryl moiety wherein at least one of its carbon atoms has been replaced with a heteroatom (e.g., N, O or S).
  • heteroatom e.g., N, O or S.
  • examples include acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, thiazolyl, and tri
  • heteroarylalkyl or “heteroaryl-alkyl” means a heteroaryl moiety bound to an alkyl moiety.
  • heterocycle refers to an aromatic, partially aromatic or non-aromatic monocyclic or polycyclic ring or ring system comprised of carbon, hydrogen and at least one heteroatom (e.g., N, O or S).
  • a heterocycle may comprise multiple (i.e., two or more) rings fused or bound together.
  • Heterocycles include heteroaryls. Particular heterocycles are 5- to 13-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur. Others are 5- to 10-membered heterocycles containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulphur.
  • heterocycles include benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl, cinnolinyl, furanyl, hydantoinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and valerolactamyl.
  • heterocyclealkyl or “heterocycle-alkyl” refers to a heterocycle moiety bound to an alkyl moiety.
  • heterocycloalkyl refers to a non-aromatic heterocycle.
  • heterocycloalkylalkyl or “heterocycloalkyl-alkyl” refers to a heterocycloalkyl moiety bound to an alkyl moiety.
  • prodrug encompasses pharmaceutically acceptable esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino-acid conjugates, phosphate esters, metal salts and sulfonate esters of compounds disclosed herein.
  • prodrugs include compounds that comprise a biohydrolyzable moiety (e.g., a biohydrolyzable amide, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzable ester, biohydrolyzable phosphate, or biohydrolyzable ureide analog).
  • Prodrugs of compounds disclosed herein are readily envisioned and prepared by those of ordinary skill in the art. See, e.g., Design of Prodrugs , Bundgaard, A. Ed., Elseview, 1985; Bundgaard, hours., “Design and Application of Prodrugs,” A Textbook of Drug Design and Development , Krosgaard-Larsen and hours. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, hours., Advanced Drug Delivery Review, 1992, 8, 1-38.
  • protecting group when used to refer to part of a molecule subjected to a chemical reaction, means a chemical moiety that is not reactive under the conditions of that chemical reaction, and which may be removed to provide a moiety that is reactive under those conditions.
  • Protecting groups are well known in the art. See, e.g., Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis (3 rd ed., John Wiley & Sons: 1999); Larock, R. C., Comprehensive Organic Transformations (2 nd ed., John Wiley & Sons: 1999). Some examples include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, and pthalimido.
  • pseudohalogen refers to a polyatomic anion that resembles a halide ion in its acid-base, substitution, and redox chemistry, generally has low basicity, and forms a free radical under atom transfer radical polymerization conditions.
  • pseudohalogens include azide ions, cyanide, cyanate, thiocyanate, thiosulfate, sulfonates, and sulfonyl halides.
  • stereomerically enriched composition of a compound refers to a mixture of the named compound and its stereoisomer(s) that contains more of the named compound than its stereoisomer(s).
  • a stereoisomerically enriched composition of (S)-butan-2-ol encompasses mixtures of (S)-butan-2-ol and (R)-butan-2-ol in ratios of, e.g., about 60/40, 70/30, 80/20, 90/10, 95/5, and 98/2.
  • stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one stereocenter will be substantially free of the opposite stereoisomer of the compound.
  • a stereomerically pure composition of a compound having two stereocenters will be substantially free of other diastereomers of the compound.
  • stereomerically pure ((1R)-1,2-dichloropropyl)benzene refers to ((1R)-1,2-dichloropropyl)benzene that is substantially free of ((1S)-1,2-dichloropropyl)benzene.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound.
  • substituted when used to describe a chemical structure or moiety, refers to a derivative of that structure or moiety wherein one or more of its hydrogen atoms is substituted with an atom, chemical moiety or functional group such as alcohol, aldehyde, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (—OC(O)alkyl), amide (—C(O)NH-alkyl- or -alkylNHC(O)alkyl), amidinyl (—C(NH)NH-alkyl- or —C(NR)NH 2 ), amine (primary, secondary and tertiary such as alkylamino, arylamino, arylalkylamino), aroyl, aryl, aryloxy,
  • the phrase “greater than X,” where X is a number, has the same meaning as “X or greater than X.”
  • the phrase “greater than about X,” where X is a number, has the same meaning as “about X or greater than about X.”
  • the phrase “less than X,” where X is a number, has the same meaning as “X or less than X.”
  • the phrase “less than about X,” where X is a number, has the same meaning as “about X or less than about X.”
  • the phrase “between X and Y” encompasses values between X and Y as well as X and Y themselves.
  • the term “include” has the same meaning as “include” and the term “includes” has the same meaning as “includes, but is not limited to.” Similarly, the term “such as” has the same meaning as the term “such as, but not limited to.”
  • one or more adjectives immediately preceding a series of nouns is to be construed as applying to each of the nouns.
  • the phrase “optionally substituted alky, aryl, or heteroaryl” has the same meaning as “optionally substituted alky, optionally substituted aryl, or optionally substituted heteroaryl.”
  • a structure or name of a compound or genus of compounds encompasses all forms of that compound or genus of compounds, and all compositions comprising that compound or genus of compounds.
  • a chemical moiety that forms part of a larger compound may be described herein using a name commonly accorded it when it exists as a single molecule or a name commonly accorded its radical.
  • the terms “pyridine” and “pyridyl” are accorded the same meaning when used to describe a moiety attached to other chemical moieties.
  • the two phrases “XOH, wherein X is pyridyl” and “XOH, wherein X is pyridine” are accorded the same meaning, and encompass the compounds pyridin-2-ol, pyridin-3-ol and pyridin-4-ol.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or the portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof.
  • any atom shown in a drawing with unsatisfied valences is assumed to be attached to enough hydrogen atoms to satisfy the valences.
  • chemical bonds depicted with one solid line parallel to one dashed line encompass both single and double (e.g., aromatic) bonds, if valences permit.
  • This invention encompasses methods of preparing compounds of formula I:
  • a 1 is aromatic; in others, it is not. In others, A 1 is optionally substituted with one or more of halogen or lower alkyl.
  • the compound of formula I is of formula I(a):
  • the compound of formula I(a) is formula I(b):
  • each R 5 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3.
  • R 1 is hydrogen or halogen. In some, m is 1. In some, R 2 is hydrogen or amino. In some, R 3 is hydrogen or lower alkyl. In some, R 3 is C(O)OR A and R A is alkyl. In some, R 4 is hydrogen or lower alkyl. In some, R 5 is hydrogen or lower alkyl (e.g., methyl). In some, n is 1.
  • a particular compound of formula I(b) is (S)-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoic acid:
  • Another compound of formula I(b) is (S)-ethyl 3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoate:
  • Another compound of formula I(b) is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate:
  • the compound of formula I is prepared according to the general approach shown below in Scheme 1:
  • a compound of formula II is contacted with one of formula III under suitable reaction conditions.
  • suitable reaction conditions include the use of a base (e.g., alkyllithium, alkylmagnesium, alkoxides, alkaline metal hydroxides, alkaline metal phosphates, and alkaline metal carbonates), a temperature of from about 50 to about 150° C., a reaction time of from about 10 to about 40 hours, and polar aprotic solvents.
  • a particular base is cesium carbonate.
  • the compound of formula II is of formula II(a):
  • R 1 is chloro and m is 1.
  • a particular compound is (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol:
  • a particular crystalline form of this compound has a melting point of about 120° C. as measured by differential scanning calorimetry (DSC) (onset temperature).
  • DSC differential scanning calorimetry
  • the term “about” means ⁇ 5.0° C.
  • the form provides a X-ray powder diffraction (XRPD) pattern with peaks at one or more of about 9.9, 11.0, 19.2, 19.9, 24.4, 30.0, 31.0 and/or 40.4 degrees 2 ⁇ .
  • the term “about” means ⁇ 0.3 degrees.
  • the relative intensities of peaks in a X-ray diffraction pattern of a crystalline form can vary depending on how the sample is prepared and how the data is collected. With this in mind, an example of a XRPD pattern of this crystalline form is provided in FIG. 1 .
  • Noyori hydrogenation uses methods generally known as Noyori hydrogenation and Noyori transfer hydrogenation.
  • the reduction is achieved using a platinum group metal (e.g., iridium, ruthenium, rhodium) catalyst with a Noyori-type chiral ligand, such as (1R,2R)-( ⁇ )-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine.
  • platinum group metal e.g., iridium, ruthenium, rhodium
  • Noyori-type chiral ligand such as (1R,2R)-( ⁇ )-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine.
  • a particular compound of formula IV is 1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone:
  • a particular crystalline form of this compound has a melting point of about 83° C. as measured by DSC (onset temperature).
  • the term “about” means ⁇ 5.0° C.
  • the form provides a XRPD pattern with peaks at one or more of about 8.1, 11.3, 16.3, 22.7 and/or 27.3 degrees 2 ⁇ . In this context, the term “about” means ⁇ 0.3 degrees.
  • An example of a XRPD pattern of this crystalline form is provided in FIG. 2 .
  • X is bromine or iodine.
  • a compound of formula V can be reacted with an alkyllithium or alkylmagnesium reagent to form the corresponding lithium or magnesium compound, which can then be reacted with ethyl 2,2,2-trifluoroacetate.
  • alkyl lithium reagents include n-butyllithium, sec-butyllithium, and t-butyllithium.
  • Particular magnesium reagents include isopropyl magnesium chloride and tributylmagnesium chloride. Suitable reaction conditions include temperatures of from about ⁇ 80 to about 40° C., reaction times of from about 10 minutes to about 10 hours, and aprotic solvents.
  • the compound I-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone can be prepared from 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole:
  • a particular crystalline form of this compound has a melting point of about 76° C. as measured by DSC (onset temperature).
  • the term “about” means ⁇ 5.0° C.
  • the form provides a X-ray powder diffraction (XRPD) pattern with peaks at about 8.2, 16.4, 17.3, 19.0, 22.7, 25.8, 28.4, 31.0 and/or 33.6 degrees 2 ⁇ .
  • the term “about” means ⁇ 0.3 degrees.
  • An example of a XRPD pattern of this crystalline form is provided in FIG. 3 .
  • each R′ is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane.
  • Suitable Suzuki coupling conditions are well known in the art, and include the use of a palladium catalyst.
  • palladium catalysts include bis(triphenylphosphine)-palladium(II) chloride, mixture of a palladium salt, such as palladium chloride or palladium acetate, and a ligand, such as triphenylphosphine, dihydrogen dichlorobis(di-tert-butylphosphinito-kP)palladate(2-) (POPd), dihydrogen di- ⁇ -chlorotetrakis(di-tert-butylphosphinito-kP)dipalladate(2-) (POPd1), dihydrogen di- ⁇ -chlorodichlorobis(di-tert-butylphosphinito-kP)dipalladate(2-) (POPd2), dihydrogen dichlorobis(tert-butylcyclohexylphosphinito-kP)palladate(2-) (POPd3), dihydrogen di- ⁇ -chlorod
  • the compound of formula III(a) is of the formula:
  • one embodiment of the invention encompasses a method of forming a co-crystal of a compound of formula I, which comprises contacting a compound of formula I with a pharmaceutically acceptable amino acid under conditions sufficient to provide a co-crystal of the compound of formula I and the amino acid.
  • the above THF solution was transferred to a jacketed 3L 3-neck round bottom flask equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet. After diluting with THF (800 mL), the water content in the solution was checked by KF (0.053%). To the above solution was added a solution of i-PrMgCl in THF (Aldrich 2 M, 286 mL, 0.572 mol) at 0-10° C. over 1 hours. The resulting solution was stirred for 30 minutes at 10° C. (GC showed the completion of magnesium-bromine exchange reaction).
  • the 3.5 ⁇ heptane solution was then transferred to a 1L 3-neck jacketed round bottom flask equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet.
  • the solution was heated at 60° C., and the resulting homogeneous solution was slowly (1-2 h) cooled to room temperature with stirring, further cooled to 0° C. and stirred for 30 minutes at the same temperature.
  • the crystals were collected and washed with ice-cold heptane (200 mL), dried under vacuum at 50° C. to afford a pale yellow solid (Compound 5, 85.7 g, 99% pure by GC, 62% yield from fluoride 1). M.p.: 83° C.
  • the organic layer (ca. 600 mL, 6 ⁇ ) was treated with activated carbon (Darco G-60, 20 g, 0.2 ⁇ ) at 45° C. for 2 hours and filtered through 1 ⁇ 4 inch bed of Celpure P65 (USP-NF, Pharmaceutical grade, Sigma) and washed with CH 3 CN (200 mL, 2 ⁇ ).
  • the filtrate was concentrated to 250 mL (2.5 ⁇ ) and transferred to a 2 L 3-neck jacketed round bottom flask equipped with a mechanical stirrer and a temperature controller. More CH 3 CN (50 mL, 0.5 ⁇ ) was added to increase the solution volume to 300 mL (3 ⁇ ). This solution was warmed to 60° C.
  • the above organic layer of the ester was stirred with aqueous lithium hydroxide solution (23 g in 500 mL water) at r.t. for 30 minutes.
  • the pH of the resulting slurry was adjusted to about 10 with 6 N hydrochloric acid and filtered.
  • the cake was washed with water (200 mL).
  • Acetonitrile was removed from the filtrate under reduced pressure to give an aqueous slurry (950 mL, additional water was added during distillation).
  • the slurry was filtered through a pad of 20 micron cellulose and washed with water (200 mL).
  • the filtrate was washed with MTBE (500 mL) and rediluted with 700 mL MTBE.
  • the mixture was acidified to pH about 4.5 with 6 N hydrochloric acid.
  • the organic layer was washed with water (500 mL) and concentrated under reduced pressure to the acid compound as a brown oil (206 g, 95% yield based on estimated purity by NMR).
  • the crude product can be used directly in the following step.
  • the compound can be purified by crystallization from MTBE/heptane to give a white solid, which contains a small amount of the corresponding boronic acid, (S)-3-(4-boronophenyl)-2-(tert-butoxycarbonylamino)propanoic acid.
  • the aqueous solution was treated with Darco-G60 (6.0 g) at 60° C. for 2 hours, filtered through celite (Celpure 300, 10 g), and diluted with THF (240 mL) and toluene (180 mL). 6N HCl was slowly added to the mixture at room temperature until the pH reached 4.0. The organic layer was separated and washed with water (180 mL), and Darco-G60 (6.0 g) was added: the resulting mixture was heated at 60° C. for 2 hours. The solution was cooled to room temperature and filtered through celite (Celpure 300, 10 g). The cake was washed with THF (30 mL ⁇ 2).
  • Insolubles were filtered at room temperature and wet cake washed with water. The filtrate was washed with ethyl acetate twice. The aqueous layer was mixed with THF (664 kg) and toluene (512 kg) and the pH was adjusted to about 2.5-3.5 by 6 N HCl. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were treated with charcoal at 40-50° C. and filtered through a pad of cellulose and sodium sulfate. The cake was washed with 1:1 THF/toluene. The filtrate was concentrated and the product was crystallized from toluene/THF. After drying at 40-45° C.
  • the mixture was stirred under nitrogen and the temperature was increased to 100° C. with good stirring.
  • the reaction mixture was stirred at 100° C. for 1 hour and additional Cs 2 CO 3 (33.2 g, 102 mmol, 2.0 equiv.) was added.
  • the reaction mixture was then stirred for 18 hours at 100° C.
  • the heterogeneous reaction mixture was cooled to 90° C. and water (150 mL, 7.5 ⁇ ) was added with good stirring.
  • the mixture was cooled to room temperature.
  • Di-tert-butyl dicarbonate (1.11 g, 5.1 mmol, 0.1 equiv.) at room temperature and stirred for 2 hours at the same temperature.
  • Toluene 100 mL, 5 ⁇ was added, the resulting mixture was stirred for 15 minutes at room temperature, and the phases were split.
  • Water 100 mL, 5 ⁇ was added to the organic layer, and the resulting mixture was stirred for 15 minutes at room temperature, and the phases were split.
  • EtOAc (100 mL, 5 ⁇ ) was added to this mixture, and further acidification to pH 4 was carried out using 6 N HCl at room temperature with good stirring. After splitting the organic layer, the aqueous layer was extracted with EtOAc (100 mL, 5 ⁇ ). The combined organic layers were washed with brine (100 mL, 5 ⁇ ). The EtOAc layer was then concentrated under vacuum to a total volume of about 40 mL (2 ⁇ ). EtOH (100 mL, 5 ⁇ ) was added, and concentrated to 2 ⁇ solution.
  • Methanesulfonic acid (4.14 kg; 3.25 equiv.) was added to the above solution at 22-32° C. inner temperature within 6 minutes.
  • the addition tank was rinsed with acetonitrile (2.5 L; 0.5 volumes).
  • the reaction mixture was heated to 45° C. within 40 minutes and stirred for 2.5 hours at this temperature.
  • 60° C. jacket temperature and reduced pressure (170-140 mbar; keeping inner temperature below 35° C.)
  • 6.9 volumes of solvent were removed by distillation.
  • Water 26 L; 5 volumes
  • the aqueous solution was washed four times with MTBE (per portion: 16 L; 3 volumes).
  • the aqueous layer was added to a solution of potassium carbonate (8.89 kg; 4.85 equiv.) in water (36 L; 6.8 volumes) and the product was extracted with MTBE (26 L; 5 volumes). The aqueous layer was extracted with a second portion of MTBE (16 L; 3 volumes). The combined organic layers were washed with a mixture of water (10.5 L; 2 volumes) and ethanol (1.5 L; 0.3 volumes). At 60° C. jacket temperature and reduced pressure (272-262 mbar; keep inner temperature below 35° C.), the filtrate was concentrated to 3 remaining volumes. Ethanol (16 L; 3 volumes) was added and distillation at 60° C. jacket temperature and reduced pressure (206-104 mbar; keeping inner temperature below 35° C.) was continued.
US12/196,341 2007-08-24 2008-08-22 Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds Abandoned US20090062540A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US12/196,341 US20090062540A1 (en) 2007-08-24 2008-08-22 Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds
US12/732,311 US7968729B2 (en) 2007-08-24 2010-03-26 1-phenyl-1H-pyrazole-based compounds
US13/160,678 US8575362B2 (en) 2007-08-24 2011-06-15 Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95774407P 2007-08-24 2007-08-24
US12/196,341 US20090062540A1 (en) 2007-08-24 2008-08-22 Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/732,311 Division US7968729B2 (en) 2007-08-24 2010-03-26 1-phenyl-1H-pyrazole-based compounds

Publications (1)

Publication Number Publication Date
US20090062540A1 true US20090062540A1 (en) 2009-03-05

Family

ID=40040082

Family Applications (3)

Application Number Title Priority Date Filing Date
US12/196,341 Abandoned US20090062540A1 (en) 2007-08-24 2008-08-22 Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds
US12/732,311 Active US7968729B2 (en) 2007-08-24 2010-03-26 1-phenyl-1H-pyrazole-based compounds
US13/160,678 Active US8575362B2 (en) 2007-08-24 2011-06-15 Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12/732,311 Active US7968729B2 (en) 2007-08-24 2010-03-26 1-phenyl-1H-pyrazole-based compounds
US13/160,678 Active US8575362B2 (en) 2007-08-24 2011-06-15 Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds

Country Status (16)

Country Link
US (3) US20090062540A1 (es)
EP (3) EP2529740A1 (es)
JP (1) JP5553752B2 (es)
KR (1) KR101582697B1 (es)
CN (1) CN101801384B (es)
AU (1) AU2008293679B2 (es)
BR (1) BRPI0815754B1 (es)
CA (1) CA2697368C (es)
ES (2) ES2656798T3 (es)
HK (1) HK1143749A1 (es)
IL (2) IL203669A (es)
MX (1) MX2010001938A (es)
NZ (1) NZ583017A (es)
RU (1) RU2493156C2 (es)
WO (1) WO2009029499A1 (es)
ZA (1) ZA201000785B (es)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110152220A1 (en) * 2008-03-31 2011-06-23 Gerard Karsenty Methods of diagnosing, preventing and treating bone mass diseases

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA99270C2 (en) * 2006-12-12 2012-08-10 Лексикон Фармасьютикалз, Инк. 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use
TWI439457B (zh) * 2007-09-28 2014-06-01 Lexicon Pharmaceuticals Inc （ｓ）－２－胺基－３－（４－（２－胺基－６－（（ｒ）－１－（４－氯－２－（３－甲基－１ｈ－吡唑－１－基）苯基）－２，２，２－三氟乙氧）－嘧啶－４－基）苯基）丙酸乙酯之固體形式與其使用方法
WO2011053977A1 (en) 2009-11-02 2011-05-05 The Trustees Of Columbia University In The City Of New York Compounds and methods for inhibiting serotonin synthesis
TW201245183A (en) 2010-11-05 2012-11-16 Lexicon Pharmaceuticals Inc Solid forms of (S)-2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoic acid
JP6221148B2 (ja) * 2012-02-09 2017-11-01 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング カルボキサミジン化合物の調製方法
WO2018060949A1 (en) 2016-09-30 2018-04-05 Roivant Sciences Gmbh Tryptophan hydroxylase inhibitors for use in the treatment of liver diseases

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4866181A (en) * 1986-08-29 1989-09-12 Aldrich-Boranes, Inc. Process for producing optically active alcohols
US4916074A (en) * 1986-10-30 1990-04-10 Chisso Corporation Process for producing optically active compounds
US5233111A (en) * 1991-03-21 1993-08-03 Monsanto Company Catalytic process for selective alkylation of aromatic hydrocarbons
US5859020A (en) * 1991-09-25 1999-01-12 Hoechst Schering Agrevo Gmbh Substituted 4-Alkoxypyrimidines, Process for their preparation, agents containing them, and their use as pesticides
US20030144541A1 (en) * 2000-01-27 2003-07-31 Roland Jacquot Process for preparing alpha-halogenated retones
US20050096353A1 (en) * 2003-11-05 2005-05-05 Jean Ackermann Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents
US6916933B2 (en) * 1999-12-06 2005-07-12 Hoffman-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
US20050282900A1 (en) * 2000-08-31 2005-12-22 Takayuki Kawaguchi Inhibitors of alpha4 mediated cell adhesion
US20060128956A1 (en) * 2003-04-21 2006-06-15 Ustav Organicke Chemie A Biochemie Akademie Ved Ceske Republiky (Purin-6-yl) amino acid and production method thereof
US20060148862A1 (en) * 2003-06-20 2006-07-06 Galderma Research & Development, S.N.C. Novel compounds that modulate PPARy type receptors and cosmetic/pharmaceutical compositions comprised thereof
US20070191370A1 (en) * 2005-12-29 2007-08-16 Arokiasamy Devasagayaraj Multicyclic amino acid derivatives and methods of their use
US20090048280A1 (en) * 2005-12-29 2009-02-19 Burgoon Jr Hugh Alfred Process for the preparation of substituted phenylalanines
US20090088447A1 (en) * 2007-09-28 2009-04-02 Bednarz Mark S Solid forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)phenyl)propanoate and methods of their use
US7553840B2 (en) * 2006-12-12 2009-06-30 Lexicon Pharmaceuticals, Inc. 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2268953A1 (en) * 1996-10-02 1998-04-09 Du Pont Pharmaceuticals Company 4,4-disubstituted-1,4-dihydro-2h-3,1-benzoxazin-2-ones useful as hiv reverse transcriptase inhibitors and intermediates and processes for making the same
GB0213122D0 (en) 2002-06-07 2002-07-17 Glaxo Group Ltd Compounds
AU2003232941A1 (en) 2002-06-07 2003-12-22 Glaxo Group Limited N-mercaptoacyl phenyalanine derivatives, process for their preparation, and pharmaceutical compositions containing them
BRPI0813835A2 (pt) * 2007-07-26 2017-06-06 Lexicon Pharmaceuticals Inc métodos de afetar o trânsito gastrointestinal e esvaziamento gástrico, e compostos úteis a esse respeito

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4866181A (en) * 1986-08-29 1989-09-12 Aldrich-Boranes, Inc. Process for producing optically active alcohols
US4916074A (en) * 1986-10-30 1990-04-10 Chisso Corporation Process for producing optically active compounds
US5233111A (en) * 1991-03-21 1993-08-03 Monsanto Company Catalytic process for selective alkylation of aromatic hydrocarbons
US5859020A (en) * 1991-09-25 1999-01-12 Hoechst Schering Agrevo Gmbh Substituted 4-Alkoxypyrimidines, Process for their preparation, agents containing them, and their use as pesticides
US6916933B2 (en) * 1999-12-06 2005-07-12 Hoffman-La Roche Inc. 4-pyridinyl-n-acyl-l-phenylalanines
US20030144541A1 (en) * 2000-01-27 2003-07-31 Roland Jacquot Process for preparing alpha-halogenated retones
US20050282900A1 (en) * 2000-08-31 2005-12-22 Takayuki Kawaguchi Inhibitors of alpha4 mediated cell adhesion
US20060128956A1 (en) * 2003-04-21 2006-06-15 Ustav Organicke Chemie A Biochemie Akademie Ved Ceske Republiky (Purin-6-yl) amino acid and production method thereof
US20060148862A1 (en) * 2003-06-20 2006-07-06 Galderma Research & Development, S.N.C. Novel compounds that modulate PPARy type receptors and cosmetic/pharmaceutical compositions comprised thereof
US20050096353A1 (en) * 2003-11-05 2005-05-05 Jean Ackermann Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents
US20070191370A1 (en) * 2005-12-29 2007-08-16 Arokiasamy Devasagayaraj Multicyclic amino acid derivatives and methods of their use
US20090048280A1 (en) * 2005-12-29 2009-02-19 Burgoon Jr Hugh Alfred Process for the preparation of substituted phenylalanines
US7553840B2 (en) * 2006-12-12 2009-06-30 Lexicon Pharmaceuticals, Inc. 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use
US20090088447A1 (en) * 2007-09-28 2009-04-02 Bednarz Mark S Solid forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)phenyl)propanoate and methods of their use

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110152220A1 (en) * 2008-03-31 2011-06-23 Gerard Karsenty Methods of diagnosing, preventing and treating bone mass diseases
US8759364B2 (en) 2008-03-31 2014-06-24 The Trustees Of Columbia University In The City Of New York Methods of treating bone mass diseases

Also Published As

Publication number Publication date
EP3318260A1 (en) 2018-05-09
CA2697368A1 (en) 2009-03-05
US8575362B2 (en) 2013-11-05
AU2008293679A1 (en) 2009-03-05
JP2010536879A (ja) 2010-12-02
BRPI0815754A2 (pt) 2017-05-30
KR101582697B1 (ko) 2016-01-05
JP5553752B2 (ja) 2014-07-16
CN101801384A (zh) 2010-08-11
NZ583017A (en) 2012-02-24
CA2697368C (en) 2016-06-21
EP3318260B1 (en) 2020-09-23
MX2010001938A (es) 2010-03-11
RU2493156C2 (ru) 2013-09-20
EP2529740A1 (en) 2012-12-05
BRPI0815754B1 (pt) 2022-03-22
EP2187887A1 (en) 2010-05-26
ZA201000785B (en) 2011-04-28
US20100240906A1 (en) 2010-09-23
CN101801384B (zh) 2012-03-21
IL226441A (en) 2014-06-30
EP2187887B1 (en) 2017-11-15
US7968729B2 (en) 2011-06-28
HK1143749A1 (en) 2011-01-14
AU2008293679B2 (en) 2013-09-12
ES2848152T3 (es) 2021-08-05
ES2656798T3 (es) 2018-02-28
KR20100046026A (ko) 2010-05-04
IL226441A0 (en) 2013-06-27
US20110301349A1 (en) 2011-12-08
WO2009029499A1 (en) 2009-03-05
IL203669A (en) 2015-07-30
RU2010111125A (ru) 2011-09-27

Similar Documents

Publication Publication Date Title
US8575362B2 (en) Methods of preparing 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds
US7855291B2 (en) Process for the preparation of substituted phenylalanines
US8653094B2 (en) Solid forms of (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)phenyl)propanoate and methods of their use
US8093280B2 (en) Methods of preparing imidazole-based compounds
CA2733397A1 (fr) Composes d'azetidines polysubstitues, leur preparation et leur application en therapeutique
US8450532B2 (en) Compounds useful in the preparation of tryptophan hydroxylase inhibitors
US20110124865A1 (en) Process for the preparation of substituted phenylalanines
KR20110074875A (ko) 치환된 페닐알라닌의 제조 방법
US7968726B2 (en) Methods of preparing imidazole-based bicyclic compounds
US7919618B2 (en) Synthesis of piperazines, piperidines and related compounds

Legal Events

Date Code Title Description
AS Assignment

Owner name: LEXICON PHARMACEUTICALS, INC., TEXAS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BEDNARZ, MARK S.;BURGOON, HUGH ALFRED;IIMURA, SHINYA;AND OTHERS;REEL/FRAME:021775/0767;SIGNING DATES FROM 20080925 TO 20081016

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: BIOPHARMA CREDIT PLC, UNITED KINGDOM

Free format text: SECURITY INTEREST;ASSIGNOR:LEXICON PHARMACEUTICALS, INC.;REEL/FRAME:044958/0377

Effective date: 20171204

AS Assignment

Owner name: LEXICON PHARMACEUTICALS, INC., TEXAS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:BIOPHARMA CREDIT PLC;REEL/FRAME:053767/0445

Effective date: 20200908