WO2014126954A1 - Synthèse régiosélective de pyrimidines substituées - Google Patents

Synthèse régiosélective de pyrimidines substituées Download PDF

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Publication number
WO2014126954A1
WO2014126954A1 PCT/US2014/015925 US2014015925W WO2014126954A1 WO 2014126954 A1 WO2014126954 A1 WO 2014126954A1 US 2014015925 W US2014015925 W US 2014015925W WO 2014126954 A1 WO2014126954 A1 WO 2014126954A1
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WO
WIPO (PCT)
Prior art keywords
compound
optionally substituted
formula
triazol
basic conditions
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PCT/US2014/015925
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English (en)
Inventor
Arlindo L. Castelhano
Josef A. Rechka
Chandrawansha Senanayake
Krishnaswamy DEVANATHAN
Karunanidhi GNANAVELU
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OSI Pharmaceuticals, LLC
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Publication of WO2014126954A1 publication Critical patent/WO2014126954A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/14—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 three or more hetero rings

Definitions

  • the present invention pertains at least in part to chemical compounds, substituted pyrimidines, including intermediates, and to chemical synthesis, and regioselective chemical synthesis.
  • the compounds and syntheses can be useful, for example, in connection with the preparation of biologically active compounds.
  • the present invention concerns compounds of general Formula I , as shown below, and methods of preparing the compounds, which can be useful in application such as pharmaceutical intermediates.
  • the inventio d of Formula I or a salt thereof:
  • Ri is F or is selected from halogen, OH, or -NR 2 R3;
  • R 1 is a leaving group such as alkyl or aryl sulfonate, or alkyl or aryl sulfinate;
  • R 2 and R 3 are independently H , optionally substituted Ci-i 2 aliphatic, or optionally substituted 4-iocyclic, except R 2 and R 3 are not both H;
  • R 2 and R 3 together with the N to which they are attached, form an optionally substituted 4 -iocyclic.
  • each R 4 is 1 ,2,3-triazol-1 -yl or 1 ,2,4-triazol-1 -yl, either of which is optionally substituted;
  • R 5 is -CF 3 , -CN, halogen , or Ci_ 3 aliphatic.
  • the invention includes a process for preparing a compound of Formula I I I , according to the scheme:
  • the invention includes a process for preparing compounds of Formula IV accordin
  • the hydrolyzing is regioselective.
  • the basic conditions are aqueous basic conditions.
  • the basic conditions include at least one of pyridine, DIPEA, or lutidine.
  • the basic conditions include pyridine.
  • the process is carried out at about 90-100 °C.
  • IV is isolated by evaporating the reaction mixture, slurrying the crude product in an alcohol or alcohol mixture, and separating the liquid.
  • IV is obtained in a purity of about 98% or greater. In some aspects thereof, IV is obtained in an amount of about 1 kg or more per reaction. In some aspects thereof, IV is obtained from III in a yield of about 70% or more.
  • the invention includes a process for preparing a compound of Formula V according to t
  • the invention includes chlorinating with POCI 3 .
  • the chlorination is carried out in the presence of catalytic phosphoric acid or DMF.
  • V is obtained from IV in a purity of about 98% or greater. In some aspects thereof, V is obtained in an amount of about 1 kg or more. In some aspects thereof, V is obtained from IV in a yield of about 65% or more.
  • the invention includes a process for preparing a compound of Formula I, wherein R 1 is -NR 2 R 3 (Formula VI), comprising reacting III or V with a compound of the formula NHR2R3.
  • the invention includes a process of treating a compound of Formula VI with an amine NHR 6 R 7 , such as an aniline, to obtain a compound of Formula VII:
  • R 6 and R 7 are independently defined as in R 2 and R 3 of Formula I.
  • the compounds of the Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatizations that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-lnterscience)). Preferred methods include those described below.
  • any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1981 ; T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , and T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, which are hereby incorporated by reference.
  • conventional protecting groups such as those described in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1981 ; T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , and T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis
  • the present invention concerns compounds of general Formula I, as shown below, and methods of preparing the compounds, which can be useful in application such as pharmaceutical intermediates.
  • the invention includes a compound of Formula la, or a salt thereof, wherein:
  • Ri is selected from halogen, -OH, _ or -NR 2 R3;
  • R 2 and R 3 are independently H, optionally substituted Ci_ 12 aliphatic, or optionally substituted 4 -iocyclic, except R 2 and R 3 are not both H;
  • R 2 and R 3 together with the N to which they are attached, form an optionally substituted 4 -iocyclic.
  • the invention includes a compound of Formula la, wherein Ri is
  • the invention includes a compound of Formula I, described above, wherein: R 1 and R 4 are 1 ,2,3-triazol-1-yl or 1 ,2,4-triazol-1-yl; and R 5 is -CF 3 . In some aspects, the invention includes Compound 3.
  • the invention includes a compound of Formula I, described above, wherein: R 1 is 1 ,2,3-triazol-1-yl or 1 ,2,4-triazol-1-yl; R 4 is OH; and R 5 is -CF 3 . In some aspects, the invention includes Compound 4.
  • the invention includes a compound of Formula I, described above, wherein: R 1 is 1 ,2,3-triazol-1-yl or 1 ,2,4-triazol-1-yl; R 4 is CI; and R 5 is -CF 3 . In some aspects, the invention includes Compound 5.
  • 5-trifluoromethyluracil (Compound 2 herein) is disclosed in published literature. It can be prepared by known methods, such as disclosed in Heidelberger et al., JACS, 84, 3597-98 (1962), and US7884202, example 1 thereof, which are incorporated herein by this reference. Also known are halouracils such as 5-chlorouracil.
  • the invention includes a process for preparing Compound 3 of Formula I, according to
  • Compound 3 (2,4-bis[1 ,2,4]triazol-1-yl-5-trifluoromethyl-pyrimidine) can be prepared from Compound 2 basically according to literature procedures.
  • Compound 2 is treated with phosphorous oxychloride (POCI 3 ) and 1 ,2,4-triazole.
  • POCI 3 phosphorous oxychloride
  • 1 ,2,4-triazole See, e.g., Webb et al., Nucl. Acid. Res., 14, 7661-74 (1986), which is incorporated herein by this reference. The skilled artisan can vary and further optimize particular conditions as desired.
  • a base such as Et 3 N is used, which in some embodiments can be included in an amount of about 5 or more, 10 or more, or 15 or more eq.
  • the reaction can be carried out in a suitable solvent, which is not limited, such as CH 2 CI 2 and/or CH 3 CN. In some embodiments, the reaction is carried out at about 0-5 °C. In some embodiments, the reaction is carried out at a scale of about 1 kg or more of starting Compound 2. In some embodiments, the yield of Compound 3 is about 85% or greater.
  • a suitable solvent which is not limited, such as CH 2 CI 2 and/or CH 3 CN.
  • the reaction is carried out at about 0-5 °C.
  • the reaction is carried out at a scale of about 1 kg or more of starting Compound 2. In some embodiments, the yield of Compound 3 is about 85% or greater.
  • the invention includes a process for preparing Compound 4 (2-
  • the basic conditions are aqueous basic conditions.
  • the basic conditions include at least one amine based such as pyridine, DIPEA, DMAP, Et 3 N, NMP, or lutidine.
  • the basic conditions include pyridine.
  • the basic conditions include one or more of NaOH or LiOH.
  • the process is carried out with heating, such as at about 40- 100, 60-100, or about 90-100 °C.
  • Compound 4 is isolated by evaporating the reaction mixture, slurrying the crude product in an alcohol or alcohol mixture, and separating the liquid.
  • the separating may be by filtration.
  • Compound 4 is obtained in a purity of about 90% or greater, 95 or greater, or 98% or greater. In some aspects thereof, Compound 4 is obtained in an amount of about 1 kg or more or about 5 kg or more per reaction. In some aspects thereof, Compound 4 is obtained from Compound 3 in a yield of about 60% or more, 70% or more, 80% or more, or 90% or more.
  • the invention includes a process for preparing Compound 5 (4-chloro- 2-[1 ,2,4]tria
  • the invention includes chlorinating with POCI3. In some aspects thereof, the chlorination is carried out in the presence of catalytic phosphoric acid or DMF.
  • Compound 5 is obtained from Compound 4 in a purity of about 90% or more, 95% or more, 98% or more. In some aspects thereof, Compound 5 is obtained in an amount of about 1 kg or more or 5 kg or more. In some aspects thereof, Compound 5 is obtained from Compound 4 in a yield of about 65% or more, 75% or more, or 85% or more. In some aspects, the invention includes a process for preparing a compound of Formula
  • R 5 is -CF 3 , comprising reacting Compound 3 or Compound 5 with a compound of the formula NHR 2 R 3 .
  • R 2 and R 3 are not limited by the representative possibilities described above.
  • the invention includes a process of treating a compound of Formula VI, wherein R 5 is -CF 3 , with an amine NHR 6 R 7 , such as an aniline, to obtain a compound of the formula:
  • R 6 and R 7 are independently H, optionally substituted Ci_i 2 aliphatic, or optionally substituted 4 -i 0 cyclic, except R 6 and R 7 are not both H; or R 6 and R 7 , together with the N to which they are attached, form an optionally substituted 4 -i 0 cyclic.
  • N-methyl-2- ⁇ [2-(1 /-/-1 , 2, 4-triazol-1 - yl)-5- (trifluoromethyl) pyrimidin-4-yl] amino ⁇ benzamide Compound 6, 0.200 g, 0.550 mmol
  • 2-methoxy-4-methyl aniline 0.083 g, 0.606 mmol, 1 .1 eq.
  • trimethylacetic acid (1 .0 g, 9.791 mmol, 17.8 eq.
  • Formula I include any combination of such variables or variable subsets.
  • the invention includes the compounds and salts thereof, and their physical forms, preparation of the compounds.
  • the compounds of the invention and term "compound” in the claims include any pharmaceutically acceptable salts or solvates, and any amorphous or crystal forms, or tautomers, whether or not specifically recited in context.
  • a recitation of a compound herein is open to and embraces any material or composition containing the recited compound (e.g., a composition containing a racemic mixture, tautomers, epimers, stereoisomers, impure mixtures, etc.).
  • a salt, solvate, or hydrate, polymorph, or other complex of a compound includes the compound itself, a recitation of a compound embraces materials containing such forms. Isotopically labeled compounds are also encompassed except where specifically excluded.
  • hydrogen is not limited to hydrogen containing zero neutrons.
  • substituted and substitutions contained in formulas herein refer to the replacement of one or more hydrogen radicals in a given structure with a specified radical, or, if not specified, to the replacement with any chemically feasible radical.
  • substituents can be either the same or different at every position (independently selected) unless otherwise indicated.
  • two positions in a given structure can be substituted with one shared substituent. It is understood that chemically impossible or highly unstable configurations are not desired or intended, as the skilled artisan would appreciate.
  • C b meaning that the moiety can contain any number of from “a” to “b” carbon atoms.
  • C 0 alkyl means a single covalent chemical bond when it is a connecting moiety, and a hydrogen when it is a terminal moiety.
  • x-y can indicate a moiety containing from x to y atoms, e.g., 5 . eheterocycloalkyl means a heterocycloalkyl having either five or six ring members.
  • C x . y may be used to define number of carbons in a group.
  • Co- V alkyr means alkyl having 0-12 carbons, wherein C 0 alkyl means a single covalent chemical bond when a linking group and means hydrogen when a terminal group.
  • heteroarylthioCi_ 4 alkyl is a heteroaryl group connected through a thio sulfur to a Ci-4 alkyl, which alkyl connects to the chemical species bearing the substituent.
  • aliphatic means any hydrocarbon moiety, and can contain linear, branched, and cyclic parts, and can be saturated or unsaturated.
  • alkyl means any saturated hydrocarbon group that is straight-chain or branched. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.
  • cyclic means any ring system with or without heteroatoms (N, O, or S(O) 0 - 2 ), and which can be saturated or unsaturated. Ring systems can be bridged and can include fused rings. The size of ring systems may be described using terminology such as " x . y cyclic," which means a cyclic ring system that can have from x to y ring atoms.
  • g-iocarbocyclic means a 5,6 or 6,6 fused bicyclic carbocyclic ring system which can be satd., unsatd. or aromatic. It also means a phenyl fused to one 5 or 6 membered satd. or unsatd. carbocyclic group. Nonlimiting examples of such groups include naphthyl, 1 ,2,3,4 tetrahydronaphthyl, indenyl, indanyl, and the like.
  • halo or halogen means fluoro, chloro, bromo, or iodo.
  • protecting group means a suitable chemical group that can be attached to a functional group and removed at a later stage to reveal the intact functional group. Examples of suitable protecting groups for various functional groups are described in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d Ed., John Wiley and Sons (1991 and later editions); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
  • hydroxy protecting group as used herein, unless otherwise indicated, includes Ac, CBZ, and various hydroxy protecting groups familiar to those skilled in the art including the groups referred to in Greene.

Abstract

L'invention concerne des composés de formule I : (I) dans laquelle R1, R4 et R5 sont tels que décrits dans la description, et des procédés de fabrication de ces composés, comprenant une fonctionnalisation régiosélective.
PCT/US2014/015925 2013-02-13 2014-02-12 Synthèse régiosélective de pyrimidines substituées WO2014126954A1 (fr)

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US61/764,202 2013-02-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2021106539A1 (fr) * 2019-11-25 2021-06-03

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WO2001064654A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab Composes de pyrimidine
WO2003030909A1 (fr) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- et 4-aminopyrimidines n-substituees par un noyau bicyclique utilisees comme inhibiteurs de kinases dans le traitement du cancer
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WO2012168817A1 (fr) * 2011-06-07 2012-12-13 Pfizer Inc. Composés pyrazolo[3,4-d]pyrimidine et leur utilisation comme inhibiteurs de la pde2 et/ou inhibiteurs du cyp3a4

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WO2003030909A1 (fr) * 2001-09-25 2003-04-17 Bayer Pharmaceuticals Corporation 2- et 4-aminopyrimidines n-substituees par un noyau bicyclique utilisees comme inhibiteurs de kinases dans le traitement du cancer
US7122670B2 (en) 2003-09-05 2006-10-17 Pfizer Inc Selective synthesis of CF3-substituted pyrimidines
US7884202B2 (en) 2005-11-09 2011-02-08 Tosoh Corporation Nucleobase having perfluoroalkyl group and process for producing the same
WO2008116139A2 (fr) * 2007-03-22 2008-09-25 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs des kinases de janus
WO2012168817A1 (fr) * 2011-06-07 2012-12-13 Pfizer Inc. Composés pyrazolo[3,4-d]pyrimidine et leur utilisation comme inhibiteurs de la pde2 et/ou inhibiteurs du cyp3a4

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2021106539A1 (fr) * 2019-11-25 2021-06-03
WO2021106539A1 (fr) * 2019-11-25 2021-06-03 ユニマテック株式会社 Composé de pyrimidine contenant du fluor et son procédé de production
CN114585617A (zh) * 2019-11-25 2022-06-03 优迈特株式会社 含氟嘧啶化合物及其制备方法
JP7159485B2 (ja) 2019-11-25 2022-10-24 ユニマテック株式会社 含フッ素ピリミジン化合物およびその製造方法

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