WO2019040589A1 - Methods for production of emodepside from pf1022a derivatives - Google Patents

Methods for production of emodepside from pf1022a derivatives Download PDF

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WO2019040589A1
WO2019040589A1 PCT/US2018/047471 US2018047471W WO2019040589A1 WO 2019040589 A1 WO2019040589 A1 WO 2019040589A1 US 2018047471 W US2018047471 W US 2018047471W WO 2019040589 A1 WO2019040589 A1 WO 2019040589A1
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ligand
compound
halo
biphenyl
formula
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French (fr)
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Nigel WALSHE
Helen Pointon
Nikzad NIKBIN
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Chalante, Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • PF1022A is a fungally-derived, non-ribosomal peptide natural product octadepsipeptide anthelmintic agent.
  • Emodepside a complex semi-synthetic derivative of PF1022A, is a resistance breaking anthelmintic used exclusively for the more profitable companion animal market owing to high cost of production (Ohyama et al, Biosci,
  • PF1022A The unique and highly complex core structure of the PF1022A natural product has provided challenging opportunities for synthesis.
  • Conversion of PF1022A to the bis-4- morpholino derivative (emodepside) entails low-yielding chemistry such as nitration of the phenyl rings followed by reduction and subsequent functionalization.
  • the generation of regioisomers further reduces the yield of useful intermediates and necessitates expensive purification of the desired ra-regioisomers.
  • Lower cost of goods for emodepside would enable the use of the compound in livestock herds, an application prohibited by its present high cost of manufacture.
  • Substituted derivatives of PF1022A such as emodepside and related compounds, hold great promise as parasiticides useful in treating humans and animals. Access to substituted derivatives of PF1022A would allow for the exploration of new compounds with greater potency and broadened spectrum of activity.
  • a method of producing a compound such as emodepside from a PF1022A derivative comprising the steps of:
  • R 1 and R 2 are independently selected from hydrogen, halo and triflate, subject to the proviso that at least one of Ri and R 2 is not hydrogen;
  • R 3 and R4 are independently selected from the group consisting of hydrogen, halo (e.g., chloro or bromo), triflate and morpholino, wherein at least one of R 3 and R4 is morpholino.
  • the base is selected from the group consisting of cesium carbonate, potassium carbonate, and lithium bis(trimethylsilyl)amide (LHDMS).
  • the palladium source is selected from the group consisting of Pd(OAc) 2 and Pd 2 (dba) 3 .
  • the catalytic ligand comprises one or more phosphine ligands.
  • the catalytic ligand comprises a biarylphosphine ligand. In some embodiments, the palladium source and catalytic ligand are present in a precatalyst.
  • the palladium source and catalytic ligand are present in a precatalyst and the catalytic ligand further comprises one or more phosphine ligands.
  • the solvent is selected from the group consisting of tert- butanol, DMF, THF, and toluene.
  • the reaction is carried out at a temperature of from about 30 °C to about 200 °C.
  • the reacting comprises heating by microwave irradiation.
  • FIG. 1 shows MS data obtained in Example 4.
  • Processes and methods in accordance with the present disclosure include those generally described above and below, and are further illustrated by the embodiments, sub- embodiments, and species disclosed herein.
  • the term "and/or” includes any and all combinations of one or more of the associated listed items.
  • Halo refers to fluoro, chloro, bromo or iodo.
  • Triflate also known as “trifluoromethanesulfonate,” refers to the group:
  • structures depicted herein are also meant to include all enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention, Tautomeric forms include keto-enol tautomers of a compound.
  • “Isomers” refers to compounds having the same number and kind of atoms and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms. It will be understood, however, that some isomers or racemates or others mixtures of isomers may exhibit more activity than others. "Stereoisomers” refers to isomers that differ only in the arrangement of the atoms in space. "Diastereoisomers” refers to stereoisomers that are not mirror images of each other. “Enantiomers” refers to stereoisomers that are non-superimposable mirror images of one another.
  • Aromatic positional isomers are isomers in which substituents (other than hydrogen) may differ in position along an aromatic ring in relation to each other.
  • the ortho isomer has substituents that occupy positions next to each other; meta isomer substituents occupy positions 1 and 3; and para isomer substitutents occupy positions 1 and 4 (e.g., opposite ends of a phenyl ring).
  • enantiomeric compounds taught herein may be "enantiomerically pure" isomers that comprise substantially a single enantiomer, for example, greater than or equal to 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.5%, or equal to 100% of a single enantiomer.
  • enantiomeric compounds as taught herein may be stereochemically pure.
  • “Stereochemically pure” as used herein means a compound or composition thereof that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • R and S as terms describing isomers are descriptors of the stereochemical configuration at an asymmetrically substituted carbon atom.
  • the designation of an asymmetrically substituted carbon atom as “R” or “S” is done by application of the Cahn-Ingold-Prelog priority rules, as are well known to those skilled in the art, and described in the International Union of Pure and Applied Chemistry (IUPAC) Rules for the Nomenclature of Organic Chemistry.
  • compounds of the invention may be substituted with one or more substituents, such as those generally described herein, such as those illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as those generally described herein, such as those illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituted refers to the replacement of hydrogen in a given structure with a specified substituent.
  • a "ring” in the chemical structures described herein may be an aryl, a cycloalkyl, or a heterocycle such as heteroaryl or heterocycloalkyl.
  • Aryl refers to an aromatic carbocyclic moiety having one or more closed rings.
  • Examples include, without limitation, phenyl, naphthyl, anthracenyl, phenylanthracenyl, biphenyl, and pyrenyl.
  • Heteroaryl refers to a cyclic moiety having one or more closed rings, with one or more heteroatoms (oxygen, nitrogen, or sulfur) in at least one of the rings, wherein at least one of the rings is aromatic, and wherein the ring or rings may independently be fused, and/or bridged. Examples include, without limitation, pyridyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, quinoxalinyl, pyrrolyl, indazolyl, thiazolyl, oxazolyl, and isoxazolyl.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons or more.
  • Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Heteroatom refers to O, S or N.
  • Heterocycle or “heterocyclyl” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle containing at least one heteroatom in a ring.
  • Heterocycloalkyl as used herein, means a monocyclic, bicyclic or tricyclic cycloalkyl containing at least one heteroatom in a ring.
  • Rj and R 2 are independently selected from hydrogen and halogen, with the proviso that at least one of Ri and R 2 is not hydrogen;
  • R and R" are each independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkoxy, amino, trialkylsilyl, and triarylsilyl; or R and R" together form an optionally substituted ring consisting of 3-10 backbone atoms inclusive; and wherein said ring may optionally comprise one or more heteroatoms selected from O, S, or N, in addition to the nitrogen to which R and R" are bonded; to produce a compound of Formula I:
  • R 3 and R4 are each independently selected from the group consisting of hydrogen and -N(R')R", wherein at least one of R 3 and R4 is -N(R')R", wherein R' and R" are as defined above.
  • both R ⁇ and R 2 in the compound of Formula II are in the para positions of the phenyl rings to which they are attached.
  • both Ri and R 2 in the compound of Formula II are chloro. In some embodiments, both R ⁇ and R 2 in the compound of Formula II are bromo.
  • the amine of formula HN(R')R" is morpholine.
  • both R 3 and R4 in the compound of Formula I are in the para positions of the phenyl rings to which they are attached.
  • R ⁇ and R 2 of the compound of Formula II are both para- chloro. In some embodiments, R ⁇ and R 2 of the compound of Formula II are both para- bromo.
  • R 3 and R of the compound of Formula I are both para-N- morpholino.
  • the palladium source is Pd(OAc) 2 or Pd 2 (dba) 3 .
  • the catalytic ligand is one or more phosphine ligands. In some embodiments, the catalytic ligand is a biarylphosphine ligand. In some embodiments, the catalytic ligand is one or more phosphine ligands selected from the group consisting of 2,2'- bis(diphenylphosphino)-l,l'-biphenyl ('BiPHEP'), 2-di[3,5- bis(trifluoromethyl)phenylphosphino] -3 ,6-dimethoxy-2',4',6'-trii-propyl- 1 , 1 '-biphenyl (' JackiePhos'), 2-(di-tert-butylphosphino)-3 ,6-dimethoxy-2',4',6'-triisopropyl- 1 , 1 '-biphenyl (' BuBretfPhos'), 2-(di-
  • the catalytic ligand is 2-dicyclohexylphosphino-2'6'- diisopropoxybiphenyl ('RuPhos'). In some embodiments, the catalytic ligand is a combination of 2-dicyclohexylphosphino-2'6'-diisopropoxybiphenyl ('RuPhos') and 2- dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1 '-biphenyl ('XPhos').
  • the palladium source and catalytic ligand are present in a precatalyst.
  • the precatalyst comprises a dialkylbiaryl phosphine ligand with an organopalladium species.
  • Palladium precatalysts suitable for the present invention include those described generally in Bruno and Buchwald, The Strem Chemiker Vol. XXVII, January 2014. Exemplary Buchwald precatalysts are conveniently denoted as 1 st generation (Gl), 2 nd generation (G2), third generation (G3), and 4 th generation (G4), depending on the identity of the organopalladium species.
  • the organopalladium species ('palladacycle') corresponding to the four generations as typically denoted are shown below.
  • BrettPhos Gl precatalyst would comprise 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl- 1,1 '-biphenyl ('BrettPhos') complexed with the Gl organopalladium species shown above.
  • Non-limiting examples of precatalysts that may be used in the present invention include BrettPhos Gl (CAS 1148148-01-90, BrettPhos G2 (CAS 1451002-39-3), BrettPhos G3 (CAS 1470372-59- 8), tBuBrettPhos G3 (CAS 1536473-72-9), JackiePhos G3 (CAS 2102544-35-2), RockPhos G3 (CAS 2009020-38-4), RuPhos Gl (CAS 1028206-60-1), RuPhos G2 (CAS 1375325-68- 0), RuPhos G3 (CAS 1445085-77-7), SPhos Gl (CAS 1028206-58-7), SPhos G2 (CAS 1375325-65-6), SPhos G3 (CAS 1445085-82-4), XPhos Gl
  • the precatalyst is RuPhos G2 (CAS 1375325-68-0).
  • the precatalyst is mixed with and/or in contact with one or more of the above listed phosphine ligands. In some embodiments, the precatalyst is mixed with and/or in contact with phosphine ligand 2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl ('XPhos').
  • the precatalyst RuPhos G2 (CAS 1375325- 68-0) is mixed with and/or in contact with phosphine ligand 2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1,1 '-biphenyl ('XPhos').
  • the amount of palladium source and/or catalytic ligand can vary. In some embodiments, the amount of palladium source and/or catalytic ligand is from about 0.01% mol to about 10%> mol, 0.5% mol to about 10% mol, 1% mol to about 5% mol, or 1.5% mol to about 3% mol, (or about 0.5% , 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%. 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or about 3.0% mol).
  • the amount of precatalyst and/or phosphine ligand can vary. In some embodiments, the amount of precatalyst and/or phosphine ligand is from about 1% to about 50%, 5% to about 45%, 10% to about 40%, 15% to about 40%, 20% to about 40%, or from about 30 to about 40% mol. In some embodiments, the amount of precatalyst is about 1%, 5%>, 10%, 15%, 20%>, 25%, 30%>, 35%o, 40%, 45%, or about 50% mol. In some embodiments, the amount of phosphine ligand is about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or about 50% mol.
  • the precatalyst is present in an amount of about 20%) mol or about 40%> mol. In some embodiments, the phosphine ligand is present in an amount of about 20% mol or about 40%. In some embodiments, the amount of precatalyst and phosphine ligand is the same.
  • Bases which may be used in the method of the present invention include, but are not limited to, sodium tert-butoxide, lithium bis(trimethylsilyl)amide (LHDMS, also known as lithium hexamethyl-disilylamide, LHMDS), potassium carbonate, and/or cesium carbonate.
  • LHDMS lithium bis(trimethylsilyl)amide
  • LHMDS lithium hexamethyl-disilylamide
  • cesium carbonate cesium carbonate.
  • the base is potassium carbonate.
  • Solvents which may be used in the present invention include, but are not limited to, toluene, tetrahydrofuran (THF), tert-butanol or any combination thereof.
  • the solvent is tert-butanol.
  • the solvent is toluene.
  • the solvent is a polar solvent such as, but not limited to, dimethylformamide .
  • the reacting is carried out at a temperature or temperature range that is above room temperature.
  • the temperature is from about 30 °C to about 200 °C, 50 °C to about 175 °C, 75 °C to about 150 °C, 100 °C to about 130 °C (or about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 °C or about 200 °C.
  • the temperature is about 120 °C or about 150 °C.
  • the reacting includes heating the reagent(s) with microwave irradiation. See, e.g., U.S. Patent No. 5,532,462 to Butwell et al. and U.S. Patent No. 6,403,939 to Fagrell. However, additional heating sources can also be used in the invention.
  • the time period for heating can vary.
  • the heating period is from about 5 minutes to about 90 minutes, 10 minutes to about 75 minutes, 20 minutes to about 60 minutes, or from about 30 minutes to about 60 minutes (or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 1 15, or about 120 minutes.
  • the time period for heating is about 30 minutes or about 60 minutes.
  • 2,5,8,11,14,17,20,23-octaone (3) (20 mg, 20.3 ⁇ ), morpholine (2.1 mg, 24.4 ⁇ ⁇ ), cesium carbonate (8.0 mg, 24.4 ⁇ ⁇ ) and chloro(2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1 '-biphenyl)[2-(2 '-amino- l,r-biphenyl)]palladium(II) (RuPhos Pd G2) (3.1 mg, 4.0 ⁇ ⁇ ) were suspended in tert-butanol (0.5 mL), sealed in a 0.5-2.0 mL microwave vial, and heated to 120 °C for 1 hour in the microwave.
  • Morpholine (9 mg, 103 ⁇ ), potassium carbonate (15 mg, 108 ⁇ ), chloro(2-dicyclohexylphosphino-2',6'- diisopropoxy-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) (RuPhos Pd G2) (5.6 mg, 7.2 ⁇ ), and 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, -biphenyl (XPhos) (3.4 mg; 7.2 ⁇ ) were added. The vial was sealed and heated to 120 °C for 1 hour in the microwave. Full consumption of starting material was observed by HPLC/MS together with observation of product 2 (FIG. 1).

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Abstract

Provided is a method of producing a PF1022A derivative, said method comprising the steps of: reacting a compound of Formula II: wherein R1 and R2 are independently selected from hydrogen, halo and triflate, subject to the proviso that at least one of R1 and R2 is not hydrogen; with morpholine and a suitable palladium source in the presence of a suitable catalytic ligand and a suitable base in a suitable solvent; to produce a compound of Formula I: wherein R3 and R4 are independently selected from the group consisting of hydrogen, halo, triflate and morpholino, wherein at least one of R3 and R4 is morpholino.

Description

Methods for Production of Emodepside from PF1022A Derivatives
BACKGROUND
Every year, the loss of valuable livestock/fishes to invertebrate parasites, both endoparasites (nematodes or helminths) and ectoparasites (flies, ticks, mites and sea lice) totals >£34 billion globally. This is despite the fact that farmers spend ~£4.5 billion globally on compounds to protect their animals from parasites (Parasitol Res (2005) 97:S11-S16, - Jeschke et al.). New products are continually needed as new parasites emerge and existing parasites evolve resistance to current treatments.
PF1022A is a fungally-derived, non-ribosomal peptide natural product octadepsipeptide anthelmintic agent. Emodepside, a complex semi-synthetic derivative of PF1022A, is a resistance breaking anthelmintic used exclusively for the more profitable companion animal market owing to high cost of production (Ohyama et al, Biosci,
Figure imgf000002_0001
PF1022A Emodepside
The unique and highly complex core structure of the PF1022A natural product has provided challenging opportunities for synthesis. Conversion of PF1022A to the bis-4- morpholino derivative (emodepside) entails low-yielding chemistry such as nitration of the phenyl rings followed by reduction and subsequent functionalization. In addition to the poor chemical yields arising from nitration (or acetylation, another route), the generation of regioisomers further reduces the yield of useful intermediates and necessitates expensive purification of the desired ra-regioisomers. Lower cost of goods for emodepside would enable the use of the compound in livestock herds, an application prohibited by its present high cost of manufacture. Additionally, with the increase of insect resistance, new PF1022A derived compounds and methods for their synthesis are needed. The recent demonstration that emodepside may have utility in the treatment of African river disease in humans only sharpens the need for new methods for the preparation of emodepside and related structures.
Semisynthetic routes to the bis-hydroxy PF1022A derivative, PF1022H, have recently been described by Scherkenbeck et al. (Bioorg. Med. Chem. 2016, 24, 873-876). One route proceeds from PF1022A by nitration of the phenyl rings followed by reduction to the amine and diazotization followed by hydrolysis to the phenol. A second route utilizes Friedel-Crafts acylation of the phenyl rings followed by Baeyer-Villiger oxidation and subsequent ester cleavage. The nature of the electrophilic substitution chemistry results in mixtures of para and meta isomers, with para predominating. The para-bis-h droxy compound PF1022H has been shown to be a useful intermediate for the preparation of lipophilic PF1022A derivatives. (Ohyama 2011).
Substituted derivatives of PF1022A, such as emodepside and related compounds, hold great promise as parasiticides useful in treating humans and animals. Access to substituted derivatives of PF1022A would allow for the exploration of new compounds with greater potency and broadened spectrum of activity.
There exists a need in the art for the development of an industrially feasible, cost effective, and simple process capable of delivering substituted PF1022A derivatives.
Efficient conversion of a PF 1022A derivative into emodepside such as those described above, would provide new processes for the manufacture of this important anthelmintic agent. In addition, methods allowing the efficient incorporation of moieties other than morpholine onto the PF1022A would give access to novel, hitherto inaccessible, compounds for evaluation as parasiticides.
Accordingly, as embodiments of the present invention, new conditions have been developed for the synthesis of derivatives of PF 1022 A.
SUMMARY
Disclosed herein is a method of producing a compound such as emodepside from a PF1022A derivative, said method comprising the steps of:
reacting a compound of Formula II:
Figure imgf000004_0001
wherein R1 and R2 are independently selected from hydrogen, halo and triflate, subject to the proviso that at least one of Ri and R2 is not hydrogen;
with morpholine and a suitable palladium source in the presence of a suitable catalytic ligand and a suitable base in a suitable solvent;
to produce a compound of Formula I:
Figure imgf000004_0002
I
wherein R3 and R4 are independently selected from the group consisting of hydrogen, halo (e.g., chloro or bromo), triflate and morpholino, wherein at least one of R3 and R4 is morpholino.
In some embodiments, the base is selected from the group consisting of cesium carbonate, potassium carbonate, and lithium bis(trimethylsilyl)amide (LHDMS).
In some embodiments, the palladium source is selected from the group consisting of Pd(OAc)2 and Pd2(dba)3.
In some embodiments, the catalytic ligand comprises one or more phosphine ligands.
In some embodiments, the catalytic ligand comprises a biarylphosphine ligand. In some embodiments, the palladium source and catalytic ligand are present in a precatalyst.
In some embodiments, the palladium source and catalytic ligand are present in a precatalyst and the catalytic ligand further comprises one or more phosphine ligands.
In some embodiments, the solvent is selected from the group consisting of tert- butanol, DMF, THF, and toluene.
In some embodiments, the reaction is carried out at a temperature of from about 30 °C to about 200 °C.
In some embodiments, the reacting comprises heating by microwave irradiation.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows MS data obtained in Example 4.
DETAILED DESCRIPTION OF EMBODIMENTS
Provide herein are processes and methods useful for the preparation of emodepside from certain PF1022A derivatives.
A. DEFINITIONS
Processes and methods in accordance with the present disclosure include those generally described above and below, and are further illustrated by the embodiments, sub- embodiments, and species disclosed herein. As used herein the term "and/or" includes any and all combinations of one or more of the associated listed items.
As used herein, the following definitions shall apply unless otherwise indicated.
"Halo" refers to fluoro, chloro, bromo or iodo.
"Triflate," also known as "trifluoromethanesulfonate," refers to the group:
Figure imgf000005_0001
O NH
"Morpholine" refers to the compound: \—— / . "Morpholino" refers to the
Figure imgf000005_0002
Unless otherwise stated, structures depicted herein are also meant to include all enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention, Tautomeric forms include keto-enol tautomers of a compound. In addition, unless otherwise stated, all rotamer forms of the compounds of the invention are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C -enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
"Isomers" refers to compounds having the same number and kind of atoms and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms. It will be understood, however, that some isomers or racemates or others mixtures of isomers may exhibit more activity than others. "Stereoisomers" refers to isomers that differ only in the arrangement of the atoms in space. "Diastereoisomers" refers to stereoisomers that are not mirror images of each other. "Enantiomers" refers to stereoisomers that are non-superimposable mirror images of one another.
"Aromatic positional isomers" are isomers in which substituents (other than hydrogen) may differ in position along an aromatic ring in relation to each other. As known in the art, the ortho isomer has substituents that occupy positions next to each other; meta isomer substituents occupy positions 1 and 3; and para isomer substitutents occupy positions 1 and 4 (e.g., opposite ends of a phenyl ring).
In some embodiments, enantiomeric compounds taught herein may be "enantiomerically pure" isomers that comprise substantially a single enantiomer, for example, greater than or equal to 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.5%, or equal to 100% of a single enantiomer.
In some embodiments, enantiomeric compounds as taught herein may be stereochemically pure. "Stereochemically pure" as used herein means a compound or composition thereof that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
In some embodiments, "R" and "S" as terms describing isomers are descriptors of the stereochemical configuration at an asymmetrically substituted carbon atom. The designation of an asymmetrically substituted carbon atom as "R" or "S" is done by application of the Cahn-Ingold-Prelog priority rules, as are well known to those skilled in the art, and described in the International Union of Pure and Applied Chemistry (IUPAC) Rules for the Nomenclature of Organic Chemistry.
As described herein, compounds of the invention may be substituted with one or more substituents, such as those generally described herein, such as those illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the invention. In general the term "substituted" refers to the replacement of hydrogen in a given structure with a specified substituent. When a structure is described as "substituted" without further specification, it is understood that said group may be substituted with one or more substituents chosen from the group consisting of hydrogen, halo, carboxylate, carboxyalkyl, nitro, hydroxyl, amine such as amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl.
A "ring" in the chemical structures described herein may be an aryl, a cycloalkyl, or a heterocycle such as heteroaryl or heterocycloalkyl.
"Aryl" refers to an aromatic carbocyclic moiety having one or more closed rings.
Examples include, without limitation, phenyl, naphthyl, anthracenyl, phenylanthracenyl, biphenyl, and pyrenyl.
"Heteroaryl" refers to a cyclic moiety having one or more closed rings, with one or more heteroatoms (oxygen, nitrogen, or sulfur) in at least one of the rings, wherein at least one of the rings is aromatic, and wherein the ring or rings may independently be fused, and/or bridged. Examples include, without limitation, pyridyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, quinoxalinyl, pyrrolyl, indazolyl, thiazolyl, oxazolyl, and isoxazolyl.
"Cycloalkyl" as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons or more. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
"Heteroatom" refers to O, S or N.
"Heterocycle" or "heterocyclyl" as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle containing at least one heteroatom in a ring. "Heterocycloalkyl" as used herein, means a monocyclic, bicyclic or tricyclic cycloalkyl containing at least one heteroatom in a ring.
B. METHODS FOR PRODUCTION
In some embodiments, there is provided a process for producing a compound of
Formula I from a compound of Formula II comprising the steps of: reacting a compound of Formula II:
Figure imgf000008_0001
II
wherein Rj and R2 are independently selected from hydrogen and halogen, with the proviso that at least one of Ri and R2 is not hydrogen;
with an amine of formula HN(R')R" and a suitable palladium source in the presence of a suitable catalytic ligand and a suitable base in a suitable solvent, wherein R and R" are each independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl, alkoxy, amino, trialkylsilyl, and triarylsilyl; or R and R" together form an optionally substituted ring consisting of 3-10 backbone atoms inclusive; and wherein said ring may optionally comprise one or more heteroatoms selected from O, S, or N, in addition to the nitrogen to which R and R" are bonded; to produce a compound of Formula I:
Figure imgf000009_0001
wherein R3 and R4 are each independently selected from the group consisting of hydrogen and -N(R')R", wherein at least one of R3 and R4 is -N(R')R", wherein R' and R" are as defined above.
In some embodiments, both R\ and R2 in the compound of Formula II are in the para positions of the phenyl rings to which they are attached.
In some embodiments, both Ri and R2 in the compound of Formula II are chloro. In some embodiments, both R\ and R2 in the compound of Formula II are bromo.
In some embodiments, the amine of formula HN(R')R" is morpholine.
In some embodiments, both R3 and R4 in the compound of Formula I are in the para positions of the phenyl rings to which they are attached.
In some embodiments, R\ and R2 of the compound of Formula II are both para- chloro. In some embodiments, R\ and R2 of the compound of Formula II are both para- bromo.
In some embodiments, R3 and R of the compound of Formula I are both para-N- morpholino.
In some embodiments, the palladium source is Pd(OAc)2 or Pd2(dba)3.
In some embodiments, the catalytic ligand is one or more phosphine ligands. In some embodiments, the catalytic ligand is a biarylphosphine ligand. In some embodiments, the catalytic ligand is one or more phosphine ligands selected from the group consisting of 2,2'- bis(diphenylphosphino)-l,l'-biphenyl ('BiPHEP'), 2-di[3,5- bis(trifluoromethyl)phenylphosphino] -3 ,6-dimethoxy-2',4',6'-trii-propyl- 1 , 1 '-biphenyl (' JackiePhos'), 2-(di-tert-butylphosphino)-3 ,6-dimethoxy-2',4',6'-triisopropyl- 1 , 1 '-biphenyl (' BuBretfPhos'), 2-(di-tert-butylphosphino)biphenyl ('JohnPhos'), 2-di-tert-butylphosphino- 2'-(N,N-dimethylamino)biphenyl, 2-di-t-butylphosphino)-3-methoxy-2',4',6'-triisopropyl- 1,1'- biphenyl ('RockPhos'), 2-(di-tert-butylphosphino)-2'-methylbiphenyl ('tBuMePhos'), 2-dit- butylphosphino-3 ,4,5,6-tetramethyl-2',4',6'-tri-i-propylbiphenyl ('Me4-tBuXPhos'), 2-di-tert- butylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl ('tBuXPhos'), 2-
(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2',6'-dimethoxy- 1 , 1 '-biphenyl ('SPhos'), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl
('BrettPhos'), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2- dicyclohexylphosphino-2'-methylbiphenyl ('MePhos'), 2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1 , 1 '-biphenyl ('XPhos'), 2-(diphenylphosphino)-2'-(N,N- dimethylamino)biphenyl, sodium 2'-dicyclohexylphosphino-2,6-dimethoxy- 1 , 1 !-biphenyl-3- sulfonate hydrate ('Water soluble SPhos'), and 2-dicyclohexylphosphino-2'6'- diisopropoxybiphenyl ('RuPhos').
In some embodiments, the catalytic ligand is 2-dicyclohexylphosphino-2'6'- diisopropoxybiphenyl ('RuPhos'). In some embodiments, the catalytic ligand is a combination of 2-dicyclohexylphosphino-2'6'-diisopropoxybiphenyl ('RuPhos') and 2- dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1 '-biphenyl ('XPhos').
In some embodiments, the palladium source and catalytic ligand are present in a precatalyst. In some embodiments, the precatalyst comprises a dialkylbiaryl phosphine ligand with an organopalladium species. Palladium precatalysts suitable for the present invention include those described generally in Bruno and Buchwald, The Strem Chemiker Vol. XXVII, January 2014. Exemplary Buchwald precatalysts are conveniently denoted as 1st generation (Gl), 2nd generation (G2), third generation (G3), and 4th generation (G4), depending on the identity of the organopalladium species. The organopalladium species ('palladacycle') corresponding to the four generations as typically denoted are shown below.
Figure imgf000010_0001
L denotes a Buchwald catalytic ligand as described herein. Thus a "BrettPhos Gl " precatalyst would comprise 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl- 1,1 '-biphenyl ('BrettPhos') complexed with the Gl organopalladium species shown above.
In the following recitation of non-limiting examples of precatalysts that may be utilized in the method of the present invention, catalog numbers, PubChem Substance ID Numbers, or Chemical Abstract Registry Numbers are provided for clarity. Non-limiting examples of precatalysts that may be used in the present invention include BrettPhos Gl (CAS 1148148-01-90, BrettPhos G2 (CAS 1451002-39-3), BrettPhos G3 (CAS 1470372-59- 8), tBuBrettPhos G3 (CAS 1536473-72-9), JackiePhos G3 (CAS 2102544-35-2), RockPhos G3 (CAS 2009020-38-4), RuPhos Gl (CAS 1028206-60-1), RuPhos G2 (CAS 1375325-68- 0), RuPhos G3 (CAS 1445085-77-7), SPhos Gl (CAS 1028206-58-7), SPhos G2 (CAS 1375325-65-6), SPhos G3 (CAS 1445085-82-4), XPhos Gl (CAS 1028206-56-5), XPhos G2 (CAS 1310584-14-5), XPhos G3 (CAS 1445085-55-1), tBuXPhos Gl (CAS 114281 1-12-8), tBuXPhos G3 (CAS 1447963-75-8), BrettPhos G4 (CAS 1599466-83-7), RuPhos G4 (CAS 1599466-85-9), SPhos G4 (CAS 1599466-87-1), tBuBrettPhos G4 (Aldrich cat. no. 807877, available at Scientific Sales, Inc., Oak Ridge, TN) {see also King and Buchwald, Organic Letters, 2016, 18, 4128-4131), XPhos G4 (CAS 1599466-81-5) and tBuXPhos G4 (Aldrich cat. no. 804266, available at Scientific Sales, Inc., Oak Ridge, TN). In some embodiments, the precatalyst is RuPhos G2 (CAS 1375325-68-0).
In some embodiments, the precatalyst is mixed with and/or in contact with one or more of the above listed phosphine ligands. In some embodiments, the precatalyst is mixed with and/or in contact with phosphine ligand 2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl ('XPhos'). In some embodiments, the precatalyst RuPhos G2 (CAS 1375325- 68-0) is mixed with and/or in contact with phosphine ligand 2-dicyclohexylphosphino-2',4',6'- triisopropyl- 1,1 '-biphenyl ('XPhos').
The amount of palladium source and/or catalytic ligand can vary. In some embodiments, the amount of palladium source and/or catalytic ligand is from about 0.01% mol to about 10%> mol, 0.5% mol to about 10% mol, 1% mol to about 5% mol, or 1.5% mol to about 3% mol, (or about 0.5% , 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%. 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or about 3.0% mol).
The amount of precatalyst and/or phosphine ligand can vary. In some embodiments, the amount of precatalyst and/or phosphine ligand is from about 1% to about 50%, 5% to about 45%, 10% to about 40%, 15% to about 40%, 20% to about 40%, or from about 30 to about 40% mol. In some embodiments, the amount of precatalyst is about 1%, 5%>, 10%, 15%, 20%>, 25%, 30%>, 35%o, 40%, 45%, or about 50% mol. In some embodiments, the amount of phosphine ligand is about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or about 50% mol. In some embodiments, the precatalyst is present in an amount of about 20%) mol or about 40%> mol. In some embodiments, the phosphine ligand is present in an amount of about 20% mol or about 40%. In some embodiments, the amount of precatalyst and phosphine ligand is the same.
Bases which may be used in the method of the present invention include, but are not limited to, sodium tert-butoxide, lithium bis(trimethylsilyl)amide (LHDMS, also known as lithium hexamethyl-disilylamide, LHMDS), potassium carbonate, and/or cesium carbonate. In some embodiments, the base is cesium carbonate. In some embodiments, the base is potassium carbonate.
Solvents which may be used in the present invention include, but are not limited to, toluene, tetrahydrofuran (THF), tert-butanol or any combination thereof. In some embodiments, the solvent is tert-butanol. In some embodiments, the solvent is toluene. In some embodiments, the solvent is a polar solvent such as, but not limited to, dimethylformamide .
In some embodiments, the reacting is carried out at a temperature or temperature range that is above room temperature. In some embodiments, the temperature is from about 30 °C to about 200 °C, 50 °C to about 175 °C, 75 °C to about 150 °C, 100 °C to about 130 °C (or about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 °C or about 200 °C. In some embodiments, the temperature is about 120 °C or about 150 °C. In some embodiments, the reacting includes heating the reagent(s) with microwave irradiation. See, e.g., U.S. Patent No. 5,532,462 to Butwell et al. and U.S. Patent No. 6,403,939 to Fagrell. However, additional heating sources can also be used in the invention.
The time period for heating can vary. In some embodiments, the heating period is from about 5 minutes to about 90 minutes, 10 minutes to about 75 minutes, 20 minutes to about 60 minutes, or from about 30 minutes to about 60 minutes (or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 1 15, or about 120 minutes. In some embodiments, the time period for heating is about 30 minutes or about 60 minutes.
The present invention is further illustrated by the following non-limiting examples. EXAMPLE 1
Figure imgf000013_0001
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl- 12,24-bis(4-morpholinobenzyl)- 1,7,13,19-tetraoxa-4, 10, 16,22-tetraazacyclotetracosan- 2,5,8,11,14,17,20,23 -octaone (2)
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-chlorobenzyl)-3,9,15,21-tetraisobutyl- 4,10,12,16,22,24-hexamethyl- 1,7,13,19-tetraoxa-4, 10,16,22-tetraazacyclotetracosan- 2,5,8,11,14, 17,20,23-octaone (1) (20 mg, 19.6 μπιοΐ), morpholine (4.1 mg, 47.0 μηιοΐ), cesium carbonate (15 mg, 47.0 μιηοΐ) and chloro(2-dicyclohexylphosphino-2',6'- diisopropoxy-l,r-biphenyl)[2-(2'-amino-l,l '-biphenyl)]palladium(II) (RuPhos Pd G2) (6.0 mg, 7.8 μη οΐ) were suspended in tert-butanol (0.5 mL), sealed in a 0.5-2.0 mL microwave vial, and heated to 120 °C for 30 minutes in the microwave. The reaction mixture was diluted with ethyl acetate (5 mL), washed with water (2 x 1 mL), then brine (1 mL), dried over magnesium sulphate and concentrated under reduced pressure to give a yellow oil. The crude material was purified by preparative HPLC (XSelect C18 column, 19x150 mm, 20 mL/min flow rate, 70-80% MeCN in 0.1% aqueous formic acid for 10 mins) to give (3 S,6R,9S, 12R, 15 S, 18R,21 S,24R)-3,9, 15,21 -tetraisobutyl-4,6, 10,16,18,22-hexamethyl- 12,24-bis(4-morpholinobenzyl)- 1,7,13,19-tetraoxa-4, 10,16,22-tetraazacyclotetracosan- 2,5,8,11,14, 17,20,23 -octaone (2) (1.5 mg, 7%) as a colourless solid. 1H-NMR (301 MHz, CHLOROFORM-D) δ 7.12-7.18 (m, 4H), 6.80-6.83 (m, 4H), 5.31-5.65 (m, 6H), 5.24-4.98 (m, 1H), 4.28-4.49 (m, 1H), 3.85 (t, 8H), 2.97-3.13 (m, 15H), 1.78-1.66 (m, 6H), 2.61-2.83 (m, 10H*), 1.25-1.41 (m, 3H), 0.80-1.15 (m, 32H). *Estimated. Signal partially obscured. UPLC (acidic): Column: CSH CI 8 1.7 μτη 2.1 x 50 mm, Run Time: 5.0 min, solvents: A) 2% formic acid in water B) 2% formic acid in MeCN, gradient: 50-95%, rt = 2.52 min (91.87%, (M+H+)+ 1119.30)
EXAMPLE 2
Figure imgf000014_0001
(3 S ,6R,9S , 12R, 15 S, 18R,21 S,24R)-6-benzyl-3 ,9,15,21 -tetraisobutyl-4, 10, 12, 16,22,24- hexamethyl- 18-(4-morpholinobenzyl)- 1 ,7, 13, 19-tetraoxa-4, 10, 16,22-tetraazacyclotetracosan- 2,5,8,11,14,17,20,23-octaone (4)
(3 S,6R,9S, 12R, 15 S, 18R,21 S,24R)-6-benzyl- 18-(4-chlorobenzyl)-3,9, 15,21 -tetraisobutyl- 4,10,12,16,22,24-hexamethyl- 1,7,13,19-tetraoxa-4, 10, 16,22-tetraazacyclotetracosan-
2,5,8,11,14,17,20,23-octaone (3) (20 mg, 20.3 μηιοΐ), morpholine (2.1 mg, 24.4 μη οΐ), cesium carbonate (8.0 mg, 24.4 μη οΓ) and chloro(2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1 '-biphenyl)[2-(2 '-amino- l,r-biphenyl)]palladium(II) (RuPhos Pd G2) (3.1 mg, 4.0 μη οΐ) were suspended in tert-butanol (0.5 mL), sealed in a 0.5-2.0 mL microwave vial, and heated to 120 °C for 1 hour in the microwave. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (2 x 2 mL), dried over magnesium sulphate and concentrated under reduced pressure to give a yellow oil. The crude material was purified by preparative HPLC (XSelect CI 8 column, 19x150 mm, 20 mL/min flow rate, 80% MeCN in 0.1% aqueous formic acid for 10 mins) to give (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl- 3 ,9, 15,21 -tetraisobutyl-4, 10,12,16,22,24-hexamethyl- 18-(4-morpholinobenzyl)- 1,7,13,19- tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,l 1,14,17,20,23-octaone (4) (7.2 mg, 34%) as a colorless solid. IH-NMR (301 MHz, CHLOROFORM-D) δ 7.25-7.28 (m, 4H*), 7.13 (dd, 2H), 6.79-6.83 (m, 2H), 5.31-5.69 (m, 6H), 5.04-5.20 (m, 1H), 4.44-4.49 (m, 1H), 3.85 (t, 4H), 2.95-3.19 (m, 10H), 2.71-2.83 (m, 10H), 1.23-1.84 (m, 14H), 0.80-1.04 (m, 29H).
UPLC (acidic): Column: CSH C18 1.7 μπι 2.1 x 50 mm, Run Time: 5.0 min, solvents: A) 2% formic acid in water B) 2% formic acid in MeCN, gradient: 50-95%, rt = 2.85 min (98.85%, (M+H+)+ 1034.35)
EXAMPLE 3
Figure imgf000015_0001
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl- 12,24-bis(4-morpholinobenzyl)- 1,7,13,19-tetraoxa-4, 10,16,22-tetraazacyclotetracosan- 2,5,8,1 1,14, 17,20,23-octaone (2)
((3 S,6R,9S, 12R, 15S, 18R,21 S,24R)-6, 18-bis(4-bromobenzyl)-3 ,9, 15,21 -tetraisobutyl- 4,10,12,16,22,24-hexamethyl- 1 ,7,13,19-tetraoxa-4, 10, 16,22-tetraazacyclotetracosan- 2,5,8,11,14, 17,20,23-octaone (5) (5 mg, 4.5 μπιοι), morpholine (0.9 mg, 10.8 μηιοΐ), cesium carbonate (3.5 mg, 10.8 μηιοΐ) and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l '- biphenyl)[2-(2'-amino-l, l '-biphenyl)]palladium(II) (RuPhos Pd G2) (1.4 mg, 1.8 μιηοΐ) were suspended in tert-butanol (0.2 mL), sealed in a 0.2-0.5 mL microwave vial, and heated to 120 °C for 1 hour in the microwave. Full consumption of starting material was observed by UPLC. The compounds 2, 4, and 6 were observed in a 2: 1 :2 ratio, based on UV:
Figure imgf000016_0001
This reaction was not worked-up or purified.
Figure imgf000016_0002
(3S,6R,9S,12R,15S,18R,21 S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl- 12,24-bis(4-morpholinobenzyl)- 1,7,13,19-tetraoxa-4, 10,16,22-tetraazacyclotetracosan- 2,5,8, 11, 14,17,20,23 -octaone (2)
((3 S,6R,9S , 12R, 15 S, 18R,21 S ,24R)-6, 18-bis(4-bromobenzyl)-3 ,9,15,21 -tetraisobutyl- 4,10,12,16,22,24-hexamethyl- 1 ,7, 13 , 19-tetraoxa-4, 10, 16,22-tetraazacyclotetracosan- 2,5,8,1 1,14, 17,20,23 -octaone (5, as a mixture of regioisomers) (20 mg, 18 μηιοΐ) was dissolved in 0.7 mL of toluene in a 0.2-0.5 mL microwave vial. Morpholine (9 mg, 103 μηιοΐ), potassium carbonate (15 mg, 108 μιηοΐ), chloro(2-dicyclohexylphosphino-2',6'- diisopropoxy-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) (RuPhos Pd G2) (5.6 mg, 7.2 μηιοΐ), and 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, -biphenyl (XPhos) (3.4 mg; 7.2 μηιοΐ) were added. The vial was sealed and heated to 120 °C for 1 hour in the microwave. Full consumption of starting material was observed by HPLC/MS together with observation of product 2 (FIG. 1).
Modification of the above reaction conditions essentially rendered the same results. These modificatons included (a) increasing the reaction temperature to 150 °C; or (b) adding additional amounts of precatalyst and/or phosphine ligand to the reaction mixture hourly until the reaction was complete. For example additional amounts of chloro(2- dicyclohexylphosphino-2',6'-diisopropoxy- 1 , 1 '-biphenyl) [2-(2'-amino- 1 , Γ- biphenyl)]palladium(II) (RuPhos Pd G2) and/or 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl (XPhos) were added every hour to the heating reaction mixture until the reaction was complete.
The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

What is claimed is:
1. A process for producing a compound of Formula I:
Figure imgf000018_0001
I
wherein R3 and R4 are each independently selected from the group consisting of hydi halo and morpholino, wherein at least one of R3 and R4 is morpholino,
said method comprising reacting a compound of Formula II:
Figure imgf000018_0002
II
wherein Ri and R2 are each independently selected from hydrogen and halo, and wherein at least one of R] and R2 is halo,
with morpholine and a suitable palladium source in the presence of a suitable catalytic ligand and a suitable base in a suitable solvent,
to produce the compound of Formula I.
2. The process of claim 1, wherein the base is selected from the group consisting of cesium carbonate, potassium carbonate, and lithium bis(trimethylsilyl)amide (LHDMS).
3. The process of claim 1 or claim 2, wherein the palladium source is selected from the group consisting of Pd(OAc)2 and Pd2(dba)3.
4. The process of any one of claims 1-3, wherein the catalytic ligand comprises one or more phosphine ligands.
5. The process of claim 4, wherein the catalytic ligand comprises a biarylphosphine ligand.
6. The process of claim 4, wherein the catalytic ligand comprises RuPhos.
7. The process of any one of claims 1-6, wherein the palladium source and catalytic ligand are present in a precatalyst.
8. The process of claim 7, wherein the precatalyst comprises a dialkylbiaryl phosphine ligand with an organopalladium species.
9. The process of claim 7, wherein the precatalyst is RuPhos Pd G2.
10. The process of claim 7, wherein the catalytic ligand further comprises one or more phosphine ligands.
11. The process of claim 10, wherein the one or more phosphine ligands comprises 2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl ('XPhos').
12. The process of any one of claims 1-11, wherein the solvent is selected from the group consisting of tert-butanol, DMF, THF, and toluene.
13. The process of claim 1 , wherein the reaction is carried out at a temperature of from about 30 °C to about 200 °C.
14. The process of any one of claims 1-13, wherein said halo is chloro.
15. The process of any one of claims 1-13, wherein said halo is bromo .
16. The process of any one of claims 1-15, wherein the reacting comprises heating by microwave irradiation.
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