WO2020092239A1 - Processes for the preparation of fungicidal compounds - Google Patents

Processes for the preparation of fungicidal compounds Download PDF

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Publication number
WO2020092239A1
WO2020092239A1 PCT/US2019/058347 US2019058347W WO2020092239A1 WO 2020092239 A1 WO2020092239 A1 WO 2020092239A1 US 2019058347 W US2019058347 W US 2019058347W WO 2020092239 A1 WO2020092239 A1 WO 2020092239A1
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WIPO (PCT)
Prior art keywords
formula
salt
compound
base
bicarbonate
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PCT/US2019/058347
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French (fr)
Inventor
William H. Miller
Daniel P. Walker
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Gilead Apollo, Llc
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Publication of WO2020092239A1 publication Critical patent/WO2020092239A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Phytopathogenic fungi can infect crop plants either in the field or after harvesting, resulting in considerable economic losses to farmers and producers worldwide.
  • a number of debilitating diseases or death can occur.
  • Approximately 10,000 species of fungi are known to damage crops and affect quality and yield. Crop rotation, breeding of resistant cultivars, the application of agrochemicals and combinations of these strategies is commonly employed to stem the spread of fungal pathogens and the diseases they cause.
  • Acetyl-CoA carboxylase is an essential catalyst for the rate-limiting step of fatty acid biosynthesis in both eukaryotes and prokaryotes.
  • Certain N1,N3-dialkylated thienopyrimidinediones that are effective inhibitors of ACC, exhibit fungicidal activity and are useful in the preparation of compositions and in accordance with methods for control of fungal pathogens in agriculture, are described in U.S. Publication Nos.2017/0166584 A1,
  • N1,N3-dialkylated thienopyrimidinediones that are useful as fungicides, and related precursors and intermediates.
  • R 1 is 2H-1,2,3-triazol-2- yl, 1-pyrazolyl, or -C(O)OR 3 ;
  • R 2 is -C(O)OR 3 ;
  • R 3 is a straight or branched C 1 –C 4 alkyl;
  • R 4 is hydrogen or CH 3 ;
  • R 5 is OR 6 or NR 7 R 8 ;
  • R 6 is straight or branched C 1 –C 4 alkyl or benzyl;
  • R 7 is hydrogen or CH3; and
  • R 8 is ethyl, isopropyl, or cyclobutyl; or R 7 and R 8 are joined to form a 5- membered or 6-membered heterocycloalkyl ring.
  • Another embodiment is directed to a process for preparing a compound of Formula III:
  • the process comprises preparing a compound of Formula IV or a salt thereof as set forth above and contacting the compound of Formula IV or a salt thereof with an alkali metal alkoxide base or alkaline earth metal alkoxide base in a cyclization reaction medium to produce the compound of Formula III or a salt thereof.
  • the process comprises preparing a compound of Formula III or a salt thereof as set forth above and contacting the compound of Formula III or a salt thereof with a compound of Formula II:
  • the process for the preparation of a compound of Formula I or a salt thereof comprises contacting a compound of Formula IV:
  • a mineral acid is added to the cyclization reaction medium comprising the compound of Formula III or a salt thereof.
  • the compound of Formula III or salt thereof is contacted with a compound of Formula II:
  • the process for the preparation of a compound of Formula I or a salt thereof comprises contacting a compound of Formula III:
  • an alkylation reaction medium comprising an alkali metal bicarbonate base or alkaline earth metal bicarbonate base to produce the compound of Formula I or a salt thereof.
  • the process for preparing a compound of Formula I or a salt thereof comprises contacting a compound of Formula III:
  • an alkylation reaction medium comprising a base and a solvent selected from the group consisting of diethyl carbonate, 2-methyltetrahydrofuran, dimethylacetamide, and a combination thereof, to produce the compound of Formula I or a salt thereof.
  • the process for preparing a compound of Formula I or a salt thereof comprises contacting a compound of Formula III:
  • an alkylation reaction medium comprising a base and an alkylation catalyst comprising a tetrabutylammonium halide to produce the compound of Formula I or a salt thereof.
  • R 1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR 3 ;
  • R 4 is hydrogen;
  • R 5 is NR 7 R 8 ;
  • R 7 is hydrogen or CH 3 ;
  • R 8 is ethyl, isopropyl, or cyclobutyl; or
  • R 7 and R 8 are joined to form a 5-membered or 6-membered heterocycloalkyl ring; and
  • R 9 is hydrogen or F.
  • the process comprises contacting a monomethylamide compound of Formula IV:
  • an alkylation reaction medium comprising an alkali metal or alkaline earth metal carbonate or bicarbonate base to produce the compound of Formula I or a salt thereof.
  • the process comprises preparing a compound of Formula I or salt thereof as set forth above and contacting the compound of Formula I or salt thereof with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound of Formula VIII or a salt thereof.
  • the present invention is directed to a process for preparing a compound of Formula IV:
  • R 1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR 3 ;
  • R 2 is -C(O)OR 3 ;
  • R 3 is straight or branched C1–C4 alkyl;
  • R 4 is hydrogen or CH3;
  • R 5 is OR 6 or NR 7 R 8 ;
  • R 6 is straight or branched C 1 -C 4 alkyl or benzyl;
  • R 7 is hydrogen or CH 3 ; and
  • R 8 is ethyl, isopropyl, or cyclobutyl; or R 7 and R 8 are joined to form a 5-membered or 6-membered heterocycloalkyl ring.
  • the process comprises contacting a compound of Formula VII:
  • compounds of Formula VI can be prepared by contacting compound of Formula VII at low temperature with phosgene in the presence of a trialkylamine base (e.g., triethylamine).
  • a trialkylamine base e.g., triethylamine
  • the temperature range is from -20 to 20 °C. In other embodiments the temperature range is from -10 to 10 °C. In other embodiments, the temperature range is from -5 to 5 °C. Stoichiometric ratios are those described below.
  • preparation of Formula VI involves concurrent addition of a solution of a compound of Formula VII into a solvent, such as diethyl carbonate (DEC), with gaseous phosgene addition at elevated temperatures in the absence of a trialkylamine base.
  • a solvent such as diethyl carbonate (DEC)
  • gaseous phosgene addition at elevated temperatures in the absence of a trialkylamine base.
  • the temperature range is from 80 to 120 °C. In other embodiments, the temperature range is from 90 to 110 °C. In yet other embodiments, the temperature range is from 90 to 95 °C. Stoichiometry is that described below.
  • R 1 and R 2 are the same.
  • R 1 and R 2 may both be -C(O)OR 3 and R 3 may be ethyl.
  • R 1 and R 2 are both -C(O)OR 3 and R 3 is isopropyl.
  • R 4 is methyl. In another embodiment, R 4 is hydrogen.
  • R 5 is OR 6 .
  • R 5 is OR 6 and R 6 is tert-butyl.
  • R 5 is or NR 7 R 8 and R 7 and R 8 are as described above.
  • the phosgene reagent contacted with a compound of Formula VII may comprise phosgene, diphosgene, triphosgene, or a mixture thereof.
  • the phosgene reagent comprises phosgene.
  • a molar excess of the phosgene reagent relative to the compound of Formula VII is employed.
  • the molar ratio of the phosgene reagent to the compound of Formula VII is typically greater than 1:1 to about 4:1, more typically from about 2:1 to about 3:1, or greater than 1:1 to about 2.5:1.
  • any chemically acceptable salt may be used as the salt of the amine of Formula V contacted with the isocyanate intermediate of Formula VI.
  • the amine salt is an acid addition salt such as a hydrohalide salt or methanesulfonic acid addition salt.
  • suitable hydrohalide salts include hydrochloride, hydrofluoride, hydrobromide, and hydroiodide salts.
  • the salt of the amine of Formula V is the hydrochloride salt.
  • a molar excess of the amine salt of Formula V relative to the isocyanate intermediate of Formula VI is employed.
  • the molar ratio of the amine salt of Formula V to the isocyanate intermediate of Formula VI is typically greater than 1:1 to about 2.5:1, more typically greater than 1:1 to about 1.5:1, or greater than 1:1 to about 1.25:1.
  • each contacting step is optionally independently conducted in the presence of a solvent.
  • suitable solvents include toluene, xylene, acetonitrile, 2- methyltetrahydrofuran, diethyl carbonate, or a combination thereof.
  • the solvent comprises a non-polar solvent such as an aromatic non-polar solvent (e.g., toluene, xylene or a mixture thereof), optionally in combination with one or more additional solvents (e.g., acetonitrile).
  • the solvent comprise toluene.
  • the solvent comprises xylene.
  • the solvent comprises a mixture of toluene and acetonitrile.
  • the solvent comprises a mixture of xylene and acetonitrile.
  • each contacting step is optionally independently conducted in the presence of a base.
  • suitable bases comprise triethylamine, diisopropylethylamine, potassium tert-butoxide, pyridine, sodium bicarbonate, potassium carbonate, sodium hydroxide, or a combination thereof.
  • the base comprises triethylamine.
  • the compound of Formula VII when conducted in the presence of an external base, is contacted with the phosgene reagent at a temperature of from about -20 °C to about 20 °C, more typically from about -5 °C to about 5 °C, and the isocyanate intermediate of Formula VI or salt thereof is contacted with the amine salt of Formula V at a temperature of from about 0 °C to about 50 °C, more typically from about 0 °C to about 30 °C.
  • each contacting step in the preparation of a compound of Formula IV is optionally independently conducted in the absence of an external base.
  • the process can comprise contacting the compound of Formula VII or salt thereof with the phosgene reagent and heating in the absence of an external base to produce the isocyanate intermediate of Formula VI or salt thereof and hydrochloric acid gas.
  • the reaction proceeds through a chloroimidate intermediate of Formula IX:
  • the process can comprise contacting the isocyanate intermediate of Formula VI or salt thereof with the salt of the amine of Formula V and heating in the absence of an external base to produce a compound of Formula IV or a salt thereof.
  • the reaction mixture in which the compound of Formula VII or salt thereof is contacted with the phosgene reagent and/or in which the isocyanate intermediate of Formula VI or salt thereof is contacted with the salt of the amine of Formula V is typically heated to a temperature of at least about 20 °C, at least about 30 °C, at least about 40 °C, at least about 50 °C, at least about 60 °C, at least about 70 °C, at least about 80 °C, at least about 90 °C, at least about 100 °C, at least about 110 °C, at least about 120 °C, at least about 130 °C, at least about 140 °C, at least about 150 °C, at least about 160
  • the reaction mixture is heated to a temperature of from about 20 °C to about 180 °C, from about 30 °C to about 170 °C, from about 40 °C to about 160 °C, from about 50 °C to about 150 °C, from about 60 °C to about 140 °C, from about 70 °C to about 130 °C, from about 80 °C to about 120 °C, from about 90 °C to about 110 °C, from about 95 °C to about 105 °C, or from about 80 °C to about 100 °C.
  • the reaction mixture is heated to a temperature of from about 80 °C to about 120 °C. Addition of the amine salt of Formula V to the isocyanate intermediate of Formula VI or salt thereof may require more energy than formation of the isocyanate
  • the optimal temperature of the reaction mixture will vary depending on the identity of the optional solvent and other process conditions.
  • the temperature to which the reaction mixture is heated can be reduced by the addition of an external base. Accordingly, the addition of a lesser amount of external base can be optimized against the temperature to which the reaction mixture is heated to in preparing a compound of Formula IV.
  • each contacting step is conducted in the absence of an external base with heating of the reaction mixture and in the presence of a solvent comprising a non-polar solvent such as an aromatic non-polar solvent (e.g., toluene, xylene or a mixture thereof), optionally in combination with one or more additional solvents (e.g., acetonitrile).
  • a solvent comprising a non-polar solvent such as an aromatic non-polar solvent (e.g., toluene, xylene or a mixture thereof), optionally in combination with one or more additional solvents (e.g., acetonitrile).
  • the present invention is also directed to a process for preparing an alkylated thienopyrimidinedione compound of Formula III:
  • R 1 , R 4 , and R 5 are each as described above with respect to Formula IV.
  • this process comprises contacting a compound of Formula IV or a salt thereof (e.g., prepared as described herein) with an alkali metal alkoxide base or an alkaline earth metal alkoxide base in a cyclization reaction medium to produce the compound of Formula III or a salt thereof.
  • a compound of Formula IV or a salt thereof e.g., prepared as described herein
  • Suitable alkali metal or alkaline earth metal alkoxide bases include straight or branched C 1 –C 4 alkoxides.
  • the alkoxide may be selected from methoxide, ethoxide, propoxide, or butoxide.
  • Suitable branched alkoxides include isopropoxide, isobutoxide, sec-butoxide, and tert-butoxide.
  • Suitable alkali metal and alkaline earth metals for the alkoxide base include, but are not limited to, sodium, potassium, magnesium, calcium, cesium, or a combination thereof.
  • the compound of Formula IV or a salt thereof is contacted with an alkali metal alkoxide base comprising a potassium alkoxide base, for example, potassium tert-butoxide.
  • R 4 is hydrogen and R 5 is NR 7 R 8 (i.e., a
  • an alkali metal or alkaline earth metal carbonate or bicarbonate base is used in place of the alkali metal or alkaline earth metal alkoxide base.
  • Use of an alkali metal or alkaline earth metal carbonate or bicarbonate base during the cyclization step is believed to advantageously minimize racemization at the adjacent chiral center.
  • the cyclization of a monomethylamide compound of Formula IV is carried out in a reaction medium comprising an alkali metal or alkaline earth metal carbonate or bicarbonate base or a combination thereof.
  • the cyclization of a monomethylamide compound of Formula IV is carried out in the presence of an alkali metal or alkaline earth metal carbonate base.
  • Suitable alkali metal and alkaline earth metal carbonate bases include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, and combinations thereof.
  • Suitable alkali metal and alkaline earth metal bicarbonate bases include lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, and combinations thereof.
  • the base present in the cyclization reaction medium comprises potassium carbonate.
  • the base i.e., alkali metal or alkaline earth metal alkoxide base, or alkali metal or alkaline earth metal carbonate or bicarbonate base
  • the molar ratio of the base to the compound of Formula IV or salt thereof is typically at least about 1:1, at least about 1.5:1, at least about 2:1, or at least about 2.5:1.
  • the molar ratio of the base relative to the compound of Formula IV or salt thereof is from about 1:1 to about 2.5:1 or from about 2:1 to about 2.5:1.
  • the compound of Formula IV or salt thereof is contacted with the base in a cyclization reaction medium under a nitrogen or other suitably inert atmosphere.
  • the cyclization reaction can be conducted at various temperatures. In some embodiments, the reaction is suitably conducted at a temperature of from about -15 °C to about 30° C or from about -10 °C to about 25 °C.
  • the cyclization reaction medium can optionally comprise a solvent suitably selected from dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, 2- methyltetrahydrofuran, diethyl carbonate, or a combination thereof.
  • the cyclization solvent comprises dimethylacetamide.
  • the cyclization solvent comprises diethyl carbonate.
  • the cyclization solvent comprises acetonitrile.
  • Another aspect of the invention is a process for preparing a N1,N3-dialkylated thienopyrimidinedione compound of Formula I:
  • this process comprises contacting a compound of Formula III or a salt thereof (e.g., prepared as described herein) with an a-halo ketone reagent of Formula II:
  • R 9 is as described above with respect to Formula I and X is Cl, Br, or I.
  • X is Cl such that the alkylation of the compound of Formula III is carried out using an a-chloro ketone reagent of Formula II.
  • the base is typically added to the compound of Formula III or salt thereof before adding the a-halo ketone reagent of Formula II and typically is added to the alkylation reaction medium before or contemporaneously with the optional alkylation catalyst.
  • the compound of Formula II is typically added to the alkylation reaction medium in a molar equivalent amount or in slight molar excess relative to the compound of Formula III or salt thereof.
  • the ratio of the compound of Formula II to the compound of Formula III or salt thereof is typically at least about 1:1, at least about 1.1:1, at least about 1.2:1, or at least about 1.3:1.
  • the ratio of the compound of Formula II to the compound of Formula IV or salt thereof is from about 1:1 to about 1.5:1 or from about 1:1 to about 1.25:1.
  • the base suitably comprises an alkali metal carbonate base, an alkaline earth metal carbonate base, an alkali metal bicarbonate base, an alkaline earth metal bicarbonate base, or a combination thereof.
  • the base comprises lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, or a combination thereof.
  • the base comprises potassium carbonate. It has been discovered that by using an alkali metal or an alkaline earth metal bicarbonate base, fewer alkylation by-products are produced. Accordingly, in another embodiment, the base comprises potassium bicarbonate. In a still further embodiment, the base comprises sodium bicarbonate.
  • R 4 is hydrogen and R 5 is NR 7 R 8 (i.e., a
  • an alkali metal or alkaline earth metal carbonate or bicarbonate base as described above is used in the alkylation step.
  • Use of an alkali metal or alkaline earth metal carbonate or bicarbonate base is believed to minimize racemization and preserve the chiral center in the N1,N3-dialkylated thienopyrimidinedione compound of Formula I.
  • the cyclization of a monomethylamide compound of Formula IV is carried out in the presence of an alkali metal or alkaline earth metal carbonate base (e.g., potassium carbonate) and the subsequent alkylation of the monomethylamide compound of Formula III is carried out in a reaction medium comprising an alkali metal or alkaline earth metal carbonate base (e.g., potassium carbonate).
  • an alkali metal or alkaline earth metal carbonate base e.g., potassium carbonate
  • the base is added to the alkylation reaction medium at a near equivalent amount or in molar excess relative to the compound of Formula III or salt thereof.
  • the base is added in an amount of from about 0.9 to about 5 molar equivalents, from about 1 to about 5 molar equivalents, from about 1 to about 4 molar equivalents, from about 1 to about 3 molar equivalents, from about 1 to about 2 molar equivalents, or from about 2 to about 3 molar equivalents relative to the compound of Formula III or salt thereof.
  • the alkylation reaction medium can optionally include a solvent.
  • Suitable alkylation solvents may be selected from dimethylformamide, dimethylacetamide, N-methyl-2- pyrrolidone, acetonitrile, 2-methyltetrahydrofuran, diethyl carbonate, or a combination thereof.
  • the alkylation solvent comprises acetonitrile.
  • the alkylation solvent comprises 2-methyltetrahydrofuran.
  • the alkylation solvent comprises dimethylformamide. It has been discovered that by using diethyl carbonate as the alkylation solvent, the quantity of a-halo ketone reagent of Formula II needed to convert all or substantially all of the compound of Formula III to the compound of Formula I is
  • the amount of a-halo ketone reagent of Formula II required may be reduced from 1.25 molar equivalents to less than 1.1 molar equivalents.
  • Diethyl carbonate is also more environmentally friendly as compared to other solvents, such as dimethylformamide and N-methyl-2-pyrrolidone. Further, diethyl carbonate is less expensive and easier to recycle, due in part to its relatively low boiling point. Accordingly, in another embodiment, the alkylation solvent comprises diethyl carbonate.
  • the alkylation reaction medium further comprises an alkylation catalyst.
  • the alkylation catalyst can comprise an alkali metal halide catalyst, for example, potassium halide or sodium halide such as sodium bromide.
  • the alkylation catalyst can comprise a tetrabutylammonium halide.
  • tetrabutylammonium halide comprises tetrabutylammonium bromide, tetrabutylammonium chloride, or a combination thereof.
  • the tetrabutylammonium halide is tetrabutylammonium chloride.
  • the molar ratio of alkylation catalyst added to the alkylation reaction medium relative to the compound of Formula II is not more than about 1:10, not more than about 1:20, not more than about 1:24, or not more than about 1:26. In some embodiments, the molar ratio of alkylation catalyst added to the alkylation reaction medium relative to the compound of Formula II is from about 1:10 to about 1:30 or from about 1:20 to about 1:30.
  • a tetrabutylammonium halide is used as the alkylation catalyst, it can be present in an amount of from about 1 mol% to about 20 mol%, from about 1 mol% to about 15 mol%, from about 1 mol% to about 10 mol%, from about 1 mol% to about 9 mol%, from about 1 mol% to about 8 mol%, from about 1 mol% to about 5 mol%, from about 1 mol% to about 3 mol%, from about 2 mol% to about 8 mol%, from about 3 mol% to about 8 mol%, from about 3 mol% to about 7 mol%, from about 3 mol% to about 6 mol%, from about 4 mol% to about 6 mol%, from about 5 mol% to about 6 mol%, or from about 4 mol% to about 5 mol% based on the amount of the compound of Formula II.
  • the base, the a-halo ketone reagent of Formula II and optional alkylation catalyst are suitably added to the compound of Formula III or salt thereof in the alkylation reaction medium at a temperature of about 25 °C and the alkylation reaction is typically allowed to proceed at a temperature of at least about 25 °C, at least about 30 °C, at least about 40 °C, or at least about 50 °C.
  • the alkylation reaction is typically conducted at a temperature of from about 25 °C to about 90 °C, more typically from about 40 °C to about 60 °C.
  • the alkylation reaction medium is agitated or stirred at an elevated temperature after addition of the compound of Formula II and for a time sufficient to ensure substantial conversion of the compound of Formula III or a salt thereof.
  • the period of time required for completion of the alkylation reaction can be readily determined by a person skilled in the art and can be monitored by any means known in the art, such as by high performance liquid
  • the alkylation reaction is allowed to proceed for less than about 1 hour to up to about 20 hours or more. Depending on the temperature and other reaction conditions employed, the alkylation reaction is typically allowed to proceed for a period of from about 1 hour to about 25 hours, from about 3 hours to about 18 hours, or from about 6 hours to about 18 hours.
  • the compound of Formula III or salt thereof can be contacted with the compound of Formula II without first isolating the compound of Formula III from the cyclization reaction medium to provide the compound of Formula I or salt thereof.
  • the overall yield of the compound of Formula I or salt thereof is greater than 65%.
  • the overall yield of Formula I can be greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95%.
  • the compound of Formula I or salt thereof prepared from the processes described herein can be greater than 70% pure, greater than 75% pure, greater than 80% pure, greater than 85% pure, greater than 90% pure, greater than 95% pure, greater than 97% pure, or greater than 99% pure. Acid Quench After Cyclization and Before Alkylation
  • the compound of Formula III or salt thereof is suitably prepared by a process comprising contacting a compound of Formula IV or a salt thereof (e.g., prepared as described herein) with an alkali metal alkoxide base or an alkaline earth metal alkoxide base in a cyclization reaction medium to produce the compound of Formula III or a salt thereof. It has been discovered that quenching the resulting cyclization reaction medium comprising the compound of Formula III or a salt thereof (e.g., by addition of a mineral acid) prior to contact with the a-halo ketone reagent of Formula II significantly increases the yield of the compound of Formula I in the subsequent alkylation reaction.
  • the process further comprises quenching the cyclization reaction medium comprising the compound of Formula III or a salt thereof (e.g., by addition of a mineral acid) and subsequently contacting the compound of Formula III or a salt thereof with the a-halo ketone reagent of Formula II in the alkylation reaction to produce the compound of Formula I or a salt thereof.
  • the alkylation reaction medium to which the a- halo ketone reagent of Formula II is added comprises the compound of Formula III or a salt thereof, the mineral acid and a base.
  • Suitable mineral acids comprise hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, sulfuric acid, or a combination thereof.
  • the mineral acid added after the cyclization reaction comprises hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, or a combination thereof.
  • the mineral acid comprises hydrochloric acid.
  • the mineral acid is typically added to the cyclization reaction medium in an amount of at least about 1 molar equivalents, at least about 1.25 molar equivalents, or at least about 1.5 molar equivalents based on the amount of the alkali metal alkoxide base or alkaline earth metal alkoxide base employed in the cyclization reaction as described herein.
  • the mineral acid can be added to the cyclization reaction medium in an amount of from about 1 to about 2 molar equivalents based on the amount of the alkali metal alkoxide base or alkaline earth metal alkoxide base employed.
  • the mineral acid can be replaced in whole or in part by other quenching agents.
  • carbon dioxide or potassium bicarbonate can be used in place of the mineral acid.
  • the mineral acid or alternative quenching agent is typically added to the cyclization reaction medium at the temperature that the cyclization reaction is conducted as described herein.
  • the amount of base e.g., alkali or alkaline earth metal carbonate, alkali or alkaline earth metal bicarbonate or a combination thereof
  • the amount of base e.g., alkali or alkaline earth metal carbonate, alkali or alkaline earth metal bicarbonate or a combination thereof
  • the amount of base e.g., alkali or alkaline earth metal carbonate, alkali or alkaline earth metal bicarbonate or a combination thereof
  • a further aspect of the present invention is a process for preparing a
  • R 1 , R 4 , R 5 and R 9 are as described above with respect to Formula I.
  • R 9 is F.
  • R 4 is hydrogen.
  • R 4 is CH 3 .
  • R 1 is -C(O)OR 3 and R 3 is ethyl.
  • R 1 is -C(O)OR 3 and R 3 is isopropyl.
  • R 5 is OR 6 and R 6 is, for example, tert-butyl.
  • the process comprises contacting a compound of Formula I or salt thereof (e.g., prepared as described herein) with a hydrogen source in the presence of an organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound of Formula VIII or a salt thereof.
  • a compound of Formula I or salt thereof e.g., prepared as described herein
  • a hydrogen source in the presence of an organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound of Formula VIII or a salt thereof.
  • the chiral organometallic catalyst can be a chiral ruthenium catalyst.
  • the chiral ruthenium catalyst comprises a compound of chiral (S,S)-ruthenium- diamine complex.
  • the chiral ruthenium catalyst can be selected from the group consisting of Ru(OTf)[(R,R)-BnSO2-dpen](p-cymene), RuCl[(R,R)-Ts-dpen](p-cymene), RuCl[(R,R)-Ts-dpen](p-cymene), (S)-RUCY TM -XylBINAP], RuCl2[(R)-xylyl- Phanephos][1S,2S-DPEN], RuCl 2 [(S)-xylbinap][(S,S)-dpen], RuCl 2 [(S)-dm-segphos][(S,S)- dpen], RuCl 2 [(R)-xylbinap][(R)-daipen], RuCl 2 [(S)-xylbinap][(S)-daipen], RuCl 2 [(S
  • the chiral organometallic catalyst is a chiral ruthenium catalyst
  • the chiral ruthenium catalyst can be present in the asymmetrical reduction zone in an amount of from about 0.1 mol% to about 10 mol%, relative to the compound of Formula I.
  • the chiral organometallic catalyst can be a non-ruthenium containing catalyst.
  • the chiral organometallic catalyst can be selected from, but not limited to, (S)-2-methyl-CBS-oxazaborolidine, (S,S)-Me-DuPhos; Pd 2 (CF 3 CO 2 ) 2 , [Rh(NBD)(TangPhos)]SbF 6 .
  • the hydrogen source in the asymmetrical reduction zone can be substantially hydrogen gas.
  • the hydrogen source in the asymmetrical reduction zone can be a hydrogen transfer agent.
  • hydrogen transfer agents include formic acid, formates, and mixtures thereof.
  • suitable formates include alkali metal formates, ammonium formate, and trialkylammonium formates.
  • the hydrogen source in the asymmetrical reduction zone can comprise sodium formate.
  • the hydrogen source in the asymmetrical reduction zone comprises trialkylammonium formate that is formed in situ by mixing formic acid and trialkylamine in the reaction medium of the asymmetrical reduction zone.
  • the trialkylammonium formate can be triethylammonium formate.
  • Phosgene (428 mg, 4.33 mmol, 15 wt% in toluene) was added dropwise to a stirred mixture of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate (Formula VII; 1.00 g, 3.89 mmol) in acetonitrile (30.0 mL) at 0 °C. After 10 minutes, triethylamine (1.30 g, 12.84 mmol) was added dropwise at 0 °C. After 10 minutes, the cooling bath was removed.
  • tert-butyl 2-amino-2-methylpropanoate hydrochloride (Formula V; 1.38 g, 7.05 mmol) was charged into the reaction mixture. After 30 minutes, the conversion was >99% by HPLC, and the selectivity of reaction to prepare diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)ureido)-3-methylthiophene-2,4-dicarboxylate (Formula IV) was >99%.
  • Phosgene (856 mg, 8.66 mmol, 15 wt% in toluene) was added dropwise to a stirred mixture of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate (Formula VII; 2.00 g, 7.78 mmol) in toluene (60.0 mL) at 0 °C. After 5 minutes, triethylamine (2.60 g, 25.68 mmol) was added dropwise over 10 min at 0 °C. The cooling bath was removed.
  • tert- butyl 2-amino-2-methylpropanoate hydrochloride (Formula V; 2.76 g, 14.1 mmol) was added portion-wise to the reaction mixture. After 3 hours, the conversion was 90% by HPLC, and the selectivity of reaction to prepare diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)ureido)-3-methylthiophene-2,4-dicarboxylate (Formula IV) was 96%.
  • Example 3 Preparation of ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) in dimethylacetamide with no acid quench
  • the organic layer (450 g) was distilled down to a weight of 388 g.
  • the mixture was seeded and cooled to 0 °C in an ice bath.
  • the solid precipitate was filtered and washed with diethyl carbonate (30 mL) at 0 °C.

Abstract

Provided herein are processes for the preparation of N1,N3-dialkylated thienopyrimidinediones that are useful as fungicides, and related precursors and intermediates.

Description

PROCESSES FOR THE PREPARATION OF FUNGICIDAL COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Number 62/752,030, filed October 29, 2018, the entirety of which is incorporated herein by reference. FIELD
[0002] Provided herein are processes for the preparation of N1,N3-dialkylated thienopyrimidinediones that are useful as fungicides, and related precursors and intermediates. BACKGROUND
[0003] Phytopathogenic fungi can infect crop plants either in the field or after harvesting, resulting in considerable economic losses to farmers and producers worldwide. In addition to the agricultural impact, when food and feed contaminated with fungi or the toxins they produce are ingested by humans or livestock, a number of debilitating diseases or death can occur. Approximately 10,000 species of fungi are known to damage crops and affect quality and yield. Crop rotation, breeding of resistant cultivars, the application of agrochemicals and combinations of these strategies is commonly employed to stem the spread of fungal pathogens and the diseases they cause.
[0004] Acetyl-CoA carboxylase (ACC) is an essential catalyst for the rate-limiting step of fatty acid biosynthesis in both eukaryotes and prokaryotes. Certain N1,N3-dialkylated thienopyrimidinediones that are effective inhibitors of ACC, exhibit fungicidal activity and are useful in the preparation of compositions and in accordance with methods for control of fungal pathogens in agriculture, are described in U.S. Publication Nos.2017/0166584 A1,
2017/0166582 A1, 2017/0166583 A1, and 2017/0166585 A1, and in International Application No. PCT/US2018020728, filed March 2, 2018, the entirety of which are incorporated herein by reference.
[0005] There is a need in the art to provide processes for the synthesis of N1,N3- dialkylated thienopyrimidinediones and other related compounds exhibiting fungicidal activity, especially processes that produce the compounds in a high yield, on a large scale, and in a cost- effective manner. SUMMARY
[0006] Provided herein are processes for the preparation of N1,N3-dialkylated thienopyrimidinediones that are useful as fungicides, and related precursors and intermediates.
[0007] In one embodiment, a process for preparing a compound of Formula IV:
Figure imgf000003_0001
Formula IV
or a salt thereof is provided. The process comprises contacting a compound of Formula VII:
Figure imgf000003_0002
Formula VII
or a salt thereof, with phosgene to produce an isocyanate intermediate of Formula VI:
Figure imgf000003_0003
Formula VI
or a salt thereof. The isocyanate intermediate of Formula VI or salt thereof is contacted with a salt of an amine of Formula V:
Figure imgf000003_0004
Formula V
to produce a compound of Formula IV or a salt thereof. In this process, R1 is 2H-1,2,3-triazol-2- yl, 1-pyrazolyl, or -C(O)OR3; R2 is -C(O)OR3; R3 is a straight or branched C1–C4 alkyl; R4 is hydrogen or CH3; R5 is OR6 or NR7R8; R6 is straight or branched C1–C4 alkyl or benzyl; R7 is hydrogen or CH3; and R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5- membered or 6-membered heterocycloalkyl ring.
[0008] Another embodiment is directed to a process for preparing a compound of Formula III:
Figure imgf000003_0005
Formula III or a salt thereof, wherein R1, R4 and R5 are as defined above. The process comprises preparing a compound of Formula IV or a salt thereof as set forth above and contacting the compound of Formula IV or a salt thereof with an alkali metal alkoxide base or alkaline earth metal alkoxide base in a cyclization reaction medium to produce the compound of Formula III or a salt thereof.
[0009] Also provided herein are processes for preparing N1,N3-dialkylated
thienopyrimidinedione compounds of Formula I:
Figure imgf000004_0001
Formula I
or a salt thereof, wherein R1, R4 and R5 are as defined above and R9 is hydrogen or F. In one embodiment, the process comprises preparing a compound of Formula III or a salt thereof as set forth above and contacting the compound of Formula III or a salt thereof with a compound of Formula II:
Figure imgf000004_0002
Formula II
in an alkylation reaction medium comprising a base to produce the compound of Formula I or a salt thereof, wherein X in Formula II is Cl, Br, or I.
[0010] In another embodiment, the process for the preparation of a compound of Formula I or a salt thereof comprises contacting a compound of Formula IV:
Figure imgf000004_0003
Formula IV
or a salt thereof with an alkali metal alkoxide base or alkaline earth metal alkoxide base in a cyclization reaction medium to produce a compound of Formula III:
Figure imgf000005_0001
Formula III
or a salt thereof. A mineral acid is added to the cyclization reaction medium comprising the compound of Formula III or a salt thereof. The compound of Formula III or salt thereof is contacted with a compound of Formula II:
Figure imgf000005_0002
Formula II
in an alkylation reaction medium comprising the mineral acid and a base to produce the compound of Formula I or a salt thereof.
[0011] In another embodiment, the process for the preparation of a compound of Formula I or a salt thereof comprises contacting a compound of Formula III:
Figure imgf000005_0003
Formula III
or a salt thereof with a compound of Formula II:
Figure imgf000005_0004
Formula II
in an alkylation reaction medium comprising an alkali metal bicarbonate base or alkaline earth metal bicarbonate base to produce the compound of Formula I or a salt thereof.
[0012] In another embodiment, the process for preparing a compound of Formula I or a salt thereof comprises contacting a compound of Formula III:
Figure imgf000005_0005
Formula III
or a salt thereof with a compound of Formula II:
Figure imgf000006_0001
Formula II
in an alkylation reaction medium comprising a base and a solvent selected from the group consisting of diethyl carbonate, 2-methyltetrahydrofuran, dimethylacetamide, and a combination thereof, to produce the compound of Formula I or a salt thereof.
[0013] In a further embodiment, the process for preparing a compound of Formula I or a salt thereof comprises contacting a compound of Formula III:
Figure imgf000006_0002
Formula III
or a salt thereof with a compound of Formula II:
Figure imgf000006_0003
Formula II
in an alkylation reaction medium comprising a base and an alkylation catalyst comprising a tetrabutylammonium halide to produce the compound of Formula I or a salt thereof.
[0014] In a still further embodiment a process is provided for preparing
monomethylamide analogs of a compound of Formula I:
Figure imgf000006_0004
Formula I
or a salt thereof, wherein R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3; R4 is hydrogen; R5 is NR7R8; R7 is hydrogen or CH3; R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6-membered heterocycloalkyl ring; and R9 is hydrogen or F. The process comprises contacting a monomethylamide compound of Formula IV:
Figure imgf000007_0001
Formula IV
or a salt thereof with an alkali metal or alkaline earth metal carbonate or bicarbonate base in a cyclization reaction medium to produce a monomethylamide compound of Formula III:
Figure imgf000007_0002
Formula III
or a salt thereof. The compound of Formula III or a salt thereof is contacted with a compound of Formula II:
Figure imgf000007_0003
Formula II
in an alkylation reaction medium comprising an alkali metal or alkaline earth metal carbonate or bicarbonate base to produce the compound of Formula I or a salt thereof.
[0015] Also provided is a process for preparing stereomerically enriched N1,N3- dialkylated thienopyrimidinedione compounds of Formula VIII:
Figure imgf000007_0004
Formula VIII
or a salt thereof. The process comprises preparing a compound of Formula I or salt thereof as set forth above and contacting the compound of Formula I or salt thereof with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound of Formula VIII or a salt thereof.
[0016] Other objects and features will be in part apparent and in part pointed out hereinafter. DETAILED DESCRIPTION OF THE INVENTION
[0017] Provided herein are processes for the preparation of thienopyrimidinediones of Formula I, alkylated thienopyrimidinediones of Formulas III, and VIII, salts thereof, and intermediates and precursors thereof. Preparation of Compounds of Formula IV
[0018] The present invention is directed to a process for preparing a compound of Formula IV:
Figure imgf000008_0001
Formula IV
or a salt thereof, wherein R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3; R2 is -C(O)OR3; R3 is straight or branched C1–C4 alkyl; R4 is hydrogen or CH3; R5 is OR6 or NR7R8; R6 is straight or branched C1-C4 alkyl or benzyl; R7 is hydrogen or CH3; and R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6-membered heterocycloalkyl ring. Generally, the process comprises contacting a compound of Formula VII:
Figure imgf000008_0002
Formula VII
or a salt thereof with a phosgene reagent to produce an isocyanate intermediate of Formula VI:
Figure imgf000008_0003
Formula VI
or a salt thereof, wherein R1 and R2 are as defined above with respect to Formula IV. The isocyanate intermediate of Formula VI or salt thereof is then contacted with a salt of an amine of Formula V:
Figure imgf000008_0004
Formula V
to produce the compound of Formula IV or a salt thereof, wherein R4 and R5 are as defined above with respect to Formula IV. [0019] In some embodiments, compounds of Formula VI can be prepared by contacting compound of Formula VII at low temperature with phosgene in the presence of a trialkylamine base (e.g., triethylamine). In some embodiments the temperature range is from -20 to 20 °C. In other embodiments the temperature range is from -10 to 10 °C. In other embodiments, the temperature range is from -5 to 5 °C. Stoichiometric ratios are those described below.
[0020] In other embodiments, preparation of Formula VI involves concurrent addition of a solution of a compound of Formula VII into a solvent, such as diethyl carbonate (DEC), with gaseous phosgene addition at elevated temperatures in the absence of a trialkylamine base. In some embodiments, the temperature range is from 80 to 120 °C. In other embodiments, the temperature range is from 90 to 110 °C. In yet other embodiments, the temperature range is from 90 to 95 °C. Stoichiometry is that described below.
[0021] In some embodiments, R1 and R2 are the same. For example, R1 and R2 may both be -C(O)OR3 and R3 may be ethyl. In an alternative embodiment, R1 and R2 are both -C(O)OR3 and R3 is isopropyl.
[0022] In one embodiment, R4 is methyl. In another embodiment, R4 is hydrogen.
[0023] In some embodiments, R5 is OR6. For example, R5 is OR6 and R6 is tert-butyl.
[0024] In some embodiments, R5 is or NR7R8 and R7 and R8 are as described above.
[0025] The phosgene reagent contacted with a compound of Formula VII may comprise phosgene, diphosgene, triphosgene, or a mixture thereof. In one embodiment, the phosgene reagent comprises phosgene. Typically, a molar excess of the phosgene reagent relative to the compound of Formula VII is employed. For example, the molar ratio of the phosgene reagent to the compound of Formula VII is typically greater than 1:1 to about 4:1, more typically from about 2:1 to about 3:1, or greater than 1:1 to about 2.5:1.
[0026] Any chemically acceptable salt may be used as the salt of the amine of Formula V contacted with the isocyanate intermediate of Formula VI. In some embodiments, the amine salt is an acid addition salt such as a hydrohalide salt or methanesulfonic acid addition salt. For example, suitable hydrohalide salts include hydrochloride, hydrofluoride, hydrobromide, and hydroiodide salts. In one embodiment, the salt of the amine of Formula V is the hydrochloride salt. Typically, a molar excess of the amine salt of Formula V relative to the isocyanate intermediate of Formula VI is employed. For example, the molar ratio of the amine salt of Formula V to the isocyanate intermediate of Formula VI is typically greater than 1:1 to about 2.5:1, more typically greater than 1:1 to about 1.5:1, or greater than 1:1 to about 1.25:1.
[0027] Each contacting step is optionally independently conducted in the presence of a solvent. For example, suitable solvents include toluene, xylene, acetonitrile, 2- methyltetrahydrofuran, diethyl carbonate, or a combination thereof. In some embodiments, the solvent comprises a non-polar solvent such as an aromatic non-polar solvent (e.g., toluene, xylene or a mixture thereof), optionally in combination with one or more additional solvents (e.g., acetonitrile). For example, in one embodiment the solvent comprise toluene. In another embodiment, the solvent comprises xylene. In some embodiments, the solvent comprises a mixture of toluene and acetonitrile. In a still further embodiment, the solvent comprises a mixture of xylene and acetonitrile.
[0028] Furthermore, each contacting step is optionally independently conducted in the presence of a base. For example, suitable bases comprise triethylamine, diisopropylethylamine, potassium tert-butoxide, pyridine, sodium bicarbonate, potassium carbonate, sodium hydroxide, or a combination thereof. In one embodiment, the base comprises triethylamine.
[0029] Typically, when conducted in the presence of an external base, the compound of Formula VII is contacted with the phosgene reagent at a temperature of from about -20 °C to about 20 °C, more typically from about -5 °C to about 5 °C, and the isocyanate intermediate of Formula VI or salt thereof is contacted with the amine salt of Formula V at a temperature of from about 0 °C to about 50 °C, more typically from about 0 °C to about 30 °C.
[0030] Alternatively, each contacting step in the preparation of a compound of Formula IV is optionally independently conducted in the absence of an external base. For example, the process can comprise contacting the compound of Formula VII or salt thereof with the phosgene reagent and heating in the absence of an external base to produce the isocyanate intermediate of Formula VI or salt thereof and hydrochloric acid gas. In such an embodiment, it is believed that the reaction proceeds through a chloroimidate intermediate of Formula IX:
Figure imgf000010_0001
Formula IX
or a salt thereof, wherein R1 and R2 are as described above with respect to Formula IV. The chloroimidate intermediate of Formula IX or salt thereof decomposes when heated to produce the isocyanate intermediate of Formula VI or a salt thereof and hydrochloric acid gas.
Alternatively, where no external base is added, and higher reaction temperatures are employed, the reaction proceeds directly to the isocyanate intermediate of Formula VI.
[0031] Similarly, the process can comprise contacting the isocyanate intermediate of Formula VI or salt thereof with the salt of the amine of Formula V and heating in the absence of an external base to produce a compound of Formula IV or a salt thereof. [0032] In various embodiments where no external base is employed, the reaction mixture in which the compound of Formula VII or salt thereof is contacted with the phosgene reagent and/or in which the isocyanate intermediate of Formula VI or salt thereof is contacted with the salt of the amine of Formula V, is typically heated to a temperature of at least about 20 °C, at least about 30 °C, at least about 40 °C, at least about 50 °C, at least about 60 °C, at least about 70 °C, at least about 80 °C, at least about 90 °C, at least about 100 °C, at least about 110 °C, at least about 120 °C, at least about 130 °C, at least about 140 °C, at least about 150 °C, at least about 160 °C, at least about 170 °C, or at least about 180 °C. For example, the reaction mixture is heated to a temperature of from about 20 °C to about 180 °C, from about 30 °C to about 170 °C, from about 40 °C to about 160 °C, from about 50 °C to about 150 °C, from about 60 °C to about 140 °C, from about 70 °C to about 130 °C, from about 80 °C to about 120 °C, from about 90 °C to about 110 °C, from about 95 °C to about 105 °C, or from about 80 °C to about 100 °C. In typical embodiments, the reaction mixture is heated to a temperature of from about 80 °C to about 120 °C. Addition of the amine salt of Formula V to the isocyanate intermediate of Formula VI or salt thereof may require more energy than formation of the isocyanate
intermediate. Accordingly, it may be desirable to increase the temperature of the reaction mixture after formation of the isocyanate intermediate and prior to or at the same time of adding the amine salt. As readily understood by a person skilled in the art, the optimal temperature of the reaction mixture will vary depending on the identity of the optional solvent and other process conditions. Furthermore, the temperature to which the reaction mixture is heated can be reduced by the addition of an external base. Accordingly, the addition of a lesser amount of external base can be optimized against the temperature to which the reaction mixture is heated to in preparing a compound of Formula IV.
[0033] In accordance with one particular embodiment, each contacting step is conducted in the absence of an external base with heating of the reaction mixture and in the presence of a solvent comprising a non-polar solvent such as an aromatic non-polar solvent (e.g., toluene, xylene or a mixture thereof), optionally in combination with one or more additional solvents (e.g., acetonitrile). Preparation of Compounds of Formula III (Cyclization)
[0034] The present invention is also directed to a process for preparing an alkylated thienopyrimidinedione compound of Formula III:
Figure imgf000012_0001
Formula III
or a salt thereof, wherein R1, R4, and R5 are each as described above with respect to Formula IV.
[0035] Generally, this process comprises contacting a compound of Formula IV or a salt thereof (e.g., prepared as described herein) with an alkali metal alkoxide base or an alkaline earth metal alkoxide base in a cyclization reaction medium to produce the compound of Formula III or a salt thereof.
[0036] Suitable alkali metal or alkaline earth metal alkoxide bases include straight or branched C1–C4 alkoxides. For example, the alkoxide may be selected from methoxide, ethoxide, propoxide, or butoxide. Suitable branched alkoxides include isopropoxide, isobutoxide, sec-butoxide, and tert-butoxide. Suitable alkali metal and alkaline earth metals for the alkoxide base include, but are not limited to, sodium, potassium, magnesium, calcium, cesium, or a combination thereof. In accordance with one embodiment, the compound of Formula IV or a salt thereof is contacted with an alkali metal alkoxide base comprising a potassium alkoxide base, for example, potassium tert-butoxide.
[0037] In some embodiments, when R4 is hydrogen and R5 is NR7R8 (i.e., a
monomethylamide compound of Formula IV), an alkali metal or alkaline earth metal carbonate or bicarbonate base is used in place of the alkali metal or alkaline earth metal alkoxide base. Use of an alkali metal or alkaline earth metal carbonate or bicarbonate base during the cyclization step is believed to advantageously minimize racemization at the adjacent chiral center. Thus, in some embodiments, the cyclization of a monomethylamide compound of Formula IV is carried out in a reaction medium comprising an alkali metal or alkaline earth metal carbonate or bicarbonate base or a combination thereof. In one particular embodiment, the cyclization of a monomethylamide compound of Formula IV is carried out in the presence of an alkali metal or alkaline earth metal carbonate base.
[0038] Suitable alkali metal and alkaline earth metal carbonate bases include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, and combinations thereof. Suitable alkali metal and alkaline earth metal bicarbonate bases include lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, and combinations thereof. In one embodiment, the base present in the cyclization reaction medium comprises potassium carbonate.
[0039] Typically, at least a molar equivalent of the base (i.e., alkali metal or alkaline earth metal alkoxide base, or alkali metal or alkaline earth metal carbonate or bicarbonate base) relative to the compound of Formula IV or salt thereof is employed. For example, the molar ratio of the base to the compound of Formula IV or salt thereof is typically at least about 1:1, at least about 1.5:1, at least about 2:1, or at least about 2.5:1. Typically, the molar ratio of the base relative to the compound of Formula IV or salt thereof is from about 1:1 to about 2.5:1 or from about 2:1 to about 2.5:1.
[0040] In typical embodiments, the compound of Formula IV or salt thereof is contacted with the base in a cyclization reaction medium under a nitrogen or other suitably inert atmosphere.
[0041] The cyclization reaction can be conducted at various temperatures. In some embodiments, the reaction is suitably conducted at a temperature of from about -15 °C to about 30° C or from about -10 °C to about 25 °C.
[0042] The cyclization reaction medium can optionally comprise a solvent suitably selected from dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, 2- methyltetrahydrofuran, diethyl carbonate, or a combination thereof. In one embodiment, the cyclization solvent comprises dimethylacetamide. In another embodiment, the cyclization solvent comprises diethyl carbonate. In a still further embodiment, the cyclization solvent comprises acetonitrile. Preparation of Compounds of Formula I (Alkylation)
[0043] Another aspect of the invention is a process for preparing a N1,N3-dialkylated thienopyrimidinedione compound of Formula I:
Figure imgf000013_0001
Formula I
or a salt thereof, wherein R1, R4 and R5 are each as described above with respect to Formula IV; and R9 is hydrogen or F. [0044] Generally, this process comprises contacting a compound of Formula III or a salt thereof (e.g., prepared as described herein) with an a-halo ketone reagent of Formula II:
Figure imgf000014_0001
Formula II
in an alkylation reaction medium comprising a base and optional alkylation catalyst to produce the compound of Formula I or a salt thereof. R9 is as described above with respect to Formula I and X is Cl, Br, or I. Typically, X is Cl such that the alkylation of the compound of Formula III is carried out using an a-chloro ketone reagent of Formula II. The base is typically added to the compound of Formula III or salt thereof before adding the a-halo ketone reagent of Formula II and typically is added to the alkylation reaction medium before or contemporaneously with the optional alkylation catalyst.
[0045] The compound of Formula II is typically added to the alkylation reaction medium in a molar equivalent amount or in slight molar excess relative to the compound of Formula III or salt thereof. For example, the ratio of the compound of Formula II to the compound of Formula III or salt thereof is typically at least about 1:1, at least about 1.1:1, at least about 1.2:1, or at least about 1.3:1. In some embodiments, the ratio of the compound of Formula II to the compound of Formula IV or salt thereof is from about 1:1 to about 1.5:1 or from about 1:1 to about 1.25:1.
[0046] The base suitably comprises an alkali metal carbonate base, an alkaline earth metal carbonate base, an alkali metal bicarbonate base, an alkaline earth metal bicarbonate base, or a combination thereof. In various embodiments, the base comprises lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, or a combination thereof. For example, in one embodiment, the base comprises potassium carbonate. It has been discovered that by using an alkali metal or an alkaline earth metal bicarbonate base, fewer alkylation by-products are produced. Accordingly, in another embodiment, the base comprises potassium bicarbonate. In a still further embodiment, the base comprises sodium bicarbonate.
[0047] In some embodiments, when R4 is hydrogen and R5 is NR7R8 (i.e., a
monomethylamide compound of Formula III), an alkali metal or alkaline earth metal carbonate or bicarbonate base as described above is used in the alkylation step. Use of an alkali metal or alkaline earth metal carbonate or bicarbonate base is believed to minimize racemization and preserve the chiral center in the N1,N3-dialkylated thienopyrimidinedione compound of Formula I. In one particular embodiment, the cyclization of a monomethylamide compound of Formula IV is carried out in the presence of an alkali metal or alkaline earth metal carbonate base (e.g., potassium carbonate) and the subsequent alkylation of the monomethylamide compound of Formula III is carried out in a reaction medium comprising an alkali metal or alkaline earth metal carbonate base (e.g., potassium carbonate).
[0048] In various embodiments, the base is added to the alkylation reaction medium at a near equivalent amount or in molar excess relative to the compound of Formula III or salt thereof. For example, in some embodiments, the base is added in an amount of from about 0.9 to about 5 molar equivalents, from about 1 to about 5 molar equivalents, from about 1 to about 4 molar equivalents, from about 1 to about 3 molar equivalents, from about 1 to about 2 molar equivalents, or from about 2 to about 3 molar equivalents relative to the compound of Formula III or salt thereof.
[0049] The alkylation reaction medium can optionally include a solvent. Suitable alkylation solvents may be selected from dimethylformamide, dimethylacetamide, N-methyl-2- pyrrolidone, acetonitrile, 2-methyltetrahydrofuran, diethyl carbonate, or a combination thereof. In one embodiment, the alkylation solvent comprises acetonitrile. In another embodiment, the alkylation solvent comprises 2-methyltetrahydrofuran. In a further embodiment, the alkylation solvent comprises dimethylformamide. It has been discovered that by using diethyl carbonate as the alkylation solvent, the quantity of a-halo ketone reagent of Formula II needed to convert all or substantially all of the compound of Formula III to the compound of Formula I is
significantly reduced. For example, in some embodiments, the amount of a-halo ketone reagent of Formula II required may be reduced from 1.25 molar equivalents to less than 1.1 molar equivalents. Diethyl carbonate is also more environmentally friendly as compared to other solvents, such as dimethylformamide and N-methyl-2-pyrrolidone. Further, diethyl carbonate is less expensive and easier to recycle, due in part to its relatively low boiling point. Accordingly, in another embodiment, the alkylation solvent comprises diethyl carbonate.
[0050] In various embodiments, the alkylation reaction medium further comprises an alkylation catalyst. The alkylation catalyst can comprise an alkali metal halide catalyst, for example, potassium halide or sodium halide such as sodium bromide. Alternatively, the alkylation catalyst can comprise a tetrabutylammonium halide. By utilizing a
tetrabutylammonium halide instead of an alkali metal halide as the alkylation catalyst, it has been discovered that fewer alkylation by-products are produced. Typically, the
tetrabutylammonium halide comprises tetrabutylammonium bromide, tetrabutylammonium chloride, or a combination thereof. In accordance with one particular embodiment, the tetrabutylammonium halide is tetrabutylammonium chloride. [0051] Typically, the molar ratio of alkylation catalyst added to the alkylation reaction medium relative to the compound of Formula II is not more than about 1:10, not more than about 1:20, not more than about 1:24, or not more than about 1:26. In some embodiments, the molar ratio of alkylation catalyst added to the alkylation reaction medium relative to the compound of Formula II is from about 1:10 to about 1:30 or from about 1:20 to about 1:30.
[0052] Where a tetrabutylammonium halide is used as the alkylation catalyst, it can be present in an amount of from about 1 mol% to about 20 mol%, from about 1 mol% to about 15 mol%, from about 1 mol% to about 10 mol%, from about 1 mol% to about 9 mol%, from about 1 mol% to about 8 mol%, from about 1 mol% to about 5 mol%, from about 1 mol% to about 3 mol%, from about 2 mol% to about 8 mol%, from about 3 mol% to about 8 mol%, from about 3 mol% to about 7 mol%, from about 3 mol% to about 6 mol%, from about 4 mol% to about 6 mol%, from about 5 mol% to about 6 mol%, or from about 4 mol% to about 5 mol% based on the amount of the compound of Formula II.
[0053] The base, the a-halo ketone reagent of Formula II and optional alkylation catalyst are suitably added to the compound of Formula III or salt thereof in the alkylation reaction medium at a temperature of about 25 °C and the alkylation reaction is typically allowed to proceed at a temperature of at least about 25 °C, at least about 30 °C, at least about 40 °C, or at least about 50 °C. For example, the alkylation reaction is typically conducted at a temperature of from about 25 °C to about 90 °C, more typically from about 40 °C to about 60 °C. In various embodiments, the alkylation reaction medium is agitated or stirred at an elevated temperature after addition of the compound of Formula II and for a time sufficient to ensure substantial conversion of the compound of Formula III or a salt thereof. The period of time required for completion of the alkylation reaction can be readily determined by a person skilled in the art and can be monitored by any means known in the art, such as by high performance liquid
chromatography (HPLC). In some embodiments, where stirring is used after addition of the compound of Formula II, the alkylation reaction is allowed to proceed for less than about 1 hour to up to about 20 hours or more. Depending on the temperature and other reaction conditions employed, the alkylation reaction is typically allowed to proceed for a period of from about 1 hour to about 25 hours, from about 3 hours to about 18 hours, or from about 6 hours to about 18 hours.
[0054] In some embodiments, the compound of Formula III or salt thereof can be contacted with the compound of Formula II without first isolating the compound of Formula III from the cyclization reaction medium to provide the compound of Formula I or salt thereof.
[0055] In various embodiments, the overall yield of the compound of Formula I or salt thereof is greater than 65%. For example, the overall yield of Formula I can be greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95%. The compound of Formula I or salt thereof prepared from the processes described herein can be greater than 70% pure, greater than 75% pure, greater than 80% pure, greater than 85% pure, greater than 90% pure, greater than 95% pure, greater than 97% pure, or greater than 99% pure. Acid Quench After Cyclization and Before Alkylation
[0056] As described herein, the compound of Formula III or salt thereof is suitably prepared by a process comprising contacting a compound of Formula IV or a salt thereof (e.g., prepared as described herein) with an alkali metal alkoxide base or an alkaline earth metal alkoxide base in a cyclization reaction medium to produce the compound of Formula III or a salt thereof. It has been discovered that quenching the resulting cyclization reaction medium comprising the compound of Formula III or a salt thereof (e.g., by addition of a mineral acid) prior to contact with the a-halo ketone reagent of Formula II significantly increases the yield of the compound of Formula I in the subsequent alkylation reaction.
[0057] Accordingly, in this embodiment, the process further comprises quenching the cyclization reaction medium comprising the compound of Formula III or a salt thereof (e.g., by addition of a mineral acid) and subsequently contacting the compound of Formula III or a salt thereof with the a-halo ketone reagent of Formula II in the alkylation reaction to produce the compound of Formula I or a salt thereof. That is, the alkylation reaction medium to which the a- halo ketone reagent of Formula II is added comprises the compound of Formula III or a salt thereof, the mineral acid and a base.
[0058] Suitable mineral acids comprise hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, sulfuric acid, or a combination thereof. Typically, the mineral acid added after the cyclization reaction comprises hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, or a combination thereof. In one embodiment, the mineral acid comprises hydrochloric acid. The mineral acid is typically added to the cyclization reaction medium in an amount of at least about 1 molar equivalents, at least about 1.25 molar equivalents, or at least about 1.5 molar equivalents based on the amount of the alkali metal alkoxide base or alkaline earth metal alkoxide base employed in the cyclization reaction as described herein. For example, the mineral acid can be added to the cyclization reaction medium in an amount of from about 1 to about 2 molar equivalents based on the amount of the alkali metal alkoxide base or alkaline earth metal alkoxide base employed.
[0059] In various embodiments, the mineral acid can be replaced in whole or in part by other quenching agents. For example, carbon dioxide or potassium bicarbonate can be used in place of the mineral acid. [0060] The mineral acid or alternative quenching agent is typically added to the cyclization reaction medium at the temperature that the cyclization reaction is conducted as described herein.
[0061] In an embodiment wherein the cyclization reaction medium comprising the compound of Formula III or a salt thereof is quenched with a mineral acid, the amount of base (e.g., alkali or alkaline earth metal carbonate, alkali or alkaline earth metal bicarbonate or a combination thereof) subsequently added to the alkylation reaction medium prior to adding the a-halo ketone reagent of Formula II is adjusted to neutralize the mineral acid quench and provide a near equivalent amount or molar excess relative to the compound of Formula III or salt thereof as described herein. Preparation of Compounds of Formula VIII (Asymmetric Reduction)
[0062] A further aspect of the present invention is a process for preparing a
stereomerically enriched compound of Formula VIII:
Figure imgf000018_0001
Formula VIII
or a salt thereof, wherein R1, R4, R5 and R9 are as described above with respect to Formula I. Typically, R9 is F. In some embodiments, R4 is hydrogen. Alternatively, R4 is CH3. In various embodiments, R1 is -C(O)OR3 and R3 is ethyl. Alternatively, R1 is -C(O)OR3 and R3 is isopropyl. In some embodiments, R5 is OR6 and R6 is, for example, tert-butyl.
[0063] Generally, the process comprises contacting a compound of Formula I or salt thereof (e.g., prepared as described herein) with a hydrogen source in the presence of an organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound of Formula VIII or a salt thereof.
[0064] The chiral organometallic catalyst can be a chiral ruthenium catalyst. In some embodiments, the chiral ruthenium catalyst comprises a compound of chiral (S,S)-ruthenium- diamine complex.
[0065] For example, the chiral ruthenium catalyst can be selected from the group consisting of Ru(OTf)[(R,R)-BnSO2-dpen](p-cymene), RuCl[(R,R)-Ts-dpen](p-cymene), RuCl[(R,R)-Ts-dpen](p-cymene), (S)-RUCYTM-XylBINAP], RuCl2[(R)-xylyl- Phanephos][1S,2S-DPEN], RuCl2[(S)-xylbinap][(S,S)-dpen], RuCl2[(S)-dm-segphos][(S,S)- dpen], RuCl2[(R)-xylbinap][(R)-daipen], RuCl2[(S)-xylbinap][(S)-daipen], RuCl2[(S)- binap][(S)-daipen], RuCl2[(S)-xyl-PPhos][(S)-daipen], [NMe2H2][{RuCl(S-TunePhos)}2(m- Cl)3], [NMe2H2][{RuCl(MeO-BIPHEP)}2(m-Cl)3], [NMe2H2][{RuCl((S)-binap)}2(m-Cl)3], [NMe2H2][{RuCl((S)-xylbinap)}2(m-Cl)3], and [NMe2H2][{RuCl((S)-dm-segphos®)}2(m-Cl)3].
[0066] When the chiral organometallic catalyst is a chiral ruthenium catalyst, the chiral ruthenium catalyst can be present in the asymmetrical reduction zone in an amount of from about 0.1 mol% to about 10 mol%, relative to the compound of Formula I.
[0067] In other embodiments, the chiral organometallic catalyst can be a non-ruthenium containing catalyst. In some embodiments, the chiral organometallic catalyst can be selected from, but not limited to, (S)-2-methyl-CBS-oxazaborolidine, (S,S)-Me-DuPhos; Pd2(CF3CO2)2, [Rh(NBD)(TangPhos)]SbF6.
[0068] In the processes described above, the hydrogen source in the asymmetrical reduction zone can be substantially hydrogen gas. Alternatively, the hydrogen source in the asymmetrical reduction zone can be a hydrogen transfer agent. Non-limiting examples of hydrogen transfer agents include formic acid, formates, and mixtures thereof. Non-limiting examples of suitable formates include alkali metal formates, ammonium formate, and trialkylammonium formates. For example, the hydrogen source in the asymmetrical reduction zone can comprise sodium formate. In some embodiments, the hydrogen source in the asymmetrical reduction zone comprises trialkylammonium formate that is formed in situ by mixing formic acid and trialkylamine in the reaction medium of the asymmetrical reduction zone. For example, the trialkylammonium formate can be triethylammonium formate.
[0069] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims. EXAMPLES
[0070] The following non-limiting examples are provided to further illustrate the present invention. Analytical Method
[0071] RP-LCMS analysis used to monitor reactions was conducted on an AGILENT 1260 INFINITY HPLC System equipped with a diode array UV detector monitored at 244/300 nm and a 6120 quadrupole mass spectrometer with ESI. The column was an AGILENT
POROSHELL 120 EC-C18, 2.7 um, 4.6 x 50 mm. The RP-HPLC was conducted at a flow rate of 2 mL/min with a 40°C column temperature. Mobile Phase: Solvent A: 0.1% aqueous formic acid, Solvent B: acetonitrile, Gradient: 30% B/70% A (0.25 minute hold), ramp to 95% B/5% A over 3.75 minutes. Example 1: Preparation of diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)ureido)-3-methylthiophene-2,4-dicarboxylate (Formula IV) in acetonitrile-toluene
[0072] Phosgene (428 mg, 4.33 mmol, 15 wt% in toluene) was added dropwise to a stirred mixture of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate (Formula VII; 1.00 g, 3.89 mmol) in acetonitrile (30.0 mL) at 0 °C. After 10 minutes, triethylamine (1.30 g, 12.84 mmol) was added dropwise at 0 °C. After 10 minutes, the cooling bath was removed. After 85 minutes, tert-butyl 2-amino-2-methylpropanoate hydrochloride (Formula V; 1.38 g, 7.05 mmol) was charged into the reaction mixture. After 30 minutes, the conversion was >99% by HPLC, and the selectivity of reaction to prepare diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)ureido)-3-methylthiophene-2,4-dicarboxylate (Formula IV) was >99%. Example 2: Preparation of diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)ureido)-3-methylthiophene-2,4-dicarboxylate (Formula IV) in toluene
[0073] Phosgene (856 mg, 8.66 mmol, 15 wt% in toluene) was added dropwise to a stirred mixture of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate (Formula VII; 2.00 g, 7.78 mmol) in toluene (60.0 mL) at 0 °C. After 5 minutes, triethylamine (2.60 g, 25.68 mmol) was added dropwise over 10 min at 0 °C. The cooling bath was removed. After 2 hours, tert- butyl 2-amino-2-methylpropanoate hydrochloride (Formula V; 2.76 g, 14.1 mmol) was added portion-wise to the reaction mixture. After 3 hours, the conversion was 90% by HPLC, and the selectivity of reaction to prepare diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)ureido)-3-methylthiophene-2,4-dicarboxylate (Formula IV) was 96%. Example 3: Preparation of ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) in dimethylacetamide with no acid quench
[0074] Potassium tert-butoxide (152 mg, 1.33 mmol) was charged into a stirred mixture of diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3-methylthiophene-2,4- dicarboxylate (Formula IV; 300 mg, 0.678 mmol) in dimethylacetamide (4.2 mL) under nitrogen atmosphere at 0 °C. After 20 minutes, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-5-methyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 77%. Potassium bicarbonate (67.9 mg, 0.678 mmol) was added to the reaction mixture at 25°C. After 10 minutes, 2-chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 151 mg, 0.745 mmol) and sodium bromide (7.0 mg, 0.068 mmol) were added to the reaction mixture at 25 °C. After stirring for 1 hour at 70 °C, the conversion was 11% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5-fluoro-2- methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6- carboxylate (Formula I) was 50%. Further heating did not produce any additional product. Example 4: Reaction in dimethylacetamide and carbon dioxide quench after cyclization
[0075] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 5 minutes to a stirred mixture of potassium tert-butoxide (398 mg, 3.48 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at -10 °C. After 4 hours, the conversion was >98% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 88%. Dry ice (300 mg, 6.82 mmol) was added to the reaction mixture at -10 °C. After 15 minutes, the reaction mixture was heated to 50 °C and sodium bromide (8.7 mg, 0.084 mmol) and potassium bicarbonate (338 mg, 3.38 mmol) were added. After 3 minutes, 2- chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 428 mg, 2.11 mmol) was added at 50 °C. After stirring for 1 hour at 70 °C, the conversion was 54% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) was 70%. Example 5: Reaction in dimethylacetamide with sulfuric acid quench after cyclization and TBAB alkylation catalyst
[0076] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 5 minutes to a stirred mixture of potassium tert-butoxide (387 mg, 3.38 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at -10 °C. After 2 hours, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 89%. Aqueous sulfuric acid (9 M, 0.047 mL, 0.85 mmol) was added to the reaction mixture at -10 °C. After 40 minutes, potassium bicarbonate (338 mg, 3.38 mmol) and tetrabutylammonium bromide (27 mg, 0.084 mmol) were added at 25 °C. After 5 minutes, 2- chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 411 mg, 2.03 mmol) was added at 25 °C. After stirring for 21 hours at 55 °C, the conversion was 26% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) was 58%. Example 6: Reaction in acetonitrile with hydrochloric acid quench after cyclization and TBAC alkylation catalyst
[0077] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 4.00 g, 9.04 mmol) was added portion-wise over 25 minutes to a stirred mixture of potassium tert-butoxide (2.13 g, 19.0 mmol) in acetonitrile (9.0 mL) under nitrogen atmosphere at 25 °C. After 4 hours, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl-1- oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 65%. Aqueous hydrochloric acid (12 M; 0.83 mL, 10 mmol) was added to the reaction mixture at 0 °C. After 15 minutes, potassium bicarbonate (1.81g, 18.1 mmol) and tetrabutylammonium chloride (126 mg, 0.45 mmol) were added at 25 °C. After 8 minutes, 2- chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 2.20 g, 10.9 mmol) was added at 25 °C. After stirring for 3.5 hours at 70 °C, the conversion was 52% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) was 43%. Example 7: Reaction in dimethylacetamide with hydrochloric acid cyclization quench and TBAC alkylation catalyst
[0078] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 10 minutes to a stirred mixture of potassium tert-butoxide (398 mg, 3.48 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at 15 °C. After 1 hour, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 90%. Aqueous hydrochloric acid (12 M; 0.155 mL, 1.86 mmol) was added to the reaction mixture at 0 °C. After 15 minutes, potassium bicarbonate (338 mg, 3.38 mmol) and tetrabutylammonium chloride (23.5 mg, 0.084 mmol) were added at 25 °C. After 8 minutes, 2- chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 411 mg, 2.03 mmol) was added at 25 °C. After stirring for 3.5 hours at 40 °C, the conversion was 44% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) was 71%. Example 8: High temperature reaction in dimethylacetamide with hydrochloric acid cyclization quench and TBAC alkylation catalyst
[0079] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 10 minutes to a stirred mixture of potassium tert-butoxide (398 mg, 3.48 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at 15 °C. After 1 hour, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 90%. Aqueous hydrochloric acid (12 M; 0.155 mL, 1.86 mmol) was added to the reaction mixture at 0 °C. After 15 minutes, potassium bicarbonate (338 mg, 3.38 mmol) and tetrabutylammonium chloride (23.5 mg, 0.084 mmol) were added at 25 °C. After 8 min, 2- chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 411 mg, 2.03 mmol) was added at 25 °C. After stirring for 3.5 hours at 70 °C, the conversion was 72% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) was 82%. Example 9: Reaction in dimethylacetamide with hydrochloric acid cyclization quench and no alkylation catalyst
[0080] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 5 minutes to a stirred mixture of potassium tert-butoxide (387 mg, 3.38 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at -10 °C. After 2 hours, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 90%. Aqueous hydrochloric acid (12 M; 0.15 mL, 1.8 mmol) was added to the reaction mixture at 0 °C. After 30 minutes, potassium bicarbonate (338 mg, 3.38 mmol) was added at 25 °C. After 5 minutes, 2-chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 411 mg, 2.03 mmol) was added at 25 °C. After stirring for 20 hours at 50 °C, the conversion was 61% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1- oxopropan-2-yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) was 74%. Example 10: Reaction in dimethylacetamide with potassium bicarbonate cyclization quench and TBAB alkylation catalyst
[0081] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 10 minutes to a stirred mixture of potassium tert-butoxide (379 mg, 3.31 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at -10 °C. After 3 hours, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 88%. Potassium bicarbonate (508 mg, 5.07 mmol) was added at 25 °C. After 35 minutes, the reaction mixture was heated to 55 °C. After 1 hour, tetrabutylammonium bromide (27 mg, 0.084 mmol) and 2-chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 412 mg, 2.03 mmol) were added at 55 °C. After stirring for 18 hours at 55 °C, the conversion was 30% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1- oxopropan-2-yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) was 66%. Example 11: Reaction in 2-methyltetrahydrofuran with hydrochloric acid cyclization quench and TBAC alkylation catalyst
[0082] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 3.50 g, 7.91 mmol) was added portion-wise over 9 minutes to a stirred mixture of potassium tert-butoxide (1.90 g, 16.59 mmol) in 2- methyltetrahydrofuran (7.9 mL) under nitrogen atmosphere at 0 °C. After 1 hour, the conversion was >98% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 84%. Aqueous hydrochloric acid (12 M; 0.725 mL, 8.7 mmol) was added to the reaction mixture at 0 °C. After 29 minutes, tetrabutylammonium chloride (110 mg, 0.396 mmol) and potassium bicarbonate (1.58 g, 15.8 mmol) were added at 25 °C.2-Chloro-1-(5- fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 1.76 g, 8.69 mmol) was added at 30 °C. After stirring for 1 hour at 70 °C plus 6h at 80 °C, the conversion was 100% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) was 85%. Example 12: Reaction in 2-methyltetrahydrofuan with external base, hydrochloric acid cyclization quench, and TBAC alkylation catalyst
[0083] Potassium tert-butoxide (1.90 g, 16.59 mmol) was added portion-wise over 7 minutes to a stirred mixture of diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)- 3-methylthiophene-2,4-dicarboxylate (Formula IV; 3.50 g, 7.91 mmol) in 2- methyltetrahydrofuran (7.9 mL) under nitrogen atmosphere at 0 °C. After 2 hours, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert- butoxy)-2-methyl-1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula III) was 89%. Aqueous hydrochloric acid (12 M; 0.725 mL, 8.7 mmol) was added to the reaction mixture at 0 °C. After 23 minutes,
tetrabutylammonium chloride (110 mg, 0.396 mmol) and potassium bicarbonate (1.58 g, 15.8 mmol) were added at 25 °C.2-Chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 1.76g, 8.69 mmol) was added at 30 °C. After stirring for 1 hour at 70 °C plus 6 hours at 80 °C, the conversion was >99% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert- butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl- 2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) was 85%. Example 13: Reaction in diethyl carbonate with hydrochloric acid cyclization quench and TBAC alkylation catalyst
[0084] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 3.50 g, 7.91 mmol) was added portion-wise over 15 minutes to a stirred mixture of potassium tert-butoxide (1.90 g, 16.59 mmol) in diethyl carbonate (7.9 mL) under nitrogen atmosphere at 15 °C. After 2 hours at 25 °C, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 83%. Aqueous hydrochloric acid (12 M; 0.725 mL, 8.7 mmol) was added to the reaction mixture at 0 °C. After 20 minutes, tetrabutylammonium chloride (110 mg, 0.396 mmol) and potassium bicarbonate (1.58 g, 15.8 mmol) were added at 25 °C.2-Chloro-1-(5- fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 1.76g, 8.69 mmol) was added at 40 °C. After stirring for 2 hours at 70 °C plus 2 hours at 80 °C and 4 hours at 90 °C, the conversion was >99% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1- oxopropan-2-yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) was 80%. Example 14: Reaction in diethyl carbonate with hydrochloric acid cyclization quench and sodium bromide alkylation catalyst
[0085] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 3.50 g, 7.91 mmol) was added portion-wise over 15 minutes to a stirred mixture of potassium tert-butoxide (1.90 g, 16.59 mmol) in diethyl carbonate (7.9 mL) under nitrogen atmosphere at 15 °C. After 2 hours at 25 °C, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 84%. Aqueous hydrochloric acid (12 M; 0.725 mL, 8.7 mmol) was added to the reaction mixture at 0 °C. After 20 minutes, sodium bromide (40.7 mg, 0.396 mmol) and potassium bicarbonate (1.58 g, 15.8 mmol) were added at 25 °C.2-Chloro-1-(5-fluoro-2- methoxyphenyl)ethan-1-one (Formula II; 1.76g, 8.69 mmol) was added at 40 °C. After stirring for 2 hours at 70 °C plus 2 hours at 80 °C and 4 hours at 90 °C, the conversion was 95% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) was 79%. Example 15: Reaction in dimethylacetamide with hydrochloric acid cyclization quench and TBAB alkylation catalyst
[0086] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 5 minutes to a stirred mixture of potassium tert-butoxide (379 mg, 3.31 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at -10 °C. After 3 hours, the cooling bath was replaced with a 0 °C cooling bath. After 35 minutes, the conversion was 97% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 68%. Aqueous hydrochloric acid (12 M; 0.15 mL, 1.8 mmol) was added to the reaction mixture at -5 °C. After 19 minutes, potassium bicarbonate (339 mg, 3.39 mmol),
tetrabutylammonium bromide (27 mg, 0.084 mmol) and 2-chloro-1-(5-fluoro-2- methoxyphenyl)ethan-1-one (Formula II; 411 mg, 2.03 mmol) were added at 25 °C. After stirring for 46 minutes at 40 °C plus 16 hours at 55 °C, the conversion was 81% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5- fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3- d]pyrimidine-6-carboxylate (Formula I) was 79%. Example 16: Reaction in dimethylacetamide with hydrochloric acid cyclization quench and NaHCO3/TBAB alkylation catalyst
[0087] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 750 mg, 1.69 mmol) was added portion-wise over 5 minutes to a stirred mixture of potassium tert-butoxide (379 mg, 3.31 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at -10 °C. After 3.5 hours, the cooling bath was replaced with a 0 °C cooling bath. After 1.5 hours, the conversion was 96% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-5- methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 57%. Aqueous hydrochloric acid (12 M; 0.20 mL, 2.4 mmol) was added to the reaction mixture at -5 °C. After 15 minutes, sodium bicarbonate (341 mg, 4.06 mmol), tetrabutylammonium bromide (27 mg, 0.084 mmol) and 2-chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 411 mg, 2.03 mmol) were added at 25 °C. After stirring for 17 hours at 55 °C, the conversion was 69% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1- oxopropan-2-yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) was 73%. Example 17: Reaction in dimethylacetamide with hydrochloric acid cyclization quench and TBAB alkylation catalyst
[0088] Potassium tert-butoxide (387 mg, 3.38 mmol) was charged into a stirred mixture of diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3-methylthiophene-2,4- dicarboxylate (Formula IV; 750 mg, 1.69 mmol) in dimethylacetamide (1.7 mL) under nitrogen atmosphere at -10 °C. After 3.5 hours, the cooling bath was replaced with a 0 °C cooling bath. After 40 minutes, the conversion was 96% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 84%. Aqueous hydrochloric acid (12 M; 0.15 mL, 1.8 mmol) was added to the reaction mixture at 0 °C. After 31 minutes, potassium bicarbonate (338 mg, 3.38 mmol), tetrabutylammonium bromide (27 mg, 0.084 mmol) and 2-chloro-1-(5-fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 480 mg, 2.37 mmol) were added at 25 °C. After stirring for 17 hours at 55 °C, the conversion was 99% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4- tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) was 80%. Example 18: Lower temperature reaction in diethyl carbonate with hydrochloric acid cyclization quench and TBAC alkylation catalyst
[0089] Diethyl 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)ureido)-3- methylthiophene-2,4-dicarboxylate (Formula IV; 4.00 g, 9.04 mmol) was added portion-wise over 25 minutes to a stirred mixture of potassium tert-butoxide (2.13 g, 18.6 mmol) in diethyl carbonate (9.0 mL) under nitrogen atmosphere at 15 °C. After 1 hour at 25 °C, the conversion was >99% by HPLC, and the selectivity of the cyclization to ethyl 3-(1-(tert-butoxy)-2-methyl- 1-oxopropan-2-yl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula III) was 88%. Aqueous hydrochloric acid (12 M; 0.83 mL, 10 mmol) was added to the reaction mixture at 0 °C. After 14 minutes, tetrabutylammonium chloride (126 mg, 0.45 mmol) and potassium bicarbonate (1.81 g, 18.1 mmol) were added at 25 °C.2-Chloro-1-(5-fluoro-2- methoxyphenyl)ethan-1-one (Formula II; 2.20g, 10.8 mmol) was added at 40 °C. After stirring for 10 hours at 70 °C, the conversion was 81% by HPLC, and the selectivity of the alkylation to ethyl 3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2- oxoethyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate
(Formula I) was 79%. Example 19: Reaction in diethyl carbonate with hydrochloric acid cyclization quench and TBAC alkylation catalyst
[0090] To a stirred mixture of potassium tert-butoxide (39.9 g, 355.9 mmol) in diethyl carbonate (375 mL) at 0 °C was added solid 5-(3-(1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)ureido)-3-methylthiophene-2,4-dicarboxylate (Formula IV; 75 g, 169.5 mmol) in portions over 8 minutes. After complete addition, the mixture was warmed to 10 °C and stirred for 1 hour. Concentrated hydrochloric acid (12 M; 16.8 mL, 203.4 mmol) was added dropwise via pipet. After complete addition, the mixture was warmed to 30 °C before tetrabutylammonium chloride (2.36 g, 8.47 mmol), potassium bicarbonate (33.9 g, 339 mmol) and 2-chloro-1-(5- fluoro-2-methoxyphenyl)ethan-1-one (Formula II; 37.8 g, 186.4 mmol) were added. After complete addition, the mixture was warmed to 75-80 °C for 16 hours. The mixture was cooled to 50 °C and water (375 mL) was added over a 40-minute period while being stirred. The layers were separated, and the organic layer was washed with additional 250 mL of water. The organic layer (450 g) was distilled down to a weight of 388 g. The mixture was seeded and cooled to 0 °C in an ice bath. The solid precipitate was filtered and washed with diethyl carbonate (30 mL) at 0 °C. The solid was dried in vacuo to afford 58.2 g (61%) of ethyl 3-(1-(tert-butoxy)-2- methyl-1-oxopropan-2-yl)-1-(2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl)-5-methyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (Formula I) as a solid with 98% purity. Concentration of the mother liquor to half its original volume, seeding, cooling and precipitation afforded an additional 4.1 g (4%) of product with similar purity as the first crop.
[0091] When introducing elements of the present invention or the embodiments(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.
[0092] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
[0093] As various changes could be made in the above processes without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

Claims

WHAT IS CLAIMED IS: 1. A process for preparing a compound of Formula IV:
Figure imgf000030_0001
Formula IV
or a salt thereof, the process comprising contacting a compound of Formula VII:
Figure imgf000030_0002
Formula VII
or a salt thereof, with phosgene to produce an isocyanate intermediate of Formula VI:
Figure imgf000030_0003
Formula VI
or a salt thereof, contacting the isocyanate intermediate of Formula VI or salt thereof with a salt of an amine of Formula V:
Figure imgf000030_0004
Formula V
to produce a compound of Formula IV or a salt thereof, wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R2 is -C(O)OR3;
R3 is a straight or branched C1–C4 alkyl;
R4 is hydrogen or CH3;
R5 is OR6 or NR7R8; and
R6 is straight or branched C1–C4 alkyl or benzyl;
R7 is hydrogen or CH3; and
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring.
2. The process of claim 1, wherein the compound of Formula VII or a salt thereof is contacted with phosgene in the presence of a base.
3. The process of claim 2, wherein the base comprises triethylamine,
diisopropylethylamine, potassium t-butoxide, pyridine, sodium bicarbonate, potassium carbonate, sodium hydroxide, or a combination thereof.
4. The process of claim 2 or claim 3, wherein the base comprises triethylamine.
5. The process of any one of claims 1 to 4, wherein the isocyanate intermediate of Formula VI is contacted with the salt of the amine of Formula V in the presence of a base.
6. The process of claim 5, wherein the base comprises triethylamine,
diisopropylethylamine, potassium t-butoxide, pyridine, sodium bicarbonate, potassium carbonate, sodium hydroxide, or a combination thereof.
7. The process of claim 5 or claim 6, wherein the base comprises triethylamine.
8. The process of any one of claims 5 to 7, wherein the base present during contacting the compound of Formula VII or salt thereof with phosgene and contacting the isocyanate intermediate of Formula VI or salt thereof with the salt of an amine of Formula V is the same.
9. The process of claim 1, wherein the process comprises contacting the compound of Formula VII or salt thereof with phosgene and heating in the absence of an external base to produce the isocyanate intermediate Formula VI or salt thereof and hydrochloric acid gas.
10. The process of claim 1 or claim 9, wherein the process comprises contacting the isocyanate intermediate of Formula VI or salt thereof with the salt of the amine of Formula V and heating in the absence of an external base to produce a compound of Formula IV or a salt thereof.
11. The process of claim 9 or 10, wherein the heating step comprises heating to a
temperature of at least about 20 °C, at least about 30 °C, at least about 40 °C, at least about 50 °C, at least about 60 °C, at least about 70 °C, at least about 80 °C, at least about 90 °C, at least about 100 °C, at least about 110 °C, at least about 120 °C, at least about 130 °C, at least about 140 °C, at least about 150 °C, at least about 160 °C, at least about 170 °C, or at least about 180 °C.
12. The process of claim 9 or 10, wherein the heating step comprises heating to a
temperature of from about 20 °C to about 180 °C, from about 30 °C to about 170 °C, from about 40 °C to about 160 °C, from about 50 °C to about 150 °C, from about 60 °C to about 140 °C, from about 70 °C to about 130 °C, from about 80 °C to about 120 °C, from about 90 °C to about 110 °C, from about 95 °C to about 105 °C, or from about 80 °C to about 100 °C.
13. The process of any one of claims 1 to 12, wherein R1 and R2 are the same.
14. The process of any one of claims 1 to 13. wherein R1 and R2 are -C(O)OR3 and R3 is ethyl.
15. The process of any one of claims 1 to 13, wherein R1 and R2 are -C(O)OR3 and R3 is isopropyl.
16. The process of any one of claims 1 to 15, wherein R4 is hydrogen.
17. The process of any one of claims 1 to 15, wherein R4 is CH3.
18. The process of any one of claims 1 to 17, wherein R5 is OR6.
19. The process of claim 18, wherein R6 is tert-butyl.
20. The process of any one of claims 1 to 19. wherein each contacting step is optionally independently conducted in the presence of a solvent.
21. The process of claim 20. wherein the solvent comprises toluene, acetonitrile, 2- methyltetrahydrofuran, diethyl carbonate, xylene, or a combination thereof.
22. The process of claim 21, wherein the solvent comprises toluene, acetonitrile, xylene, or a combination thereof.
23. The process of claim 20, wherein the solvent a solvent comprises a non-polar solvent.
24. The process of claim 23, wherein the non-polar solvent comprises an aromatic non-polar solvent selected from the group consisting of toluene, xylene and mixtures thereof, optionally in combination with one or more additional solvents.
25. A process for preparing a compound of Formula III:
Figure imgf000033_0001
Formula III
or a salt thereof, the process comprising preparing a compound of Formula IV or a salt thereof in accordance of any one of claims A1 to A24 and contacting the compound of Formula IV or a salt thereof with an alkali metal alkoxide base or alkaline earth metal alkoxide base in a cyclization reaction medium to produce the compound of Formula III or a salt thereof, wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen or CH3;
R5 is OR6 or NR7R8;
R6 is straight or branched C1–C4 alkyl or benzyl;
R7 is hydrogen or CH3; and
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring.
26. The process of claim 25, wherein the alkali metal alkoxide base or alkaline earth metal alkoxide base comprises sodium alkoxide, potassium alkoxide, magnesium alkoxide, calcium alkoxide, cesium alkoxide, or a combination thereof.
27. The process of claim 25 or 26, wherein the compound of Formula IV or a salt thereof is contacted with an alkali metal alkoxide base comprising potassium alkoxide.
28. The process of claim 26 or 27, wherein the potassium alkoxide comprises potassium t- butoxide.
29. The process of any one of claims 25 to 28, wherein the cyclization reaction medium comprises a solvent comprising dimethylformamide, dimethylacetamide, N-methyl-2- pyrrolidone, acetonitrile, 2-methyltetrahydrofuran, diethyl carbonate, or a combination thereof.
30. A process for preparing a compound of Formula I:
Figure imgf000034_0001
Formula I
or a salt thereof, the process comprising preparing a compound of Formula III or a salt thereof in accordance with any one of claims B1 to B5 and contacting the compound of Formula III or a salt thereof with a compound of Formula II:
Figure imgf000034_0002
Formula II
in an alkylation reaction medium comprising a base to produce the compound of Formula I or a salt thereof; wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen or CH3;
R5 is OR6 or NR7R8;
R6 is straight or branched C1–C4 alkyl or benzyl;
R7 is hydrogen or CH3;
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring;
R9 is hydrogen or F; and
X is Cl, Br, or I.
31. The process of claim 30, wherein the alkylation reaction medium comprises a solvent comprising dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, 2- methyltetrahydrofuran, diethyl carbonate, or a combination thereof.
32. The process of claim 30 or claim 31, wherein the base comprises an alkali metal carbonate base, an alkaline earth metal carbonate base, an alkali metal bicarbonate base, an alkaline earth metal bicarbonate base, or a combination thereof.
33. The process of any one of claims 30 to 32, wherein the base comprises lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, or a combination thereof.
34. The process of claim 32 or claim 33, wherein the base comprises potassium carbonate.
35. The process of claim 32 or claim 33, wherein the base comprises potassium bicarbonate.
36. The process of claim 32 or claim 33, wherein the base comprises sodium bicarbonate.
37. The process of any one of claims 30 to 36 wherein the alkylation reaction medium further comprises an alkylation catalyst.
38. The process of claim 37, wherein the alkylation catalyst comprises an alkali metal halide catalyst.
39. The process of claim 38. wherein the alkali metal halide catalyst comprises potassium halide or sodium halide.
40. The process of claim 38 or claim 39, wherein the alkali metal halide catalyst comprises sodium bromide.
41. The process of claim 37, wherein the alkylation catalyst comprises tetrabutylammonium halide.
42. The process of claim 41, wherein the tetrabutylammonium halide comprises tetrabutylammonium bromide, tetrabutylammonium chloride, or a combination thereof.
43. The process of claim 42, wherein the tetrabutylammonium halide comprises tetrabutylammonium chloride.
44. The process of any one of claims 30 to 43, wherein X is Cl.
45. A process for the preparation of a compound of Formula I:
Figure imgf000036_0001
Formula I
or a salt thereof, the process comprising contacting a compound of Formula IV:
Figure imgf000036_0002
Formula IV
or a salt thereof with an alkali metal alkoxide base or alkaline earth metal alkoxide base in a cyclization reaction medium to produce a compound of Formula III:
Figure imgf000036_0003
Formula III
or a salt thereof;
adding a mineral acid to the cyclization reaction medium comprising the compound of Formula III or a salt thereof;
contacting the compound of Formula III or salt thereof with a compound of Formula II:
Figure imgf000037_0001
Formula II
in an alkylation reaction medium comprising the mineral acid and a base to produce the compound of Formula I or a salt thereof; wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R2 is -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen or CH3;
R5 is OR6 or NR7R8;
R6 is straight or branched C1–C4 alkyl or benzyl;
R7 is hydrogen or CH3;
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring;
R9 is hydrogen or F; and
X is Cl, Br, or I.
46. The process of claim 45, wherein the mineral acid is present in the cyclization reaction medium in an amount of at least about 1 molar equivalents, at least about 1.25 molar
equivalents, or at least about 1.5 molar equivalents based on the amount of the alkali metal alkoxide base or alkaline earth metal alkoxide base.
47. The process of claim 45, wherein the mineral acid is added to the cyclization reaction medium in an amount of from about 0.5 to about 2.0 molar equivalents, from about 1.0 to about 2.0 molar equivalents, or from about 1.0 to about 1.5 molar equivalents based on the amount of the alkali metal alkoxide base or alkaline earth metal alkoxide base.
48. The process of any one of claims 45 to 47, wherein the mineral acid comprises hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, or a combination thereof.
49. The process of any one of claims 45 to 48, wherein the mineral acid comprises hydrochloric acid.
50. The process of any one of claims 45 to 49, wherein the mineral acid is hydrochloric acid.
51. The process of any one of claims 45 to 50, wherein the alkali metal alkoxide base or alkaline earth metal alkoxide base comprises sodium alkoxide, potassium alkoxide, magnesium alkoxide, calcium alkoxide, or a combination thereof.
52. The process of any one of claims 45 to 51, wherein the alkali metal alkoxide base comprises potassium alkoxide.
53. The process of claim 51 or claim 52, wherein the potassium alkoxide comprises potassium t-butoxide.
54. A process for preparing a compound of Formula I:
Figure imgf000038_0001
Formula I
or a salt thereof, the process comprising contacting a compound of Formula III:
Figure imgf000038_0002
Formula III
or a salt thereof with a compound of Formula II:
Figure imgf000038_0003
Formula II
in an alkylation reaction medium comprising an alkali metal bicarbonate base or alkaline earth metal bicarbonate base to produce the compound of Formula I or a salt thereof, wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen or CH3; R5 is OR6 or NR7R8;
R6 is straight or branched C1–C4 alkyl or benzyl;
R7 is hydrogen or CH3;
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring;
R9 is hydrogen or F; and
X is Cl, Br, or I.
55. A process for preparing a compound of Formula I:
Figure imgf000039_0001
Formula I
or a salt thereof, the process comprising contacting a compound of Formula III:
Figure imgf000039_0002
Formula III
or a salt thereof with a compound of Formula II:
Figure imgf000039_0003
Formula II
in an alkylation reaction medium comprising a base and a solvent selected from the group consisting of diethyl carbonate, 2-methyltetrahydrofuran, dimethylacetamide, and a combination thereof, to produce the compound of Formula I or a salt thereof; wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen or straight or CH3;
R5 is OR6 or NR7R8; R6 is straight or branched C1–C4 alkyl or benzyl;
R7 is hydrogen or CH3;
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring;
R9 is hydrogen or F; and
X is Cl, Br, or I.
56. A process for preparing a compound of Formula I:
Figure imgf000040_0001
Formula I
or a salt thereof, the process comprising contacting a compound of Formula III:
Figure imgf000040_0002
Formula III
or a salt thereof with a compound of Formula II:
Figure imgf000040_0003
Formula II
in an alkylation reaction medium comprising a base and an alkylation catalyst comprising a tetrabutylammonium halide to produce the compound of Formula I or a salt thereof, wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen or CH3;
R5 is OR6 or NR7R8;
R6 is straight or branched C1–C4 alkyl or benzyl;
R7 is hydrogen or CH3; R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring;
R9 is hydrogen or F; and
X is Cl, Br, or I.
57. The process of any one of claims 45 to 55, wherein the alkylation reaction medium further comprises an alkylation catalyst.
58. The process of claim 57, wherein the alkylation catalyst comprises an alkali metal halide catalyst.
59. The process of claim 58, wherein the alkali metal halide catalyst comprises potassium halide or sodium halide.
60. The process of claim 59, wherein sodium halide comprises sodium bromide.
61. The process of claim 57, wherein the alkylation catalyst comprises tetrabutylammonium halide.
62. The process of claim 56 or 61, wherein the tetrabutylammonium halide comprises tetrabutylammonium bromide, tetrabutylammonium chloride, or a combination thereof.
63. The process of any one of claims 56, 61, or 62, wherein the tetrabutylammonium halide comprises tetrabutylammonium chloride.
64. The process of any one of claims 45 to 53 or 55 to 63, wherein the base comprises an alkali metal carbonate base, alkaline earth metal carbonate base, an alkali metal bicarbonate base, an alkaline earth metal bicarbonate base, or a combination thereof.
65. The process of any one of claims 45 to 53 or 55 to 63, wherein the base comprises an alkali metal bicarbonate base or an alkaline earth metal bicarbonate base.
66. The process of any one of claims 54, 64, or 65, wherein base comprises an alkali metal bicarbonate base or an alkaline earth metal bicarbonate base comprising lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, or a combination thereof.
67. The process of claim 66, wherein the base comprises an alkali metal bicarbonate base comprising sodium bicarbonate, potassium bicarbonate, or a combination thereof.
68. The process of any one of claims 45 to 54 and 56 to 67, wherein the alkylation reaction medium comprises a solvent comprising toluene, acetonitrile, dimethylformamide, N-methyl-2- pyrrolidone, 2-methyltetrahydrofuran, dimethylacetamide, diethyl carbonate, xylene, or a combination thereof.
69. The process of any one of claims 56 or 61 to 63, wherein the tetrabutylammonium halide is present in an amount of from about 1 mol% to about 20 mol%, from about 1 mol% to about 15 mol%, from about 1 mol% to about 10 mol%, from about 1 mol% to about 9 mol%, from about 1 mol% to about 8 mol%, from about 1 mol% to about 5 mol%, from about 1 mol% to about 3 mol%, from about 2 mol% to about 8 mol%, from about 3 mol% to about 8 mol%, from about 3 mol% to about 7 mol%, from about 3 mol% from about 6 mol%, from about 4 mol% to about 6 mol%, from about 5 mol% to about 6 mol%, or from about 4 mol% to about 5 mol% based on the amount of the compound of Formula II.
70. The process of any one of claims 45 or 64 to 67, wherein the alkali metal bicarbonate base or alkaline earth metal bicarbonate base is present in the reaction medium in an amount of from about 1.0 to about 5.0 molar equivalents, from about 1.0 to about 4.0 molar equivalents, from about 1.0 to about 3.0 molar equivalents, from about 1.0 to about 2.0 molar equivalents, or from about 2.0 to about 3.0 molar equivalents based on the amount of the compound of Formula III or salt thereof.
71. The process of any one of claims 45 or 64 to 67, wherein the alkali metal bicarbonate base or alkaline earth metal bicarbonate base is present in the reaction medium in an amount of at least about 1 molar equivalents, at least about 1.25 molar equivalents, at least about 1.5 molar equivalents, at least 2 molar equivalents, at least 2.5 molar equivalents, at least 3 molar equivalents, at least 4 molar equivalents, or at least 5 molar equivalents based on the amount of the compound of Formula III or salt thereof.
72. The process of any one of claims 45 to 71, wherein the compound of Formula III or salt thereof is contacted with the compound of Formula II without first isolating the compound of Formula III or salt thereof from the alkylation reaction medium to provide the compound of Formula I or salt thereof.
73. The process of any one of claims 45 to 72, wherein R1 and R2 are the same.
74. The process of any one of claims 45 to 73, wherein R1 and R2 are -C(O)OR3 and R3 is ethyl.
75. The process of any one of claims 45 to 73, wherein R1 and R2 are -C(O)OR3 and R3 is isopropyl.
76. The process of any one of claims 45 to 75, wherein R4 is hydrogen.
77. The process of any one of claims 45 to 75, wherein R4 is CH3.
78. The process of any one of claims 45 to 77, wherein R5 is OR6.
79. The process of claim 78, wherein R6 is tert-butyl.
80. The process of any one of claims 45 to 79, wherein R9 is F.
81. The process of any one of claims 45 to 80, wherein X is Cl.
82. A process for preparing a compound of Formula I:
Figure imgf000043_0001
Formula I
or a salt thereof, the process comprising contacting a compound of Formula IV:
Figure imgf000044_0001
Formula IV
or a salt thereof with an alkali metal or alkaline earth metal carbonate or bicarbonate base in a cyclization reaction medium to produce a compound of Formula III:
Figure imgf000044_0002
Formula III
or a salt thereof; and
contacting the compound of Formula III or a salt thereof with a compound of Formula II:
Figure imgf000044_0003
Formula II
in an alkylation reaction medium comprising an alkali metal or alkaline earth metal carbonate or bicarbonate base to produce the compound of Formula I or a salt thereof, wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R2 is -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen;
R5 is NR7R8;
R7 is hydrogen or CH3;
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring;
R9 is hydrogen or F; and
X is Cl, Br, or I.
83. The process of claim 82, wherein the alkali metal or alkaline earth metal carbonate or bicarbonate base is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, magnesium bicarbonate, calcium bicarbonate, and combinations thereof.
84. The process of claim 82, wherein the compound of Formula IV or a salt thereof is contacted with an alkali metal or alkaline earth metal carbonate base and the alkylation reaction medium comprises an alkali metal or alkaline earth metal carbonate base.
85. The process of claim 84, wherein the compound of Formula IV or a salt thereof is contacted with potassium carbonate and the alkylation reaction medium comprises potassium carbonate.
86. A process for preparing a stereomerically enriched compound of Formula VIII:
Figure imgf000045_0001
Formula VIII
or a salt thereof, the process comprising preparing a compound of Formula I or salt thereof in accordance with any one of claims C1 to C15 or D1 to D41 and contacting the compound of Formula I or salt thereof with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound of Formula VIII or a salt thereof, wherein:
R1 is 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OR3;
R3 is straight or branched C1–C4 alkyl;
R4 is hydrogen or CH3;
R5 is OR6 or NR7R8;
R6 is straight or branched C1–C4 alkyl or substituted or unsubstituted benzyl;
R7 is hydrogen or CH3;
R8 is ethyl, isopropyl, or cyclobutyl; or R7 and R8 are joined to form a 5-membered or 6- membered heterocycloalkyl ring; and
R9 is hydrogen or F.
87. The process of claim 86, wherein R9 is F.
88. The process of claim 86 or 87, wherein R4 is hydrogen.
89. The process of claim 86 or 87, wherein R4 is CH3.
90. The process of any one of claims 86 to 89, wherein R1 is -C(O)OR3 and R3 is ethyl.
91. The process of any one of claims 86 to 89, wherein R1 is -C(O)OR3 and R3 is isopropyl.
92. The process of any one of claims 86 to 91, wherein R5 is OR6.
93. The process of claim 92, wherein R6 is tert-butyl.
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