Synthesis of 2-hydroxy-N,N-dimethyl-3-[ [2-[1 (R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]aminobenzamide

A process for making a compound of formula XI or XII:

• comprising:
• (a) converting the compound of formula III
• to a compound of formula VI:
• (b) mixing a protecting group with the compound of formula VI to yield a compound of formula VII:
• wherein G represents a protecting group;
• (c) reacting the compound of formula VII with a suitable organometallic reagent, followed by work-up, to yield a compound of formula VIII:
• (d) removing the protecting group (G) from the compound of formula VIII to yield a compound of formula IX:
• (e) converting the compound of formula IX into an imine intermediate compound of formula X:
• (f) converting the imine intermediate compound of formula X into the salt of formula XI:
• (g) converting the compound of formula XI to the free amine:

A process for preparing a compound of the formula XIII:

• comprising:
• (a) converting the compound of formula III
• to a compound of formula VI:
• (b) adding a protecting group to the compound of formula VI to yield a compound of formula VII:
• wherein G represents a protecting group;
• (c) reacting the compound of formula VII with a suitable organometallic reagent, followed by work-up, to yield a compound of formula VIII:
• (d) removing the protecting group (G) from the compound of formula VIII to yield a compound of formula IX:
• (e) converting the compound of formula IX into an imine intermediate compound of formula X:
• (f) converting the imine intermediate compound of formula X into the salt of formula XI:
• and reacting said compound of formula XI with a compound of formula Q:
• wherein R represents (C1–C10)alkyl to produce the compound of formula XIII;
• or
• (g) converting the compound of formula XI to the free amine:
• by reacting the compound of formula XI in a suitable solvent with a suitable base, and reacting said compound of formula XII with Q:
• wherein R represents (C1–C10)alkyl to produce the compound of formula XIII.

A process for producing a compound of the formula I:

• comprising:
• (a) converting the compound of formula III
• to a compound of formula VI:
• (b) adding a protecting group to the compound of formula VI to yield a compound of formula VII:
• wherein G represents a protecting group;
• (c) reacting the compound of formula VII with a suitable organometallic reagent, followed by work-up, to yield a compound of formula VIII:
• (d) removing the protecting group (G) from the compound of formula VIII to yield a compound of formula IX:
• (e) converting the compound of formula IX into an imine intermediate compound of formula X:
• (f) converting the imine intermediate compound of formula X into the salt of formula XI:
• (g) reacting the compound of formula XI with the compound of formula Q:
• to yield a compound of formula XIII:
• wherein R represents (C1–C10)alkyl in formulas Q and XIII;
• or
• (h) converting the compound of formula XI to a compound of formula XII:
• and reacting the compound of formula XII with a compound of formula Q:
• to yield a compound of formula XIII:
• wherein R represents (C1–C10)alkyl in formulas Q and XIII;
• (i) converting the compound of formula II
• wherein A is selected from the group consisting of Br, Cl and I, to a compound of formula IV:
• (j) hydrogenating the compound of formula IV with a suitable hydrogenation catalyst under hydrogen pressure, to form the intermediate compound of formula IV(i):
• (k) reacting the compound of formula IV(i) with the compound of formula XIII to yield the compound of formula I.

A process for preparing a compound of formula I:

• comprising:
• (a) dissolving the compound of formula II:
• in:
• a solvent selected from the group consisting of:
• acetonitrile, THF, t-butylmethylether, methylenechloride, toluene, ethylacetate, diethylether, and chloroform, and
• an acid chloride selected from the group consisting of:
• thionyl chloride and oxalyl chloride, wherein a catalytic amount of DMF is optionally used when oxalyl chloride is used;
• and adjusting the temperature of the resulting reaction mixture to a about −20° C. to about 110° C.;
• cooling the reaction mixture, when the reaction is complete, to a temperature of about 5° C. to about 10° C.;
• adding dimethylamine gas or a solution of dimethylamine, at a concentration of at least about 1 molar equivalent with respect to the compound of formula II, wherein the solvent used in said dimethylamine is selected from the group consisting of:
• acetonitrile, THF, t-butylmethylether, methylenechloride, toluene, ethylacetate, diethylether, and chloroform;
• adjusting the temperature of the resulting reaction mixture to a temperature of about −20° C. to about 50° C.;
• acidifying the resulting reaction mixture with an aqueous acid to a pH of about 0 to about 7, to produce a compound of formula IV:
• wherein A is in the compounds of formulas II and IV is selected from the group consisting of Br, Cl and I;
• (b) hydrogenating the compound of formula IV by mixing said compound of formula IV with:
• a base selected from the group consisting of:
• KOH, NaOH, Na2CO3, K2CO3, NaHCO3, KHCO3, tetramethylguanidine, DBU, diisopropylethylamine and mixtures thereof, wherein said base is in a concentration of at least about 1 molar equivalent with respect to the compound of formula IV,
• a hydrogenation catalyst selected from the group consisting of:
• Pd/C, Pt/C, PdOH, and Raney nickel;
• and
• a solvent selected from the group consisting of:
• THF, methanol, ethanol, propanol, isopropanol, acetonitrile, ethyl acetate, and mixtures thereof;
• and
• pressurizing the resulting mixture under hydrogen at a pressure of about 10 to about 500 psi to produce the intermediate compound of formula IV(i):
• (c) adding the compound of formula Q:
• in a concentration of at least 1 molar equivalent with respect to the compound of formula IV(i), to the reaction mixture comprising the compound of formula IV(i) obtained in step (b), and adjusting the temperature to about 0° C. to about 80° C. to produce a compound of formula V:
• wherein R in said compound of formula Q is selected from the group consisting of:
• methyl, ethyl, propyl and isopropyl, and wherein said reaction is optionally catalyzed by a base selected from the group consisting of:
• KOH, NaOH, Na2CO3, K2CO3, K2CO3, NaHCO3, KHCO3, tetramethylguanidine, DBU, diisopropylethylamine, and mixtures thereof;
• (d1) mixing:
• the compound of formula V from step (c) with the compound of formula XI
• and a base in a solvent, heating the resulting reaction mixture to a temperature of about 20° C. to about 150° C., and then acidifying the reaction mixture to a pH of about 3 to about 7, to produce a compound of formula I;
• said base being selected from the group consisting of:
• pyridine, dimethylaminopyridine (DMAP), diisopropylethylamine and —N(R2)3;
• wherein each R2 is independently selected from the group consisting of:
• alkyl and cycloalkyl;
• and said base being used in a concentration of at least about 1 molar equivalent with respect to the compound of formula IV;
• and said solvent being selected from the group consisting of:
• nitrile, ether, and alcohol solvents;
• or
• (d2) mixing the compound of formula XI:
• with water and solvent selected from the group consisting of:
• ethers and methylene chloride;
• basifying the resulting reaction mixture in a base selected from the group consisting of:
• NaOH, KOH, Mg(OH)2, Na2CO3 and K2CO3, to a pH of about 7 to about 14, said basification being done at a temperature of about 0° C. to about 50° C. to produce a compound of formula XII:
• dissolving said compound of formula V from step (c) in a solvent selected from the group consisting of:
• alcohol solvents, nitrile solvents, ether solvents and toluene;
• mixing the resulting solution with the compound of formula XII, and optionally adding a catalytic amount of a base to the resulting solution, wherein said base is selected from the group consisting of:
• pyridine and —N(R3)3, wherein R3 is selected from the group consisting of:
• alkyl, aryl, aralkyl, and arylalkyl, and wherein the temperature of the resulting solution is about 10° C. to about 150° C., to produce a compound of formula I;
• (e) wherein said compound of formula XI is prepared by:
• mixing the compound of formula III:
• with 0.01 molar equivalent, with respect to the compound of formula III, of R-2-(−)-phenylglycinol in a solvent selected from the group consisting of:
• aromatic solvents, halogenated solvents, alcohol solvents, nitrile solvents, ether solvents, and mixtures thereof, and heating the resulting mixture at reflux to produce a compound of formula VI:
• mixing the solution comprising the compound of formula VI with a silylating reagent selected from the group consisting of:
• hexamethyldisilazane, TMS chloride, and TMSOTF, wherein the TMS chloride or TMSOTF is used in combination with an aryl or alkyl base, and an acid in a concentration of at least about 0.2 molar equivalent with respect to the compound of formula VI, said acid being selected from the group consisting of:
• ammonium sulphate, ammonium nitrate, ammonium chloride, H2SO4, HCl, H3PO4, citric acid, mesyl chloride, paratoluenesulfonic acid, paratoluenesulfonic acid pyridinium salt, and alkylsulfonic acid, and heating the resulting reaction mixture at reflux to produce an imine compound of formula VII:
• wherein G represents a protecting group that is the silylating reagent used;
• mixing said imine compound of formula VII with an organometallic reagent in a solvent at a temperature of about 0° C. to about 80° C., said organometallic reagent being selected from the group consisting of:
• diethyl zinc, ethylzinc bromide, ethylzinc chloride, ethylmagnesium bromide, ethylmagnesium chloride and ethyllithium, said organometallic reagent being used in a concentration of 0.1 to about 5 molar equivalents with respect to the compound of formula VII, said solvent being selected from the group consisting of:
• benzene, toluene, TBME, THF, DME, dimethoxyethane, and mixtures thereof, to produce a compound of formula VIII:
• adding the compound of formula VIII to a cooled aqueous acid, said acid being at a concentration of about 2.5 to about 5 molar equivalents with respect to the compound of formula VIII, adding water and a cosolvent and mixing the resulting mixture, adding a base to said mixture to adjust the pH of the aqueous phase to about 9 to about 13, to produce a compound of formula IX:
• said co-solvent being selected from the group consisting of:
• methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, pentanol, hexanol, heptanol, octanol, and mixtures thereof,
• said base being selected from the group consisting of:
• ammonium hydroxide, metal hydroxide, metal oxide, metal carbonate, metal bicarbonate, and mixtures thereof, wherein said metal is selected from the group consisting of:
• lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, strontium, barium, aluminum, indium, thallium, titanium, zirconium, cobalt, copper, silver, zinc cadmium, mercury and cerium, or
• said base being selected from the group consisting of:
• a metal salt of a (C1–C12)alkanol and a (C3–C12)cycloalkanol, wherein the metal is selected from the group consisting of:
• Li, Na, K, and Mg;
• dissolving the compound of formula IX in solvent selected from the group consisting of:
• water, methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, pentanol, hexanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxymethane, diglyme, 1,4-dioxane, and mixtures thereof,
• cooling the resulting solution to a temperature of about −5° C. to about 20° C., adding R4NH2 to said solution, and then adding an agent selected from the group consisting of:
• NaIO4, Pb(OAc)4, H5IO6, and mixtures thereof, to produce a compound of X:
• and wherein R4 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and aralkyl;
• dissolving the compound of formula X in a solvent and adding the resulting solution to an acid solution at a temperature ranging preferably from about −50° C. to about 80° C. to produce the compound of formula XI:
• said compound XI being a salt,
• wherein said solvent is selected from the group consisting of:
• hydrocarbon solvents and ethers and mixtures thereof, and
• said acid is selected from the group consisting of:
• sulfonic acids, tartaric acids, H2SO4, HCl, H3PO4, HBr, carboxylic acids and mixtures thereof.