Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
  • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

• TEI-6720 The compound ethyl 2-(4-hydroxyphenyl)-4-methyl-l,3-thiazole-5-carboxylate, also known as TEI-6720, is useful for treatment of gout and hyperuricemia.
• This compound belongs to a class of substituted thiazoles that inhibit xanthine oxidase and thus block uric acid production.
• the synthesis of TEI-6720 involves two steps. In the first step, an aryl nitrile is converted to a thioamide. In the second step the thioamide is converted to a thiazole. Because of the therapeutic usefulness of TEI-6720 there is sustained interest in improving the synthesis of substituted thiazoles in general and TEI-6720 in particular.
• R is selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl, C 2 -C 6 - alkenyl, and C 2 -C 6 -alkynyl; and R 3 is selected from the group consisting of hydrogen, Ci-C ⁇ -alkyl, C 2 -C 6 -alkenyl, and C 2 - C 6 -alkynyl.
• a second embodiment of this invention is directed to a process for making the compound of formula (TV), the process comprising: (b) reacting the compound having formula (I) and a compound having formula (V)
• This invention discloses a novel process for isolating thioamides, key intermediates in the synthesis of TEI-6720.
• the isolation of the thioamide intermediate allows for cleaner synthesis of the thiazole and avoids the aqueous workup that was formerly required.
• the invention discloses a synthesis that eliminates the need for a catalyst, yet decreases processing time and increases the product yield.
• this invention allows large-scale synthesis and a commercially feasible process for making TEI-6720.
• DEFINITION OF TERMS As used throughout this specification and the appended claims, the following terms have the following meanings: All of the processes of the instant invention can be conducted as continuous processes.
• alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 6 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
• Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
• alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
• alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
• alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond.
• alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
• aryl as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system wherein one or more of the fused rings is a phenyl group.
• Bicyclic fused ring systems are exemplified by a phenyl group fused to a cycloalkyl group, as defined herein, or another phenyl group.
• Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group, as defined herein, or another phenyl group.
• Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.
• heteroaryl refers to an aromatic five- or six-membered ring wherein 1, 2, 3, or 4 heteroatoms are independently selected from N, O, or S. The five membered rings have two double bonds and the six membered rings have three double bonds.
• heteroaryl groups are connected to the parent molecular moiety through a carbon or nitrogen atom.
• heteroaryl also includes bicyclic systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group; and tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
• heteroaryl include, but are not limited to, benzothienyl, benzoxadiazolyl, cinnolinyl, dibenzofuranyl, fiiropyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.
• bases represents a reagent capable of accepting protons during the course of a reaction.
• bases include carbonate salts such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and cesium carbonate; halides such as cesium fluoride; phosphates such as potassium phosphate, potassium dihydrogen phosphate, and potassium hydrogen phosphate; hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; disilylamides such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, and sodium hexamethyldisilazide; trialkylamines such as triethylamine, diisopropylamine, and diisopropylethylamine; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclic amines such as DBN and DBU; and
• solvent refers to the dispersing medium of a solution.
• solvents include, C 2 -C 5 alkylamides such as formaldehyde, N,N- dimethylformamide, N,N-dimethylacetamide, and the like; C 4 -C 6 dialkoxyalkyls such as DME, 1 ,2-diethoxyethane, and the like; C ⁇ -C 4 alcohols such as methanol, ethanol, propanol, iso- propanol, butanol, iso-butanol, sec-butanol, tert-butanol, and the like; C 3 -C ⁇ o ketones such as acetone, 2-butanone, 3-pentanone, 2-butanone, 2-pentanone, 2,5-heptanedione,
• alkoxyalkyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
• Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl, and methoxymethyl. Percentages such as % yield were obtained by HPLC analyses of starting materials and products. Values were calculated from the peak area.
• conversion of compounds of formula (II) to compounds of formula (I) can be achieved by reaction of the former with H 2 S and a base in a solvent.
• the base is a compound having formula (III) (M) + (YH)- (III), in which M is sodium, potassium, lithium, or ammonium and Y is oxygen or sulfur.
• the reaction generally proceeds under a pressure of at least 10 psi and at a temperature of about 0°C to about 150°C for about 15 minutes to several days depending on the temperature and nature of the reactants. In a preferred embodiment this conversion is achieved at a pressure of 60 psi, a temperature of 70°C, and in a solvent of water.
• Conversion of compounds of formula (I) to compounds of formula (IV) can be achieved by reacting compounds of formula (I) with compounds of formula (V) in a solvent.
• the reaction generally proceeds at a temperature of about 0°C to about 150°C for about 15 minutes to several days depending on the temperature and nature of the reactants. In a preferred embodiment this conversion is achieved at a temperature of 80°C and in a solvent of ethanol.
• 4-hydroxybenzene carbothioamide (a compound of formula (I)) is prepared by reacting 4-hydroxybenzonitrile (a compound of formula (II)), H 2 S, and sodium hydrogen sulfide (a base and compound of formula (III)) under a pressure of at least 10 psi at a temperature of about 0°C to about 150°C in a solvent.
• the pressure is 60 psi
• the temperature is 70°C
• the solvent is water.
• ethyl 2-(4 hydroxyphenyl)-4-methyl-l, 3- thiazole-S-carboxylate (a compound of formula (IV)) is prepared by reacting 4-hydroxybenzene carbothiomide (a compound of formula (I)) with ethyl-2-chloroacetoacetate (a compound of formula (V)) at a temperature of about 0°C to about 150°C in a solvent.
• the temperature is 80°C and the solvent is ethanol.
• ethyl 2-(4 hydroxyphenyl)-4-methyl-l, 3- thiazole-S-carboxylate (a compound of formula (IV)) is prepared by:
• step (b) reacting the product of step (a) and ethyl-2-chloroacetoacetate at a temperature of about 0°C to about 150°C in a solvent.
• the pressure is 60 psi
• the temperature is 70°C
• the solvent is water.
• the temperature is 80°C and the solvent is ethanol.
• the pressure is 60 psi
• the temperature is 70°C
• the solvent is ethanol.
• the temperature is 80°C and the solvent is ethanol.
• Example 1 4-hydroxybenzene carbothioamide
• 4-Cyanophenol 50.0 g, 0.42mol
• NaSH 15.5g, .21mol
• distilled water 125mL
• the mixture was then put under a vacuum, flushed with H 2 S, and the pressure was brought to 40-50 psi for a period of a few minutes.
• the mixture was then heated to 70°C and stirred for 40-45 minutes.
• the mixture was stirred vigorously at 70°C under constant pressure of 56 psi for 5 hours and 15 minutes.
• the H 2 S pressure was removed and the reaction was cooled to room temperature.
• the reaction was neutralized to pH 5-7 with 2 M HC1 (66 mL).
• the product was filtered, and the filter cake washed with distilled water (2x50 mL), and dried under a vacuum at 80-85°C for 22 hours to provide 62.74 g (97.57%) desired product.
• Example 2 Ethyl 2-(4-hydroxyphenyl " )-4-methyl-l .3-thiazole-5-carboxylate A mixture of 4-Cyanophenol (23.82 g, 0.2mol), NaOH (8g, .2mol), and 200 mL ethanol were mixed in a pressure bottle while heated to 80°C. Hydrogen sulfide gas was then introduced and the pressure increased to 30-60 psi until the thioamidation was determined to be complete by HPLC. Without isolating the thioamide product, HC1 was added to the bottle until the pH was below 3.5, the H 2 S gas was removed, and the bottle was placed under a vacuum for 20 minutes at 30-40°C.
• reaction was then heated to 70°C and ethyl 2-chloroacetoacetate(l.l eq.) was added to the reaction solution.
• the reaction was mixed under reflux for 2-3 hours, treated with enough H 2 O to dissolve the NaCl salt in the reaction mixture, cooled to room temperature, treated with enough water to precipitate the product, and the solid was collected by filtration.
• the precipitate was washed with water and dried at 80°C with nitrogen bleeding to provide 50.50 g (84.2%) of desired product.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Thiazole And Isothizaole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 2003
  • 2003-07-30 US US10/630,043 patent/US20050027128A1/en not_active Abandoned
• 2004
  • 2004-07-30 JP JP2006522112A patent/JP4975435B2/ja not_active Expired - Lifetime
  • 2004-07-30 CA CA2533658A patent/CA2533658C/en not_active Expired - Fee Related
  • 2004-07-30 EP EP11170183A patent/EP2386548A2/en not_active Withdrawn
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  • 2004-07-30 WO PCT/US2004/024758 patent/WO2005012273A2/en not_active Ceased
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