Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C327/00—Thiocarboxylic acids
  • C07C327/02—Monothiocarboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
  • C07J31/003—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring the S atom directly linked to a ring carbon atom of the cyclopenta(a)hydrophenanthrene skeleton

Definitions

• This invention relates to a novel method for the conversion of carboxylic acids to carbothioic acids, use of the method for the preparation of androstane 17 ⁇ -carbothioic acids, and methods for the preparation of fluticasone propionate.
• Fluticasone propionate belongs to a class of androstane 17 ⁇ -carbothioic esters which are well-known in the art as antiinflammatories. Because of the therapeutic usefulness of these compounds, there is sustained interest in improving the synthesis of androstane 17 ⁇ -carbothioic esters in general, and fluticasone propionate in particular.
• flumethasone ((6 ⁇ ,11 ⁇ ,16 ⁇ )-6,9-difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione) typically contains from about 0.5% to 2% of (6 ⁇ ,11 ⁇ ,16 ⁇ )-6-chloro-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione as an impurity (hereinafter referred to as the Cl impurity), the removal of which is achieved by column chromatography, a method not amenable to large scale manufacture.
• Cl impurity an impurity
• R 7 and R 8 are independently C 1 -C 6 alkyl; or R 7 and R 8 together are C 1 -C 6 alkylene;
• step (b) reacting the product of step (a) and a hydrolyzing agent;
• step (b) reacting the product from step (a) and an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof at about ⁇ 40° C. to about 35° C.; and
• a method for dehalogenating a 4-halo-2,3-unsaturated carbonyl group comprising reacting a compound having the 4-halo-2,3-unsaturated carbonyl group, a palladium catalyst, and an additive, optionally in the presence of a reducing agent.
• R 1 or R 2 is hydrogen and the other is optionally protected hydroxyl; or R 1 and R 2 together are oxo; R 3 and R 4 are independently hydrogen or halide; and R 5 and R 6 are independently C 1 -C 6 alkyl;
• step (b) reacting the product of step (a) and an alkanoyl halide and the first base to provide a compound of formula (3)
• step (c) reacting the product of step (b) and a first base, an iodide salt, and the compound of formula (4) to provide a compound of formula (5)
• step (d) reacting the product of step (c) and a hydrolyzing agent to provide a compound of formula (6)
• M is Li, Na, or K
• step (e) optionally reacting the product of step (d) and acid;
• step (f) reacting the product of step (e) and chlorofluoromethane optionally in the presence of a second base;
• the compound of formula (1) is commercial grade flumethasone
• the compound of formula (2) is 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ ,17 ⁇ -dihydroxy-16 ⁇ -methyl-3-oxoandrosta-1,4-diene-17 ⁇ -carboxylic acid;
• the compound of formula (3) is 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(propionyloxy)androsta-1,4-diene-17 ⁇ -carboxylic acid;
• the compound of formula (5) is 17 ⁇ -(N,N-(dimethylcarbamoyl)thio)carbonyl-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -propionyloxy-3-oxoandrosta-1,4-diene;
• the compound of formula (7) is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -(((fluoromethyl)sulfanyl)-carbonyl)-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxoandrosta-1,4-dien-17 ⁇ -yl propionate.
• This invention discloses a novel method for the conversion of carboxylic acids to carbothioic acids and application of the method to the preparation of androstane carbothiolates, such as fluticasone propionate, which avoids column chromatography.
• the term “acid,” as used herein, refers to reagents capable of donating protons during the course of a chemical reaction.
• acids include mineral acids such as hydrofluoric, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, and the like; organic acids such as formic, acetic, propionic, trifluoroacetic, and the like; and sulfonic acids such as para-toluenesulfonic, para-bromosulfonic, para-nitrosulfonic, and the like.
• the acid chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
• additive refers to monodentate phosphorus-containing ligands of formulas P(R C ) 3 (phosphines) and P(OR D ) 3 (phosphites), wherein each R C is independently hydrogen; C 1 -C 6 alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-tolyl; and optionally substitted heteroaryl such as furyl and pyridyl; and wherein each R D is independently C 1 -C 6 alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho-
• additives include tri(alkyl)phosphines such as trimethylphosphine, triethylphosphine, tributylphosphine, and the like; tri(cycloalkyl)phosphines such as tricyclopropylphosphine, tricyclohexylphosphine, and the like; tri(aryl)phosphines such as triphenylphosphine, trinaphthylphosphine, and the like; tri(heteroaryl)phosphines such as tri(fury-2-yl)phosphine, tri(pyrid-3-yl)phosphine, and the like; tri(alkyl)phosphites such as trimethylphosphite, triethylphosphite, tributylphosphite, and the like; tri(cycloalkyl)-phosphites such as tricyclopropylphosphite, tricyclo
• additive also refers to bidentate phosphines such as 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(diphenyl-phosphino)ethane (dppe), 1,1-bis(diphenylphosphino)methane (dppm), 1,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1′-bis(diphenylphosphino)ferrocene (dppf), and the like.
• dppb 1,4-bis(diphenylphosphino)butane
• dppe 1,2-bis(diphenyl-phosphino)ethanethanethane
• dppm 1,1-bis(diphenylphosphino)methane
• dmpe 1,2-bis(dimethyl-phosphino)ethanethane
• dppf 1,1′-bis(diphenylphosphino)ferrocene
• alkali metal iodide refers to lithium iodide, sodium iodide, potassium iodide, cesium iodide, and the like.
• alkali earth metal iodides refers to magnesium iodide, calcium iodide, barium iodide, and the like.
• alkanoyl halide refers to R A C(O)X, wherein R A is C 1 -C 6 alkyl, and X is chloride or bromide.
• C 2 -C 6 alkenyl refers to a straight or branched chain hydrocarbon radical having from 2 to 6 carbons and at least one carbon-carbon double bond.
• alkoxide salt refers to [M] + [OR A ] ⁇ , wherein M is Li, Na, or K, and R A is C 1 -C 6 alkyl.
• alkoxy refers to an alkyl group attached to the parent molecular group through an oxygen atom.
• C 1 -C 6 alkyl refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbons.
• C 1 -C 6 alkylene refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbons.
• amino refers to —NH 2 or a derivative thereof formed by replacement of a hydrogen atom thereon or independent replacement of both hydrogen atoms thereon by an alkyl, cycloalkyl, cycloalkylalkyl, or arylalkyl group.
• aryl refers to a cyclic, aromatic carbocyclic ring such as phenyl or two fused aromatic carbocyclic rings such as naphthyl.
• the aryl groups of this invention can be optionally independently substituted with one, two, or three alkyl, amino, halo, and nitro substituents.
• the aryl groups of this invention can be optionally independently substituted with one, two, three, four, or five C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, carboxyl, carboxaldehyde, alkoxycarbonyl, C 1 -C 6 perfluoroalkyl, or nitro substituents.
• arylalkyl refers to an aryl group attached to the parent molecular group through an alkyl group.
• borane refers to compounds containing at least one boron-hydrogen bond and are exemplified by diborane, 9-borabicyclo[3.3.1]nonane (9-BBN), dilongifoylborane, thexylborane, catecholborane, sodium borohydride, tetrabutylammonium borohydride, borane-4-methylmorpholine complex, borane-4-ethylmorpholine complex, borane-dimethylsulfide complex, borane-triethylamine complex, borane-pyridine complex, borane-2,6-lutidine complex, and the like.
• carbonate salt refers to lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and the like.
• commercial grade flumethasone refers to (6 ⁇ ,11 ⁇ ,16 ⁇ )-6,9-difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione containing up to 2% of (6 ⁇ ,11 ⁇ ,16 ⁇ )-6-chloro-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione as an impurity.
• cycloalkyl refers to a saturated, cyclic hydrocarbon group having three to six carbon atoms.
• cycloalkylalkyl refers to a cycloalkyl group attached to the parent molecular group through an alkyl group.
• dehalogenating refers to the removal of a chloride bromide, or iodide radical of a 4-halo-2,3-unsaturated carbonyl group.
• first base refers to reagents capable of accepting protons during the course of a chemical reaction.
• first and second bases include carbonates such as lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and the like; phosphates such as potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, and the like; trialkylamines such as triethylamine, diisopropylethylamine, and the like; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like; and bicyclic amines such as DBN, DBU, and the like.
• the base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
• halide and “halo,” as used herein, refer to F, Cl, Br, and I.
• 4-halo-2,3-unsaturated carbonyl refers to a endogenous or exogenous group comprising at least four carbon atoms, wherein carbon-1 is substituted with oxo, carbon-2 and carbon-3 are connected by a carbon-carbon double bond, and carbon-4 bears a chloride, bromide, or iodide substituent.
• heteroaryl refers to aromatic rings having five or six atoms, wherein at least one of the atoms is nitrogen, oxygen, or sulfur and the remainder are carbon.
• the five-membered rings have two double bonds, and the six-membered rings have three double bonds.
• the heteroaryls of this invention are connected to the phosphorus atom through a carbon atom in the ring.
• heteroaryl groups of this invention can be optionally independently substituted with one, two, or three C 1 -C 6 alkyl, C 2 -C 6 alkenyl, halo, carboxyl, carboxaldehyde, alkoxycarbonyl, C 1 -C 6 perfluoroalkyl, or nitro substituents.
• hydroxyl refers to —OH.
• hydroxyl protecting group refers to selectively introducible and removable groups which protect hydroxyl groups against undesirable side reactions during synthetic procedures.
• hydroxyl protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-
• nitro refers to —NO 2 .
• organic component refers to a solvent which is not reactive with the starting materials and in which the starting materials are at least partially soluble.
• organic components include, C 2 -C 5 alkylamides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, and the like; C 4 -C 6 dialkoxyalkyls such as DME, 1,2-diethoxyethane, and the like; C 1 -C 4 alcohols such as methanol, ethanol, propanol, iso-propanol, butanol, iso-butanol, sec-butanol, tert-butanol, and the like; C 3 -C 10 ketones such as acetone, 2-butanone, 3-pentanone, 2-butanone, 2-pentanone, 2,5-heptanedione, and the like; C 5 -C 7 hydrocarbons such as pentane, hexan
• oxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
• palladium catalyst refers to optionally supported palladium such as palladium metal, palladium metal on carbon, and palladium metal on acidic, basic, or neutral alumina; palladium(O) complexes such as tetrakis(triphenylphosphine)palladium(O); palladium salts such as palladium(II) acetate or palladium(II) chloride; and palladium(II) complexes such as allylpalladium(II) chloride dimer, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II), bis(acetato)bis(triphenylphosphine)palladium(II), and bis(acetonitrile)dichloropalladium(II).
• palladium(O) complexes such as tetrakis(triphenylphosphine)palladium(O)
• palladium salts such
• C 1 -C 6 perfluoroalkyl refers to a C 1 -C 6 alkyl group, wherein all of the hydrogen radicals have been replaced by fluoride radicals.
• protected hydroxyl refers to a hydroxyl to which is attached a hydroxyl protecting group.
• reducing agent refers to boranes, silanes and stannes.
• silane refers to Si(R E )(R F ) 3 , wherein R E is hydrogen, and each R F is independently hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, aryl, or heteroaryl.
• Specific examples of silanes include diethylsilane, dimethylisopropylsilane, tributylsilane, cyclohexyldimethylsilane, diisopropyloctylsilane, triisopropylsilane, dimethylethylsilane, dimethyloctadecylsilane, triethylsilane, and the like.
• stannane refers to Sn(R E )(R F ) 3 , wherein R E is hydrogen, and each R F is independently hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl, aryl, or heteroaryl.
• stannanes include diethylstannane, dimethylisopropylstannane, tributylstannane, cyclohexyldimethylstannane, diisopropyloctylstannane, triisopropylstannane, dimethylethylstannane, dimethyloctadecylstannane, triethylstannane, and the like.
• sulfide salt refers to lithium sulfide, lithium hydrosulfide, sodium sulfide, sodium hydrosulfide, potassium sulfide, potassium hydrosulfide, and the like.
• the sulfide salts of this invention can be optionally hydrated.
• hydrolyzing agent refers to alkoxide salts, thioalkoxide salts, optionally hydrated sulfide salts, and mixtures thereof.
• iodide salt refers to alkali metal iodides, alkali earth metal iodides, and tetraalkylammonium iodides.
• tetraalkylammonium iodide refers to compounds of formula [(R B ) 4 N] + [I] ⁇ , wherein R B is C 1 -C 20 alkyl.
• thioalkoxide salt refers to [M] + [SR A ] ⁇ , wherein M is Li, Na, or K, and R A is C 1 -C 6 alkyl.
• This invention contemplates stereoisomers and mixtures thereof.
• Individual stereoisomers of compounds are prepared by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
• Starting compounds of particular stereochemistry are either commercially available or are made by the methods described herein and resolved by techniques well-known in the art.
• Percentages such as mole % and %Cl impurity were obtained by HPLC analyses of starting materials and products. Values were calculated from the the peak area.
• DBN for 1,5-diazobicyclo[4.3.0]non-5-ene
• DBU for 1,8-diazobicyclo[5.4.0]undec-7-ene
• DBA for dibenzylidine acetone
• DMA for N,N-dimethylacetamide
• DME for dimethoxyethane
• DMF for N,N-dimethylformamide
• HPLC high pressure liquid chromatography
• THF for tetrahydrofuran.
• conversion of compounds of formula (1) to compounds of formula (2) can be achieved by reaction of the former and an oxidizing agent acid in a solvent such as C 1 -C 4 alcohols, THF, dioxane, mixtures thereof, and mixtures of these solvents with water.
• a solvent such as C 1 -C 4 alcohols, THF, dioxane, mixtures thereof, and mixtures of these solvents with water.
• the reaction generally proceeds at room temperature, it can be run at lower or higher temperatures, as needed.
• the reaction time is generally about 1 hour to about 18 hours and can be selected depending on the types of starting materials and the reaction temperature.
• this conversion is achieved by reaction of compounds of formula (1) in a THF/water mixture and periodic acid at about 0° C. to about 5° C. for about 3 hours.
• the conversion of compounds of formula (2) to compounds of formula (3) can be achieved by reaction of the former and an alkanoyl halide in a solvent such as pyridine, diisopropylethylamine, triethylamine, THF, dioxane, benzene, toluene, diethyl ether, C 2 -C 5 alkylamides, C 3 -C 20 ketones, or mixtures thereof. Since acid is liberated with the progress of the reaction, it is preferable to run the reaction with at least a stoichiometric amount of base such as diisopropylethylamine, pyridine, or triethylamine.
• a solvent such as pyridine, diisopropylethylamine, triethylamine, THF, dioxane, benzene, toluene, diethyl ether, C 2 -C 5 alkylamides, C 3 -C 20 ketones, or mixtures thereof. Since
• reaction time is generally about 30 minutes to about 5 hours and can be selected depending on the types of starting materials and the reaction temperature. In a preferred embodiment, this conversion is achieved by reaction of compounds of formula (3) in acetone and triethylamine at about ⁇ 10° C. to about 0° C. and an alkanoyl chloride for about 30 minutes.
• the conversion of compounds of formula (3) to compounds of formula (5) can be achieved by reaction of the former and compounds of formula (4) and an iodide salt such as an alkali metal iodide, an alkali earth metal iodide, or a tetraalkylammonium iodide in solvents such as water, C 2 -C 5 alkylamides, C 4 -C 6 dialkoxyalkyls, C 1 -C 4 alcohols, C 1 -C 4 haloalkyls, C 3 -C 10 ketones, or mixtures thereof.
• an iodide salt such as an alkali metal iodide, an alkali earth metal iodide, or a tetraalkylammonium iodide in solvents such as water, C 2 -C 5 alkylamides, C 4 -C 6 dialkoxyalkyls, C 1 -C 4 alcohols, C 1 -C 4 haloalkyl
• a first base such as diisopropylethylamine, pyridine, or triethylamine.
• a first base such as diisopropylethylamine, pyridine, or triethylamine.
• Compounds of formula (4) are available commercially or can be prepared by means well known in the art ( Tetrahedron, 1980, 36(4), 539; Chem. Ber. 1980, 113(5), 1898; and Justus Liebigs Ann. Chem., 1954, 590, 123).
• the reaction generally proceeds at about 0° C. to about 30° C. for about 1 hour to about 48 hours, depending on the reaction temperature and the nature of the reactants.
• this conversion is achieved by reaction of compounds of formula (3) and compounds of formula (4), triethylamine, and sodium iodide in 2-butanone and water, the water present in about one quarter percent by weight to about ten percent by weight of the compound of formula (3), for about 24 hours.
• the conversion of compounds of formula (5) to compounds of formula (6) can be achieved by reaction of the former and a hydrolyzing agent such as an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof in solvents such as water, C 2 -C 5 alkylamides, C 4 -C 6 dialkoxyalkyls, C 3 -C 10 ketones, or mixtures thereof.
• a hydrolyzing agent such as an alkoxide salt, a thioalkoxide salt, an optionally hydrated sulfide salt, or a mixture thereof in solvents such as water, C 2 -C 5 alkylamides, C 4 -C 6 dialkoxyalkyls, C 3 -C 10 ketones, or mixtures thereof.
• this conversion is achieved by reaction of compounds of formula (5) and sodium hydrosulfide hydrate in DMA at about 0° C. to about 5° C. for about 2 hours then at room temperature for about 2 hours.
• the carbothioic acid salt thus formed can be acidified with an acid such as hydrochloric, hydrobromic, sulfuric, sulfonic, phosphoric, or trifluoroacetic or used directly in the next step without acidification.
• the conversion of compounds of formula (6) to compounds of formula (7) can be achieved by reaction of the former and chlorofluoromethane in a C 2 -C 5 alkylamide solvent such as DMF or DMA.
• the reaction generally proceeds at about ⁇ 20° C. to about 30° C. for about 1 hour to about 12 hours, depending on the reaction temperature and the nature of the reactants. If the carbothioic acid salt has been acidified, then acid will be liberated during the course of the conversion, and the reaction is run in the presence of a second base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, or potassium carbonate.
• the compounds of formula (6) can be reacted with chlorofluoromethane without isolation or purification.
• this conversion is achieved as a continuous process by in situ reaction of compounds of formula (6) and chlorofluoromethane as a solution in DMA at about 0° C. for about 3 hours then at room temperature and atmospheric pressure for about 12 hours.
• the compound of formula (1) is commercial grade flumethasone;
• the compound of formula (2) is 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ ,17 ⁇ -dihydroxy-16 ⁇ -methyl-3-oxoandrosta-1,4-diene-17 ⁇ -carboxylic acid;
• the compound of formula (3) is 6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -(propionyloxy)androsta-1,4-diene-17 ⁇ -carboxylic acid;
• the compound of formula (5) is 17 ⁇ -(N,N-(dimethylcarbamoyl)thio)carbonyl-6 ⁇ ,9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ -propionyloxy-3-oxoandrosta-1,4-diene;
• the compound of formula (7) is 6 ⁇ ,9 ⁇ -difluoro-17 ⁇ -(((fluoromethyl)sulfanyl)-carbonyl)-11 ⁇ -hydroxy-16 ⁇ -(
• Any one of these compounds can be reacted with a palladium catalyst and an additive, optionally in the presence of a reducing agent, in a solvent such as a C 2 -C 5 alkylamide, a C 4 -C 6 dialkoxyalkyl, an optionally substituted aromatic hydrocarbon, a C 1 -C 4 haloalkyl a C 3 -C 10 ketone, or a mixture thereof, to facilitate the removal the Cl impurity introduced by the commercial grade flumethasone.
• a solvent such as a C 2 -C 5 alkylamide, a C 4 -C 6 dialkoxyalkyl, an optionally substituted aromatic hydrocarbon, a C 1 -C 4 haloalkyl a C 3 -C 10 ketone, or a mixture thereof.
• the palladium catalyst includes optionally supported palladium such as palladium metal, palladium metal on carbon, and palladium metal on acidic, basic, or neutral alumina; palladium(O) complexes such as tetrakis(triphenylphosphine)palladium(O); palladium salts such as palladium(II) acetate or palladium(II) chloride; and palladium(II) complexes such as allylpalladium(II) chloride dimer, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II), bis(acetato)bis(triphenylphosphine)palladium(II), and bis(acetonitrile)dichloropalladium(II).
• palladium(O) complexes such as tetrakis(triphenylphosphine)palladium(O)
• palladium salts such as
• Additives useful for this reaction include tri(alkyl)phosphines such as trimethylphosphine, triethylphosphine, tributylphosphine, and the like; tri(cycloalkyl)phosphines such as tricyclopropylphosphine, tricyclohexylphosphine, and the like; tri(aryl)phosphines such as triphenylphosphine, trinaphthylphosphine, and the like; tri(heteroaryl)phosphines such as tri(fury-2-yl)phosphine, tri(pyrid-3-yl)phosphine, and the like; tri(alkyl)phosphites such as trimethylphosphite, triethylphosphite, tributylphosphite, and the like; tri(cycloalkyl)-phosphites such as tricyclopropylphosphite, tri
• bidentate phosphines such as 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(diphenyl-phosphino)ethane (dppe), 1,1-bis(diphenylphosphino)methane (dppm), 1,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1′-bis(diphenylphosphino)ferrocene (dppf), and the like.
• bidentate phosphines such as 1,4-bis(diphenylphosphino)butane (dppb), 1,2-bis(diphenyl-phosphino)ethane (dppe), 1,1-bis(diphenylphosphino)methane (dppm), 1,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1′-bis(diphenylphosphino)ferrocene (dppf), and the like.
• Reducing agents useful for this reaction include boranes such as diborane, 9-borabicyclo[3.3.1]nonane (9-BBN), dilongifoylborane, thexylborane, catecholborane, sodium borohydride, tetrabutylammonium borohydride, borane-4-methylmorpholine complex, borane-4-ethylmorpholine complex, borane-dimethylsulfide complex, borane-triethylamine complex, borane-pyridine complex, borane-2,6-lutidine complex, and the like; silanes such as diethylsilane, dimethylisopropylsilane, tributylsilane, cyclohexyldimethylsilane, diisopropyloctylsilane, triisopropylsilane, dimethylethylsilane, dimethyloctadecylsilane, trie
• 1 mole % palladium catalyst is 1 mole of palladium catalyst per 100 moles of commercial grade flumethasone; 2 mole % of additive is 2 moles of additive per 100 moles of commercial grade flumethasone; 20 mole % of reducing agent is 20 moles of reducing agent per 100 moles of commercial grade flumethasone; and so forth.
• the palladium catalyst is present in about 0.3 mol % to about 5 mol % of commercial grade flumethasone; the additive can be present in about 0.8 mol % to about 15 mol % of commercial grade flumethasone; and the reducing agent can be present in about 1 mol % to about 30 mol % of commercial grade flumethasone.
• palladium(II) acetate is present in about 1 mol % of commercial grade flumethasone; triphenylphosphine is present in about 2 mol % of commercial grade flumethasone; and triethylsilane is present in about 13 mol % of commercial grade flumethasone.
• Example 1 A solution of Example 1 (95.2 g, 240 mmol) and triethylamine (55.9 g, 552 mmol) in acetone (1.45 L) at ⁇ 15° C. was treated with pre-distilled propionyl chloride (51.1 g, 552 mmol), stirred for 1 hour, treated with diethylamine (52.7 g, 720 mmol), stirred for 1 hour, and treated with 1M HCl (1.90 L); warmed to 0° C., stirred for 1 hour, and filtered. The solid was washed with water (475 mL), dried for 12 hours at 60° C.
• Example 2 A solution of Example 2 (86.7 g, 192 mmol) and N,N-dimethylthiocarbamoyl chloride (47.5 g, 384 mmoles) in 2-butanone (2.17 L) at room temperature was treated sequentially with triethylamine (42.7 g, 422 mmoles), anhydrous sodium iodide (28.8 g, 192 mmol), and water (8.67 mL, 10% w/w with Example 2), stirred for 2 hours, treated sequentially with DMA (694 mL) and water (4.34 L); cooled to 0° C., stirred for 2 hours, and filtered to provide a solid. The solid was washed with water (500 mL) and dried at 60° C. under vacuum with a nitrogen purge to provide 96.4 g (93%) of the desired product.
• triethylamine 42.7 g, 422 mmoles
• anhydrous sodium iodide 28.8 g, 192
• Example 3 A solution of Example 3 (96.4 g, 179 mmol) and sodium hydrosulfide hydrate (45.3 g, 808 mmol) in dimethylacetamide (386 mL) at 0° C. was stirred for 2 hours; warmed to room temperature and stirred for 2 hours; cooled to ⁇ 5° C., treated slowly with a solution of chlorofluoromethane (92.7 g, 1.354 mol) in dimethylacetamide (313 mL), and stirred for 4 hours; warmed to room temperature, stirred for 18 hours and treated slowly with a solution of sodium bicarbonate (29.9 g) in water (1.45 L); cooled to ⁇ 5° C., stirred for two hours, and filtered to provide a solid.
• the solid was washed sequentially with water (145 mL) and 1-butanol (145 mL) and treated with ethyl acetate (540 mL) and 1-butanol (2.16 L) to provide a mixture.
• the mixture was heated to reflux for 40 minutes and filtered hot (without rinsing) through a less than 1 micron filter.
• the filtrate was stirred while cooling to room temperature, stirred for eight hours, and filtered to provide a solid.
• This solid was washed with 1-butanol, (145 mL), recrystallized from 1-butanol (2.70 L), and dried under vacuum with a nitrogen purge at 60° C. to provide 62.7 g (70%) of the desired product.
• Example 5 A solution of Example 5 (5.0 g, 9.51 mmol) in DMA (50 mL) at ⁇ 15° C. was treated with sodium thiomethoxide (0.73 g, 10.46 mmol) in one portion, and stirred for 4.5 hours; warmed to 0° C., treated with cold 1M HCl (100 mL), stirred for 1 hour, and filtered. The solid was washed with water until the wash was pH 6 or higher and dried under vacuum at 60° C. with a nitrogen purge to provide 4.32 g, (93%) of the desired product.
• the filtrate was concentrated under reduced pressure.
• the concentrate was treated sequentially with DMA (150 mL) and water (190 mL); cooled to 0° C., and stirred for 1 hour.
• the resulting solid was collected by filtration, washed with water, and dried under vacuum at 60° C. with a nitrogen purge to provide 10.2 g, (85%) of the desired product.
• Example 7 A solution of Example 7 (5.0 g, 9.58 mmol) in DMA (50 mL) at ⁇ 15° C. was treated with sodium thiomethoxide (0.74 g, 10.54 mmol) in one portion, stirred for 2 hours; warmed to 0° C., treated with cold 1M HCl (100 mL), stirred for 1 hour at 0° C., and filtered. The resulting solid was washed with water until the wash was pH 6 or higher and dried under vacuum at 60° C. with a nitrogen purge to provide 4.10 g, (95%) of the desired product.

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