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 ofthe 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 ofthe 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.
• Prior art such as United States patents 4,188,385, 4,198,403, 4,335,121, and 4,578,221; British patents 2,088,877 and 2,137,206; and published Israeli patent application IL 109,656-A1 teach the synthesis of fluticasone propionate from commercial grade flumethasone. These syntheses involve complicating factors such as chromatography of intermediates, low-yielding steps, and high pressure addition of chlorofluoromethane.
• flumethasone ((6 ⁇ ,l l ⁇ ,16 ⁇ )-6,9-difluoro-l l,17,21-trihydroxy-16- methylpregna-l,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
• step (b) reacting the product of step (a) and a hydrolyzing agent
• step (c) reacting the product from step (b) and acid.
• a method for the conversion of a carboxylic acid group to a carbothioic acid group comprising: (a) reacting a compound having the carboxylic acid group and a first base, an iodide salt, and N,N-dimethylthiocarbamoyl chloride at about 10 °C to about 30 °C in a solvent system comprising an organic component and water, the water present in about one quarter percent by weight to about ten percent by weight ofthe compound having the carboxylic acid group;
• 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
• step (c) reacting the product from step (b) and acid.
• 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.
• 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 (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; and (g) optionally deprotecting the product of step (f).
• the compound of formula (1) is commercial grade flumethasone;
• the compound of formula (2) is 6 ,9 ⁇ -difluoro-l l ⁇ ,17 ⁇ -dihydroxy-16 ⁇ -methyl-3- oxoandrosta-l,4-diene-17 ⁇ -carboxylic acid;
• the compound of formula (3) is 6 ⁇ ,9 ⁇ -difluoro-l 1 ⁇ -hy droxy- 16 ⁇ -methyl-3 -oxo- 17 ⁇ -
• a method for the purification of 6 ⁇ ,9 ⁇ -difluoro- 11 ⁇ -hy droxy- 16 ⁇ -methyl-3 -oxo- 17 -(propiony loxy)androsta- 1 ,4-diene- 17 ⁇ - carboxylic acid by recrystallization In another embodiment of this invention is disclosed a method for the purification of 6 ⁇ ,9 -difluoro- 11 ⁇ -hydroxy- 16 -methyl-3 -oxo- 17 ⁇ -(propionyloxy)androsta- 1 ,4-diene- 17 ⁇ - carboxylic acid by repeated recrystallization.
• an improved method for the preparation of 6 ⁇ ,9 -difluoro-17 ⁇ -(((fluoromethyl)sulfanyl)carbonyl)-l l ⁇ -hydroxy-16 ⁇ - methyl-3 -oxoandrosta- 1 ,4-dien- 17 ⁇ -yl propionate (fluticasone propionate) which omits the use of column chromatography and is applicable to large scale.
• Cl impurity from commercial grade flumethasone using a palladium catalyst and an additive, optionally in the presence of a reducing agent.
• This invention discloses a novel method for the conversion of carboxylic acids to carbothioic acids and application ofthe 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 ofthe 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 r 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 r 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
• 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 l,4-bis(diphenylphosphino)butane (dppb), l,2-bis(diphenyl-phosphino)ethane (dppe), l,l-bis(diphenylphosphino)methane (dppm), l,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1'- bis(diphenylphosphino)ferrocene (dppf), and the like.
• phosphines such as l,4-bis(diphenylphosphino)butane (dppb), l,2-bis(diphenyl-phosphino)ethane (dppe), l,l-bis(diphenylphosphino)methane (dppm), l,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1'- bis(diphenylphos
• 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(0)X, wherein R A is C r C 6 alkyl, and X is chloride or bromide.
• alkoxide salt refers to [M] + [OR ] , wherein M is Li, Na, or K, and R A is C r C 6 alkyl.
• alkoxy refers to an alkyl group attached to the parent molecular group through an oxygen atom.
• C C 6 alkyl refers to a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbons.
• C j -Cg alkylene refers to a straight or branched chain saturated hydrocarbon diradical 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.
• 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.
• dehalogenating refers to the removal of a chloride bromide, or iodide radical of a 4-halo-2,3-unsaturated carbonyl group.
• 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-methoxybenzyloxy carbonyl, 3 ,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy carbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-
• 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, hexane, heptane, and the like; optionally substituted aromatic hydrocarbons such as benzene, toluene, 1,4-dichlorobenzene, nitrobenzene, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; and esters such as ethyl acetate isopropyl acetate, and the like.
• oxo refers to a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
• 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 is independently hydrogen, C j -C 20 alkyl, C 2 -C 20 alkenyl, aryl, or heteroaryl.
• thioalkoxide salt refers to [M] + [SR A ] , wherein M is Li, Na, or K, and R A is C r C 6 alkyl.
• Percentages such as mole% and %C1 impurity were obtained by HPLC analyses of starting materials and products. Values were calculated from the the peak area.
• DBN for l,5-diazobicyclo[4.3.0]non-5-ene
• DBU for l,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 ofthe former and an oxidizing agent acid in a solvent such as C r C 4 alcohols, THF, dioxane, mixtures thereof, and mixtures of these solvents with water.
• a solvent such as C r 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.
• 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 ofthe reactants.
• the conversion of compounds of formula (6) to compounds of formula (7) can be achieved by reaction ofthe 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 ofthe reactants. If the carbothioic acid salt has been acidified, then acid will be liberated during the course ofthe 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 compound of formula (1) is commercial grade flumethasone;
• the compound of formula (2) is 6 ⁇ ,9 ⁇ -difluoro-l l ⁇ ,17 ⁇ -dihy droxy- 16 - methyl-3-oxoandrosta-l,4-diene-17 ⁇ -carboxylic acid;
• the compound of formula (3) is 6 ⁇ ,9 ⁇ - diffuoro- 11 ⁇ -hydroxy- 16 ⁇ -methyl-3-oxo- 17 ⁇ -(propionyloxy)androsta- 1 ,4-diene- 17 ⁇ - carboxylic acid;
• the compound of formula (5) is 17 ⁇ -(N,N-
• 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(0); 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(0)
• palladium salts such as palla
• additives useful for this reaction include bidentate phosphines such as 1,4- bis(diphenylphosphino)butane (dppb), l,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), l,2-bis(diphenyl-phosphino)ethane (dppe), 1,1- bis(diphenylphosphino)methane (dppm), 1 ,2 -bis(dimethyl-phosphino)ethane (dmpe), 1,1'- bis(diphenylpho
• 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
• Reaction was conducted using 1 mole% palladium(II) chloride, 2 mole% monodentate additive or 1 mole% bidentate additive and 26 mole% triethylsilane in DMF at 22 °C.
• 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 6 ⁇ ,9 ⁇ -difluoro-l 1 ⁇ , 17 ⁇ -dihvdroxy- 16 -methyl-3-oxoandrosta- 1 ,4-diene- 17 ⁇ -carboxylic acid
• Flumethasone 100 g, 243.6 mmoles
• palladium(II) acetate 0.552 g, 2.46 mmol
• triphenylphosphine 1.284 g, 4.89 mmol
• Example 2 6 ,9 ⁇ -difluoro- 11 ⁇ -hy droxy- 16 ⁇ -methyl-3 -oxo- 17 ⁇ -fpropionyloxy ' )androsta- 1 ,4-diene- 17 ⁇ - carboxylic acid
• 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 HC1 (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 under vacuum with a nitrogen purge, and treated sequentially with 3-pentanone (459 mL), 2-butanone (51 mL), and water (5.1 mL). This mixture was heated to reflux for one hour; cooled to room temperature over two hours, stirred for 18 hours, and filtered to provide a solid. This solid was washed with 3- pentanone (100 mL) and dried under vacuum with a nitrogen purge at 60 °C for 18 hours to provide 86.7 g (79.8%) ofthe desired product.
• Example 8 9 -fluoro- 11 ⁇ -hydroxy- 17 ⁇ -f propionyloxyV 16 ⁇ -methyl-3 -oxoandrostat- 1 ,4-diene- 17 ⁇ - thiocarboxylic acid
• 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 HC1 (100 mL), stirred for 1 hour at 0 °C, and filtered.

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