WO2008065522A2 - Process for the synthesis of 4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d] furan-an intermediate for pde iv inhibitors - Google Patents

Process for the synthesis of 4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d] furan-an intermediate for pde iv inhibitors Download PDF

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WO2008065522A2
WO2008065522A2 PCT/IB2007/003698 IB2007003698W WO2008065522A2 WO 2008065522 A2 WO2008065522 A2 WO 2008065522A2 IB 2007003698 W IB2007003698 W IB 2007003698W WO 2008065522 A2 WO2008065522 A2 WO 2008065522A2
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formula
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PCT/IB2007/003698
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WO2008065522A3 (en
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Laxmikant Atmaram Gharat
Jitendra Maganbhai Gajera
Sandip Damodar Patil
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Glenmark Pharmaceuticals S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans

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  • the present invention relates to a process for preparing 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, which is useful as an intermediate for preparing compounds with PDE4 inhibitory activity.
  • the invention further provides a process for preparing a PDE4 inhibitor, such as oglemilast.
  • the phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGMP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGMP levels and alters intracellular responses to extracellular signals by affecting the processes mediated by cyclic nucleotides. It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation, which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF- ⁇ .
  • PDE4 inhibitors including, for example, oglemilast (and its pharmaceutically acceptable salts), which is N-(3,5-dichloropyridm-4-yl)-4-difluoromethoxy-8- methanesulfonamidodibenzo[b,d]furan-l-carboxamide, a selective PDE4 inhibitor.
  • 4- Difluoromethoxy-8-nitro-l-formyldibenzo[b,d]furan is useful as an intermediate for preparing compounds with PDE4 inhibitory activity such as oglemilast.
  • WO '940 discloses processes for preparing compounds of Formula I.
  • PCT Publication No. WO 2006/040652 discloses another process for preparing PDE4 inhibitors such as oglemilast.
  • the present invention provides an alternative process, which is economical, convenient, efficient and easily scalable. Furthermore, the yields and purity of intermediates, including 4-difluoromethoxy-8-nitro-l-formyldibenzo[b,d]furan, and final products are high.
  • the present invention provides a process for preparing 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, which is useful as an intermediate for preparing compounds with PDE4 inhibitory activity.
  • the invention further provides a process for preparing PDE4 inhibitors such as oglemilast.
  • One embodiment of the present invention is a process for preparing 4- difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan of Formula 8
  • the process comprises the steps of: a) hydroxylating dibenzofuran of Formula 2,
  • Another embodiment is a process for preparing 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan by performing one or more steps (a)-(e) described above and converting the product to 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan.
  • 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan can be converted into, for example, oglemilast or any of the compounds of Formula 13 shown below by methods known in the art, such as those described in International Publication Nos. WO 2004/089940 and WO 2006/040652 and U.S. Patent Publication Nos. 2005/0027129 and 2006/0135779, all of which are hereby incorporated by reference.
  • Yet another embodiment is a process for preparing 4-hydroxybenzo[b,d]furan by hydroxylating dibenzofuran to form 4-hydroxybenzo[b,d]furan.
  • This process can be carried out by (i) reacting the dibenzofuran with one or more trialkylborates, preferably in the presence of a base, and (ii) hydrolyzing the resulting compound, for example, with hydrogen peroxide.
  • 4-hydroxybenzo[b,d]furan can be converted to 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 4
  • P is a hydroxyl protecting group, comprising the step of protecting the hydroxyl group in the compound of Formula 3
  • Suitable hydroxyl protecting groups include, but are not limited to, optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxy alkyl.
  • a preferred hydroxyl protecting group is cyclopentyl.
  • the reaction is performed in the presence of a base (e.g., an alkali metal carbonate, alkali metal hydroxide, metal hydride, alkaline earth metal hydroxide or a mixture thereof).
  • the compound of formula 4 can be converted to 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 5
  • the formylation can be performed by reacting the compound of Formula 4 with one or more formylating agents.
  • suitable formylating agents include, but are not limited to, dichloromethyl methylether, diformamide, triformamide, N,N,N,N-tetrafoimylhydrazine, tris(diformylamino)methane and any mixture thereof.
  • the compound of Formula 5 can be converted to 4-difmoromemoxy-8-nitro-l-formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 6
  • the deprotecting step can be performed by reacting the compound of Formula 5 with, for example, hydrobromic acid (e.g., in acetic acid), boron tribromide, aluminium chloride, sodium alkyl, aryl thiolate, tetra-n-butylammonium fluoride or a mixture thereof.
  • the deprotecting reaction is performed in the presence of a hydrogenating catalyst.
  • Suitable hydrogenating catalysts include, but are not limited to, palladium on carbon, palladium chloride, ruthenium, platinum oxide, platinum black, rhodium on carbon and mixtures thereof.
  • the compound of Formula 6 can be converted to 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 7
  • Suitable difluoromethylating agents include, but are not limited to, chlorodifluoromethane, sodium chlorodifluoroacetate, and mixtures thereof.
  • the reaction is performed in the presence of a base, such as an alkali metal carbonate, alkali metal hydroxide, metal hydride, alkaline earth metal hydroxide or a mixture thereof.
  • the compound of Formula 7 can be converted to 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a process for preparing 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan comprising nitrating a compound of Formula 7
  • Formula 7 with one or more nitrating agents is nitric acid.
  • suitable nitrating agents include, but are not limited to, potassium nitrate (e.g., in sulfuric acid), copper nitrate (e.g., in sulfuric acid), and mixtures thereof.
  • the nitrating reaction is performed in the presence of an acid, such as an aliphatic acid, glacial acetic acid, propionic acid, formic acid, or a mixture thereof.
  • 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan can be converted to a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
  • Yet another embodiment is a process for preparing a compound of Formula 13,
  • R is alkyl, aryl or heteroaryl
  • Y' is CO, CS or SO 2 ;
  • R 1 , R 2 and R 3 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl optionally containing one or more heteroatoms selected from N, S, and O.
  • the process comprises the steps of: a) hydroxylating dibenzofuran of Formula 2,
  • Yet another embodiment is a process for preparing a compound of Formula 13 by performing one or more of steps (a)-(j) described above and converting the product to the compound of Formula 13 or a pharmaceutically acceptable salt thereof.
  • composition comprising: (a) a compound of the formula
  • R is alkyl, aryl or heteroaryl
  • Y' is CO, CS or SO 2 ;
  • R 1 , R 2 and R 3 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl optionally containing one or more heteroatoms selected from N, S, and O; and
  • any one compound in component (b) is present in an amount up to 2% (and more preferably up to 0.2%), based upon 100% total weight of components (a) and (b).
  • the compounds in component (b) in aggregate are present in an amount up to 2% (and more preferably up to 0.2%), based upon 100% total weight of components (a) and (b).
  • the compound in component (a), i.e., the active component is preferably present in an amount greater than 95% (and more preferably greater than 98% or 99%), based upon 100% total weight of components (a) and (b).
  • P is a hydroxyl protecting group.
  • Suitable hydroxy! protecting groups include, but are not limited to, optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetraliydropyran, alkoxyalkyl and silyloxyalkyl.
  • a preferred hydroxyl protecting group is cyclopentyl.
  • the one or more bases are selected from alkyl lithium, for example, butyl lithium or methyl lithium; lithium amides, for example, lithium diisopropylamide; alkali metal carbonates or hydroxide, for example, potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide; alkoxides, for example, sodium methoxide, potassium tert-butoxide or a mixture thereof.
  • the one or more solvents are selected from water, diethyl ether, tetrahydrofuran, hexane, dioxane, toluene, xylene, dichloromethane, dimethylformamide or a mixture thereof.
  • the one or more formylating agents are selected from dichloromethyl methylether, diformamide, triformamide, dimethylformamide, N,N,N,N- tetraformylhydrazine, tris(diformylamino)methane, hexamethylenetetramine or a mixture thereof, preferably in the presence of one or more acids such as tin chloride, titanium chloride, phosphoryl chloride, trifluoroacetic acid, hydrochloric acid or a mixture thereof.
  • the one or more deprotecting agents are selected from hydrobromic acid (e.g., in acetic acid), boron tribromide, aluminium chloride, sodium alkyl or aryl thiolate, tetra-n-butylammonium fluoride or hydrogenating catalysts such as palladium on carbon, rhodium on carbon, platinum black, palladium chloride, platinum oxide, ruthenium or a mixture thereof.
  • hydrobromic acid e.g., in acetic acid
  • boron tribromide aluminium chloride
  • sodium alkyl or aryl thiolate tetra-n-butylammonium fluoride
  • hydrogenating catalysts such as palladium on carbon, rhodium on carbon, platinum black, palladium chloride, platinum oxide, ruthenium or a mixture thereof.
  • the one or more difluoromethylating agents are selected from chlorodifluoromethane, sodium chlorodifluoroacetate or a mixture thereof.
  • the one or more nitrating agents are selected from nitric acid (e.g., in sulfuric acid), nitric acid (e.g., in acetic acid), potassium nitrate (e.g., in sulfuric acid), copper nitrate in sulfuric acid or a mixture thereof.
  • the hydroxyl protecting group 'P' is cyclopentyl.
  • R 1 is hydrogen
  • R 2 is 3,5-dichloropyridin-4-yl
  • R is methyl
  • R 3 is H
  • Y' is SO 2 .
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkoxy refers to an alkyl group as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples of those groups are -OCH 3 , and -OC 2 H 5 .
  • alkoxyalkyl refers to an alkoxy radical attached to an alkyl group, which is attached to the main structure at any carbon atom from the alkyl group.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to a cyclic ring-containing radical containing in the range of 3 up to about 8 carbon atoms directly attached to an alkyl group, which is attached to the main structure at any carbon atom from the alkyl group, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
  • aryl refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like.
  • heterocyclic ring refers to a stable 3 to 15 member ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic or heteroaryl aromatic).
  • heterocyclic ring radicals include, but are not limited to azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl
  • heteroaryl refers to a heterocyclic ring radical as defined above.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclyl refers to a heterocyclic ring radical as defined above.
  • the heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • dibenzofuran of Formula 2 is hydroxylated to form a compound of Formula 3.
  • the compound of Formula 3 is hydroxyl protected to form a compound of Formula 4 (wherein P is a hydroxyl protecting group).
  • the compound of Formula 4 is formylated to form a compound of Formula 5.
  • the compound of Formula 5 is deprotected to form a compound of Formula 6.
  • the compound of Formula 6 is reacted with one or more difluoromethylating agents to form a compound of Formula 7.
  • the compound of Formula 7 is finally nitrated to form 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan.
  • Dibenzofuran of Formula 2 (Aldrich Chemical, 2005-2006) can be hydroxylated using trialkylborates, for example, trimethylborate or triethylborate and one or more bases, in one or more solvents, followed by hydrolysis using various hydrolyzing agents known in the art including, for example, hydrogen peroxide.
  • the one or more bases can be selected from alkyl lithium (e.g., methyl lithium or butyl lithium), lithium diisopropylamide, lithium or potassium hexamethyldisilazane, alkali metal hydroxides (e.g., sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g., potassium carbonate or sodium carbonate), alkali metal alkoxides (e.g., sodium methoxide or potassium ⁇ -butoxide) or a mixture thereof.
  • alkyl lithium e.g., methyl lithium or butyl lithium
  • lithium diisopropylamide lithium or potassium hexamethyldisilazane
  • alkali metal hydroxides e.g., sodium hydroxide or potassium hydroxide
  • alkali metal carbonates e.g., potassium carbonate or sodium carbonate
  • alkali metal alkoxides e.g., sodium methoxide or potassium ⁇ -butoxide
  • the one or more solvents are selected from ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), hydrocarbons (e.g., hexane, heptane, toluene, or xylene), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide) or a mixture thereof.
  • ethers e.g., diethyl ether, tetrahydrofuran or dioxane
  • hydrocarbons e.g., hexane, heptane, toluene, or xylene
  • halogenated solvents e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride
  • the compound of Formula 3 can be hydroxyl protected in the presence of one or more bases, for example, alkali metal carbonates (e.g., potassium carbonate or sodium carbonate), alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), metal hydride (e.g., sodium hydride or potassium hydride), alkaline earth metal hydroxide (e.g., calcium hydroxide or magnesium hydroxide) or a mixture thereof, in one or more solvents, for example, ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), hydrocarbons (e.g., hexane, heptane, toluene, or xylene), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide
  • the hydroxyl protecting group can be selected from optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxyalkyl.
  • the compound of Formula 4 can be formylated with one or more formylating agents known in the art including, for example, dichloromethyl methylether, diformamide, triformamide, N,N,N,N-tetraformylhydrazine, tris(diformylamino)methane or a mixture thereof, preferably in presence of one or more acids, for example, tin chloride, aluminium chloride, titanium chloride, phosphoryl chloride (e.g., in dimethylformamide), hexamethylenetetramine (e.g. in trifmoroacetic acid), hydrochloric acid or a mixture thereof.
  • formylating agents known in the art including, for example, dichloromethyl methylether, diformamide, triformamide, N,N,N,N-tetraformylhydrazine, tris(diformylamino)methane or a mixture thereof, preferably in presence of one or more acids, for example, tin chloride, aluminiu
  • the reaction can also be carried out in one or more solvents, for example, ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g., hexane or heptane), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide) or a mixture thereof.
  • solvents for example, ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g., hexane or heptane), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents
  • the compound of Formula 5 can be deprotected with one or more deprotecting agents under appropriate acidic or basic conditions, for example, hydrobromic acid (e.g., in acetic acid), boron tribromide, aluminium chloride, sodium alkyl or aryl thiolate, tetra-n- butylammonium fluoride or a mixture thereof.
  • the deprotection can also be carried out in the presence of one or more hydro genating catalysts, for example, palladium on carbon, palladium chloride, ruthenium, platinum oxide, platinum black, rhodium on carbon or a mixture thereof.
  • the compound of Formula 6 can be reacted with one or more difluoromethylating agents known in the art including, for example, chlorodifiuoromethane, sodium chlorodifluoroacetate or a mixture thereof.
  • This reaction can also be carried out in the presence of one or more bases, for example, alkali metal carbonates (e.g., potassium carbonate or sodium carbonate), alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), metal hydride (e.g., sodium hydride or potassium hydride), alkaline earth metal hydroxide (e.g., calcium hydroxide or magnesium hydroxide) or a mixture thereof, in one or more solvents, for example, ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g., hexane or heptane), halogenated solvents (e.g., dichloromethane
  • the compound of formula 7 can be nitrated with one or more nitrating agents known in the art including, for example, nitric acid (e.g., in sulfuric acid), potassium nitrate (e.g., in sulfuric acid), copper nitrate (e.g., in sulfuric acid) or a mixture thereof.
  • nitric acid e.g., in sulfuric acid
  • potassium nitrate e.g., in sulfuric acid
  • copper nitrate e.g., in sulfuric acid
  • This reaction can also be carried out in one or more aliphatic acids, for example, glacial acetic acid, propionic acid, formic acid or a mixture thereof.
  • the compound of Formula 8 is prepared by the method described in Scheme I.
  • the compound of Formula 8 can then be converted to a compound of Formula 13 following the procedures described in International Publication Nos. WO 2004/089940 and WO 2006/040652 and U.S. Patent Publication Nos. 2005/0027129 and 2006/0135779, all of which are hereby incorporated by reference.
  • the present invention also provides a process for preparing a compound of Formula I,
  • R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, formyl, acetyl, halogen, protecting groups, -C(O)-R 3 , -C(O)O-R a
  • R 4 is -NR 5 R 6 , wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, halogen, -C(O)-R 3 , -C(O)O-R 3 , -
  • Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heteroaryl ring;
  • X is selected from the group consisting of O, S(0) q and NR a ;
  • Y is selected from the group consisting of -C(O)NR 7 , -NR 7 S(O) q , -S(0) q NR 7 and - NR 7 C(O);
  • R 7 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -0R a , substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring ;
  • R a and R b is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, -OH, cyano,
  • Ar is optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyrimidine, optionally substituted pyridyl selected from 4-pyridyl, 3- pyridyl and 2-pyridyl or optionally substituted pyridyl-N-oxide selected from 4-pyridyl-N- oxide, 3 -pyridyl-N-oxide and 2-pyridyl-N-oxide in which optional substituents (one or more) are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or
  • the process includes the reaction sequences depicted in Scheme II using the appropriate substituted dibenzofuran, substituted dibenzothiophene or substituted dibenzothiophene sulfone as the starting compound.
  • the substituents in Formula I have the same meaning as defined in International Publication No. WO 2004/089940 and U.S. Patent Publication No. 2005/0027129.

Abstract

The present invention relates to a process for preparing 4-difluoromethoxy-8- nitro-1-formyl dibenzo[b,d]furan, which is useful as an intermediate for preparing compounds with PDE4 inhibitory activity. The invention further provides a process for preparing a PDE4 inhibitor, such as oglemilast.

Description

PROCESS FOR THE SYNTHESIS OF 4-DIFLUOROMETHOXY-8-NITRO-1- FORMYL DIBENZO [b,d]FURAN - AN INTERMEDIATE FOR PDE IV INHIBITORS
Field of the Invention
The present invention relates to a process for preparing 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, which is useful as an intermediate for preparing compounds with PDE4 inhibitory activity. The invention further provides a process for preparing a PDE4 inhibitor, such as oglemilast.
Background of the Invention
The phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGMP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGMP levels and alters intracellular responses to extracellular signals by affecting the processes mediated by cyclic nucleotides. It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation, which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF-α. Since eosinophils are believed to be a critical pro-inflammatory target for asthma, identification of the expression of the PDE4 gene family in eosinophils led to PDE4 as a potential therapeutic target for asthma [Rogers, D.F., Giembycz, M.A., Trends Pharmacol Set, 19, 160-164, (1998); Barnes, PJ., Trends Pharmacol. ScL, 19, 415-423, (1998)].
PCT Publication No. WO 2004/089940 (WO '940) discloses compounds of Formula
Figure imgf000002_0001
Formula I as PDE4 inhibitors including, for example, oglemilast (and its pharmaceutically acceptable salts), which is N-(3,5-dichloropyridm-4-yl)-4-difluoromethoxy-8- methanesulfonamidodibenzo[b,d]furan-l-carboxamide, a selective PDE4 inhibitor. 4- Difluoromethoxy-8-nitro-l-formyldibenzo[b,d]furan is useful as an intermediate for preparing compounds with PDE4 inhibitory activity such as oglemilast. WO '940 discloses processes for preparing compounds of Formula I. PCT Publication No. WO 2006/040652 discloses another process for preparing PDE4 inhibitors such as oglemilast.
The inventors have found that processes described in these references require expensive reagents such as silver sulfate or palladium acetate. Further, the yields and purity of intermediates, including 4-difIuoromethoxy-8-nitro-l-formyldibenzo[b,d]furan, and final products are low.
The present invention provides an alternative process, which is economical, convenient, efficient and easily scalable. Furthermore, the yields and purity of intermediates, including 4-difluoromethoxy-8-nitro-l-formyldibenzo[b,d]furan, and final products are high.
Summary of the Invention
The present invention provides a process for preparing 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, which is useful as an intermediate for preparing compounds with PDE4 inhibitory activity. The invention further provides a process for preparing PDE4 inhibitors such as oglemilast.
One embodiment of the present invention is a process for preparing 4- difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan of Formula 8
Figure imgf000003_0001
Formula 8
The process comprises the steps of: a) hydroxylating dibenzofuran of Formula 2,
Figure imgf000003_0002
for example, by using trialkylborates, preferably in the presence of one or more bases, and optionally in one or more solvents, followed by hydrolysis (for example, with hydrogen peroxide), to form a compound of Formula 3,
Figure imgf000003_0003
Formula 3 b) protecting the compound of Formula 3 with a hydroxyl protecting group, preferably in the presence of one or more bases, and optionally in one or more solvents, to form a compound of Formula 4 (wherein P is a hydroxyl protecting group),
Figure imgf000004_0001
c) formylating the compound of Formula 4, for example, with one or more formylating agents, preferably in the presence of one or more acids, and optionally in one or more solvents, to form a compound of Formula 5,
Figure imgf000004_0002
d) deprotecting the compound of Formula 5, for example, with one or more deprotecting agents, to form a compound of Formula 6,
Figure imgf000004_0003
Formula 6
e) reacting the compound of Formula 6 with one or more difluoromethylating agents, preferably in the presence of one or more bases, and optionally in one or more solvents, to form a compound of Formula 1, and
Figure imgf000004_0004
Formula 7 f) nitrating the compound of Formula 7, for example with one or more nitrating agents, to form 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan of Formula 8. Another embodiment is a process for preparing 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan by performing one or more steps (a)-(e) described above and converting the product to 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan.
4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan can be converted into, for example, oglemilast or any of the compounds of Formula 13 shown below by methods known in the art, such as those described in International Publication Nos. WO 2004/089940 and WO 2006/040652 and U.S. Patent Publication Nos. 2005/0027129 and 2006/0135779, all of which are hereby incorporated by reference.
Yet another embodiment is a process for preparing 4-hydroxybenzo[b,d]furan by hydroxylating dibenzofuran to form 4-hydroxybenzo[b,d]furan. This process can be carried out by (i) reacting the dibenzofuran with one or more trialkylborates, preferably in the presence of a base, and (ii) hydrolyzing the resulting compound, for example, with hydrogen peroxide. 4-hydroxybenzo[b,d]furan can be converted to 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 4
Figure imgf000005_0001
wherein P is a hydroxyl protecting group, comprising the step of protecting the hydroxyl group in the compound of Formula 3
Figure imgf000005_0002
Formula 3
Suitable hydroxyl protecting groups include, but are not limited to, optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxy alkyl. A preferred hydroxyl protecting group is cyclopentyl. Preferably, the reaction is performed in the presence of a base (e.g., an alkali metal carbonate, alkali metal hydroxide, metal hydride, alkaline earth metal hydroxide or a mixture thereof). The compound of formula 4 can be converted to 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof. Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 5
Figure imgf000006_0001
comprising the step of formylating a compound of Formula 4
Figure imgf000006_0002
The formylation can be performed by reacting the compound of Formula 4 with one or more formylating agents. Suitable formylating agents include, but are not limited to, dichloromethyl methylether, diformamide, triformamide, N,N,N,N-tetrafoimylhydrazine, tris(diformylamino)methane and any mixture thereof. The compound of Formula 5 can be converted to 4-difmoromemoxy-8-nitro-l-formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 6
Figure imgf000006_0003
Formula 6 comprising the step of deprotecting a compound of Formula 5
Figure imgf000006_0004
The deprotecting step can be performed by reacting the compound of Formula 5 with, for example, hydrobromic acid (e.g., in acetic acid), boron tribromide, aluminium chloride, sodium alkyl, aryl thiolate, tetra-n-butylammonium fluoride or a mixture thereof. Preferably, the deprotecting reaction is performed in the presence of a hydrogenating catalyst. Suitable hydrogenating catalysts include, but are not limited to, palladium on carbon, palladium chloride, ruthenium, platinum oxide, platinum black, rhodium on carbon and mixtures thereof. The compound of Formula 6 can be converted to 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
Yet another embodiment is a process for preparing a protected dibenzo[b,d]furan of Formula 7
Figure imgf000007_0001
Formula 7 comprising the step of reacting a compound of Formula 6
Figure imgf000007_0002
Formula 6 with a difluoromethylating agent. Suitable difluoromethylating agents include, but are not limited to, chlorodifluoromethane, sodium chlorodifluoroacetate, and mixtures thereof. Preferably, the reaction is performed in the presence of a base, such as an alkali metal carbonate, alkali metal hydroxide, metal hydride, alkaline earth metal hydroxide or a mixture thereof. The compound of Formula 7 can be converted to 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan, a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
Yet another embodiment is a process for preparing 4-difluoromethoxy-8-nitro-l- formyl dibenzo[b,d]furan comprising nitrating a compound of Formula 7
Figure imgf000007_0003
Formula 7 with one or more nitrating agents. One suitable nitrating agent is nitric acid. Other suitable nitrating agents include, but are not limited to, potassium nitrate (e.g., in sulfuric acid), copper nitrate (e.g., in sulfuric acid), and mixtures thereof. Preferably, the nitrating reaction is performed in the presence of an acid, such as an aliphatic acid, glacial acetic acid, propionic acid, formic acid, or a mixture thereof. 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan can be converted to a compound of Formula 13 (described below), oglemilast or a pharmaceutically acceptable salt thereof.
Yet another embodiment is a process for preparing a compound of Formula 13,
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein
R is alkyl, aryl or heteroaryl;
Y' is CO, CS or SO2; and
R1, R2 and R3 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl or R1 and R2 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl optionally containing one or more heteroatoms selected from N, S, and O. The process comprises the steps of: a) hydroxylating dibenzofuran of Formula 2,
Figure imgf000008_0002
for example, by using trialkylborates, preferably in the presence of one or more bases, and optionally in one or more solvents, followed by hydrolysis, for example by using hydrogen peroxide, to form a compound of Formula 3,
Figure imgf000008_0003
Formula 3 b) protecting the compound of Formula 3 with a hydroxyl protecting group, preferably in the presence of one or more bases, and optionally in one or more solvents, to form a compound of Formula 4 (wherein P is a hydroxyl protecting group),
Figure imgf000008_0004
c) formylating the compound of Formula 4, for example with one or more formylating agents, preferably in the presence of one or more acids, and optionally in one or more solvents, to form a compound of Formula 5,
Figure imgf000009_0001
d) deprotecting the compound of Formula 5, for example with one or more deprotecting agents, to form a compound of Formula 6,
Figure imgf000009_0002
Formula 6 e) reacting the compound of Formula 6 with one or more difluoromethylating agents, preferably in the presence of one or more bases, and optionally in one or more solvents, to form a compound of Formula 7,
Figure imgf000009_0003
Formula 7 f) nitrating the compound of Formula 7, for example with one or more nitrating agents, to form a compound of Formula 8,
Figure imgf000009_0004
Formula 8 g) oxidizing the compound of Formula 8 to form a compound of Formula 9,
Figure imgf000009_0005
Formula 9 h) converting the compound of Formula 9 into a compound of Formula 10 (wherein L is a leaving group),
Figure imgf000010_0001
i) coupling the compound of Formula 10 with an amine of the formula R1R2NH (wherein R1 and R2 are as defined earlier) to form a compound of Formula 11,
Figure imgf000010_0002
j) i) reducing the compound of Formula 11 to form a compound of Formula 12 (wherein R3 is hydrogen), and ii) optionally reacting the compound of Formula 12 (wherein R3 is hydrogen),
"X "X with a compound of the formula R -X (wherein R is alkyl, aryl, heteroaryl or heterocyclyl; and X is a leaving group (e.g., halogen)) to form a compound of Formula 12 (wherein R3 is alkyl, aryl, heteroaryl
Figure imgf000010_0003
k) reacting the compound of Formula 12 with a compound of the formula RY'X (wherein R and Y' are as defined earlier and X is a leaving group (such as halogen)) to form a compound of Formula 13 which is optionally converted into a pharmaceutically acceptable salt.
Yet another embodiment is a process for preparing a compound of Formula 13 by performing one or more of steps (a)-(j) described above and converting the product to the compound of Formula 13 or a pharmaceutically acceptable salt thereof.
Yet another embodiment is a pharmaceutical composition comprising: (a) a compound of the formula
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein
R is alkyl, aryl or heteroaryl;
Y' is CO, CS or SO2;
R1, R2 and R3 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl, or R1 and R2 together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl optionally containing one or more heteroatoms selected from N, S, and O; and
(b) one or more compounds selected from
Figure imgf000011_0002
wherein P is a hydroxyl protecting group. Preferably, any one compound in component (b) is present in an amount up to 2% (and more preferably up to 0.2%), based upon 100% total weight of components (a) and (b). According to a preferred embodiment, the compounds in component (b) in aggregate are present in an amount up to 2% (and more preferably up to 0.2%), based upon 100% total weight of components (a) and (b). The compound in component (a), i.e., the active component, is preferably present in an amount greater than 95% (and more preferably greater than 98% or 99%), based upon 100% total weight of components (a) and (b).
Yet another embodiment is a compound selected from compounds of the formulae
Figure imgf000012_0001
Formula 7 5 wherein P is a hydroxyl protecting group. Suitable hydroxy! protecting groups include, but are not limited to, optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetraliydropyran, alkoxyalkyl and silyloxyalkyl. A preferred hydroxyl protecting group is cyclopentyl.
Processes described herein can include one or more of the following embodiments. For example, the one or more bases are selected from alkyl lithium, for example, butyl lithium or methyl lithium; lithium amides, for example, lithium diisopropylamide; alkali metal carbonates or hydroxide, for example, potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide; alkoxides, for example, sodium methoxide, potassium tert-butoxide or a mixture thereof.
In another embodiment, the one or more solvents are selected from water, diethyl ether, tetrahydrofuran, hexane, dioxane, toluene, xylene, dichloromethane, dimethylformamide or a mixture thereof.
In another embodiment, the one or more formylating agents are selected from dichloromethyl methylether, diformamide, triformamide, dimethylformamide, N,N,N,N- tetraformylhydrazine, tris(diformylamino)methane, hexamethylenetetramine or a mixture thereof, preferably in the presence of one or more acids such as tin chloride, titanium chloride, phosphoryl chloride, trifluoroacetic acid, hydrochloric acid or a mixture thereof.
In another embodiment, the one or more deprotecting agents are selected from hydrobromic acid (e.g., in acetic acid), boron tribromide, aluminium chloride, sodium alkyl or aryl thiolate, tetra-n-butylammonium fluoride or hydrogenating catalysts such as palladium on carbon, rhodium on carbon, platinum black, palladium chloride, platinum oxide, ruthenium or a mixture thereof.
In another embodiment, the one or more difluoromethylating agents are selected from chlorodifluoromethane, sodium chlorodifluoroacetate or a mixture thereof. In another embodiment, the one or more nitrating agents are selected from nitric acid (e.g., in sulfuric acid), nitric acid (e.g., in acetic acid), potassium nitrate (e.g., in sulfuric acid), copper nitrate in sulfuric acid or a mixture thereof.
In another embodiment, the hydroxyl protecting group 'P' is cyclopentyl.
In another embodiment, R1 is hydrogen, R2 is 3,5-dichloropyridin-4-yl, R is methyl, R3 is H, and Y' is SO2.
Other embodiments are described in the following detailed description. However, it should be understood that the detailed description is given by way of illustration only and various changes and modifications will be apparent to those skilled in the art and are included within the scope of this invention.
Detailed Description of the Invention The following definitions apply to terms as used herein
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
The term "alkoxy" refers to an alkyl group as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples of those groups are -OCH3, and -OC2H5.
The term "alkoxyalkyl" refers to an alkoxy radical attached to an alkyl group, which is attached to the main structure at any carbon atom from the alkyl group.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Non-limiting examples of multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical containing in the range of 3 up to about 8 carbon atoms directly attached to an alkyl group, which is attached to the main structure at any carbon atom from the alkyl group, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
The term "aryl" refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like. The term "heterocyclic ring" refers to a stable 3 to 15 member ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic or heteroaryl aromatic). Examples of such heterocyclic ring radicals include, but are not limited to azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone, dioxaphospholanyl , oxadiazolyl , chromanyl, isochromanyl and the like. Also included are substituted or unsubstituted pyridyl N-oxides.
The term "heteroaryl" refers to a heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocylcyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "substituted" refers to one or more substituents selected from hydroxy, halogen, carboxyl, cyano, amino, nitro, oxo (=0), thio (=S), optionally substituted alkyl, optionally substituted alkoxy, optionally substituted' alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclic ring, -COORX, -C(O)R*, -C(S)RX, - C(O)NRxRy, -C(O)ONRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), - NRxC(O)ORy, -NRxRy, -NRxC(O)Ry-, -NRxC(S)Ry -NRxC(S)NRyRz, -SONRxRy-, - SO2NRxRy-, -ORX, -ORxC(O)NRyRz, -ORxC(O)ORy-, -OC(O)RX, -OC(O)NRxRy, -RxNRyRz, - RxRyRz, -RXCF3, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, -RxC(O)NRyRz, -RXC(O)RX, - RxOC(O)Ry, -SRX, -SORX, -SO2RX, -ONO2, wherein Rx, Ry and Rz are independently hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl.
The substituents in the aforementioned "substituted" groups are not further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" is not substituted.
In one aspect of the present invention, there is provided a process for preparing A- difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan of Formula 8. This process is depicted in Scheme I below.
Figure imgf000015_0001
Formula 2
Figure imgf000015_0002
Figure imgf000015_0003
In scheme I, dibenzofuran of Formula 2 is hydroxylated to form a compound of Formula 3. The compound of Formula 3 is hydroxyl protected to form a compound of Formula 4 (wherein P is a hydroxyl protecting group). The compound of Formula 4 is formylated to form a compound of Formula 5. The compound of Formula 5 is deprotected to form a compound of Formula 6. The compound of Formula 6 is reacted with one or more difluoromethylating agents to form a compound of Formula 7. The compound of Formula 7 is finally nitrated to form 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan. Dibenzofuran of Formula 2 (Aldrich Chemical, 2005-2006) can be hydroxylated using trialkylborates, for example, trimethylborate or triethylborate and one or more bases, in one or more solvents, followed by hydrolysis using various hydrolyzing agents known in the art including, for example, hydrogen peroxide. The one or more bases can be selected from alkyl lithium (e.g., methyl lithium or butyl lithium), lithium diisopropylamide, lithium or potassium hexamethyldisilazane, alkali metal hydroxides (e.g., sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g., potassium carbonate or sodium carbonate), alkali metal alkoxides (e.g., sodium methoxide or potassium ^-butoxide) or a mixture thereof. The one or more solvents are selected from ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), hydrocarbons (e.g., hexane, heptane, toluene, or xylene), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide) or a mixture thereof.
The compound of Formula 3 can be hydroxyl protected in the presence of one or more bases, for example, alkali metal carbonates (e.g., potassium carbonate or sodium carbonate), alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), metal hydride (e.g., sodium hydride or potassium hydride), alkaline earth metal hydroxide (e.g., calcium hydroxide or magnesium hydroxide) or a mixture thereof, in one or more solvents, for example, ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), hydrocarbons (e.g., hexane, heptane, toluene, or xylene), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide) or a mixture thereof. The hydroxyl protecting group can be selected from optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxyalkyl.
The compound of Formula 4 can be formylated with one or more formylating agents known in the art including, for example, dichloromethyl methylether, diformamide, triformamide, N,N,N,N-tetraformylhydrazine, tris(diformylamino)methane or a mixture thereof, preferably in presence of one or more acids, for example, tin chloride, aluminium chloride, titanium chloride, phosphoryl chloride (e.g., in dimethylformamide), hexamethylenetetramine (e.g. in trifmoroacetic acid), hydrochloric acid or a mixture thereof. The reaction can also be carried out in one or more solvents, for example, ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g., hexane or heptane), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide) or a mixture thereof.
The compound of Formula 5 can be deprotected with one or more deprotecting agents under appropriate acidic or basic conditions, for example, hydrobromic acid (e.g., in acetic acid), boron tribromide, aluminium chloride, sodium alkyl or aryl thiolate, tetra-n- butylammonium fluoride or a mixture thereof. The deprotection can also be carried out in the presence of one or more hydro genating catalysts, for example, palladium on carbon, palladium chloride, ruthenium, platinum oxide, platinum black, rhodium on carbon or a mixture thereof.
The compound of Formula 6 can be reacted with one or more difluoromethylating agents known in the art including, for example, chlorodifiuoromethane, sodium chlorodifluoroacetate or a mixture thereof. This reaction can also be carried out in the presence of one or more bases, for example, alkali metal carbonates (e.g., potassium carbonate or sodium carbonate), alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide), metal hydride (e.g., sodium hydride or potassium hydride), alkaline earth metal hydroxide (e.g., calcium hydroxide or magnesium hydroxide) or a mixture thereof, in one or more solvents, for example, ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g., hexane or heptane), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide) or a mixture thereof.
The compound of formula 7 can be nitrated with one or more nitrating agents known in the art including, for example, nitric acid (e.g., in sulfuric acid), potassium nitrate (e.g., in sulfuric acid), copper nitrate (e.g., in sulfuric acid) or a mixture thereof. This reaction can also be carried out in one or more aliphatic acids, for example, glacial acetic acid, propionic acid, formic acid or a mixture thereof.
In a second aspect of the present invention, there is provided a process for preparing a compound of Formula 13. The process includes the reaction sequence depicted in Scheme II below.
Figure imgf000018_0001
Formula 2
Figure imgf000018_0002
Figure imgf000018_0003
Formula 6 Formula 7
Figure imgf000018_0004
Figure imgf000018_0005
In scheme II, the compound of Formula 8 is prepared by the method described in Scheme I. The compound of Formula 8 can then be converted to a compound of Formula 13 following the procedures described in International Publication Nos. WO 2004/089940 and WO 2006/040652 and U.S. Patent Publication Nos. 2005/0027129 and 2006/0135779, all of which are hereby incorporated by reference.
The present invention also provides a process for preparing a compound of Formula I,
Figure imgf000018_0006
or a pharmaceutical acceptable salt thereof, wherein
R1, R2 and R3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, formyl, acetyl, halogen, protecting groups, -C(O)-R3, -C(O)O-Ra, -C(O)NRaRb , -S(O)q-Ra, -S(O)q-NRaRb , -NRaRb, ,-0Ra, and - SRa or when two R3 substituents are ortho to each other, they may be joined to a form a saturated or unsaturated cyclic 3-7 membered ring, which may optionally include up to two heteroatoms which may be same or different selected from O, NRa or S;
R4 is -NR5R6, wherein R5 and R6 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl , nitro, -OH, cyano, halogen, -C(O)-R3, -C(O)O-R3, -C(O)NRaRb , -S(O)q-Ra, -S(0)q-NR3Rb , -C(=NR3)- Rb, -C(=NRa)-NRaRb, -C(=S)-NRaRb , -C(=S)-Ra, -N=C(RaRb), -NRaRb, -0Ra, -SRa, and protecting groups or R5 and R may be joined to a form a saturated or unsaturated 3-7 membered cyclic ring, which may optionally include up to two heteroatoms which may be same or different selected from O, NRa or S; with the proviso that R4 is not NH2;
Ar is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring and substituted or unsubstituted heteroaryl ring;
X is selected from the group consisting of O, S(0)q and NRa;
Y is selected from the group consisting of -C(O)NR7, -NR7S(O)q, -S(0)qNR7 and - NR7C(O);
R7 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -0Ra, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic ring ;
P is selected from the group consisting of O and S; m represents 0 - 3; n represents 1 - 4; q represents O, 1 or 2; each occurrence of Ra and Rb is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, -OH, cyano, formyl, acetyl, halogen, a protecting group, -C(O)-R0, -C(O)O-R0, -C(0)NR°Rd, -S(O)q-R°, -S(O)q-NRcRd , -NRcRd, -ORC and -SR0; and each occurrence of R° and Rd is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, nitro, -OH, cyano, formyl, acetyl, halogen, or a protecting group.
Preferably, Ar is optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyrimidine, optionally substituted pyridyl selected from 4-pyridyl, 3- pyridyl and 2-pyridyl or optionally substituted pyridyl-N-oxide selected from 4-pyridyl-N- oxide, 3 -pyridyl-N-oxide and 2-pyridyl-N-oxide in which optional substituents (one or more) are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino.
The process includes the reaction sequences depicted in Scheme II using the appropriate substituted dibenzofuran, substituted dibenzothiophene or substituted dibenzothiophene sulfone as the starting compound. The substituents in Formula I, have the same meaning as defined in International Publication No. WO 2004/089940 and U.S. Patent Publication No. 2005/0027129.
In the schemes above, where specific bases, acids, reagents, solvents, formylating agents, difluoromethylating agents, nitrating agents, deprotecting agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, formylating agents, difluoromethylating agents, nitrating agents, deprotecting agents, etc., known in the art may also be used and are therefore within the scope of the invention. Further, the present invention is illustrated by the following Examples. It is understood, however, that the invention is not limited by the specific details of the following Examples.
Example 1: Preparation of 4-hydroxydibenzo[&,(f|furan
To a well-stirred solution of dibenzofuran (100 g, 0.595 mol) and N,N,N',N'- tetramethylethanel,2-diamine (82.8 g, 0.744 mol) in dry diethyl ether (1.0 L) was added slowly 2.5M n-butyl lithium in hexanes (300 mL, 0.744 mol) under a nitrogen atmosphere at about -10 to 1O0C. The mixture was warmed for about 1-4 hours and then cooled to -10 to 1O0C followed by addition of trimethyl borate (73.5 g, 0.714 mol). The reaction mixture was then stirred at room temperature for about 12-13 hrs. After cooling again to about -10 to 1O0C, a 50% hydrogen peroxide solution (200 mL) was added drop wise with vigorous stirring and the mixture was refluxed for about 1-2 hours. The reaction mixture was then cooled to O0C and acidified with concentrated hydrochloric acid (100 mL). The organic phase was extracted with 2M sodium hydroxide (4 X 250 mL). The combined aqueous phase was washed with diethyl ether (2 X 100 mL), acidified with 10% aqueous hydrochloric acid solution and extracted with dichloromethane (3 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave about 65-75% of product as an off-white solid.
IR (KBr): 3192, 1604, 1312, 1248, 1193, 1087, 1052, 926, 842, 746 cm "1. 1H NMR (300 MHz, CDCl3): δ , 5.50 (br. s, 1 H), 7.03 (dd, J= 8.0 Hz, 1 H), 7.23 (t, J= 7.8 Hz, 1 H), 7.36 (t, J= 7.5 Hz, 1 H), 7.48 (t, J= 8.4 Hz, 1 H), 7.53 (d, J= 7.8 Hz, 1 H), 7.60 (d, J= 8.2 Hz, 1 H), 7.95 (d, J= 8.4 Hz, 1 H).
Example 2: Preparation of 4-CvclopentyloxydibenzorZ>,<f1furan
To a well-stirred solution of dibenzo[Z>,d]furan-4-ol (65 g, 0.353 mol) and anhydrous potassium carbonate (96.36 g, 0.77 mol) in dry dimethylformamide (325 mL) was added cyclopentyl bromide (54.8 g, 0.370 mol) and the mixture was heated to about 50-1000C for about 4-5 hours. The reaction mixture was cooled to ambient temperature and filtered to remove inorganic material. The filtrate was concentrated under reduce pressure, and the residue obtained was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give about 90-98 % of the product as a viscous liquid.
IR (neat): 2957, 2870, 1449, 1269, 1193 cm ~\ 1H NMR (300 MHz, CDCl3): δ 1.57- 1.72 (m, 2 H), 1.84-1.89 (m, 2 H), 1.93-2.04 (m, 4 H), 5.01 (quint, 1 H), 6.97 (d, J= 8.1 Hz, 1 H), 7.22 (t, J= 7.9 Hz, 1 H), 7.30 (t, J= 8.1 Hz, 1 H), 7.45 (t, J= 8.1 Hz, 1 H), 7.51 (d, J= 7.8 Hz, 1 H), 7.60 (d, J= 8.2 Hz, 1 H), 7.89 (d, J= 8.1 Hz, 1 H). Example 3: Preparation of 4-Cyclopentyloxy-l-formyldibenzo[6,^furan
To a well-stirred solution of 4-cyclopentyloxydibenzo[&,d]furan (82 g, 0.3253 mol) in dichloromethane (820 mL) was added tin(IV)chloride (144 g, 0.553 mol) at about -30 to O0C followed by the drop wise addition of α,α-dichloromethylmethylether (41.4 mg, 0.357 mmol) at about same temperature. The reaction mixture was allowed to come to an ambient temperature during 2 hours and diluted with water (2.0 L). The organic phase was separated and washed with water (2 x 250 mL) and dried over anhydrous sodium sulphate. The crude product obtained after removal of solvent was purified through a silica gel column using petroleum etherethyl acetate (8:2) as an eluent to give about 65-70 % of product as light yellow solid.
IR (KBr): 2960, 2730, 1686, 1565, 1276, 1099 cm ~K 1H NMR (300 MHz, CDCl3): δ 1.64-1.75 (m, 2 H), 1.85-1.98 (m, 2 H), 2.03-2.09 (m, 4 H), 5.11 (quint, 1 H), 7.07 (d, J= 8.2 Hz, 1 H), 7.38 (t, J= 7.9 Hz, 1 H), 7.52 (t, J= 7.8 Hz, 1 H), 7.63 (d, J= 8.4 Hz, 1 H), 7.77 (d, J= 8.2 Hz, 1 H), 8.95 (d, J= 8.4 Hz, 1 H), 10.17 (s, 1 H).
Example 4: Preparation of 4-hydroxy-l-formyldibenzorb,d~[furan
A solution of 4-cycloρentyloxy-l-formyldibenzo[έ,cT]furan (60 g, 0.214 mol) and hydrobromic acid (30-33%) in glacial acetic acid (600 mL) was stirred at about 50-1000C for about 1 -5 h. The reaction was concentrated under reduced pressure and diluted with ice water (1.0 L). The solid separated was filtered and washed with water (2 x 100 mL) and dried to give about 90-98 % of product as a light brown solid.
IR (KBr): 3192, 1693, 1604, 1312, 1248, 1193, 1087, 1052, 926, 842, 746 cm "1. 1H NMR (300 MHz, CDCl3): δ , 6.21 (br. s, 1 H), 7.58 (d, J= 8.0 Hz, 1 H), 7.17 (t, J= 7.8 Hz, 1 H), 7.28 (t, J= 7.5 Hz, 1 H), 7.49 (d, J= 7.8 Hz, 1 H), 7.53 (d, J= 8.2 Hz, 1 H), 7.87 (d, J= 8.4 Hz, I H), 10.13 (s, IH).
Example 5: Preparation of 4-difluoromethoxy-l-formyl dibenzofb,d1furan
To a well-stirred suspension of 4-hydroxy-l-formyldibenzo[b,d]furan (42 g, 0.198 mol) and anhydrous potasium carbonate (54.67 g ,0.396 mol) in dry dimethyl formamide (420 mL) was bubbled chlorodifluoromethane gas for about 1-4 hours at about 50-100 0C. The reaction mixture was cooled to ambient temperature and filtered to remove inorganic material. The filtrate was concentrated under reduced pressure. The residue obtained was diluted with ice water (500 mL). The solid separated was filtered and dried to give about 70- 75 % of product as a light yellow solid. m. pt: 60-620C. IR (KBr): 1695, 1635, 1577, 1449, 1392, 1277, 1178, 1134, 1108, 839, 759 cm -1. 1H NMR (300 MHz, d6-DMSO): δ 7.51 (t, J= 7.8 Hz, 1 H), 7.65 (t, J= 72.3 Hz, 1 H), 7.67 (m, 2 H), 7.88 (d, J- 7.8 Hz, 1 H), 8.15 (d, J= 8.1 Hz, 1 H), 8.91 (d, J= 7.5 Hz, 1 H), 10.32 (s, IH).
Example 6: Preparation of 4-difluoromethoxy-8-nitro-l-formyl dibenzo[b,d]furan
To a well-stirred solution of concentrated sulfuric acid (250 mL, 4.69 mol) and concentrated nitric acid (250 mL, 3.88 mol) was added a solution of 4-difluoromethoxy-l- formyldibenzo[Z?,<f]furan (25 g, 0.0954 mol) in glacial acetic acid (250 mL) at about 0-25 0C and the mixture was stirred for about 3-8 hours. The thick reaction mixture obtained was poured into ice cold water (1.0 L). The solid separated was filtered and dried to get about 90- 98 % of product as an off-white solid.
HPLC purity: >98 %. m. pt.: 190-192 0C. IR (KBr): 1695, 1637, 1607, 1579, 1529, 1444, 1387, 1347, 1287, 1180, 1132, 1031, 821, 751 cm "1. 1H NMR (300 MHz, d6-DMSO): δ 7.69 (t, J= 72.3 Hz, 1 H), 7.78 (d, J= 7.5 Hz, 1 H), 8.12 (d, J =8.7 Hz, 1 H), 8.27 (d, J= 7.8 Hz, 1 H), 8.56 (d, J= 6.6 Hz, 1 H), 9.77 (s, 1 H), 10.26 (s, IH).
Although the invention herein has been described with reference to particular embodiments, these embodiments are merely illustrative of the principles and applications of the present invention. Therefore, numerous modifications may be made to the illustrative embodiments and other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All publications, patents, and patent applications cited herein (including International Publication Nos. WO 2004/089940 and WO 2006/040652 and U.S. Patent Publication Nos. 2005/0027129 and 2006/0135779) are herein incorporated by reference in their entireties including, for example, the definitions of terms as used herein.

Claims

We claim:
1. A process for preparing 4-difluoromethoxy-8-nitro-l -formyl dibenzo[b,d]furan of Formula 8,
Figure imgf000024_0001
Formula 8 comprising the steps of:
a) hydroxylating dibenzofuran of Formula 2,
Figure imgf000024_0002
Formula 2 to form a compound of Formula 3,
Figure imgf000024_0003
Formula 3
b) protecting the compound of Formula 3 with a hydroxyl protecting group to form a compound of Formula 4 (wherein P is a hydroxyl protecting group),
Figure imgf000024_0004
c) formyl ating the compound of Formula 4 with one or more formylating agents to form a compound of Formula 5,
Figure imgf000024_0005
d) deprotecting the compound of Formula 5 to form a compound of Formula 6,
Figure imgf000025_0001
Formula 6 e) reacting the compound of Formula 6 with one or more difluoromethylating agents to form a compound of Formula 7, and
Figure imgf000025_0002
Formula 7 f) nitrating the compound of Formula 7 with one or more nitrating agents to form the compound of Formula 8.
2. The process according to claim 1, wherein one or more of steps (a), (b), and (e) are performed in the presence of one or more bases selected from alkyl lithium, lithium amides, alkali metal carbonates, alkali metal hydroxides alkali metal alkoxides, and mixtures thereof.
3. The process according to claim 1, wherein one or more steps are performed in the presence of one or more solvents selected from water, diethyl ether, tetrahydrofuran, hexane, dioxane, toluene, xylene, dichloromethane, dimethylformamide and mixtures thereof.
4. The process according to claim 1, wherein the one or more formylating agents are selected from dichlαromethyl methylether, diformamide, triformamide, N5N5N5N- tetraformylhydrazine, tris(diformylamino)methane, dimethylformamide, hexamethylenetetramine and mixtures thereof.
5. The process according to claim 1, wherein step (c) is performed in the presence of one or more acids selected from tin chloride, titanium chloride, phosphoryl chloride, trifluoroacetic acid, hydrochloric acid and mixtures thereof.
6. The process according to claim 1, wherein the one or more deprotecting agents are selected from hydrobromic acid, boron tribromide, aluminium chloride, sodium alkyl or aryl thiolate, tetra-?t-butylammonium fluoride, and hydrogenating catalysts selected from palladium on carbon, rhodium on carbon, platinum black, palladium chloride, platinum oxide, ruthenium and mixtures thereof.
7. The process according to claim 1, wherein the one or more difluoromethylating agents are selected from chlorodifluoromethane, sodium chlorodifluoroacetate and mixtures thereof.
8. The process according to claim 1, wherein the one or more nitrating agents are selected from nitric acid, potassium nitrate, copper nitrate and mixtures thereof.
9. The process according to claim 1, wherein the hydroxyl protecting group is cyclopentyl.
10. A process for preparing a compound of Formula 13,
Figure imgf000026_0001
or a pharmaceutically acceptable salt thereof, wherein
R1, R2 and R3 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl; or R1 and R2, together with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclyl optionally containing one or more heteroatoms selected from N, S, and O;
R is alkyl, aryl or heteroaryl; and Y' is CO, CS or SO2, comprising the steps of: a) hydroxylating dibenzofuran of Formula 2,
Figure imgf000026_0002
to form a compound of Formula 3,
Figure imgf000026_0003
Formula 3 b) protecting the compound of Formula 3 with a hydroxyl protecting group to form a compound of Formula 4 (wherein P is a hydroxyl protecting group),
Figure imgf000027_0001
Formula 4
C) formylating the compound of Formula 4 with one or more formylating agents to form a compound of Formula 5,
Figure imgf000027_0002
d) deprotecting the compound of Formula 5 to form a compound of Formula 6,
Figure imgf000027_0003
Formula 6
e) reacting the compound of Formula 6 with one or more difiuoromethylating agents to form a compound of Formula 7,
Figure imgf000027_0004
Formula 7
f) nitrating the compound of Formula 7 with one or more nitrating agents to form a compound of Formula 8.
Figure imgf000027_0005
Formula 8 g) oxidizing the compound of Formula 8 to form a compound of Formula 9,
Figure imgf000028_0001
Formula 9 h) converting the compound of Formula 9 into a compound of Formula 10 (wherein L is a leaving group),
Figure imgf000028_0002
Formula 10
i) coupling the compound of Formula 10 with an amine of the formula R1R2NH to form a compound of Formula 11,
Figure imgf000028_0003
j) i) reducing the compound of Formula 11 to form a compound of Formula 12 (wherein R3 is hydrogen), and ii) optionally reacting the compound of Formula 12 (wherein R3 is hydrogen), with a compound of formula R3 -X (wherein R3 is alkyl, aryl, heteroaryl or heterocyclyl and X is leaving group (e.g., halogen)) to form a compound of Formula 12 (wherein R3 is alkyl, aryl, heteroaryl or heterocyclyl), and
Figure imgf000028_0004
k) reacting the compound of Formula 12 with a compound of the formula RY'X (wherein X is halogen) to form a compound of Formula 13, which is optionally converted into a pharmaceutically acceptable salt.
11. The process according to claim 10, wherein one or more of steps (a), (b), and (e) are performed in the presence of one or more bases selected from alkyl lithium, lithium amides, alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides, and mixtures thereof.
12. The process according to claim 10, wherein one or more of the steps are performed in the presence of one or more solvents selected from water, diethyl ether, tefrahydrofuran, hexane, dioxane, toluene, xylene, dichloromethane, dimethylformamide and mixtures thereof.
13. The process according to claim 10, wherein the one or more formylating agents are selected from dichloromethyl methylether, diformamide, triformamide, N,N,N,N- tetraformylhydrazine, tris(diformylamino)methane, dimethylformamide, hexamethylenetetramine and mixtures thereof.
14. The process according to claim 10, wherein step (c) is performed in the presence of one or more acids selected from tin chloride, titanium chloride, phosphoryl chloride, trifluoroacetic acid, hydrochloric acid and mixtures thereof.
15. The process according to claim 10, wherein the one or more deprotecting agents are selected from hydrobromic acid in acetic acid, boron tribromide, aluminium chloride, sodium alkyl or aryl thiolate, tetra-rc-butylammonium fluoride, and hydrogenating catalysts selected from palladium on carbon, rhodium on carbon, platinum black, palladium chloride, platinum oxide, ruthenium and mixtures thereof.
16. The process according to claim 10, wherein the one or more difluoromethylating agents are selected from chlorodifluoromethane, sodium chlorodifluoroacetate and mixtures thereof.
17. The process according to claim 10, wherein the one or more nitrating agents are selected from nitric acid, potassium nitrate, copper nitrate and mixtures thereof.
18. The process according to claim 10, wherein P is cyclopentyl; R1 is hydrogen; R2 is 3,5-dichloropyridin-4-yl; R3 is hydrogen; R is methyl; and Y' is SO2.
PCT/IB2007/003698 2006-11-29 2007-11-29 Process for the synthesis of 4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d] furan-an intermediate for pde iv inhibitors WO2008065522A2 (en)

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