WO2008081282A2

WO2008081282A2 - Process for the synthesis of n9-(3,5-dichloro-4-pyridyl)-6- difluoromethoxybenzo(4,5)furo(3,2-c)pyridine-9-carboxamide and salts thereof

Info

Publication number: WO2008081282A2
Application number: PCT/IB2007/004045
Authority: WO
Inventors: Laxmikant Atmaram Gharat; Jitendra Maganbhai Gajera; Aniket Vijaykumar Farande; Suresh M. Kadam; Kasturaiah Chapala; Shailendra Bhadane
Original assignee: Glenmark Pharmaceuticals S.A.
Priority date: 2006-12-20
Filing date: 2007-12-19
Publication date: 2008-07-10
Also published as: WO2008081282A3

Abstract

The present invention relates to a process for the synthesis of N9-(3,5- dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide and salts thereof which are useful as a PDE4 inhibitor. The invention also relates to a process for the synthesis of methyl-2-formyl-7-cyclopentyloxybenzo[b]furan-4-carboxylate and salts thereof, which are useful as intermediates in preparing compounds with PDE4 inhibitory activity.

Description

PROCESS FOR THE SYNTHESIS OF NSHS-S-DICHLORO^-PYRIDYL)-O- DIFLUOROMETHOXYBENZOH₅S]FUROP-I-C]PYRIDINE^-CARBOXAMIDE

AND SALTS THEREOF

This application claims the benefit of Indian Patent Application Nos. 2087/MUM/2006, filed December 20, 2006, and 1304/MUM/2007, filed July 6, 2007, and U.S. Provisional Patent Application Nos. 60/896,579, filed March 23, 2007, and 60/950,642, filed July 19, 2007, all of which are hereby incorporated by reference.

Field of the Invention

The present invention relates to a process for the synthesis of N9-(3,5-dichloro-4- pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide and salts thereof which are useful as PDE4 inhibitors. The invention also relates to a process for the synthesis of methyl-2-formyl-7-cyclopentyloxybenzo[b]furan-4-carboxylate and salts thereof, which are useful as intermediates in preparing compounds with PDE4 inhibitory activity.

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 extra cellular 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. ScL, 19, 160-164, (1998); Barnes, P.J., Trends Pharmacol. ScL, \9, 415-423, (1998)].

PCT Publication No. WO 2006/064355 discloses compounds of Formula I,

Formula I as PDE4 inhibitors including, for example N9-(3,5-dichloro-4-pyridyl)-6- difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide sodium as a selective PDE4 inhibitor. WO 2006/064355 discloses processes for preparing compounds of Formula I.

The inventors have found that the processes described in these references are not suitable from a commercial point of view because these processes involve protection and deprotection steps which substantially reduce the yield and are also difficult to scale-up.

The present invention provides an alternative process, which is economical, convenient, efficient and easily scalable. Furthermore, the yields and purity of the intermediates and final products are high.

Summary of the Invention

The present invention provides an improved process for preparing N9-(3,5- dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide sodium which is useful as a PDE4 inhibitor.

One embodiment of the present invention is a process for preparing N9-(3,5- dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide sodium of formula 1

composing: [ 1 ] a) i) alkylating the hydroxy group of a compound of formula 2

2

(wherein P is a hydroxyl protecting group, such as optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyranyl, alkoxyalkyl or silyloxyalkyl), for example, with propargyl halide to form a compound of formula 3

3, ii) cyclizing the compound of formula 3 with one or more cyclizing agents, such as cesium fluoride, sodium fluoride or potassium fluoride, or mixtures thereof, to form a compound of Formula 4

4, and iii) formylating the compound of formula 4 with one or more suitable formylating agents, such as dichloromethyl methyl ether in the presence of tin (IV) chloride or aluminum trichloride, to form a compound of formula 4'

4', or b) i) alkylating the hydroxy group of a compound of formula 2'

T for example, with propargyl halide to form a compound of formula 3', and

ii) cyclizing the compound of formula 3' with one or more cyclizing agents, such as cesium fluoride or potassium fluoride or mixtures thereof, to form a compound of formula 4';

[2] (a) i) deprotecting the compound of formula 4', for example, with one or more deprotecting agents such as p-thiocresol/sodium hydroxide (e.g., in toluene or HBr in acetic acid), to form a compound of formula 6

6, ii) difluoromethylating the compound of formula 6 with one or more difluoromethylating agents, such as mafron gas, sodium chlorodifluoroacetate, methyl chlorodifluoroacetate or ethyl chlorodifluoroacetate, to form a compound of formula 7

7, iii) esterifying the compound of formula 7 with one or more suitable agents, such as iodine/KOH/methanol, to form a compound of formula 8 (wherein R' is alkyl)

8, and iv) oxidizing the compound of formula 8 with one or more suitable agents (such as selenium dioxide, chromium compounds (e.g., such as chromic and dichromic acids, chromium trioxide, pyridinium chlorochromate (PCC), and chromate/dichromate compounds), DDQ, sodium meta per iodate, hypochlorite and other hypohalite compounds) to form a compound of formula 9 (wherein P is CHF₂)

9, or

(b) i) oxidizing and esterifying the compound of formula 4' with one or more esterifying agents to form a compound of formula 5 (wherein R' is alkyl)

5, and ii) oxidizing the compound of formula 5 with one or more oxidizing agents to form a compound of formula 9

[3] a) i) reacting the compound of formula 9 with malonic acid to form a compound of formula 10

10, ii) reacting the compound of formula 10 with an azide (e.g., sodium azide) to form a compound of formula 1 1

11, iii) cyclizing the compound of formula 1 1 to form a compound of formula 12

iv) halogenating the compound of formula 12, for example, by reaction with phosphorous oxychloride, to form a compound of formula 13 (wherein X is halogen, e.g., chlorine)

13, and v) dehalogenating the compound of formula 13 to form a compound of formula 14

14, or

(b) i) reacting the compound of formula 9 with malonic acid to form a compound of formula 10, ii) converting the compound of formula 10 to form a compound of formula 10' by reacting with ethylchloroformate

iii) reacting the compound of formula 10' with an azide (e.g., sodium azide) to form a compound of formula 11',

1 1 ' iv) cyclizing the compound of formula 11 ' to form a compound of formula 12',

12' v) deprotecting and halogenating the compound of formula 12' (wherein P is not CHF₂), for example, by reaction with phosphorousoxychloride, to form a compound of formula 13' (wherein X is halogen), and

13' vi) haloalkylating and dehalogenating the compound of formula 13' to form a compound of formula 14

14

[4] hydrolyzing the compound of formula 14 to form a compound of formula

15

15;

[5] reacting the compound of formula 15 with 4-nitrophenol, preferably in the presence of one or more coupling agents, to form a compound of formula 16

16; [6] reacting the compound of formula 16 with 4-amino-3,5-dichloropyridine- N-oxide to form a compound of formula 17

17; and

[7] converting the compound of formula 17 to the compound of formula 1, for example by reacting the compound of formula 17 with sodium hydride.

Another embodiment is a process for preparing a compound of formula (I) by performing one or more of the steps in the process described above and converting the product to the compound of formula (I).

Another embodiment of the present invention is a process for preparing methyl-2- formyl-7-cyclopentyloxybenzo[b]furan-4-carboxylate of formula 9'a (wherein P is cyclopentyl),

comprising the steps of: a) alkylating the hydroxy group of formula 2'a,

2 a for example by reaction with propargyl halide, to form a compound of formula 3 'a,

b) cyclizing the compound of formula 3 'a with one or more cyclizing agents to form a compound of formula 4'a,

4'a; c) oxidizing and esterifying the compound of formula 4'a with one or more esterifying agents to form a compound of formula 5'a, and

5'a d) oxidizing the compound of formula 5'a with one or more oxidizing agents to form the compound of formula 9'a.

The compound of formula 9'a can be converted to 3,5-dichloro-4-(6- difluoromethoxybenzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-l-pyridiniumolate, a compound of formula 1 or a pharmaceutically acceptable salt thereof.

Yet another embodiment of the invention is a pharmaceutical composition comprising: a) a compound of the formula 17a

17a, or an N-oxide or pharmaceutically acceptable salt thereof, and b) a compound selected from

2' 3' wherein P is a hydroxyl protecting group, such as optionally substituted benzyl, alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyranyl, alkoxyalkyl or silyloxyalkyl. Preferably, the compound in component (b) is present in an amount up to 1% (and more preferably up to 0.1%), 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).

Another embodiment of the present invention is a process for preparing N9-(3,5- dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide sodium of formula 1

1 comprising the steps of: a) alkylating the hydroxy group of formula 2a,

2a for example, by reacting with propargyl halide, to form a compound of formula 3 a

3a, b) cyclizing the compound of formula 3 a with one or more cyclizing agents to form a compound of formula 4a

c) formylating the compound of formula 4a with one or more formylating agents to form a compound of formula 4' a

4 a, d) demethylating the compound of formula 4'a to form a compound of formula 6

6, e) haloalkylating the compound of formula 6 to form a compound of formula

7, f) esterifying the compound of formula 7 to form a compound of formula 8a

8a, g) oxidizing the methyl group of the compound of formula 8a to form a compound of formula 9a

9a, h) reacting the compound of formula 9a with malonic acid to form a compound of formula 10a

10a, i) reacting the compound of formula 10a with an azide (e.g., sodium azide) to form a compound of formula 11a

11a, j) cyclizing the compound of formula 11 a to form a compound of formula 12a

12a, k) chlorinating the compound of formula 12a, for example, by reaction with phosphorous oxychloride, to form a compound of formula 13a

13a,

1) dechlorinating the compound of formula 13a to form a compound of formula 14a

14a, m) hydrolyzing the compound of formula 14a to form a compound of formula 15, preferably in the presence of a base

15, n) reacting the compound of formula 15 with 4-nitrophenol to form a compound of formula 16

16, and o) reacting the compound of formula 16 with 4-amino-3,5-dichloropyridine- N-oxide to form a compound of formula 17,

17, which is optionally converted to a pharmaceutically acceptable salt, such as the compound of formula 1.

Processes described herein can include one or more of the following embodiments. According to one embodiment P is cycloalkyl, such as cyclopentyl. According to another embodiment, P is CHF₂. According to yet another embodiment, X is chlorine.

Suitable alkylating agents include, but are not limited to, propargyl halide, such as propargyl bromide or propargyl chloride. The alkylating agents may be used in the presence of one or more bases and one or more solvents. For example, the one or more bases may be selected from organic bases (e.g., N,N-dimethyl aniline, diisopropylamine, pyridine, and triethylamine), alkali metal hydroxides (e.g., sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g., potassium carbonate or sodium carbonate) or a mixture thereof. The one or more solvents may be selected from ethers (e.g., diethyl ether, tetrahydrofuran or dioxane), aliphatic hydrocarbons (e.g., hexane or heptane), aromatic hydrocarbons (e.g., toluene or xylene), halogenated solvents (e.g., dichloromethane, dibromomethane, chloroform, or carbon tetrachloride), aprotic polar solvents (e.g., dimethylformamide or dimethylsulfoxide), protic polar solvents (e.g., methanol, ethanol, isopropanol, butanol or isobutanol) or a mixture thereof.

The one or more cyclizing agents may be selected from cesium fluoride, potassium fluoride, sodium fluoride and mixtures thereof. Cyclization may be carried out in the presence of one or more bases, for example, tri-n-butylamine, di-n-butylamine, n- butylamine, piperidine, pyridine or mixtures thereof, or in a base used in a Claisen rearrangement, such as N,N-dimethyl aniline. The cyclization may also be carried out in one or more high boiling solvents, for example dimethylformamide, dimethylsulfoxide or a mixture thereof.

Suitable formylating agents include, but are not limited to, dimethylalkyl ether (e.g., dichloromethyl methyl ether) in the presence of tin (II) chloride, tin (IV) chloride, aluminum trichloride, selenium dioxide, chromium compounds (such as chromic and dichromic acids, chromium trioxide, pyridinium chlorochromate (PCC), chromate/dichromate compounds), DDQ, sodium meta per iodate, hypochlorite and other hypohalite compounds. Formylation may be carried out in one or more solvents, such as dichloromethane, ethyl methyl ether, diethylether, tetrahydrofuran or mixtures thereof.

The one or more esterifying agents may be iodine, potassium iodide, sodium iodide, in the presence of a base such as potassium hydroxide, sodium hydroxide, in one or more solvent selected from methanol, ethanol, isopropanol or mixture thereof, such as iodine/potassium hydroxide/methanol .

The one or more oxidizing agents may be selected from selenium dioxide, dichlorodicyanoquinone, sodium hypochlorite/tetrabutylammoniumsulphate, ozone/silicon dioxide, pyridiniumchlorochromate/ acetonitrile, eerie ammonium nitrate, pyridiniumchlorochromate/ acetic acid and mixtures thereof.

The compounds of formulas 9 and 9a may be reacted with malonic acid in the presence of one or more bases, such as piperidine, pyridine, triethylamine, n-butylamine, t-butylamine or mixtures thereof and in one or more solvents, for example, toluene, xylene, diisopropylether, diethylether, or mixtures thereof.

The compounds of formulas 10, 10', and 10a may be reacted with an azide (such as sodium azide) in the presence of one or more bases, such as piperidine, pyridine, triethylamine, n-butyl amine, t-butylamine or mixtures thereof and in one or more solvents, for example, acetone, ethylmethyl ketone, acetonitrile, ethanol, methanol, dimethylformamide, dimethylsufoxide water, or mixtures thereof.

Dehalogenation may be carried out in under reductive conditions using hydrogen /Pd/carbon in the presence of one or more bases, such as aqueous ammonia, triethylamine, alkali or alkaline earth metal carbonate. Hydrolysis may also be carried out in the presence of one or more bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, or cesium carbonate in water.

Suitable coupling agents include, for example, N,N'-dicyclohexylcarbodimide, N,N'-diisopropylcarbodiimide, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide and mixtures thereof. The coupling agents may be used in the presence of one or more bases, such as dimethylaminopyridine, pyridine, piperidine, n-butylamine, sodium hydride or mixtures thereof and in one or more solvents, such as tetrahydrofuran, dimethyformamide, dimethylsulfoxide, acetonitrile, or mixtures thereof.

The compound of formula 16 may be reacted with 4-amino-3,5-dichloropyridine- N-oxide in the presence of one or more bases, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide or mixtures thereof, and in one or more solvents, such as tetrahydrofuran, dimethyformamide, dimethylsulfoxide, acetonitrile, or mixtures thereof.

The compound of formula 17 may be reacted with sodium hydride in the presence of one or more solvents, such as tetrahydrofuran, dimethyformamide, acetonitrile dimethylsulfoxide, diethylether or mixtures thereof.

The present invention also provides a process for preparing compounds of Formula I,

Formula I and N-oxide or pharmaceutical acceptable salts thereof; wherein; each occurrence of R¹, R² and R³ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, 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, -NR⁵R⁶, -C(=L)-R⁵, - C(O)-R⁵, -C(O)O-R⁵, -C(O)NR⁵R⁶, -S(O)_m-R⁵, -S(O)_1n-NR⁵R⁶, nitro, -OH, cyano, oxo, formyl, acetyl, halogen, -OR⁵, -SR⁵, or a protecting group, or when two R² or two R³ substitutents are ortho to each other, they may be joined to a form a 3-7 member optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR⁵ or S; each occurrence of R⁵ and R⁶ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, 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, halo, -OH, cyano, - C(O)-R³, -C(O)O-R³, -C(O)NR^aR^b, -S(O)_m-R^a, -S(0)_m-NR^aR^b, -C(=NR^a)-R^b, -C(=NR³)- NR^aR^b, -C(=S)-NR³R^b, -C(=S)-R\ -N=C(R^aR^b), -NR^aR^b, -0R^a, -SR³, or a protecting group, or R⁵ and R may be joined together to form a 3-7 member optionally substituted saturated or unsaturated cyclic ring, which may optionally include up to two heteroatoms selected from O, NR³ or S; each occurrence of R^a and R^b is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, 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, a protecting group, -C(0)-R^c, -C(0)0-R^c, -C(O)NR^cR^d, -S(O)_m-R^c, - S(0)_m-NR^cR^d, -NR^cR^d, -OR^C, or -SR^c; each occurrence of R^c and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, 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, or a protecting group;

Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring, substituted and unsubstituted heteroaryl ring or substituted or unsubstituted heteroarylalkyl;

L represents O, S or NR^a; n represents 0 - 2; p represents 0 - 8;

T, U, V and W are each independently selected from the group consisting of C, - C=O, N, NR^a, O and S; with the proviso that at least one of T, U, V and W is N, NR^a, O or S; dotted lines [ — ] in the ring represent an optional double bond; X is O, S(O)_mor NR^a; m is O, 1 or 2;

Y is selected from the group consisting of -C(O)NR⁴-, -NR⁴SO₂-, -SO₂NR⁴- and - NR⁴C(O)-; and

R⁴ is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR^a, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heteroaryl ring and substituted or unsubstituted heteroarylalkyl.

The process includes the reaction sequences depicted in Scheme I below using the substituted compound of formula 2 as the starting compound.

Particular embodiments of the present invention are set forth in the following detailed description. However, it should be understood that the description is given by way of illustration only and various changes and modifications are included within the scope of the invention, as will be apparent to those skilled in the art. 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 "C_1-6 alkyl" refers to an alkyl chain having 1 to 6 carbon atoms.

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, and 2-butenyl.

The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred), e.g., ethynyl, propynyl, and butynyl. The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentyl ethyl. The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

The term "aryl" refers to an aromatic radical having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆Hs and -C₂HsC₆H₅.

The term "heterocyclic ring" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from 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., heterocyclic or heteroaryl). 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, and isochromanyl. The heterocyclic 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 heterocyclyl 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 "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. 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 "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group 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, -COOR^X, -C(O)R", - C(S)R", -C(O)NR"R^y, -C(O)ONR^xR^y, -NR"CONR^yR^z, -N(R")SOR^y, -N(R")SO₂R^y, -(=N- N(R")R^y), -NR"C(O)OR^y, -NR"R^y, -NR"C(O)R^y-, -NR"C(S)R^y -NR^xC(S)NR^yR^z, - SONR"R^y-, -SO₂NR"R^y-, -OR", -OR"C(O)NR^yR^z, -OR"C(O)OR^y-, -OC(O)R", - OC(O)NR"R^y, -R"NR^yR^z, -R"R^yR^z, -R"CF₃, -R"NR^yC(0)R^z, -R"0R^y, -R"C(O)OR^y, - R"C(0)NR^yR^z, -R"C(O)R", -R"OC(O)R^y, -SR", -SOR", -SO₂R", -ONO₂, wherein R", R^y and R^z is 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 substiruents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".

According to one embodiment of the present invention, there is provided a process for preparing N9-(3,5-dichloro-4-pyridyl)-6-difluoromethoxybenzo[4,5]furo[3,2- c]pyridine-9-carboxamide sodium of Formula I, which comprises the reaction sequences as depicted in Scheme I.

In scheme I, a compound of formula 2 is alkylated to form a compound of formula 3. The compound of formula 3 is cyclized to form a compound of formula 4, which on formylation gives a compound of formula 4'. Alternatively, a compound of formula 2' can be alkylated to form a compound of formula 3'. The compound of formula 3' is cyclized to form the compound of formula 4'.

The compound of formula 4' is deprotected to form a compound of formula 6, which is haloalkylated to a form compound of formula 7. The compound of formula 7 is esterified to form a compound of formula 8 which is further oxidized to form a compound of formula 9. Alternatively, the compound of formula 4' is esterified to form a compound of formula 5, which is further oxidized to form the compound of formula 9.

The compound of formula 9 is treated with malonic acid to form a compound of formula 10 which is further treated with an azide (e.g., sodium azide) to form a compound of formula 11. The compound of formula 11 is cyclized to form a compound of formula 12, which is halogenated to form a compound of formula 13. The compound of formula 13 is dehalogenated to form a compound of formula 14.

Alternatively, the compound of formula 10 is converted to a compound of formula 10', for example by reaction with ethylchloro formate. The compound of formula 10' is treated with an azide (e.g., sodium azide) to form a compound of formula 11'. The compound of formula 11 ' is cyclized to form a compound of formula 12'. The compound of formula 12' is halogenated to form a compound of formula 13', which is dehalogenated to form the compound of formula 14.

The ester of formula 14 is hydrolyzed to form an acid of formula 15. The acid of formula 15 is converted to the compound of formula I as described in WO 2006/064355.

In yet another aspect of the present invention there is provided a process for preparing a compound of formula 9'a, which comprises the reaction sequences depicted in Scheme II.

Scheme II

A compound of Formula 2'a is alkylated to form a compound of formula 3 'a. The compound of formula 3'a is cyclized to form a compound of formula 4'a, which is esterifϊed to form a compound of formula 5'a. The compound of formula 5'a is formylated to form the compound of formula 9'a.

The compound of formula 9'a can be converted to 3,5-dichloro-4-(6- difluoromethoxybenzo[4,5] furo[3,2-c]pyridin-9-ylcarboxamido)-l -pyridiniumolate, a compound of formula I or a pharmaceutically acceptable salt thereof.

In yet another aspect of the present invention there is provided a process for preparing compounds of formula 1 , which comprises the reaction sequences depicted in Scheme III.

Scheme III

The hydroxy group of formula 2a is alkylated to form a compound of formula 3a, which is cyclized to form a compound of formula 4a. The compound of formula 4a is formylated to form a compound of formula 4'a, which upon demthylation forms a compound of formula 6.

Haloalkylation of the compound of formula 6 yields a compound of formula 7, which is esterifϊed to form a compound of formula 8a. The methyl group of the compound of formula 8a is oxidized to form a compound of formula 9a. The compound of formula 9a is treated with malonic acid to form a compound of formula 10a. The compound of formula 10a is treated with an azide (e.g., sodium azide) to form a compound of formula 11a, which is cyclized to yield a compound of formula 12a.

The compound of formula 12a is chlorinated to form a compound of formula 13a, which is dechlorinated to form a compound of formula 14a. Hydrolysis of the compound of formula 14a forms a compound of formula 15, which is reacted with 4-nitrophenol to yield a compound of formula 16, which in turn is reacted with 4-amino-3,5- dichloropyridine-N-oxide to form a compound of formula 17. The compound of formula 17 is converted to a pharmaceutically acceptable salt of formula 1.

In the schemes above, where specific bases, reagents, solvents, difluoromethylating agents, deprotecting agents, oxidizing agents, esterifying agents etc., are mentioned, it is understood that other bases, acids, reagents, solvents, difluoromethylating agents, deprotecting agents, oxidizing agents, esterifying agents etc., known to in the art may also be used and are therefore envisioned within the scope of this 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.

In yet another aspect there is provided a compound of formula 18

18 and pharmaceutically acceptable salts thereof, wherein R^ai is selected from CHO and COOR' (wherein R' can be alkyl) and R^a ₂ is selected from methyl, CHO, CH=CH-COOH and CH=CHN₃. In yet another aspect there is provided a compound of formula 12a

12a and pharmaceutically acceptable salts thereof.

The appended Examples further illustrate preparation of the compounds of the formula I.

Examples Example 1 : Preparation of 4-(cyclopentyloxy)-3-(prop-2-yn-l-yloxy)benzaldehyde

To a well stirred solution of 4-cyclopentyloxy-3 -hydroxy benzaldehyde (80.Og, 0.388 mol) and propargyl bromide (63 g, 0.427 mol) in dimethyformamide (80OmL) was added anhydrous potassium carbonate (107 g, 0.776 mol) and the mixture was stirred at about 40-70 ⁰C for about 10-15 hours. The mixture was then filtered to remove inorganic material. Filtrate was concentrated under vacuum and diluted with water (1.5 L). It was then extracted with ethyl acetate (3x500 mL). The combined organic layers were washed with water (2x250 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuum give about 85-95% of 4-(cyclopentyloxy)-3-(prop-2-yn-l-yloxy) benzaldehyde as brown oil.

IR (Neat): 3430, 2984, 1681, 1598, 1499, 1421, 1282, 1192, 1082, 963, 764 Cm^'1.

¹H NMR (300 MHz, d₆-DMSO): δ 1.59-1.99 (m, 8H), 3.60 (s, IH), 4.88 (d, IH, J = 2.52

Hz), 4.95 (m IH), 7.29 (d, IH, J= 8.1 Hz), 7.49 (s, IH), 7.58 (d, IH, J= 8.1 Hz), 9.83 (s,

IH).

Example 2: Preparation of 7-(cvclopentyloxy)-2-methyl-l-benzofuran-4-carbaldehvde To a well stirred solution of intermediate- 1 (85.0 g, 0.348 mol) in N,N-diethyl aniline

(850 mL) was added cesium fluoride (74 g, 0.487 mol) and the mixture was heated to about 215-220 ⁰C for about 4-5 hours. 600 mL of N,N-diethyl aniline was distilled off under reduced pressure. Reaction mixture was cooled to room temperature and 20% aqueous hydrochloric acid solution (1.0 L) was added followed by addition of ethyl acetate (1.5 L). The mixture was the filtered through celite bed. The organic layer was separated and washed with water (2x500 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuum give crude product (85.0g) as dark brown oil. It was then purified through silica gel column using petroleum ether: ethyl acetate (8:2) as an eluent to afford about 85-95% 7-(cyclopentyloxy)-2-methyl-l-benzofuran-4-carbaldehyde as pale yellow solid.

IR (Neat): 3433, 2943, 1678, 1594, 1505, 1413, 1277, 1190, 1087, 960, 762 cm^"1.

¹H NMR (300 MHz, d₆-DMSO): δ 1.63-2.07 (m, 8H), 2.45 (s, 3H), 5.15 (m, IH), 7.04

(d, IH, J=8.4Hz), 7.11 (s, IH), 7.76 (d, IH, J= 8.1Hz), 9.98 (s, IH).

Example 3 : Methyl-7-cvclopentyloxy-2-methylbenzo[blfuran-4-carboxylate

To a well stirred solution of 7-Cyclopentyloxy-2-methylbenzo[b]furan-4-carboxaldehyde (30.0g, 0.122 moles) in methanol (150 mL) at room temp and cooled to about 0-5⁰C was added freshly-prepared solution of iodine (62.4g, 0.245 moles) in methanol (450 mL) and potassium hydroxide (27.6g, 0.492 moles) in methanol (85 mL) over a period of 30 min at about 0-10⁰C. The reaction mixture was maintained at the same temperature for 1 hr and rise the temperature slowly up to 15-20° C and maintained for 2 hrs. After ascertaining the completion of the reaction, the pH of the reaction mixture was adjusted to about 5-6 with dilute hydrochloric acid. Reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in water (250mL)and extracted with ethyl acetate(2x 10OmL) .The combined organic layer was washed with sodium metabisulphite solution (2x 100mL),10%sodium hydroxide solution (1x100 mL),water (IxIOOmL) and saturated sodium chloride solution(lxlθθml) and dried organic layer over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure at temperature about 40-45⁰C to get 57.0 g of brown color oil product, It was then purified to silica gel column using 2% ethyl acetate in n-hexane as an eluent to afford about 57-67% yield the Methyl-7- cyclopentyloxy-2-methylbenzo[b]furan-4-carboxylate as pale yellow oil having purity 99%.

IR (KBr): 3434, 1715, 1632, 1409, 1445, 1267, 1102, 1001, 938,770 cm^"1 1HNMR (300 MHz, dό-DMSO): δ 1.6-2.1 (m,8H), 2.43(s, 3H), 5.14(m,lH),7.32 (d,lH,J=9.0 Hz),8.03(d,lH,J=8.4 Hz),8.24(s,lH).

Example 4: Methyl-2-formyl-7-cvclopentyloxy-2-methylbenzo[^"b1furan-4-carboxylate

To a well stirred solution of selenium dioxide (25.5g.0.120 mole) in 1,4-dioxane (100 mL ) and water (10 mL) at room temperature. The reaction mixture was brought to about 60- 65⁰C and was added a solution of Methyl-7-cyclopentyloxy-2-methylbenzo[b]furan-4- carboxylate (2Og, 0.072 moles). After addition, the reaction mixture was brought to about 90-95⁰C and maintained the same temperature for 48 hrs. After completion of the reaction, the reaction mixture was cool to room temperature. The mixture was filtered to remove the inorganic material. The filtrate was concentrate under reduced pressure. The residue obtained was dissolved in water (150 mL) and extracted with ethyl acetate (3x100 mL).The combined organic layer was washed with water (200 mL) and dried over anhydrous sodium sulfate .The solvent was evaporated under reduced pressure at 40-45 ⁰CtO give about 88-98% yield of Methyl-2-formyl-7-cyclopentyloxy-2- methylbenzo[b]furan-4-carboxylate as pale yellow solid.

Example 5: Preparation of l-Methoxy-2-(2-propenyloxy)benzene

To a well stirred solution of guaiacol (200.Og, 1.61 moles) and anhydrous potassium carbonate (334.Og, 2.42 moles) in dimethylformamide (800 ml) was added propargyl bromide (80%w/w solution in toluene) (230.0g, 1.932 moles) at 25-60⁰C slowly for 1-2 hrs and the mixture was stirred at room temperature for 5-6 hrs. The mixture was then filtered to remove the inorganic material. Filtrate was diluted with water (3.0L) and extracted with dichloromethane (3X1000 ml).The combined organic layers were washed with water (3x1000 ml) followed by saturated sodium chloride solution (500 ml) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave the product (263.Og) as brown oil.

IR (KBr): 2949,1728,1619,1589, 1426, 1291,1107, 1001, 957, 825, 758 cm ¹ H NMR (300 MHz, dό-DMSO): 2.49(s,lH), 3.86(s,3H),4.76(s,2H),6.95 (m,4H).

Example 6: Preparation of 7-Methoxy-2-methylbenzo[b1furan

To a well stirred solution of 1 -Methoxy-2-(2-propenyloxy) benzene (260.Og, 1.604 moles) in N,N-diethyl aniline (1300 ml) was added cesium fluoride ( 301.6g, 1.984 moles) and the mixture was heated to 220-215⁰C for 6-7 hrs. Reaction mixture was cooled to room temperature and filtered to celite bed. Collect the filtrate and remove the N,N-di ethyl aniline under vacuo at 150-180⁰C to get residue. The residue was diluted with water (2.0 L) and acidified to pH ~2 and extracted with dichloromethane (3X1000 ml). The combined organic layers were washed with water (3x1000 ml) followed by saturated sodium chloride solution (2X500 ml) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave the product (150.Og) as dark brown oil.

IR (KBr): 2952,1725,1627,1599,1421,1285,1118,1005,951,818,748 cm^"1

H NMR (300 MHz, dό-DMSO): 2.47(s,3H), 4.00(s, 3H), 6.36(s,lH),7.06 (m,3H).

Example 7: 7-Methoxy-2-rnethylbenzorblfuran-4-carboxaldehyde To a well stirred solution of 7-Methoxy-2-methylbenzo[b]furan (144.Og, 0.886 moles) in dichloromethane (1440 ml) was added stannous chloride (300.6 g, 1.154 moles) followed by slow addition of 1,1-dichloromethyl methyl ether (112.2g, 0.976 moles) at -10 - O⁰C and stirred for 1-2 hrs. Ice cold water (2.0L) was added with vigorous stirring, the organic layer was separated and washed with water (3x700 ml) followed by saturated sodium bicarbonate solution (700 ml) and saturated sodium chloride solution (700 ml) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave the product (143.Og) as dark brown oil.

IR (KBr): 3017,1741,1677,1595,1512,1399,1242,1175,1098,937,755 cm^"1

H NMR (300 MHz, dδ-DMSO): d 2.50(s,3H), 4.03(s, 3H), 7.09(d,lH,J=8.1 Uz)JM (s,lH), 7.81(d,lH,J=8.4 Hz),10.00(s,lH).

Example 8: 7-Hvdroxy-2-methylbenzo[b]furan-4-carboxaldehyde

To a freshly prepared solution of sodium-4-methyl benzene thiolate (prepared from 117.6g, 0.946 moles of 4-methyl benzene thiol and 39.2g, 0.98 moles of sodium hydroxide) in toluene (560 ml) was added 7-Methoxy-2-methylbenzo[b]furan-4- carboxaldehyde (140.Og, 1.128 moles) in toluene (840 ml) at reflux. Then hexamethyl phosphoramide (HMPA) (173.6g, 0.97 moles) was added slowly and reaction mixture was stirred at same temperature for 12 hrs. Reaction mixture was then bring to 50-60⁰C, water (1120 ml) was added and layers were separated. The aqueous layer was acidified to pH 4-5.The solid was filtered and washed with water. The crude solid (71.0gms) was purified in toluene to get pure compound (58.0gms) having HPLC Purity 99.2%.

H NMR (300 MHz, dό-DMSO): d 2.50(s,3H), 7.1 l(d,lH,J=9.0 Hz),7.13 (s,lH), 7.69(d,lH, J=9.0 Hz),9.99(bs,lH).

Example 9: 7-(difluoromethoxy)-2-methylbenzo[blfuran-4-carbaldehyde To a well stirred suspension of 7-Hydroxy-2-methylbenzo[b]furan-4-carboxaldehyde (56.0g, 0.3181 moles) and anhydrous potassium carbonate (85.9 g, 0.6222 moles) in dimethylformamide (785 ml) was purged mafron gas for 2-3 hrs at 70-80⁰C. Reaction mixture was filtered through celite bed. The filtrate obtained was concentrated under high vacuum. The residue diluted with water (560 ml) and extracted with ethyl acetate (2^χ 300 ml). The combined organic layer was washed with water (2^χ 200 ml) and saturated sodium chloride solution (200 ml). Remove the solvent under vacuum to give a 41. g brown color residue. Example 10: Methyl-7-(difluoromethoxy)-2-methylbenzo[blfuran-4-carboxylate To a well stirred solution of 7-(difluoromethoxy)-2-methylbenzo[b]furan-4-carbaldehyde (40.Og, 0.1769 moles) in methanol (400 ml) at room temp and cooled 0-5⁰C was added freshly prepared solution of Iodine (89.6g, 0.3541 moles) in methanol (550 ml) and potassium hydroxide (39.6g, 0.7077 moles) in methanol (150 ml) over a period of 30 min at 0-10⁰C. The reaction mixture was maintained at the same temperature for 1 hr and rise the temperature slowly up to 15-20° C and maintained for 2 hrs. The progress of the reaction was monitored by TLC. After ascertaining the completion of the reaction, the pH of the reaction mixture was adjusted to 5-6 with dilute HCL Reaction mixture was concentrated under reduced pressure .The residue obtained was dissolved in water (lOOOml)and extracted with ethyl acetate(2x 500ml) .The combined organic layer was washed with sodium metabisulphite solution (2x 300ml), 10%Sodium hydroxide solution (1x300 ml),water (lx300ml) and saturated sodium chloride solution( 1x300ml) and dried organic layer over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure at temperature 40-45⁰C to get 45.5 g of brown color oil product.

IR (KBr) 3423,2965,1702,1596,1436,1284,1203,1121,1044,811,736 cm^"1.

IH NMR(CDCl₃ ) δ 7.888-7.916 (d, 1H),7.263 (s, 1H),6.634-7.124 (S,1H),7.O17-7.O35

(d, 1H),3.962 (s,3H), 2.533 (s,3H).

Example 11 : Methyl-7-(difluoromethoxy)-2-formyl-l-benzo[b1furan-4-carboxylate To a well stirred solution of SeO₂ (63.4g.0.1758 mole) in 1,4-Dioxane (450 ml ) and water (13.5 ml) at room temperature. The reaction mixture was brought to 60-65⁰C and was added a solution of Methyl-7-(difluoromethoxy)-2-methylbenzo[b]furan-4- carboxylate (45g, 0.1757 moles). After addition, the reaction mixture was brought to 90- 95⁰C and maintained the same temperature for 48 hrs. The progress of reaction monitor by TLC .After completion of the reaction cooled the reaction mixture to room temperature. The mixture was filtered to remove the inorganic material. The filtrate was concentrate under reduced pressure. The residue obtained was dissolved in water (1000 ml) and extracted with ethyl acetate (3x500 ml). The combined organic layer was washed with water (400 ml) and dried over anhydrous sodium sulfate .The solvent was evaporated under reduced pressure at 40-45 °c to gave 31.5g of pale yellow solid. Mass- 271.60 [M+H] +.

IR (KBr) 2855,1716,1680,1626,1593,1434,1290,1122,947,818 cm^"1

¹H NMR (DMSO) shows δ 9.981-9.985 (s, 1H),8.311-8.316 (s,lH),8.047-8.075 (d,lH),

7.355-7.838 (s,lH),7.540- 7.596(m,lH),3.963 (s, 3H). Example 12: (Z)-3-(7-difluoromethoxy)-4-methyloxycabonylbenzo[b]furan-2-yl-2- propenoic acid

To well stirred solution of malonic acid (22.1g, 0.2124 moles) and piperidine (5 ml) in toluene (120 ml) was heat to reflux and added Methyl-7-(difluoromethoxy)-2formyl-l- benzo[b]furan-4-carboxylate (30.0g, 0.111 moles) in toluene (240 ml) at reflux temperature. The mixture was then refluxed for 24 hrs. Reaction mixture was cooled to room temperature, acidified with 10% aqueous hydrochloride solution and extracted with ethyl acetate (2x500ml). The combined organic layers were washed with water (2x200 ml) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (32g) which was purified in diisopropyl ether to gave pure product (24g). Mass-311.15[M-I] -

IR(KBr) 3650,2962,1724,1693,1553,1424,1309,12051060,829,729.

IH NMR(DMSO) shows δ 12.7 (s,lH),7.94-7.96(d,lH),7.68-7.85(s,lH),7.79 (s,lH),

7.61 -7.63(d, lH),7.36-7.39(m, 1 H),6.54-6.59(d, 1 H),3.927(s,3H).

Example 13 : Methyl-2-r(Z)-2-azidocarbonyl)- 1 -ethenyll-7-difluoromethoxybenzo [b] furan-4-carboxylate

To suspension of (Z)-3-(7-difloromethoxy)-4-methyloxycabonylbenzo[b]furan-2-yl-2- propenoic acid (23.Og, 0.0737 moles) and triethylamine (18.55g, 0.1824 moles) in acetone (230 ml) was added a solution of ethyl chloroformate (15.95g, 0.1456 moles) in acetone (25 ml) at -10⁰C and stirred for 1-2 hrs. A solution of azide (14.35g, 0.2206 moles) in water (40 ml) was added at -5 - O⁰C and stirred for 1 -2 hrs. Ice cold water (500 ml) was added, the separated salt was filtered. The solid was dissolved in MDC (500 ml) and MDC layer was dried over anhydrous sodium sulfate. Removal of solvent under vacuum gave (22.5g) of product as pale yellow solid.

¹H NMR (DMSO) δ 7.954-7.982(d,lH),7.833-7.886(d, 1H),7.632 (s,lH),7.397- 7.426(d, 1H),6.610-6.663(d, 1 H),3.930(s,3H).

Example 14: Methyl-1 -hvdroxy-6-difluoromethoxybenzof4,5]furo[3,2-c1pyridine-9- carboxylate

To a well stirred refluxing solution of tri-n-butyl amine (10.4 ml) in diphenyl ether (330.0ml) was added a solution of Methyl-2-[(Z)-2-azidocarbonyl)-l-ethenyl]-7- methoxybenzo[b]furan-4-carboxylate (2Og, 0.0593 moles) in toluene (175 ml) and mean while remove toluene by distillation. The reaction mass was refluxed for 3 hrs. The diphenyl ether was removed under vacuum and the residue obtained was triturated with petroleum ether (300 ml) and filtered .The crude solid was purified in ethyl acetate to give (7.7 g) as brown yellowish solid.

Mass-310.18[M+1 ]+.IR(KBr)

3444,3103,2959,1731,1633,1579,1434,1390,1286,1208,1119,1064,792,767,733,545.The IH NMR (DMSO) shows δ l l.903(s,lH),8.115-8.139(d,lH),7.689-7.767(m,lH),7.362- 7.525 (m,lH),7.265(s,lH),,6.851-6.875(d,lH),3.859(s,3H).

Example 15: Methyl- l-chloro-6-difluoromethoxybenzo [4,51furo[3,2-clpyridine-9- carboxylate

A solution of Methyl- 1 -hydroxy-6-difluoromethoxybenzo [4,5]furo[3,2-c]pyridine-9- carboxylate (7.Og, 0.0226 moles) and phosphorous oxychloride (140 ml) was refiuxed for 4-5hrs. Phosphorous oxychloride was removed under vacuo. Strip out with toluene for two times. Then after water (250 ml) was added and neutralized with 10% sodium carbonate solution .The obtained solid was filtered and washed with water and dried to get 7.3g of product as yellow solid. Mass-310.18[M+1]+.

IR(KBr):3444,3103,2959,1731, 1633,1579,1434,1390,1286,1208,1119,1064,792,767,733, 545.The IH NMR (DMSO) shows δ 11.903(s,lH),8.115-8.139(d,lH),7.689- 7.767(m,lH),7.362-7.525 (m,lH),7.265(s,lH),,6.851-6.875(d,lH),3.859(s,3H).

Example 16: Methyl-6-difluoromethoxybenzo [4,51furo[3,2-c1pyridine-9-carboxylate

A mixture of Methyl- l-chloro-6-difluoromethyloxybenzo [4,5]furo[3,2-c]pyridine-9- carboxylate(7.0g, 0.0214 moles),ammonium hydroxide (1.75 ml) and 10%Pd/C (3.5g) in a mixture of methanol (100 ml) and dimethyl formamide (5.0 ml) was hydrogenated in a parr apparatus at 40-45 psi of hydrogen for 5-6 hrs. Catalyst was removed by filtration and the residue was diluted with water The solid product obtained was filtered and dried to get 5.8g as a white solid.

IR (KBr): 3433, 2075,1720,1634,1288,1219,11 15,1017,771 cm^"1

H NMR (300 MHz, de-DMSO):d 4.04(s, 3H),7.62 (t,lH,J=72.0 Hz),7.61 (d,lH,J=8.4

Hz),7.97 (d,lH,J=5.4Hz),8.13 (d,lH,J=8.4Hz),8.78(d,lH,J=5.4Hz),9.93(s,lH).

Example 17: 6-Difluoromethoxybenzo [4,51furo[3,2-clpyridine-9-carboxylic acid

A solution of Methyl-6-difluoromethyloxybenzo [4,5]furo[3,2-c]pyridine-9-carboxylate (5.5g, 0.0187 moles),sodium hydroxide (3.74g, 0.0935 moles) and water(8 ml) in methanol (55 ml) was refiuxed for 1-2 hrs. Methanol was removed under vacuum. The residue was diluted with water (100 ml) and acidified with acetic acid. The solid was filtered and washed with water (200 ml) and dried to get (4.7g) as a white solid.

IR (KBr): 3433, 2075, 1634, 1559, 1289, 1215, 1145, 1031,757 cm^"1

¹H NMR (300 MHz, dβ-DMSO):d 7.58 (t,lH,J=72.0 Hz),7.60 (d,lH,J=8.4 Hz),7.94

(d,1H,J=5.4Hz),8.11 (d,1H,J=8.4Hz),8.76(d,1H,J=5.4Hz),10.02(s,1H).

Example 18: 4-Nitrophenyl-6-difluoromethyloxybenzo [4,51ruro[3,2-c]pyridine-9- carboxylate

A mixture of 6-Difluoromethyloxybenzo [4,5]furo[3,2-c]pyridine-9-carboxylic acid (4.5g, 0.0161moles),p-nitro phenol (9g, 0.0647 moles), EDCI (4.61g, 0.0241 moles),dimethylaminopyridine (0.206g, 0.0016 moles) in THF (45 ml) and DMF (9 ml) was heated to 65-70⁰C for 2-3 hrs. Remove the solvent under vacuum to get residue and the residue was triturated with water (50 ml).The separated solid was filtered and washed with water (50 ml) to gave 4.Og as a yellow solid, m.p.: >250°C

IR (KBr): 3430,2082,1640,1534,1351,1276,1223,1109,1009,778 cm^"1

H NMR (300 MHz, d₆-DMSO):d 7.51 (d,lH,J=8.4 Hz),7.76 (d,2H,J=8.4 Hz),7.80

(t,lH,J=72.0 Hz),7.92 (d,lH,J=5.7Hz),8.41(m,3H),8.73 (d,lH,J=5.4 Hz),9.87(s,lH).

Example 19: 3,5-Dichloro-4-(6-difluoromethoxybenzo [4,51furo[^"3,2-c1pyridin-9- ylcarboxamido)- 1 -pyridiniumolate

To a well stirred suspension of 4-Nitrophenyl-6-difluoromethyloxybenzo [4,5]furo[3,2- c]pyridine-9-carboxylate (4.Og, 0.01 moles) ,4-amino-3,5-dichloro pyridine-N-Oxide (1.68g, 9.38 mmoles) in DMF(60 ml) was added sodium hydride (60%)(0.8g, 33.3 mmoles) at 0-5⁰C in 3 lots. The reaction mixture was then allowed to come to room temperature in 2.0 hrs. The reaction mixture was then diluted with water (200 ml) and acidified with acetic acid. The solid separated was filtered and washed with water (50 ml) and dried to get 3.4g as off-white solid. m.p.: >250°C

IR (KBr):3436,3233,3034,2923,2358,1660,1599,1555,1495,1289,l 129,1082,982,855,

810 cm^"1

H NMR (300 MHz, dό-DMSO):d 7.60 (t,lH,J=72 Hz),7.72 (d,lH,J=8.4 Hz),7.96

(d,lH,J=8.4 Hz),8.06 (d,lH,J=8.7Hz),,8.76 (d,lH,J=5.7

Hz),8.80(s,2H),9.63(s, 1 H), 10.97(s, 1 H).

Example 20: 3,5-Dichloro-4-(6-difluoromethyloxybenzo r4₁51furo[3,2-c1pyridin-9- ylcarboxamidoV 1 -pyridiniumolate sodium

To well stirred solution of 3, 5-Dichloro-4-(6-difluoromethyloxybenzo [4,5]furo[3,2- c]pyridin-9-ylcarboxamido)-l-pyridiniumolate (3.Og, 6.81 mmoles) in THF (150 ml) was added 60% sodium hydride (0.3g, 7.5 mmoles) at 5-10⁰C under nitrogen atmosphere. The reaction mixture was then stirred for 2.0 hrs at room temperature to get clear solution. The yellow solid obtained after solvent removal was triturated with diethyl ether and filtered to get 3.0g as off white solid. m.p.: >250°C

IR(KBr):3101,2928,1633,1581,1551,1533,1446,1388,1284,1203,1117,1092,1043,994,

855,810 cm^"1

H NMR (300 MHz, dό-DMSO):d 7.42 (d,lH,J=8.4 Hz),7.46 (d,lH,J=72 Hz),7.82

(d,lH,J=8.4 Hz),8.14 (d,lH,J=8.7Hz),,8.25(s,2H),8.64 (d,lH,J=5.7 Hz),10.30(s,lH).

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

We Claim:

1. A process for preparing methyl-2-formyl-7-cyclopentyloxybenzo[b]furan-4- carboxylate of formula 9'a,

Formula 9'a comprising the steps of: a) alkylating the hydroxy group of formula 2'a

2'a to form a compound of formula 3'a,

3'a b) cyclizing the compound of formula 3'a with one or more cyclizing agents to form a compound of formula 4'a,

4'a c) oxidizing and esterifying the compound of formula 4'a with one or more esterifying agents to form a compound of formula 5'a

5'a oxidizing the compound of formula 5'a with one or more oxidizing agents to form a compound of formula 9'a.

2. The process according to claim 1, wherein one or more steps is carried out in the presence of a base selected from N,N-dimethyl aniline, diisopropylamine, pyridine, triethylamine, sodium hydroxide potassium hydroxide, potassium carbonate, sodium carbonate and mixtures thereof.

3. The process according to claim 1, wherein one or more steps is carried out in the presence of a solvent selected from diethyl ether, tetrahydrofuran, dioxane, hexane, heptane, toluene, xylene, dichloromethane, dibromomethane, chloroform, carbontetrachloride, dimethylformamide or dimethylsulfoxide, N,N-dimethyl aniline and mixtures thereof.

4. The process according to claim 1 , wherein the cyclizing agent is selected from cesium fluoride, potassium fluoride, sodium fluoride and mixtures thereof.

5. The process according to claim 1, wherein one or more alkylating agents are selected from propagyl bromide and propargyl chloride.

6. The process according to claim 1, wherein the one or more esterifying agents are selected from iodine, potassium iodide, sodium iodide, in the presence of a base seleted from potassium hydroxide and sodium hydroxide, in a solvent selected from methanol, ethanol, isopropanol or mixture thereof.

7. The process according to claim 1, wherein step c) is carried out in the presence of a base selected from potassium hydroxide, sodium hydroxide and mixtures thereof.

8. The process according to claim 1, wherein step c) is carried out in the presence of a solvent selected from methanol, ethanol, isopropanol and mixtures thereof.

9. The process according to claim 1, wherein the esterifying agent is iodine in the presence of potassium hydroxide and methanol.

10. The process according to claim 1, wherein the one or more oxidizing agents are selected from selenium dioxide, dichlorodicyanoquinone, sodium hypochlorite in the presence of tetrabutylammoniumsulphate, ozone in the presence of silicon dioxide, pyridiniumchlorochromate in the presence of acetonitrile, pyridiniumchlorochromate in the presence of aceticacid, eerie ammonium nitrate, laccase diammonium salt of 2,2,azinobis-(3-ethylbenzothiazoline-6-sulfonicacid) and mixtures thereof.

11. The process according to claim 1 , wherein the one or more oxidizing agents is selenium dioxide.

12. A process for preparing a compound of formula 1,

1 comprising the steps of: a) alkylating the hydroxy group of formula 2a

to form a compound of formula 3 a

4a, c) formylating the compound of formula 4a with one or more formylating agents to form a compound of formula 4'a

4'a, d) demethylating the compound of formula 4'a to form a compound of formula 6

e) haloalkylating the compound of formula 6 with one or more halogenating agents to form a compound of formula 7

7 f) esterifying the compound of formula 7 with one or more suitable agent to form a compound of formula 8a

8a, g) oxidizing the methyl group of the compound of formula 8a with one or more oxidizing agents to form a compound of formula 9a

10a, i) reacting the compound of formula 10a with an azide to form a compound of formula 11 a

11a, j) cyclizing the compound of formula 1 Ia to form a compound of formula 12a

12a, k) chlorinating the compound of formula 12a to form a compound of formula 13a

13a,

1) dechlorinating the compound of formula 13a to form a compound of formula 14a

14a, m) hydrolyzing the compound of formula 14a to form a compound of formula 15

16, o) reacting the compound of formula 16 with 4-amino-3,5-dichloropyridine-N-oxide to form a compound of formula 17

17, and converting the compound of formula 17 to the compound of formula 1.

13. The process according to claim 10, wherein one or more steps is carried out in the presence of a base selected from N,N-dimethyl aniline, diisopropylamine, pyridine, triethylamine, sodium hydroxide potassium hydroxide, potassium carbonate, sodium carbonate and mixtures thereof.

14. The process according to claim 10, wherein one or more steps is carried out in the presence of a solvent selected from diethyl ether, tetrahydrofuran, dioxane, hexane, heptane, toluene, xylene, dichloromethane, dibromomethane, chloroform, carbontetrachloride, dimethyl formamide or dimethylsulfoxide, N,N-dimethyl aniline, N,N-diethyl aniline and mixtures thereof.

15. The process according to claim 10, wherein the cyclizing agent is selected from cesium fluoride, potassium fluoride, sodium fluoride and a mixture thereof.

16. The process according to claim 10, wherein the alkylating agent is selected from propagyl bromide and propargyl chloride.

17. The process according to claim 10, wherein the formylation is carried out with formylating agent, dichlormethylmethyl ether in the presence of tin(IV)chloride in a solvent selected from dichloromethane, ethyl methyl ether, diethylether, tetrahydrofuran and mixtures thereof.

18. The process according to claim 10, wherein the deprotecting agent is sodium- 4-methylbenzene thiolate.

19. The process according to claim 10, wherein the haloalkylating agent is mafron gas.

20. The process according to claim 10, wherein the one or more esterifying agents are selected from iodine, potassium iodide, sodium iodide, phenyliodinediacetate, N- hydroxysuccinimide, potassium peroxomonosulfate and mixtures thereof.

21. The process according to claim 10, wherein step f) is carried out in the presence of base selected from potassium hydroxide, sodium hydroxide and mixtures thereof.

22. The process according to claim 10, wherein step f) is carried out in the presence of a solvent selected from methanol, ethanol, isopropanol and mixtures thereof.

23. The process according to claim 10, wherein the one or more oxidizing agents are selected from selenium dioxide, dichlorodicyanoquinone, sodium hypochlorite in the presence of tetrabutylammoniumsulphate, ozone in the presence of silicon dioxide, pyridiniumchlorochromate in the presence of acetonitrile, pyridinium chlorochromate in the presence of acetic acid, eerie ammonium nitrate, laccase diammonium salt of 2,2, azinobis-(3-ethylbenzothiazoline-6-sulfonicacid) and mixtures thereof.

24. The process according to claim 10, wherein the halogenating agent is phosphorus oxychloride.

25. A compound of formula 12a

12a and pharmaceutically acceptable salts thereof 26. A compound of formula 18

18 and pharmaceutically acceptable salts thereof, wherein R^ai is selected from CHO and COOR' (wherein R' is alkyl); and R^a ₂ is selected from methyl, CHO, CH=CH-COOH and CH=CHN₃.