HK1034958A - Process for making 5-lipoxygenase inhibitors having varied heterocyclic ring systems - Google Patents

Description

Process for preparing 5-lipoxygenase inhibitors with variable heterocyclic ring system

Please refer to our related application No. 09/207,342 filed on 8.12.1998 (attorney docket No. PC 8708C); the above application is filed on 6.2.1998 under the application number 09/020,014 (attorney docket No. PC8708B), filed in a divisional application of us 5,883,106; itis a continuation of the following two applications: the first of these, filed on 29.5.1995 under application No. 08/809,901 (attorney docket No. PC8708A), now disclaimed, claims priority to the now disclaimed application No. PCT/JP94/01747 (attorney docket No. PC8708), on 18.10.1994; the second application, filed on 29.5.1995, § 371 application No. PCT/IB95/00408 (attorney docket No. PC8708A), which has now failed, but published under number WO96/11911 (published: 1996, 25.4.25), discloses inhibitors of 5-lipoxygenase for the treatment of inflammatory diseases and allergies. Several methods for preparing 5-lipoxygenase inhibitors are described therein, but nothing is disclosed to teach those skilled in the art to obtain the improved methods of the present invention.

See also the related application, application No. 60/113,221 (attorney docket No. PC10097), filed on 22/12/1998, which discloses a novel process for the preparation of 4- {3- [4- (2-methyl-imidazol-1-yl) -phenylthio]-phenyl } -tetrahydropyran-4-carboxylic acid amide methanesulfonate salt. But the method is different from the present invention.

Further reference is made to related applications filed on even date herewith, attorney docket numbers PC10682 and PC10683, respectively, which also relate to methods of making 5-lipoxygenase inhibitors having a variable heterocyclic ring system and some of which are in part the same as the methods of the present application.

A novel class of compounds useful as inhibitors of 5-lipoxygenase activity is disclosed in WO96/11911 and characterized by the following structural formula:wherein:-Ar¹is a heterocyclic group selected from: imidazolyl, pyrrolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, indolyl, indazolyl and benzimidazolyl, which are bonded to X1 through a ring nitrogen atom; and is substituted with 0 to 2 substituents selected from the group consisting of halogen, hydroxy, cyano, amino, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylthio group, (C)₁-C₄) Haloalkyl, (C)₁-C₄) Haloalkoxy, (C)₁-C₄) Alkylamino and di (C)₁-C₄) An alkylamino group; -X¹Is a direct bond or (C)₁-C₄) An alkylene group; -Ar²Is 0-2Phenylene substituted with a substituent, wherein the substituent is selected from the group consisting of halogen, hydroxy, cyano, amino, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylthio group, (C)₁-C₄) Haloalkyl and (C)₁-C₄) A haloalkoxy group; -X²is-A-X-or-X-A-, wherein A is a direct bond or (C)₁-C₄) Alkylene, and X is oxygen, sulfur, sulfinyl, or sulfonyl; -Ar³Selected from the group consisting of phenylene, pyridylene, thienylene, furanylene, oxazolylene, and thiazolylene; and is substituted with 0 to 2 substituents selected from the group consisting of: halogen, hydroxy, cyano, amino, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylthio group, (C)₁-C₄) Haloalkyl, (C)₁-C₄) Haloalkoxy, (C)₁-C₄) Alkylamino and di (C)₁-C₄) An alkylamino group; -R¹And R²Each is (C)₁-C₄) An alkyl group; or they together form a group of the formula: -D¹-Z-D²-, which together with the carbon atom to which they are attached form a ring having 3 to 8 atoms, in which D¹And D²Is (C)₁-C₄) Alkylene, Z is a direct bond or oxygen, sulfur, sulfinyl, sulfonyl or 1, 2-ethenylene; and D¹And D²Can be covered (C)₁-C₃) Alkyl substitution; and-Y is CONR³R⁴；CN；C(R³)=N-OR⁴；COOR³；COR³(ii) a Or CSNR³R⁴(ii) a Wherein- -R³And R⁴Each is H or (C)₁-C₄) An alkyl group.

With respect to the above compound, (C)₁-C₄) Preferred meanings of haloalkyl are trifluoromethyl, (C)₁-C₄) The preferred meaning of haloalkoxy is trifluoromethoxy. A preferred group of the above compounds includes these: wherein Ar is²Is 1, 4-phenylene and Ar³Is 1, 3-phenylene or 5-fluoro-1, 3-phenylene. Among the preferred groups, the compounds are particularly preferredCompound of formula (I) wherein Ar¹Is a 2-alkylimidazolyl group; x¹Is a direct bond and Y is CONH₂And wherein Ar¹Is a pyrrolyl group; x¹Is CH₂(ii) a And Y is CONH₂Those of (a).

A particularly preferred embodiment of the inhibitor compounds of the above class is that of the following formula (1.0.0):

these compounds that inhibit the action of lipoxygenase are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals including humans. Lipoxygenase activity is shown as part of the arachidonic acid cascade. Arachidonic acid is a biological precursor for several groups of biologically active endogenous metabolites. Arachidonic acid is first liberated from membrane phospholipids by the action of phospholipase a 2. Arachidonic acid is then (i) metabolized via the cyclooxygenase pathway to produce prostaglandins including prostacyclin and thromboxane; or (ii) metabolized via the lipoxygenase pathway to produce hydroperoxy fatty acids which can be further converted to leukotrienes.

Leukotrienes are themselves highly active substances and exhibit a wide range of biological effects. For example, the peptides leukotrienes, LTC₄,LTD₄And LTE₄Are important bronchoconstrictors and vasoconstrictors and cause plasma leakage by increasing capillary permeability. LTB₄Is a strong chemotactic agent which promotes leukocyte infiltration and subsequent degranulation at sites of inflammation. Leukotrienes are associated with a variety of human diseases including asthma, chronic obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, atopic dermatitis, Adult Respiratory Distress Syndrome (ARDS), and inflammatory bowel disease including crohn's disease. Drugs that can positively inhibit lipoxygenase, and thus leukotriene production, are of great therapeutic value for both acute and chronic inflammation. See Masamune and Melvin, annual report [ Medicinal Chemistry, 24,71-80(1989)]. EP 0462830; EP 0505122; and EP 0540165 have described certainThe lipoxygenase inhibitor of (1).

Several methods for preparing lipoxygenase inhibitors are described in the above-mentioned patent application publication WO 96/39408. An example of these preparation processes is the coupling of compounds of formula (1.2.0) and compounds of formula (1.2.1) and can be represented by the following reaction scheme:wherein X¹Is sulfur, and Q is in thiourea and a suitable catalyst (e.g., tetrakis (triphenylphosphine) palladium)Displaceable groups in the presence. See chem.lett. (chemical express) 1379-1380 (1986). Suitable displaceable groups Q are said to include halogen or sulfonyloxy.

The present invention relates to the field of processes for the synthetic preparation of compounds of formula (1.0.0), some of which are known compounds, some of which are novel compounds, and some of which are unknown to the public, since they cannot be prepared using the preparation processes known hitherto in the art. All of these compounds have biological activity as inhibitors of 5-lipoxygenase.

As noted above, it is known in the art that compounds of the formula (1.0.0) can be prepared by initially nucleophilic substitution of an aryl halide with a palladium-catalyzed thiolate anion. Further details regarding the initiation of this process can be found in Migita et al, Bull. chem. Soc., Japan (Notification of the Japanese society of chemistry) 53,1385-1389 (1980). The initiation step can be illustrated by the following reaction scheme:wherein X is I or Br; and R is phenyl or (C)₁-C₄) An alkyl group.

The specialist literature includes a large number of disclosures relating to palladium-catalyzed syntheses. See, for example, Brocato et al Tetrahedron Lett.33,7433 (1992). This document describes palladium-based, in particular Pd (PPh)₃)₄-catalytic cyclisation of a bifunctional aromatic compound with a terminal alkyne and carbon monoxide, wherein not only a palladium (0) catalyst but also a palladium (ii) catalyst is required.

Arcadi et al, in Tetrahedron Lett.34,2813(1993), describe the synthesis of 2,3, 5-trisubstituted furan compounds from aryl halides and 2-propynyl-1, 3-dicarbonyl compounds in the presence of tetrakis (triphenylphosphine) palladium (0) and potassium carbonate, and it was observed that the nature of the base had a great influence on the course of the reaction.

McClure and Danishefsky [ J.Am.chem.Soc. (J.Am.Chem.Soc.) (J.Soc. chem.Soc.) -1156094-6100 (1993)]describe that 1,5-epoxybenzazocine (1,5-epoxybenzazocine) analogs can be synthesized in 90% yield using the catalyst tetrakis (triphenylphosphine) -palladium (0) in triethylamine-containing acetonitrile.

Nuss et al [ J.Am.chem.Soc.115,6991-6992(1993)]disclose the synthesis of novel oncostatin chromophore analogues in THF using a tetrakis (triphenylphosphine) palladium (0) catalyst and an alkynylstannane reactant.

Paquette and Astles [ J.org.chem. (J.Org.Chem.). 58.165-169(1993) describe the synthesis of furanochembranoids with side chain extensions by palladium (0) catalyzed coupling of vinyl stannanes in refluxing benzene or dimethoxyethane. The reaction is said to be solvent dependent, and is particularly advantageous when the solvent is chloroform.

The specialist literature also contains a large number of contents for reactions catalysed with transition metals other than palladium. See, for example, Takagi in Chemistry Letters,2221-2224(1987), which describes the use of nickel (0) and palladium (0) complexes as catalysts in the synthesis of diaryl sulfides from aryl halides and aryl thiols.

However, none of the above documents discloses or suggests a specific method of the present invention. The process of the invention is not only simple and effective, but also allows high yields to be obtained, which have not been possible hitherto.

The present invention relates to several closely related preparation processes and novel intermediates used therein, wherein a large number of the end products of said processes are known compounds which have proven useful as inhibitors of 5-lipoxygenase. The invention furthermore relates to a large number of further end products which are obtained by the process and which are hitherto unknown since they have not been synthesized before being prepared from the processes and intermediates according to the invention. As described in further detail herein, these novel end products are also useful as inhibitors of 5-lipoxygenase. All the preparation processes and novel intermediates of the present invention are summarized in the following paragraphs.

The present invention relates to a novel intermediate tetrahydro-4- [3- (4-fluorophenyl) thio comprising formula (2.0.0)]Compounds of phenyl-2H-pyran-4-carboxamide:

the present invention further relates to a process for the preparation of a compound of formula (2.0.0) which can be illustrated by the following synthetic scheme (10.0.0): synthetic route (10.0.0)- - (a) forming a reaction mixture comprising: - - (1) tetrahydro-4- (3-bromo-or iodo-phenyl) -2H-pyran-4-carbonitrile of formula (3.0.0):

wherein X is bromine or iodine; and- (2) 4-fluorophenylthiol of the formula (4.0.0):- - (3) in a solvent constituted by linear or branched aliphatic alcohols having 2 to 7 total carbon atoms, optionally in the form of an aqueous mixture thereof; wherein more preferably the alcohol is a secondary alcohol selected from the group consisting of isopropanol, sec-butanol, isoamyl alcohol and 2-heptanol, and optionally in the form of an aqueous mixture of said secondary alcohols; - - (4) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and- - - -R⁵Is hydrogen, H; or straight or branched (C)₁-C₄) An alkyl group; the strong base is preferably selected from lithium hydroxide, LiOH; sodium hydroxide; NaOH; potassium hydroxide, KOH; rubidium hydroxide; RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH₃(ii) a Sodium methoxide, NaOCH₃(ii) a Potassium methoxide, KOCH₃(ii) a Rubidium methoxide, RbOCH₃(ii) a Cesium methoxide, CsOCH₃(ii) a Lithium ethoxide, LiOCH₂CH₃(ii) a Sodium ethoxide, NaOCH₂CH₃(ii) a Potassium ethoxide, KOCH₂CH₃(ii) a Rubidium ethoxide, RbOCH₂CH₃(ii) a Cesium ethoxide, CsOCH₂CH₃(ii) a Lithium tert-butoxide, LiOC (CH)₃)₃(ii) a Sodium tert-butoxide, NaOC (CH)₃)₃(ii) a Potassium tert-butoxide, KOC (CH)₃)₃(ii) a Rubidium tert-Butanol, RbOC (CH)₃)₃(ii) a And cesium tert-butoxide, CsOC (CH)₃)₃(ii) a Mixtures comprising the above various bases;

-and further- - (5) in the presence of a transition metal catalyst comprising a palladium metal complex, said palladium metal complex preferably being selected from: - - (tetrakis) (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd (0); - - (tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)₂PCH₃]₄Pd (0); bis (methyldiphenylphosphine) palladium (II) trans-dichloride [ (C)₆H₅)₂PCH₃]₂PdCl₂(ii) a - - (O) -bis [ methylenebis (diphenylphosphino) dichloride]A dipalladium-dichloromethane adduct; bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) a An adduct of tris (dibenzylideneacetone) dipalladium (0) -chloroform,

(C₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃(ii) a - - (dibenzylideneacetone) palladium (0), (C)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd;- - (diphenylphosphino) ferrocene [1, 1' -dichloride]Palladium (II) complexes with methylene chloride; - - (di [1, 2-di (diphenylphosphino) ethane)]Palladium (0) complex; and- - (Pi-allyl) palladium (II) chloride dimer;

followed by (b) heating the reaction mixture, preferably under reflux, and preferably for 12 to 36 hours, more preferably for 18 to 24 hours; thereby producing said compound of formula (2.0.0) which is optionally isolated using conventional isolation techniques.

The above-described production method in which the pyranyl 4-carboxamide moiety is formed in the sulfur-addition step is a preferred means for carrying out this part of the process of the present invention. Another useful embodiment includes forming prior to performing the sulfur addition step4-carboxamide moiety on pyranyl. Another embodiment of this part of the above process of the present invention relates to a process for the preparation of a compound of formula (2.0.0) which is illustrated by the following synthetic scheme: synthetic route (10.1.0)Forming a reaction mixture comprising: - - (1) tetrahydro-4- (3-bromo-or iodo-phenyl) -2H-pyran-4-carbonitrile of formula (3.0.0):

wherein X is bromine or iodine; - - (2) in a solvent constituted by the above-mentioned alcohols, optionally in the form of an aqueous mixture thereof; and preferably the above secondary alcohols; more preferably isopropanol; optionally in the form of an aqueous mixture of said secondary alcohols; - - (3) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - - -M and R⁵As defined above; wherein the strong base is preferably sodium hydroxide, NaOH; potassium hydroxide, KOH; sodiumethoxide, NaOCH₂CH₃(ii) a Or potassium tert-butoxide, KOC (CH)₃)₃；

-subsequently (b) heating the reaction mixture, preferably under reflux, and preferably for 3 to 8 hours, more preferably for 5 to 6 hours; thereby producing a compound of formula (3.1.0):

wherein X is bromine or iodine;

-further (c) forming a reaction mixture comprising: the compound of formula (3.1.0) and 4-fluorophenylthiol of formula (4.0.0):- - (1) in a solvent constituted by the above-mentioned alcohols, optionally in the form of an aqueous mixture thereof; the above secondary alcohols are preferred, and isopropanol is more preferred; optionally in the form of an aqueous mixture of said secondary alcohols;- - (2) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - - -M and R⁵As defined above; wherein preferably the strong base is sodium hydroxide; NaOH; potassium hydroxide, KOH; sodium ethoxide, NaOCH₂CH₃(ii) a Or potassium tert-butoxide, KOC (CH)₃)₃；

-and further- (3) in the presence of a transition metal catalyst comprising a palladium metal complex, wherein the palladium metal complex is preferably selected from: - - (tetrakis) (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd (0); - - (tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)₂PCH₃]₄Pd (0); - - (trans) -bis (methyldiphenylphosphine) chloride palladium (II) [ (C)₆H₅)₂PCH₃]₂PdCl₂(ii) a - - (O) -bis [ methylenebis (diphenylphosphino) dichloride]A dipalladium-dichloromethane adduct; bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) a An adduct of tris (dibenzylideneacetone) dipalladium (0) -chloroform,

(C₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃(ii) a - - (dibenzylideneacetone) palladium (0), (C)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd; - - (1, 1' -bis (diphenylphosphino) ferrocene) dichloride]Palladium (II) complexes with methylene chloride; - - (di [1, 2-di (diphenylphosphino) ethane)]Palladium (0) complex; and- - (Pi-allyl) palladium (II) chloride dimer;

-subsequently (b) heating the reaction mixture, preferably under reflux, and preferably for 5-15 hours, more preferably for 8-10 hours; thereby producing said compound of formula (2.0.0).

The invention further relates to a process for the preparation of a compound of formula (1.3.0):and is illustrated by the following synthetic scheme (10.2.0):

synthetic route (10.2.0)Wherein-a moiety of formula (1.3.1):an electron-deficient monocyclic or benzo-fused bicyclic N-heterocyclic group containing two nitrogen atoms represented by the following formula (1.3.2), (1.3.3), (1.3.4) or (1.3.5):wherein- - "represents the symbol of the connecting position of the part of formula (1.3.2), (1.3.3), (1.3.4) or (1.3.5); - - -R⁷And R⁸Independently selected from H; straight or branched chain (C)₁-C₄) An alkyl group; and (C)₆-C₁₀)An aryl group; wherein said alkyl and aryl groups are substituted with 0-2 substituents selected from the group consisting of: halogen, hydroxy, cyano, amino, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylthio (C)₁-C₄) Haloalkyl (C)₁-C₄) Haloalkoxy, (C)₁-C₄) Alkylamino, and di (C)₁-C₄) An alkylamino group;

the method comprises the following steps: forming a reaction mixture comprising: - - (1) tetrahydro-4- [3- (4-fluorophenyl) thio group of the formula (2.0.0)]phenyl-2H-pyran-4-carboxamide:and- - (2) an electron-deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms of the formula (1.3.6), (1.3.7), (1.3.8) or (1.3.9):

wherein R is⁷And R⁸Have the same meaning as described above; - - (3) in an aprotic solvent, preferably dimethyl sulfoxide (DMSO); - - (4) in the presence of a carbonate of formula (5.1.0):

(M)₂-CO₃(5.1.0) wherein M is as defined above, the carbonate is preferably cesium carbonate, Cs₂CO₃(ii) a Subsequently (b) heating the reaction mixture under nitrogen atmosphere, preferably under refluxHeating, thereby producing the compound of formula (1.3.0).

The present invention further relates to the above process for the preparation of a compound of formula (1.3.0), wherein said compound of formula (1.3.0) is selected from:

tetrahydro-4- {3- [4- (2-methyl-1H-imidazol-1-yl) phenyl]thio } phenyl

-2H-pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-imidazol-1-yl) phenyl]thio } phenyl-2H-pyranyl

Pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-benzimidazol-1-yl) phenyl]thio } phenyl-2H

-pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-pyrazol-1-yl) phenyl]thio } phenyl-2H-pyri-dine

Pyran-4-carboxamide; and

tetrahydro-4- {3- [4- (4-methyl-1H-pyrazol-1-yl) phenyl]thio } phenyl

-2H-pyran-4-carboxamide.

The present invention further relates to the above-mentioned end products, which have not been known hitherto since they had not been synthesized before being prepared from the process and intermediates of the present invention. These novel end products are also useful as 5-lipoxygenase inhibitors and include compounds selected from the group consisting of:

tetrahydro-4- {3- [4- (1H-imidazol-1-yl) phenyl]thio } phenyl-2H-pyranyl

Pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-benzimidazol-1-yl) phenyl]thio } phenyl-2H

-pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-pyrazol-1-yl) phenyl]thio } phenyl-2H-pyri-dine

Pyran-4-carboxamide; and

tetrahydro-4- {3- [4- (4-methyl-1H-pyrazol-1-yl) phenyl]thio } phenyl

-2H-pyran-4-carboxamide.

The present invention still further relates to a process for preparing a compound of formula (1.0.0):

the method comprises the following steps: - (a) forming a packetA reaction mixture comprising: - - (1) tetrahydro-4- [3- (4-fluorophenyl) thio group of the formula (2.0.0)]phenyl-2H-pyran-4-carboxamide:- - (2) 2-methylimidazole; - - (3) in an aprotic solvent, preferably dimethyl sulfoxide (DMSO); - - (4) in the presence of a carbonate of formula (5.1.0):

(M)₂-CO₃(5.1．0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; preferably cesium carbonate, Cs₂CO₃；

Followed by (b) heating the reaction mixture under a nitrogen atmosphere, preferably under reflux, preferably at a temperature of 115-145 ℃, more preferably 125-130 ℃, and preferably for 12-30 hours, more preferably for 17-24 hours; thereby producing said compound of formula (1.3.0).

The present invention is still further directed to a process for the preparation of substantially pure mesylate of formula (1.0.1) which is illustrated by the following synthetic scheme (10.3.0):synthetic route (10.3.0)

The method comprises the following steps: - (a) preparation of a compound of formula (2.0.0):the method comprises the following steps: - - (1) forming a reaction mixture comprising: - - (i) tetrahydro-4- (3-bromo-phenyl) -2H-pyran-4-carbonitrile of formula (3.2.0):

and- - (ii) 4-fluorophenylthiol of the formula (4.0.0):in a solvent selected from the group consisting of isopropanol, sec-butanol, isoamyl alcohol, and 2-heptanol, preferably isopropanol, and optionally in the form of an aqueous mixture thereof; - - (iv) in a solvent selected from sodium hydroxide, NaOH; and potassium hydroxide, in the presence of a strong base of KOH;

-and further- (v) in the presence of a transition metal catalyst comprising a metal independently selected from palladium complexes; and preferably wherein said palladium metal complex is selected from the group consisting of: - - (tetrakis) (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd (0); - - (tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)₂PCH₃]₄Pd (0); bis (methyldiphenylphosphine) palladium (II) trans-dichloride [ (C)₆H₅)₂PCH₃]₂PdCl₂(ii) a - - (O) -bis [ methylenebis (diphenylphosphino) dichloride]A dipalladium-dichloromethane adduct; bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) a An adduct of tris (dibenzylideneacetone) dipalladium (0) -chloroform,

(C₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃；- - (dibenzylideneacetone) palladium (0), (C)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd; - - (1, 1' -bis (diphenylphosphino) ferrocene) dichloride]Palladium (II) complexes with methylene chloride; - - (di [1, 2-di (diphenylphosphino) ethane)]Palladium (0) complex; and- - (Pi-allyl) palladium (II) chloride dimer;

-followed by- - (2) heating to reflux the reaction mixture at 80-84 ℃ for 18-30 hours, preferably 24 hours; thereby producing said compound of formula (2.0.0). - (b) forming a reaction mixture comprising: the compounds of formula (2.0.0) and formula (1.3.10):- - (1) in an aprotic solvent, preferably dimethyl sulfoxide (DMSO); - - (2) in cesium carbonate, Cs₂CO₃In the presence of;

-followed by (c) heating to reflux the reaction mixture under nitrogen atmosphere; thereby producing a compound of formula (1.0.0):

subsequent formation of (d) a concentrated methanolic solution of said compound of formula (1.0.0), followed by filtration, preferably by activated carbon, and subsequent addition of methanesulfonic acid, MeSO, to the filtrate₃H; followed by further concentration and continuous addition of ethyl acetate until a crystalline product comprising substantially pure mesylate of formula (1.0.1):

or, alternatively, by the subsequent formation of (e) a concentrated methanolic solution of said compound of formula (1.0.0), followed by the addition of methanesulfonic acid, MeSO₃H; the mixture is then filtered, preferably through activated carbon, followed by further concentration, with ethyl acetate being added continuously until a crystalline product comprising substantially pure mesylate of formula (1.0.1) is precipitated:

the present invention relates to an improved process for the preparation of known compounds which have proven useful as inhibitors of 5-lipoxygenase, in particular compounds of formula (1.0.0):

the invention further relates to the preparation of a large number of other compounds which have not been known to date since they have not been synthesized prior to preparation by the improved process of the invention. These novel compounds are also useful as 5-lipoxygenase inhibitors, including those of the formula (1.1.1); (1.1.2); (1.1.3); and (1.1.4):

tetrahydro-4- {3- [4- (1H-imidazol-1-yl) phenyl]Thio } phenyl-2H-pyran-4-carboxamide:

tetrahydro-4- {3- [4- (1H-benzimidazol-1-yl) phenyl]Thio } phenyl-2H-pyran-4-carboxamide:tetrahydro-4- {3- [4- (1H-pyrazol-1-yl) phenyl]Thio } phenyl-2H-pyran-4-carboxamide:

tetrahydro-4- {3- [4- (4-methyl-1H-pyrazol-1-yl) phenyl]Thio } phenyl-2H-pyran-4-carboxamide:

for the preparation of the compounds of the above formulae (1.1.1) to (1.1.4) and analogous compounds thereof, the following process of the present invention for the preparation of the compounds of the formula (1.3.0) is preferably used:wherein-a moiety of formula (1.3.1):an electron-deficient monocyclic ring containing two nitrogen atoms represented by the formula (1.3.2), (1.3.3), (1.3.4) or (1.3.5)Or a benzo-fused bicyclic N-heterocyclyl:

wherein "-" represents a symbol of a connecting position of a moiety of formula (1.3.2), (1.3.3), (1.3.4) or (1.3.5); - - -R⁷And R⁸Independently selected from H; straight or branched chain (C)₁-C₄) An alkyl group; and (C)₆-C₁₀) An aryl group; wherein said alkyl and aryl groups are substituted with 0-2 substituents selected from the group consisting of: halogen, hydroxy,cyano, amino, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylthio (C)₁-C₄) Haloalkyl (C)₁-C₄) Haloalkoxy, (C)₁-C₄) Alkylamino, and di (C)₁-C₄) An alkylamino group.

The above-described embodiment of the preparation process of the present invention can be illustrated by the following scheme (10.2.0):

synthetic route (10.2.0)^**+ wherein the reactant of formula (1.4.0):is an electron-deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms of formula (1.3.6), (1.3.7), (1.3.8) or (1.3.9) as defined above.

Thus, the above-described process of the present invention, as shown in scheme (10.2.0), can be carried out as follows: forming a reaction mixture comprising: - - (1) tetrakis of formula (2.0.0)Hydro-4- [3- (4-fluorophenyl) thio group]phenyl-2H-pyran-4-carboxamide:- - (2) an electron-deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms represented by the formula (1.3.6), (1.3.7), (1.3.8) or (1.3.9):

wherein R is⁷And R⁸Have the same meaning as described above; - - (3) in aprotic solvents, preferably selected mainly from: hexane; 1, 4-dioxane; carbon tetrachloride; benzene; toluene; xylene; diethyl ether; chloroform; ethyl acetate; tetrahydrofuran (THF); dichloromethane; hexamethylphosphoric triamide (HMPT); nitromethane; n, N-Dimethylformamide (DMF); acetonitrile, sulfolane; and Dimethylsulfoxide (DMSO); more preferably dimethyl sulfoxide(DMSO); - - (4) in the presence of a carbonate of formula (5.1.0):

(M)₂-CO₃(5.1.0) wherein M is a group 1/Ia alkali metal selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs, preferably cesium, Cs;

followed by (b) heating the reaction mixture under nitrogen atmosphere, preferably under reflux, thereby yielding a compound of formula (1.3.0).

It will be readily appreciated by those of ordinary skill in the art of preparing such organic compounds to which the present invention relates that the replacement of aryl fluorides by electron deficient nitrogen containing heterocycles in the presence of a base is relatively straightforward to form carbon-The unknown method of nitrogen bonding is, of course, a method which has not been proposed to date for preparing such compounds. To obtain an acceptable degree of displacement of the nitrogen nucleophile in the presence of a base, it is generally desirable to have a strong electron-withdrawing group, such as a nitro group, para or ortho to the fluorine atom. The yields of such metathesis reactions are generally very low and need to be carried out at elevated reaction temperatures. See, for example, Morgan et al, J.Med.chem.,33,1091-1097(1990) which discloses a method of making using a base such as K₂CO₃NaOH, or NaH, by reacting methyl or ethyl 4-fluoro-benzoic acid with the appropriate imidazole in DMSOAnd (4) carrying out oxazole reaction. The ethyl 4- (2-methyl-1H-imidazol-1-yl) -benzoate compound was obtained as an amorphous product in only 33% yield. In contrast, the preparation process of the present invention gives a higher yield and can be carried out at a temperature of 130 ℃ or lower. This result is completely unexpected because the aromatic ring of the aryl fluoride reactant in the process of the present invention has no electron withdrawing substituentsattached to it.

The most preferred solvent for use in the above-described process of the invention is Dimethylsulfoxide (DMSO), although any aprotic solvent is suitable and those described above are also preferred. In a preferred embodiment of this method, for reaction mixtures using DMSO as solvent, cesium carbonate, Cs is used₂CO₃. After the reaction mixture was formed, it was heated to reflux under nitrogen atmosphere. The reflux temperature of the reaction mixture is 120-140 deg.C, typically 125-135 deg.C, and the most common reaction temperature is 130 deg.C under the most common ambient conditions.

Preferred embodiment of the preparation process of the present invention uses cesium carbonate, Cs₂CO₃Although other metal carbonates as described above are also suitable. Cesium carbonate is preferred primarily because its higher reactivity provides correspondingly higher yields, thereby reducing the product cost of the reactant of formula (2.0.0). Although there is a possibility of limited availability due to the relative lack of cesium carbonate in the global market, cesium carbonate is preferred. In the preparation process of the present invention, cesium carbonate provides such an excellent end result that one would have to consider looking for a new supply source in order to comply with the already identified large demand. Nevertheless, the skilled worker is at no difficulty aware of the risk of maintaining a continuous preparation of the compounds prepared according to the invention, or at least of the risk of losing the economic advantages which such processes currently have.

It is necessary to heat the reaction mixture at these temperatures for up to 12 to 30 hours, preferably 16 to 24 hours, most preferably 18 to 20 hours. The appropriate reaction temperature and time required for the reaction to proceed completely can be selected according to the expertise in the organic synthesis method. Isolation of the product in the above process by, for example, vacuum filtration, water washing and vacuum oven drying can be accomplished by conventional methods, again as is well within the ordinary skill in the art.

It should be noted that in the above process of the invention, one of the important reactants is a compound of formula (2.0.0):this compound is also a novel intermediate of the present invention, namely tetrahydro-4- [3- (4-fluorophenyl) thio]phenyl-2H-pyran-4-carboxamide. In order to carry out the above process of the present invention, it is therefore necessary to provide a process by which such new reactants/intermediates can be prepared per se. Thus, another process of the present invention is described below, whereby a compound of formula (2.0.0) can be produced.

The invention further relates to a process for the preparation of a compound of formula (2.0.0):one of the preferred processes of the present invention for preparing the novel intermediates of formula (2.0.0) can be illustrated by the following synthetic scheme (10.0.1):

synthetic route (10.0.1)Wherein X, M and R⁵All have the same meaning as described above.

Thus, the process of the invention shown in the above synthetic route (10.0.1) can be carried out as follows: forming a reaction mixture comprising: - - (1) tetrahydro-4- (3-bromo-or iodo-phenyl) -2H-pyran-4-carbonitrile of formula (3.0.0):

wherein X is bromine or iodine;

and- (2) 4-fluorophenylthiol of the formula (4.0.0):- - (3) in a solvent constituted by linear or branched aliphatic alcohols having 2 to 7 total carbon atoms, optionally in the form of an aqueous mixture thereof; and more preferably the alcohol is a secondary alcohol selected from isopropanol, sec-butanol, isoamyl alcohol and 2-heptanol, optionally in the form of an aqueous mixture of said secondary alcohols; - - (4) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and- - - -R⁵Is hydrogen, H; or straight or branched (C)₁-C₄) An alkyl group; preferably the strong base is selected from lithium hydroxide, LiOH; sodium hydroxide; NaOH; potassium hydroxide, KOH; rubidium hydroxide; RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH₃(ii) a Sodium methoxide, NaOCH₃(ii) a Potassium methoxide, KOCH₃(ii) a Rubidium methanol; RbOCH₃(ii) a Cesium methoxide, CsOCH₃(ii) a Lithium ethoxide, LiOCH₂CH₃(ii) a Sodium ethoxide, NaOCH₂CH₃(ii) a Potassium ethoxide, KOCH₂CH₃(ii) a Rubidium ethoxide, RbOCH₂CH₃(ii) a Cesium ethoxide, CsOCH₂CH₃(ii) a Lithium tert-butoxide, LiOC (CH)₃)₃(ii) a Sodium tert-butoxide, NaOC (CH)₃)₃(ii) a Potassium tert-butoxide, KOC (CH)₃)₃(ii) a Rubidium tert-Butanol, RbOC (CH)₃)₃(ii) a And cesium tert-butoxide, CsOC (CH)₃)₃(ii) a Mixtures comprising the above various bases;

-and further- (5) in the presence of a transition metal catalyst comprising a palladium metal complex, preferably selected from: - - (tetrakis) (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd(0)；- - (tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)₂PCH₃]₄Pd (0); bis (methyldiphenylphosphine) palladium (II) trans-dichloride [ (C)₆H₅)₂PCH₃]₂PdCl₂(ii) a - - (O) -bis [ methylenebis (diphenylphosphino) dichloride]A dipalladium-dichloromethane adduct; bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) a An adduct of tris (dibenzylideneacetone) dipalladium (0) -chloroform,

(C₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃(ii) a - - (dibenzylideneacetone) palladium (0), (C)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd; - - (1, 1' -bis (diphenylphosphino) ferrocene) dichloride]Palladium (II) complexes with methylene chloride; - - (di [1, 2-di (diphenylphosphino) ethane)]Palladium (0) complex; and- - (Pi-allyl) palladium (II) chloride dimer;

followed by (b) heating the reaction mixture, preferably under reflux, and preferably for 12 to 36 hours, more preferably for 18 to 24 hours; thereby producing said compound of formula (2.0.0) which is optionally isolated using conventional isolation techniques.

The above process is a process for preparing an asymmetrically substituted diaryl ether. At the same time, the reaction that takes place also leads to hydrolysis of the nitrile substituent to the corresponding formamide substituent. It has been found that several factors are of importance to ensure that the process described above is carried out completely and that the novel intermediates of formula (2.0.0) are obtained in high yields.

One such factor is the solvent used in the reaction. The solvent is composed of a linear or branched aliphatic alcohol having 2 to 7 total carbon atoms. Such alcoholic solvents can also be used in the form of a mixture with water, that is to say in the form of an alcohol-water mixture in suitable proportions. Although the alcohol solvent is substantially miscible with water in various proportions, it has been found that the volume ratio of alcohol to water is suitably maintained in the range of from 25: 1 to 3: 1, preferably from 10: 1 to 5: 1, respectively.

It has also been found that the above-mentioned linear or branched aliphatic alcohols having from 2 to 7 total carbon atoms which are most suitably used as solvents in the process of the present invention are secondary alcohols selected from: isopropanol, sec-butanol, isoamyl alcohol and 2-heptanol. Of these preferred secondary alcohols, isopropanol is most preferred. The above secondary alcohols are also optionally used in the form of aqueous mixtures, as described in detail above.

It will be appreciated that the reaction temperature employed in the above-described process of the invention is controlled by the alcohol solvent selected, and will likewise depend on the degree of reaction of the substrate. For example, for a reactant of formula (3.0.0) wherein X is iodine, it has been found that the reaction can proceed smoothly in refluxing isopropanol. Whereas for the reactant of formula (3.0.0) wherein X is bromine, it was found that the reaction proceeded smoothly in refluxing sec-butanol. It will also be appreciated that in the above process of the invention, the reaction involving the aryl iodide (i.e. X in the reactant of formula (3.0.0) is iodine) proceeds rapidly and can be completed in a matter of hours. On the other hand, reactions involving aryl bromides (i.e., X in the reactant of formula (3.0.0) is bromine) proceed very slowly compared to reactions involving aryl iodides, and require heating of the reactionmixture for a considerable length of time (greater than 10 hours) to complete the reaction. However, in either case, heating the reaction mixture for a prolonged period of time does not adversely affect the yield of the desired diaryl sulfide (i.e., diaryl sulfide).

Another such factor is the use of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0) wherein M is a group 1/Ia alkali metal selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and R is⁵Is hydrogen, H; or straight or branched (C)₁-C₄) An alkyl group. Preferred strong bases include those selected from the group consisting of: lithium hydroxide, LiOH; sodium hydroxide; NaOH; potassium hydroxide, KOH; rubidium hydroxide; RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH₃(ii) a Sodium methoxide, NaOCH₃(ii) a Potassium methoxide, KOCH₃(ii) a Rubidium methanol; RbOCH₃(ii) a Cesium methoxide, CsOCH₃(ii) a Lithium ethoxide, LiOCH₂CH₃(ii) a Sodium ethoxide, NaOCH₂CH₃(ii) a Potassium ethoxide, KOCH₂CH₃(ii) a Rubidium ethoxide, RbOCH₂CH₃(ii) a Cesium ethoxide, CsOCH₂CH₃(ii) a Lithium tert-butoxide, LiOC (CH)₃)₃(ii) a Sodium tert-butoxide, NaOC (CH)₃)₃(ii) a Potassium tert-butoxide, KOC (CH)₃)₃(ii) a Rubidium tert-Butanol, RbOC (CH)₃)₃(ii) a And cesium tert-butoxide, CsOC (CH)₃)₃。

The above-mentioned strong bases may be used in the form of a mixture thereof, but it is preferable to use only the same strong base. Among the above strong bases, sodium hydroxide, NaOH; the concentration of the potassium hydroxide is controlled by the concentration of the potassium hydroxide,KOH; sodium ethoxide, NaOCH₂CH₃(ii) a And potassium tert-butoxide, KOC (CH)₃)₃。

Yet another factor that enables the above process of the present invention to be satisfactorily carried out is the use of a transition metal catalyst comprising a palladium metal complex. Among the palladium metal complexes preferably used in the process of the present invention, those catalyst species used in the above-mentioned process are more preferred. The more preferred species are selected from:

tetrakis (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd(0)；

Tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)₂PCH₃]₄Pd(0)；

Bis (methyldiphenylphosphine) bis (II) bis (trans) -dichloride [ (C)₆H₅)₂PCH₃]₂PdCl₂；Bis [ methylenebis (diphenylphosphino) dichloride of formula (6.0.0)]Dipalladium-dichloromethane adduct:bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) a Tris (dibenzylideneacetone) dipalladium (0) -chloroform adduct:

(C₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃(ii) a Bis (dibenzylideneacetone) palladium (0), (b), (c) and (d)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd; [1, 1' -bis (diphenylphosphino) ferrocene]dichloride of the formula (6.1.0)]Complex of palladium (ii) complex with dichloromethane:bis [1, 2-bis (diphenylphosphino) ethane of formula (6.2.0)]Palladium (0) complex:

-and-a (pi-allyl) palladium (ii) chloride dimer of formula (6.3.0):

of the above palladium metal complexes, tetrakis (triphenylphosphine) palladium (0) [ (C) is most preferred₆H₅)₃P]₄Pd (0). This preferred catalyst may or may not be used with a ligand. When the ligand is reacted with [ (C)₆H₅)₃P]₄When Pd (0) is used together, preferred ligands are Triphenylphosphine (TPP), ethylenebis (diphenylphosphine), and tris (2-tolyl) phosphine. The preferred ratio of catalyst to ligand is about 1: 2 molar equivalents, but the skilled artisan will readily appreciate that the use of excess ligand may result in a reduction in the overall yield of the reaction using such ligand. Other palladium metal complexes used as catalysts in the process of the present invention may also be used with and without any ligands present. The following table shows the yields of the above-described process of the invention using different palladium metal complexes with or without various ligands, and it can be seen from the values in the table that the use of ligands may have a significant effect on the yield of the final product, i.e. the compound of formula (2.0.0).

TABLE 1

Reference to Serial number	Palladium metal complex	Ligands	Yield of the compound of formula (2.0.0)
					In situIs separated from
			1	Trans-bis (triphenylphosphine) palladium (II) dichloride			Is free of	57.2％	43.4％
2	“ “	Ethylene bis (diphenylphosphine)			72.2％	71.3％
			3	“ “			Triphenylphosphine	64.2％	60.9％
4	“ “	Tris- (2-tolyl) phosphine			53.6％	38.8％
			5	Chloroform adduct of tris (dibenzylideneacetone) dipalladium (II)			Is free of	7.6％	5.7％
6	“ “	Ethylene bis (diphenylphosphine)			34％	18.3％
			7	“ “			Triphenylphosphine	75.1％	69.8％
8	[1, 1' -bis (diphenylphosphino) ferrocene ] dichloride]Palladium complex (II) Dichloromethane adduct	Is free of			46.0％	40.7％
			9	“ “			Ethylene bis (diphenylphosphine)	64.4％	53.8％
10	“ “	Triphenylphosphine			64.4％	55.0％
			11	Bis (dibenzylideneacetone) palladium (0)			Is free of	17.5％	12.4％
12	“ “	Ethylene bis (diphenylphosphine)			35.0％	33.0％
			13	“ “			Triphenylphosphine	55.9％	39.0％
14	(Pi-allyl) palladium (II) chloride dimer	Is free of			14.2％	8.3％
			15	“ “			Ethylene bis (diphenylphosphine)	43.8％	33.3％
16	“ “	Triphenylphosphine			62.4％	53.7％
			17	Tetrakis (triphenylphosphine) palladium (0) Control			Is free of	71.7％	71.6％

The above ligands, as well as other ligands known in the art, may be used with the palladium metal complex used as a catalyst in the process of the present invention.

As further indicated above, a particular advantage of the above process is that during the course of carrying out the reaction under defined conditions, whether under suitable or preferred conditions, the nitrile of the compound of formula (3.0.0) is partially hydrolysed to the corresponding carboxamide group on the end product, i.e. the compound of formula (1.0.0). Nevertheless, the present invention provides an alternative process for the preparation of a novel intermediate, i.e. a compound of formula (2.0.0), wherein the nitrile moiety is first hydrolyzed to the corresponding carboxamide to yield a compound of formula (3.1.0), after this synthetic step has been carried out, the carboxamide compound of formula (3.1.0) is then reacted with a fluorothiophenol compound of formula (4.0.0) to yield the novel intermediate compound of formula (2.0.0).

It is further noted that the second step of the alternative process described above is carried out in substantially the same manner as described above in scheme 2.

Accordingly, the present invention also relates to another process for preparing a compound of formula (2.0.0):the above process is illustrated by the following scheme (10.1.0):

synthetic route (10.1.0)Wherein X, M, and R⁵All have the same meaning as described elsewhere herein.

Another process of the present invention, illustrated by scheme (10.1.0), can be carried out as follows:forming a reaction mixture comprising: - - (1) tetrahydro-4- (3-bromo-or iodo-phenyl) -2H-pyran-4-carbonitrile of formula (3.0.0):

wherein X is bromine or iodine; - - (2) in a solvent constituted by linear or branched aliphatic alcohols having 2 to 7 total carbon atoms, optionally in the form of an aqueous mixture thereof; and more preferably the alcohol is a secondary alcohol selected from isopropanol, sec-butanol, isoamyl alcohol and 2-heptanol, optionally in the form of an aqueous mixture of said secondary alcohols; - - (3) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and- - - -R⁵Is hydrogen, H; or straight or branched (C)₁-C₄) An alkyl group; the base is preferably selected from lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH₃(ii) a Sodium methoxide, NaOCH₃(ii) a Potassium methoxide, KOCH₃(ii) a Rubidium methoxide, RbOCH₃(ii) a Cesium methoxide, CsOCH₃(ii) a Lithium ethoxide, LiOCH₂CH₃(ii) a Sodium ethoxide, NaOCH₂CH₃(ii) a Potassium ethoxide, KOCH₂CH₃(ii) a Rubidium ethoxide, RbOCH₂CH₃(ii) a Cesium ethoxide, CsOCH₂CH₃(ii) a Lithium tert-butoxide, LiOC (CH)₃)₃(ii) a Sodium tert-butoxide, NaOC (CH)₃)₃(ii) a Potassium tert-butoxide, KOC (CH)₃)₃(ii) a Rubidium tert-Butanol, RbOC (CH)₃)₃(ii) a And cesium tert-butoxide, CsOC (CH)₃)₃(ii) a Mixtures comprising the above various bases;

-then- - (b) heating the reaction mixture, preferably under reflux, and preferably for 3 to 8 hours, more preferably for 5 to 6 hours; thereby producing a compound of formula (3.1.0):

wherein X is bromine or iodine;

-further (c) forming a reaction mixture comprising: the compound of formula (3.1.0) and the 4-fluorothiophenol of formula (4.0.0):- - (1) in a solvent constituted by linear or branched aliphatic alcohols having 2 to 7 total carbon atoms, optionally in the form of an aqueous mixture thereof; and more preferably the alcohol is a secondary alcohol selected from isopropanol, sec-butanol, isoamyl alcohol and 2-heptanol, optionally in the form of an aqueous mixture of said secondary alcohols; - - (2) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and- - - -R⁵Is hydrogen, H; or straight or branched (C)₁-C₄) An alkyl group; the strong base is preferably selected from lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH₃(ii) a Sodium methoxide, NaOCH₃(ii) a Potassium methoxide, KOCH₃(ii) a Rubidium methoxide, RbOCH₃(ii) a Cesium methoxide, CsOCH₃(ii) a Lithium ethoxide, LiOCH₂CH₃(ii) a Sodium ethoxide, NaOCH₂CH₃(ii) a Potassium ethoxide, KOCH₂CH₃(ii) a Rubidium ethoxide, RbOCH₂CH₃(ii) a Cesium ethoxide, CsOCH₂CH₃(ii) a Lithium tert-butoxide, LiOC (CH)₃)₃(ii) a Sodium tert-butoxide, NaOC (CH)₃)₃(ii) a Potassium tert-butoxide, KOC (CH)₃)₃(ii) a Rubidium tert-Butanol, RbOC (CH)₃)₃(ii) a And cesium tert-butoxide, CsOC (CH)₃)₃(ii) a Mixtures comprising the above various bases;

-and further- (3) in the presence of a transition metal catalyst comprising a metal selected independently from palladium metal complexes, preferably wherein said palladium metal complex is selected from: - - (tetrakis) (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd (0); - - (tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)₂PCH₃]₄Pd (0); bis (methyldiphenylphosphine) palladium (II) trans-dichloride [ (C)₆H₅)₂PCH₃]₂PdCl₂；- - (O) -bis [ methylenebis (diphenylphosphino) dichloride]A dipalladium-dichloromethane adduct; bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) a An adduct of tris (dibenzylideneacetone) dipalladium (0) -chloroform,

(C₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃(ii) a - - (dibenzylideneacetone) palladium (0), (C)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd; - - (diphenylphosphino) ferrocene [1, 1' -dichloride]Palladium (II) complexes with methylene chloride; - - (di [1, 2-di (diphenylphosphino) ethane)]Palladium (0) complex; and- - (Pi-allyl) palladium (II) chloride dimer;

-subsequently (b) heating the reaction mixture, preferablyunder reflux, and preferably for 5-15 hours, more preferably for 8-10 hours; thereby producing said compound of formula (2.0.0).

One of the important aspects of the preparation process of the present invention relates to an improved way of producing the 5-lipoxygenase inhibitor of the known compound of formula (1.0.0):

this improved process is relevant to most of the above preferred embodiments of the present invention and can be illustrated by the following synthetic scheme (10.3.1):

synthetic route (10.3.1)

The improved process of the present invention as shown in scheme (10.3.1) is believed to comprise a total of 6 embodiments of the present invention. The first embodiment is step a, which is also the first step shown in scheme (10.3.1), and is a process for preparing the novel intermediates of the present invention of formula (2.0.0). The second embodiment, step b, the second or intermediate step shown in scheme (10.3.1), is a process for preparing a known 5-lipoxygenase inhibitor as the original form of the compound of formula (1.0.0). The third embodiment is step c, the last step in scheme (10.3.1), which is a process for the preparation of the mesylate salt of the known compound of formula (1.0.0). The fourth embodiment is step b + step c. The fifth embodiment is step a + step b. The sixth embodiment is step a + step b + step c.

For the sake of simplicity, only the second and sixth embodiments are described in detail below. Thus, the second embodiment described above, step b in scheme (10.3.1), can be performed as follows: forming a reaction mixture comprising: - - (1) tetrahydro-4- [3- (4-fluorophenyl) thio group of the formula (2.0.0)]phenyl-2H-pyran-4-carboxamide:- - (2) 2-methylimidazole; - - (3) in aprotic solvents, solvents selected mainly from: hexane; 1, 4-dioxane; carbon tetrachloride; benzene; toluene; xylene; diethyl ether; chloroform; ethyl acetate; tetrahydrofuran (THF); dichloromethane; hexamethylphosphoric triamide (HMPT); nitromethane; n, N-Dimethylformamide (DMF); acetonitrile, sulfolane; and Dimethylsulfoxide (DMSO); more preferably dimethyl sulfoxide (DMSO); - - (4) in the presence of a carbonate of formula (5.1.0):

(M)₂-CO₃(5.1.0) wherein M is a group 1/Ia alkali metal selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; preferably cesium carbonate, Cs₂CO₃；

Followed by (b) heating the reaction mixture under a nitrogen atmosphere, preferably under reflux, preferably at a temperature of 115-145 ℃, more preferably 125-130 ℃, and preferably for 12-30 hours, more preferably for 17-24 hours; thereby producing a compound of formula (1.3.0).

The above-described sixth embodiment of the present invention, step a + step b + step c of scheme (10.3.1), is a process for the preparation of substantially pure mesylate of formula (1.0.1):(1.0.1)

the method comprises the following steps: - (a) preparation of a compound of formula (2.0.0):

the method comprises the following steps: - - (1) forming a reaction mixture comprising: - - (i) tetrahydro-4- (3-bromo-phenyl) -2H-pyran-4-carbonitrile of formula (3.2.0):- - (ii) 4-fluorophenylthiol of the formula (4.0.0):- - (iii) in a solvent selected from isopropanol, sec-butanol, isoamyl alcohol, and 2-heptanol, and optionally in the form of an aqueous mixture of said alcohols; - - (iv) in a solvent selected from sodium hydroxide, NaOH; and potassium hydroxide, in the presence of a strong base of KOH;

-and further- (v) in the presence of a transition metal catalyst selected from the group consisting of: - - (tetrakis) (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd (0); - - (tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)₂PCH₃]₄Pd (0); bis (methyldiphenylphosphine) palladium (II) trans-dichloride [ (C)₆H₅)₂PCH₃]₂PdCl₂(ii) a - - (O) -bis [ methylenebis (diphenylphosphino) dichloride]A dipalladium-dichloromethane adduct; bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) a An adduct of tris (dibenzylideneacetone) dipalladium (0) -chloroform,

(C₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃(ii) a - - (dibenzylideneacetone) palladium (0), (C)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd; - - (1, 1' -bis (diphenylphosphino) ferrocene) dichloride]Palladium (II) complexes with methylene chloride; - - (di [1, 2-di (diphenylphosphino) ethane)]Palladium (0) complex; and- - (Pi-allyl) palladium (II) chloride dimer;

followed by- - (2) heating to reflux the reaction mixture at 80-84 ℃ for 18-30 hours, preferably 24 hoursWhen the current is over; thereby producing said compound of formula (2.0.0). - (b) forming a reaction mixture comprising: the compounds of formula (2.0.0) and formula (1.3.10):- - (1) in asolvent selected mainly from Tetrahydrofuran (THF); dichloromethane; n, N-Dimethylformamide (DMF); and Dimethylsulfoxide (DMSO), more preferably Dimethylsulfoxide (DMSO); - - (2) in cesium carbonate, Cs₂CO₃In the presence of;

-followed by (c) heating to reflux the reaction mixture under nitrogen atmosphere; thereby producing a compound of formula (1.0.0):

subsequent formation of (d) a concentrated methanolic solution of the compound of formula (1.0.0), followed by addition of methanesulfonic acid, MeSO₃H; followed by further concentration and continuous addition of ethyl acetate until a crystalline product comprising substantially pure mesylate of formula (1.0.1):

-or, alternatively, another method is followed by (e) forming a concentrated methanolic solution of said compound of formula (1.0.0), followed by the addition of methanesulfonic acid, MeSO₃H; the mixture is then filtered, preferably through activated carbon, followed by further concentration and continuous addition of ethyl acetate until a crystalline product comprising substantially pure mesylate of formula (1.0.1) is precipitated.

It will be appreciated that the above-described method for preparing the mesylate salt of the compound of formula (1.0.0) can be readily adapted to the preparation of other similar sulfonates, especially tosylates, of the compound of formula (1.0.0) using the expertise in the art.

The various processes, novel intermediates, and novel end products of this invention are better understood by reference to the examples which illustrate the details of their practice. The following examples of preferred embodiments of the present invention are for illustrative purposes only and are not to be construed as in any way limiting the scope of the present invention, which is to be interpreted by the claims appended hereto.

EXAMPLE 1 Synthesis of tetrahydro-4- (3-bromophenyl) -2H-pyran-4-carbonitrile

In a reaction flask apparatus for boiling reflux, 3-bromobenzacetonitrile (20.0g,102mmol, leq. (eq)), tetrahydrofuran (120ml), 40% aqueous sodium hydroxide solution (180ml, mmol, eq.) and tetrabutylammonium hydrogensulfate (3.46g, mmol,0.1eq.) were stirred. 2, 2' -dichlorodiethyl ether (13.75ml,117.3mmol,0.1eq.) was then added at 20-25 ℃ at room temperature with stirring. The resulting reaction mixture was boiled under reflux at about 64 ℃ for 5-8 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (154ml) was added. The lower aqueous layer was separated and the organic layer was evaporated to give a red oil. To this oil were added isopropanol (100ml) and water (10ml), and the mixture was stirred at 0 ℃ overnight to give a crystalline slurry. The crystalline slurry was filtered under vacuum and washed with isopropanol (2X 20 ml). The resulting white crystalline solid was dried under vacuum at 40-45 ℃. The yield is 18.57g (68.4%) mp 82-85 ℃; m/z 267(m + 1);¹H NMR(300MHz,DMSO)δ7.75(s,1H),7.6(m,2H),7.44(t,1H),4.02(m,2H),3.66(m,2H),2.14(m,4H).

EXAMPLE 2 Synthesis of tetrahydro-4- [3- (4-fluorophenyl) thio]phenyl-2H-pyran-4-carboxamide

Under nitrogen, propan-2-ol (311ml), tetrahydro-4- (3-bromophenyl) -2H-pyran-4-carbonitrile (51.91g,0.195mol,1eq.) potassium hydroxide (25.16g,0.39mol,2eq.), water (4ml,0.39mol,2eq.), tetrakis (triphenylphosphine) palladium (0) (2.26g,0.00195mol,0.01eq.) and 4-fluorobenzothiophenol (25g,0.195mol,1eq.) were added to a reaction flask apparatus for boiling reflux. The resulting mixture was boiled under reflux at about 82 ℃ for 20-24 hours. The reaction mixture was cooled to room temperature(20-25 ℃ C.), and 315ml of water was added to give a slurry. The crude product was isolated by filtration, washed with 1: 1 water: propan-2-ol (125ml) was washed and blotted dry. This dry crude was dissolved in methanol (1900ml) and treated with activated carbon, Darco KB-B (2.5g) and diatomaceous earth filter aid (10g) at reflux temperature (ca. 60 ℃) for 20 minutes. Filtering the activated carbon and the filter aid. The filter cake was washed with hot methanol (200ml) and the washings and main filtrate were combined. The combined filtrate and washings containing the product were concentrated to a volume of about 700ml by distillation. Cooling the concentrate to 10-0 deg.C, granulating at the temperature range for 1-3 hr to promote crystal formation. The product crystals were isolated by filtration, washed with cold methanol (125ml) and dried under vacuum at 40-45 ℃. Yield 40.2g (62.2%). mp 175-; m/z 332(m + 1);¹h NMR (300MHz, DMSO). delta.7.37 (m,8H),7.11(m,2H),3.60(m,2H),2.30(m,2H),2.40(m,2H),1.77(m, 2H); IR (Drift) v_max3394,3198,3078,3014,2970,2931,2880,2824,1681,1664,1664,1623,1588,1569.

EXAMPLE 3 Synthesis of tetrahydro-4- [3- [4- (2-methyl-1H-imidazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide

Under nitrogen atmosphere, add tetrahydro-4- [3- (4-fluorophenyl) thio group into the reaction flask apparatus for boiling reflux]phenyl-2H-pyran-4-carboxamide (25.0g,75.4mmol,1eq.), dimethyl sulfoxide (250ml,10 vol.), 2-methylimidazole (12.39g,150.9mmol,2.0eq.), and cesium carbonate (49.16g,150.9mmol,2.0eq.), and the reaction mixture was heated at 125-. After the reaction was complete, the reaction was cooled (<30 ℃ C.) and quenched with water (250ml,10vol) with the result that a precipitate formed. An exotherm of 10-15 ℃ was observed during the addition of water. The resulting reaction slurry was cooled to room temperature (15-25 ℃ C.), followed by granulation for 1 hour.The resulting product was isolated by vacuum filtration and washed with water (175ml,7 vol). The product was dried in a vacuum oven at 40-45 ℃ overnight. Yield 27.85g, 94%: mp 198-200 ℃; m/z 396(m + 1);¹h NMR (300MHz, DMSO). delta.7.41 (m,10H),7.12(s,1H),6.93(d,1H),3.75(m,2H),3.48(t,2H),2.48(d,2H),2.3(s,3H),1.75(m, 2H); IR (Drift) v_max3402,3301,3123,3096,2971,2930,2880,1680,1663,1622,1593,1569,1528.

EXAMPLE 4 formation of the mesylate salt

In a reaction flask set-up for boiling reflux was charged methanol (640ml,40vol), tetrahydro-4- [3- [4- (2-methyl-1H-imidazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide (16.0g,40.7mmol,1.0eq.) prepared by the method of example 3, activated carbon, Darco KB-B (0.80g) and filter aid diatomaceous earth (2.4 g). The mixture was heated to reflux (about 66 ℃) to dissolve the organics. The contents of the reaction flask were cooled to 55-60 deg.C and the activated carbon and filter aid were filtered off at 55-60 deg.C. The residue was washed with methanol (50ml) and the washings and the original filtrate were then combined. The combined clear solution of the filtrate and the washing solution thus obtained was concentrated by distillation at normal pressure to a volume of about 700 ml. To the concentrated methanol solution was added methanesulfonic acid (4.1g,42.7mmol,1.05 eq.). The resulting solution was further concentrated by atmospheric distillation to a volume of about 250ml and 500ml of ethyl acetate were added in two equal portions, the final volume being reduced to 250ml by distillation after each addition of ethyl acetate. Cooling the resulting crystalline slurry to room temperature 15-25 deg.C, and granulating at 15-25 deg.C for 4-16 hr. The white crystalline product was isolated by filtration, washed with ethyl acetate (135ml) and dried in vacuo at 45-50 ℃. Yield 18.39g, 92.3%. The resulting salt was characterized by an X-ray powder diffraction pattern and had the major peaks shown in table 2 below:

TABLE 2

Peak number	2θ(Gl.Theta)°	d space (_)	Peak number	2θ(Gl.Theta)°	d space (_)
						1	6.5	13.6	20	24.0	3.7
2	9.1	9.7	21	24.55	3.6
						3	13.35	6.6	22	25.4	3.5
4	14.2	6.2	23	26.1	3.4
						5	14.4	6.1	24	26.7	3.3
6	15.1	5.9	25	27.7	3.2
						7	15.4	5.7	26	28.65	3.1
8	16.0	5.5	27	29.3	3.0
						9	16.7	5.3	28	30.0	3.0
10	17.2	5.1	29	30.5	2.9
						11	17.85	5.0	30	31.7	2.8
12	18.25	4.85	31	32.8	2.7
						13	19.0	4.7	32	33.8	2.65
14	19.9	4.4	33	35.3	2.5
						15	21.0	4.2	34	36.0	2.5
16	22.0	4.0	35	36.7	2.4
						17	22.3	4.0	36	37.6	2.4
18	22．9	3.9	37	39.2	2.3
						19	23.6	3.8

EXAMPLE 5 recrystallization of tetrahydro-4- [3- [4- (2-methyl-1H-imidazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide

Methanol (3200 ml,40vol), tetrahydro-4- [3- [4- (2-methyl-1H-imidazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide (80.29), activated carbon, Darco KB-B (4.09), and filter aid diatomaceous earth (10g) were charged into a reaction flask set-up for boiling reflux. The mixture was heated to reflux (about 66 ℃) to dissolve the organics. The contents of the reaction flask were cooled to 55-60 deg.C and the activated carbon and filter aid were filtered off at 55-60 deg.C. The residue was washed with methanol (300ml) and the washings and the original filtrate were then combined. The combined clear solution of the filtrate and the washing solution thus obtained was concentrated by atmospheric distillation to a volume of about 1000 ml. The methanol concentrate thus obtained is cooled to 3-7 ℃ to crystallize the product and granulated in this temperature range for 6-24 hours. The white product crystals were isolated by filtration and dried under vacuum at 40-45 ℃. Yield 70.3g, 87.7%. mp 198-200 ℃; m/z 396(m + 1). Spectroscopic data as in example 3.

EXAMPLE 6 Synthesis of tetrahydro-4- [3- [4- (1H-imidazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide

Under nitrogen atmosphere, add tetrahydro-4- [3- (4-fluorophenyl) thio group into the reaction flask apparatus for boiling reflux]phenyl-2H-pyran-4-carboxamide (2.0g,6.02mmol,1eq.), dimethyl sulfoxide (20ml,10 vol.), imidazole (0.822g,12,07mmol,2.0eq.), and cesium carbonate (3.93g,12.07mmol,2.0eq.), and the reaction mixture was heated and stirred at 142 ℃ for 5 hours under a nitrogen atmosphere. After the reaction was complete, the reaction was cooled (<30 ℃ C.) and quenched by addition of water (20ml,10vol) with the formation of a precipitate. An exotherm of 10-15 ℃ was observed during the addition of water. The resulting reaction slurry was cooled to room temperature (15-25 ℃ C.), followed by granulation for 1 hour. The product was isolated by vacuum filtration and washed with water (20ml,10vol) to give the crude product. The crude product was then dried in a vacuum oven at 40 ℃ overnight. The dry solid was then dissolved in water (200ml), adjusted to pH2 with 6N dilute hydrochloric acid, followed by extraction with dichloromethane (3 × 50 ml). The product-containing aqueous layer was adjusted to pH14 with 50% aqueous sodium hydroxide solution to precipitate the product. Granulation of the resulting slurryThe solution was filtered for 5 hours then under vacuum to give a white solid after drying (1.76g, 77%): mp 176-; m/z 380(m + 1); (found: C, 65.94; H, 5.45; N, 10.76; S,8.56. C)₂₁H₂₁N₃O₂S required value: c, 66.47; h, 5.58; n, 11.07; s.8.45).¹H NMR(300MHz,DMSO)δ8.32(s,1H),7.80(s,1H),7.70(d,2H),7.44(m,3H),7.26(d,3H),7.22(s,1H),7.21(d,1H),7.13(d,2H),3.7(m,2H),3.49(t,2H),2.44(d,2H),1.81(m,2H)；¹³CNMR (75MHz, DMSO) δ 175.9,147.15,137.25,136.80,135.62,134.39,133.09,131.30,130.95,130.25,129.54,126.41,122.52,119.15,65.93,49.06, 35.21; IR (Drift) v_max3381,3177,1684,1667,1508.

EXAMPLE 7 Synthesis of tetrahydro-4- [3- [4- (1H-pyrazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide

Under nitrogen atmosphere, add tetrahydro-4- [3- (4-fluorophenyl) thio group into the reaction flask apparatus for boiling reflux]phenyl-2H-pyran-4-carboxamide (2.0g,6.02mmol,1eq.), dimethyl sulfoxide (20ml,10 vol.), pyrazole (0.822g,12,07mmol,2.0eq.), and cesium carbonate (3.93g,12.07mmol,2.0eq.), and the reaction mixture was heated and stirred at 142 ℃ for 5 hours under a nitrogen atmosphere. After the reaction was complete, the reaction was cooled (<30 ℃ C.) and quenched by addition of water (20ml,10vol) with the formation of a precipitate. An exotherm of 10-15 ℃ was observed during the addition of water. The resulting reaction slurry was cooled to room temperature (15-25 ℃ C.), followed by granulation for 1 hour. The product was isolated by vacuum filtration and washed with water (20ml,10vol) to give the crude product. The crude product was then dried in a vacuum oven at 40 ℃ overnight. This crude product was dissolved in methanol (290ml) to form a solution, which was filtered, concentrated to initiate crystallization, and after granulation at room temperature for a period of time, the product was isolated by filtration and dried to give a white solid (1.5g, 65%): mp 196-198 ℃; m/z 380(m + 1); (found: C, 66.09; H, 5.6; N, 10.87; S,9.06.C₂₁H₂₁N₃O₂S required value: c, 66.47; h, 5.58; n, 11.07; s.8.45).¹H NMR (300MHz, DMSO). delta.8.55 (d,1H),7.89(d,2H),7.79(s,1H),7.38(m,6H),7.18(d,1H),7.1(s,1H),6.58(t,1H),3.75(d,2H),3.47(t,2H),2.42(d,2H),1.76(m, 2H); IR (float)V) is moved_max3374,3180,1681,1520,1498.

EXAMPLE 8 Synthesis of tetrahydro-4- [3- [4- (1H-benzimidazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide

Under nitrogen atmosphere, add tetrahydro-4- [3- (4-fluorophenyl) thio group into the reaction flask apparatus for boiling reflux]phenyl-2H-pyran-4-carboxamide (2.0g,6.02mmol,1eq.), dimethyl sulfoxide (20ml,10 vol.), benzimidazole (1.43g,12,07mmol,2.0eq.), and cesium carbonate (3.93g,12.07mmol,2.0eq.), and the reaction mixture was heated and stirred at 142 ℃ for 5 hours under nitrogen atmosphere. After the reaction was complete, the reaction was cooled (<30 ℃ C.) and quenched by addition of water (20ml,10vol) with the formation of a precipitate. An exotherm of 10-15 ℃ was observed during the addition of water. Cooling stationThe resulting reaction slurry was brought to room temperature (15-25 ℃ C.), followed by granulation for 1 hour. The product was isolated by vacuum filtration and washed with water (20ml,10vol) to give the crude product. The crude product was then dried in a vacuum oven at 40 ℃ overnight. This crude product was dissolved in acetonitrile (130ml) to form a solution, which was filtered and cooled to initiate crystallization, after granulation at room temperature for a period of time, the product was isolated by filtration, washed with acetonitrile (36ml) and dried to give a white solid (1.9g, 74%): mp 166-168 ℃; m/z 430(m + 1); (found: C, 68.59; H, 5.27; N, 9.65; S,7.64. C)₂₅H₂₃N₃O₂S required value: c, 69.91; h, 5.40; n, 9.78; s.7.47).¹H NMR (300MHz, DMSO). delta.8.59 (s,1H),7.80(d,1H),7.72(d,2H),7.65(d,1H),7.49-7.34(m,9H),7.13(s,1H),3.76(d,2H),3.49(t,2H), 2.45(d,2H),1.82(m, 2H); IR (Drift) v_max3370,3188,1683,1669.1501．

EXAMPLE 9 Synthesis of tetrahydro-4- [3- [4- (4-methyl-1H-pyrazol-1-yl) phenyl]thio]phenyl-2H-pyran-4-carboxamide

Under nitrogen atmosphere, add tetrahydro-4- [3- (4-fluorophenyl) thio group into the reaction flask apparatus for boiling reflux]phenyl-2H-pyran-4-carboxamide (2.0g,6.02mmol,1eq.), dimethyl sulfoxide (20ml,10 vol.), 4-methylpyrazole (0.991g,12,07mmol,2.0eq.), and cesium carbonate (3.93g,12.07mmol,2.0eq.), and was heated at 142 ℃ under a nitrogen atmosphereThe reaction mixture was stirred for 5 hours. After the reaction was complete, the reaction was cooled (<30 ℃ C.) and quenched by addition of water (20ml,10vol) with the formation of a precipitate. An exotherm of 10-15 ℃ was observed during the addition of water. The thus-formed reaction slurry was cooled to room temperature (15-25 ℃ C.), followed by granulation for 1 hour. The product was isolated by vacuum filtration and washed with water (20ml,10vol) to give the crudeproduct. The crude product was then dried in a vacuum oven at 40 ℃ overnight. This crude product was dissolved in acetonitrile (70ml) and propan-2-ol (115ml) to form a solution, concentrated after filtration until the solution became cloudy, crystalline formed after a period of granulation at 3-7 ℃, the product isolated by filtration, washed with cold propan-2-ol (20ml) and dried to give a white solid (2.034g, 86%): mp 202-204 ℃; m/z 394(m + 1); (found: C, 66.99; H, 6.05; N, 10.47; S,8.21. C)₂₂H₂₃N₃O₂S required value: c, 67.15; h, 6.05; n, 10.47; s.8.21).¹H NMR(300MHz,DMSO)δ8.31(s,1H),7.82(d,2H),7.60(s,1H),7.39(m,6H),7.16(dt,1H),7.10(s,1H),3.73(d,2H),3.46(t,2H),2.47(d,2H) 2.11(s,3H),1.78(m, 2H); IR (Drift) v_max3370,3181,1682,1506.

EXAMPLE 10 Synthesis of tetrahydro-4- (3-bromophenyl) -2H-pyran-4-carboxamide

Under nitrogen, propan-2-ol (100ml), tetrahydro-4- (3-bromophenyl) -2H-pyran-4-carbonitrile (20.0g,0.075mol,1eq.) and potassium hydroxide (13.74g,0.245mol,3.26eq.) were charged to a boiling reflux reaction flask set-up and the reaction mixture was heated to reflux under nitrogen with stirring at about 82 ℃ for 5-6 hours. After the reaction was complete, the mixture was cooled (<30 ℃ C.) and quenched with water (100 ml). The resulting slurry was filtered and the product residue washed with water (30ml) and dried under vacuum at 45-50 ℃ to give a white solid. Yield 19.05g, 89.2%. mp 245-247 deg.C; m/z 285(m + 1);¹h NMR (300MHz, DMSO). delta.7.43 (m,5H),7.14(s,1H),3.76(d,2H),3.47(t,2H),2.44(d,2H),1.79(m, 2H); IR (Drift) v_max3363,3174,3062,2973,2935,2879,2828,1685,1631,1588.

EXAMPLE 11 Synthesis of tetrahydro-4- [3- (4-fluorophenyl) thio]phenyl-2H-pyran-4-carboxamide

Under nitrogen, in a reaction flask apparatus for boiling reflux,butan-1-ol (8ml), tetrahydro-4- (3-bromophenyl) -2H-pyran-4-carboxamide (2.97g,10.45mmol,1eq.), potassium tert-butoxide (2.34g,20.9mmol,2eq.), water (4ml,0.39mol,2eq.), tetrakis (triphenylphosphine) palladium (0) (0.242g,0.209mol,0.02eq.), and 4-fluorobenzothiophenol (1.34g,10.45mol,1eq.) were added. The resulting reaction mixture was heated at about 100 ℃ to drive the reaction to completion. The reaction mixture was cooled to room temperature (20-25 ℃ C.), and butan-1-ol (10ml) was added to give a syrup. The crude product was isolated by filtration, washed with butan-1-ol (3ml) and sucked dry. The dry crude product was stirred in methanol (15ml) and the resulting slurry was filtered, the product cake was washed with methanol (5ml) and dried under vacuum at 40-45 ℃. The partially purified product was heated at reflux in propan-2-ol (45ml) for 30 minutes, cooled and the resulting slurry filtered, and the product cake washed with propan-2-ol (5ml) followed by vacuum drying at 40-45 ℃. The resulting solid (3.22g) was further purified by stirring in tetrahydrofuran (240ml) at 20-25 ℃. Insoluble solid impurities were filtered off, and the filtrate containing the product was concentrated to 20ml and treated with heptane (20 ml). The resulting product slurry was filtered, and the product cake was washed with heptane (8ml) and dried under vacuum at 40-45 ℃. Yield 1.62g (46.8%). mp 175-; m/z 332(m + 1); spectral data are given in example 2.

Claims (10)

1. Tetrahydro-4- [3- (4-fluorophenyl) thio group of formula (2.0.0)]phenyl-2H-pyran-4-carboxamide:

2. a process for preparing a compound of formula (2.0.0):

the method comprises the following steps: - - (a) forming a reaction mixture comprising: - - (1) tetrahydro-4- (3-bromo-or iodo-phenyl) -2H-pyran-4-carbonitrile of formula (3.0.0):wherein X is bromine or iodine; and- (2) 4-fluorophenylthiol of the formula (4.0.0):--(3) in a solvent consisting of a linear or branched aliphatic alcohol having 2 to 7 total carbon atoms, optionally in the form of an aqueous mixture thereof; - - (4) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and- - - -R⁵Is hydrogen, H; or straight or branched (C)₁-C₄) An alkyl group;

-and further- (5) in the presence of a transition metal catalyst comprising a palladium metal complex;

followed by (b) heating the reaction mixture, thereby producing the compound of formula (2.0.0), and optionally isolating using conventional isolation techniques.

3. A process for preparing a compound of formula (2.0.0):the method comprises the following steps: forming a reaction mixture comprising: - - (1) tetrahydro-4- (3-bromo-or iodo-phenyl) -2H-pyran-4-carbonitrile of formula (3.0.0):

wherein X is bromine or iodine; - - (2) in a solvent constituted by linear or branched aliphatic alcohols having 2 to 7 total carbon atoms, optionally in the form of an aqueous mixture thereof; - - (3) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and- - - -R⁵Is hydrogen, H; or straight or branched (C)₁-C₄) An alkyl group;

-follow-up- (b) heating the reaction mixture, preferably under reflux, and preferablyHeating for 3 to 8 hours, more preferably 5 to 6 hours; thereby producing a compound of formula (3.1.0):wherein X is bromine or iodine;

-further (c) forming a reaction mixture comprising: the compound of formula (3.1.0) and 4-fluorophenylthiol of formula (4.0.0):- - (1) in a solvent constituted by the above-mentioned alcohols, optionally in the form of an aqueous mixture thereof; - - (2) in the presence of a strong base of formula (5.0.0):

M-O-R⁵(5.0.0)

wherein- - - -M and R⁵As defined above;

-and further- (3) in the presence of a transition metal catalyst comprising a palladium metal complex;

-subsequently- (d) heating the reaction mixture, preferably under reflux, and preferably for 5-15 hours, more preferably for 8-10 hours; thereby producing said compound of formula (2.0.0).

4. A process for preparing a compound of formula (1.3.0):

wherein-a moiety of formula (1.3.1):an electron-deficient monocyclic or benzo-fused bicyclic N-heterocyclic groupcontaining two nitrogen atoms represented by the following formula (1.3.2), (1.3.3), (1.3.4) or (1.3.5):

wherein "-" represents a symbol of a connecting position of a moiety of formula (1.3.2), (1.3.3), (1.3.4) or (1.3.5); - - -R⁷And R⁸Independently selected from H; straight or branched chain (C)₁-C₄) An alkyl group; and (C)₆-C₁₀) An aryl group; wherein the alkyl and aryl groups are substituted with 0 to 2 substituents selected fromGeneration: halogen, hydroxy, cyano, amino, (C)₁-C₄) Alkyl radical (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylthio (C)₁-C₄) Haloalkyl (C)₁-C₄) Haloalkoxy, (C)₁-C₄) Alkylamino, and di (C)₁-C₄) An alkylamino group;

the method comprises the following steps: forming a reaction mixture comprising: - - (1) tetrahydro-4- [3- (4-fluorophenyl) thio group of the formula (2.0.0)]phenyl-2H-pyran-4-carboxamide:

and- - (2) an electron-deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms of the formula (1.3.6), (1.3.7), (1.3.8) or (1.3.9):

wherein R is⁷And R⁸Have the same meaning as described above; - - (3) in an aprotic solvent; - - (4) in the presence of a carbonate of formula (5.1.0):

(M)₂-CO₃(5.1.0) wherein M is a group 1/Ia alkali metal selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs;

-subsequently- (b) heating the reaction mixture under nitrogen atmosphere; thereby producing a compound of formula (1.3.0).

5. A process according to claim 4 for the preparation of a compound of formula (1.3.0), wherein the compound of formula (1.3.0) is selected from:

tetrahydro-4- {3- [4- (2-methyl-1H-imidazol-1-yl) phenyl]thio } phenyl-2H-pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-imidazol-1-yl) phenyl]thio } phenyl-2H-pyranyl

Pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-benzimidazol-1-yl) phenyl]thio } phenyl-2H

-pyran-4-carboxamide;

tetrahydro-4- {3- [4- (1H-pyrazol-1-yl) phenyl]thio } phenyl-2H-pyri-dine

Pyran-4-carboxamide; and

tetrahydro-4- {3- [4- (4-methyl-1H-pyrazol-1-yl) phenyl]thio } phenyl

-2H-pyran-4-carboxamide.

6. A process for preparing a compound of formula (1.0.0):

the method comprises the following steps: forming a reaction mixture comprising: - - (1) tetrahydro-4- [3- (4-fluorophenyl) thio group of the formula (2.0.0)]phenyl-2H-pyran-4-formamide:- - (2) 2-methylimidazole; - - (3) in an aprotic solvent; - - (4) in the presence of a carbonate of formula (5.1.0):

(M)₂-CO₃(5.1.0)

wherein- - -M is a group 1/Ia alkali metal element selected from: lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs;

followed by (b) heating the reaction mixture under a nitrogen atmosphere, thereby producing the compound of formula (1.3.0).

7. The method according to claim 6, wherein said aprotic solvent is dimethyl sulfoxide (DMSO).

8. The process according to claim 6, wherein the carbonate is cesium carbonate.

9. A process for preparing a substantially pure mesylate salt of formula (1.0.1):the method comprises the following steps: - (a) preparation of a compound of formula (2.0.0):the method comprises the following steps: - - (1) forming a reaction mixture comprising: - - (i) formula(3.2.0) tetrahydro-4- (3-bromo-phenyl) -2H-pyran-4-carbonitrile:- - (ii) 4-fluorophenylthiol of the formula (4.0.0):- - (iii) in a solvent selected from isopropanol, sec-butanol, isoamyl alcohol, and 2-heptanol, optionally in the form of an aqueous mixture thereof; - - (iv) in a solvent selected from sodium hydroxide, NaOH; and potassium hydroxide, KOH; in the presence of a strong base of (a);

-and further- (v) in the presence of a transition metal catalyst comprising a metal independently selected from palladium complexes;

-subsequently- (2) heating the reaction mixture; thereby producing said compound of formula (2.0.0); - (b) forming a reaction mixture comprising: the compounds of formula (2.0.0) and formula (1.3.10):- - (1) in an aprotic solvent, preferably dimethyl sulfoxide (DMSO); - - (2) in cesium carbonate, Cs₂CO₃In the presence of;

-subsequently- (c) heating the reaction mixture under nitrogen atmosphere; thereby producing a compound of formula (1.0.0):

subsequent formation of a concentrated methanolic solution of said compound of formula (1.0.0) followed by addition of methanesulfonic acid, MeSO₃H; followed by further concentration and continuous addition of ethyl acetate until a crystalline product comprising substantially pure mesylate of formula (1.0.1):

alternatively, another method is followed by (e) forming a concentrated methanolic solution of said compound of formula (1.0.0), followed by the addition of methanesulfonic acid, MeSO₃H; the mixture is then filtered, preferably through activated carbon, followed by further concentration and continuous addition of ethyl acetate until substantially pure formula (1.0) is precipitated1) crystalline product of the mesylate salt.

10. The method according to claim 9, wherein the palladium metal complex is selected from the group consisting of: tetrakis (triphenylphosphine) palladium (0) [ (C)₆H₅)₃P]₄Pd (0); tetrakis (methyldiphenylphosphine) palladium (0) [ (C)₆H₅)2PCH₃]₄Pd (0); bis (methyldiphenylphosphine) bis (II) bis (trans) -dichloride [ (C)₆H₅)₂PCH₃]₂PdCl₂(ii) a Bis [ methylenebis (diphenylphosphino) dichloride]A dipalladium-dichloromethane adduct; bis (triphenylphosphine) palladium (II) dichloride, [ (C)₆H₅)₃P]₂PdCl₂(ii) aTris (dibenzylideneacetone) dipalladium (0) -chloroform adduct, (C)₆H₅CH=CHCOCH=CHC₆H₅)₃Pd₂·CHCl₃(ii) a Bis (dibenzylideneacetone) palladium (0), (C)₆H₅CH=CHCOCH=CHC₆H₅)₂Pd; [1, 1' -bis (diphenylphosphino) ferrocene]dichloride]Palladium (II) complexes with methylene chloride; bis [1, 2-bis (diphenylphosphino) ethane]Palladium (II) complex; and (pi-allyl) palladium (II) chloride dimer.