Process for preparing 3-chloro-4-(pyridin-3-YL)-1,2,5-thiadiazole

Abstract

Disclosed is a process for preparing 3-chloro-4-(pyridin-3-yl)-l,2,5- thiadiazole: (I)

Description

[0001] PROCESS FOR PREPARING 3-CHLORO-4-(PYRIDIN-3-YL)-l,2,5-THIADIAZOLE

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No.

[0004] 63 / 698,769 filed September 25, 2024 which is incorporated herein in its entirety.

[0005] FIELD OF THE INVENTION

[0006] The present invention generally relates to a process for preparing 3-chloro-4- (pyridin-3-yl)-l,2,5-thiadiazole.

[0007] BACKGROUND OF THE INVENTION

[0008] Xanomeline is a M1-M4 muscarinic receptor agonist being evaluated as a therapeutic agent for the treatment of bipolar, schizophrenia, cognitive impairment associated with schizophrenia, psychosis in Alzheimer disease, Alzheimer’s disease with agitation, and autism. Xanomeline has the chemical structure:

[0009] (Bymaster et al., Drug Dev. Res. 1997, 40, 158-170). U.S. Patent 5,043,345 discloses xanomeline and a preparation process from the precursor compound 3-(4-chloro-l,2,5- thiadiazol-3-yl)pyridine in Example 9.

[0010] The precursor compound, 3-(4-chloro-l,2,5-thiadiazol-3-yl)pyridine, has the structure of Formula (I):

[0011] Other chemical names for the compound of Formula (I) include 3-(3-chloro-l,2,5- thiadiazol-4-yl)pyridine and 3-chloro-4-(pyrid-3-yl)-l,2,5-thiadiazole. The compound of Formula (I) can be prepared by a process employing S2CI2, as disclosed in Example 1 of U.S. Patent 5,043,345.

[0012] U.S. Patent 6,620,940 Bl discloses the preparation of the compound of Formula (I) by reaction of 3,4-dichloro-l,2,5-thiadiazole and diethyl(3-pyridyl)borane in the presence of tetrakis(triphenylphosphine)palladium(0) with a yield of 18%. Also disclosed are preparations of the compound of Formula (I) by reaction of 3,4-dichloro-l,2,5- thiadiazole and tributyl(3-pyridyl)stannane in the presence of several palladium catalysts including tetrakis(triphenylphosphine)palladium(0), bis(acetonitrile)palladium dichloride, palladium(II) acetate, and tris(dibenzylideneacetone)dipalladium(0).

[0013] The preparation of compound of Formula (I) is disclosed in Merschaert et al., Heterocycles, 60(1), 2003, pp. 29-45 by a Suzuki cross-coupling of 3,4-dichloro-l,2,5- thiadiazole with either 3-pyridylboronic acid or diethyl(3-pyridyl)borane in the presence of a tetrakis(triphenylphosphine)palladium(0) catalyst.

[0014] The reported yields in Table 3 of the reference are 18 mol % or less. The reference discloses: “However, this cross-coupling reaction using as substrate 3,4-dichloro-l,2,5- thiadiazole suffers from a major selectivity issue due to a competitive side-reaction by degradation of the heterocyclic nucleus. Due to the intrinsic reactivity of the strong electron-deficient heterocycle 3,4-dichloro-l,2,5-thiadiazole, this unwanted desulfurization side-reaction by the Pd-catalyst cannot be avoided. Therefore, the productivity of this reaction remains limited and varies dramatically depending on the nature of the reagents and catalysts typically used in the Stille or Suzuki approaches.”

[0015] The use of sulfur monochloride, S2CI2, requires special procedures and equipment and can limit the batch size.

[0016] Desired in the art is an improved process for preparing 3-chloro-4-(pyridin-3-yl)-

[0017] 1.2.5-thiadiazole.

[0018] Desired in the art is a process for preparing 3-chloro-4-(pyridin-3-yl)-l,2,5- thiadiazole with a high yield.

[0019] Desired in the art is an improved process for preparing 3-chloro-4-(pyridin-3-yl)-

[0020] 1.2.5-thiadiazole with high yield and that does not require the use of reagents or synthesis adjuvants requiring special procedures and / or equipment.

[0021] Desired in the art is an improved process for preparing 3-chloro-4-(pyridin-3-yl)-

[0022] 1,2,5-thiadiazole with high yield and that does not require use of an organotin compound.

[0023] Desired in the art is a process for preparing 3-chloro-4-(pyridin-3-yl)-l,2,5- thiadiazole with a high yield and that minimizes the formation of side-products.

[0024] Desired in the art is a process for preparing 3-chloro-4-(pyridin-3-yl)-l,2,5- thiadiazole with a high yield and that is adaptable to large scale manufacturing.

[0025] Desired in the art is a process for preparing 3-chloro-4-(pyridin-3-yl)-l,2,5- thiadiazole with a high yield, which does not require the use of reagents or synthesis adjuvants requiring special procedures and / or equipment, and is adaptable to large scale manufacturing.

[0026] Applicants have discovered a new synthesis process for the preparation of 3- chloro-4-(pyridin-3-yl)-l,2,5-thiadiazole. The process provides 3-chloro-4-(pyridin-3- yl)-l,2,5-thiadiazole in high yield, minimizes the formation of side-products, is adaptable to large scale manufacturing, and / or does not require the use of reagents or synthesis adjuvants requiring special procedures or equipment.

[0027] SUMMARY OF THE INVENTION

[0028] The present invention provides a synthesis process for making 3-chloro-4- (pyridin-3-yl)-l,2,5-thiadiazole.

[0029] The present invention also provides (l'-(dicyclohexylphosphino)-l,2,3,4,5- pentaki s(2-naphthyl)ferrocene) .

[0030] These and other features of the invention will be set forth in expanded form as the disclosure continues.

[0031] DETAILED DESCRIPTION

[0032] The first aspect of the invention provides a process for preparing a compound of Formula (I): comprising the step of reacting a compound of Formula (II) and a compound of Formula in the presence of a catalyst and a ligand to provide said compound of Formula (I); wherein: each R is independently hydrogen or C1-4 alkyl; or two R are joined together to form a bridge selected from -C(CH3)2C(CH3)2-, -C(CH2CH3)2C(CH2CH3)2- -(CH2)3- and -CH2C(CH3)2CH2-; said catalyst is tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), (l-methylallyl)palladium(II) chloride dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(cinnamyl) chloride dimer, and (l,l-bis(diphenylphosphino)ferrocene) dichloro palladium(II); and said ligand is (l'-(dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl)ferrocene), (T- (dicyclohexylphosphino)-l,2,3,4,5-pentakis(aryl)ferrocene), where said aryl group is phenyl, 3,5-dimethyl phenyl, 3-methyl phenyl, 4-methoxy phenyl, 4-trifluoromethyl phenyl, 2 substituted 9,9-dimethyl-9 / / -fluorene, 3 substituted 9,9-dimethyl-9 / / - fluorene, 2-substituted dibenzo[Z>, t / ] furan, or 3-substituted dibenzo[Z>, t / ]furan.

[0033] The second aspect of the invention provides a compound of Formula (IV) having the structure:

[0034] The process for preparing the compound of Formula (I) is a Suzuki coupling reaction. In this process, one chlorine atom attached to 3,4-dichloro-l,2,5-thiadiazole is replaced by a 3-pyridinyl group.

[0035] One embodiment provides a process for preparing a compound of Formula (I): comprising the step of reacting a compound of Formula (Ila) and a compound of Formula (III): in the presence of a catalyst and a ligand to provide said compound of Formula (I); wherein: said catalyst is tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), (l-methylallyl)palladium(II) chloride dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(cinnamyl) chloride dimer, and (l,l-bis(diphenylphosphino)ferrocene) dichloro palladium(II); and said ligand is (l'-(dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl)ferrocene), (1'- (dicyclohexylphosphino)-l,2,3,4,5-pentakis(aryl)ferrocene), where said aryl group is phenyl, 3,5-dimethyl phenyl, 3-methyl phenyl, 4-methoxy phenyl, 4-trifluoromethyl phenyl, 2 substituted 9,9-dimethyl-9 / / -fluorene, 3 substituted 9,9-dimethyl-9 / / - fluorene, 2-substituted dibenzo[Z>, t / ] furan, or 3-substituted dibenzo[Z>, ]furan.

[0036] Included in this embodiment is a process in which said catalyst is tris(dibenzylideneacetone)dipalladium(0). Also included in this embodiment is a process in which said ligand is (l'-(dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl) ferrocene). Additionally, included in this embodiment is a process in which said catalyst is tris(dibenzylideneacetone)dipalladium(0) and said ligand is (1'- (dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl)ferrocene).

[0037] In one embodiment, a process is provided according to the first aspect of the invention wherein each R is independently hydrogen, or Ci-4 alkyl. Included in this embodiment is a process in which each R is hydrogen. Also included in this embodiment is a process in which each R is C1-3 alkyl.

[0038] In one embodiment, a process is provided according to the first aspect of the invention wherein the two R are joined together to form a -C(CH3)2-C(CH3)2- bridge.

[0039] In one embodiment, a process is provided according to the first aspect of the invention wherein said catalyst is tris(dibenzylideneacetone)dipalladium(0).

[0040] In one embodiment, a process is provided according to the first aspect of the invention wherein said catalyst is bis(dibenzylideneacetone)palladium(0).

[0041] In one embodiment, a process is provided according to the first aspect of the invention wherein said catalyst is (l-methylallyl)palladium(II) chloride dimer.

[0042] In one embodiment, a process is provided according to the first aspect of the invention wherein said catalyst is (2-methylallyl)palladium(II) chloride dimer.

[0043] In one embodiment, a process is provided according to the first aspect of the invention wherein said catalyst is palladium(cinnamyl) chloride dimer.

[0044] In one embodiment, a process is provided according to the first aspect of the invention wherein said catalyst is (l,l-bis(diphenylphosphino)ferrocene) dichloro palladium(II).

[0045] In one embodiment, a process is provided according to the first aspect of the invention wherein said ligand is (l'-(dicyclohexylphosphino)-l,2,3,4,5-pentakis(2- naphthyl)ferrocene).

[0046] In one embodiment, a process is provided according to the first aspect of the invention wherein said ligand is (l'-(dicyclohexylphosphino)-l,2,3,4,5- pentakis(aryl)ferrocene), where said aryl group is phenyl, 3,5-dimethyl phenyl, 3-methyl phenyl, 4-methoxy phenyl, 4-trifluoromethyl phenyl, 2-substituted 9,9-dimethyl-97 / - fluorene, 3-substituted 9,9-dimethyl-97 / -fluorene, 2-substituted dibenzo[Z>, t / ] furan, or 3- substituted dibenzo[Z>, ]furan.

[0047] In one embodiment, a process is provided according to the first aspect of the invention wherein said process is conducted in the presence of from 2 % to 12 % equivalents of said catalyst.

[0048] In one embodiment, a process is provided according to the first aspect of the invention wherein said process is conducted in the presence of from 2 % to 9 % equivalents of said catalyst.

[0049] In one embodiment, a process is provided according to the first aspect of the invention wherein said process is conducted in the presence of from 2 % to 6 % equivalents of said catalyst.

[0050] In one embodiment, a process is provided according to the first aspect of the invention wherein the reaction is conducted in the presence of from 2 % to 6 % equivalents of said ligand.

[0051] In one embodiment, a process is provided according to the first aspect of the invention wherein the reaction is conducted in the presence of from 2 % to 5 % equivalents of said ligand.

[0052] In one embodiment, a process is provided according to the first aspect of the invention wherein the reaction is conducted in the presence of from 2 % to 4 % equivalents of said ligand.

[0053] In one embodiment, a process is provided according to the first aspect of the invention wherein the reaction is conducted in the presence of from 2 % to 12 % equivalents of said catalyst and from 2 % to 6 % equivalents of said ligand.

[0054] In one embodiment, a process is provided according to the first aspect of the invention wherein the reaction is conducted in the presence of from 2 % to 9 % equivalents of said catalyst and from 2 % to 5 % equivalents of said ligand. In one embodiment, a process is provided according to the first aspect of the invention wherein the reaction is conducted in the presence of from 2 % to 6 % equivalents of said catalyst and from 2 % to 4 % equivalents of said ligand.

[0055] Various synthetic conditions can be employed to prepare the compound of Formula (I) by reacting the compound of Formula (II) and the compound of Formula (III).

[0056] Other synthesis adjuvants can be used in the process to prepare the compound of Formula (I), including pinacol, trimethyl borate, zinc acetate, and zinc triflate; and bases including K3PO4, NasPO4, K2CO3, Na2CO3, and CS2CO3. A suitable amount of base includes from 2 to 3 equivalents.

[0057] The reaction is sensitive to oxygen. Sparging of the reagents and / or the reaction mixture with an inert gas such as nitrogen or argon may be employed to displace any dissolved oxygen prior to the start of the reaction.

[0058] The reaction between the compound of Formula (II) and the compound of Formula (III) to provide the compound of Formula (I) can be conducted in various solvents or mixtures thereof. Examples of suitable solvents include, for example, nonpolar solvents such as toluene, O-xylene, mesitylene, water, 2-methyltetrahydrofuran, dioxane, isopropyl alcohol, tertiary amyl alcohol, diethyl carbonate, and mixtures thereof. Suitable mixtures include toluene and water mixtures within the range of from 2: 1 to 4: 1 volume ratio.

[0059] Suitable reaction temperatures for the reaction between the compound of Formula (II) and the compound of Formula (III) include temperatures in the range of from about 50 °C to about 80 °C, temperatures in the range of from about 55 °C to about 70 °C, and temperatures in the range of from about 55 °C to about 65 °C.

[0060] The compound of Formula (I) can be isolated and / or purified by various methods known in the art. Suitable methods include chromatography and crystallization from a solvent such as methanol, pentane, n-heptane, dichloromethane, toluene, ethyl acetate, methyl-tert-butyl ether, or a mixture thereof; and collection of the solids by filtration (purity >98%).

[0061] The compound of Formula (I) can be isolated and / or purified by various methods known in the art. Suitable methods include chromatography and crystallization from a water, toluene, or n-heptane, or a mixture thereof, followed by collection of the solids by filtration.

[0062] The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of the aspects and / or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

[0063] DEFINITIONS

[0064] The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0065] Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more.

[0066] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0067] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0068] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group. In addition, compounds of Formulas (I) and (IV) can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formulas (I) and (IV), respectively.

[0069] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

[0070] The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include13C and14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. For example, methyl (- CH3) also includes deuterated methyl groups such as -CD3.

[0071] EXAMPLES

[0072] The invention is further defined in the following Example. It should be understood that the Example is given by way of illustration only. From the above discussion and the Example, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather is defined by the claims appended hereto.

[0073] ABBREVIATIONS aq. aqueous

[0074] DCM dichloromethane h, hr or hrs hour(s)

[0075] HPLC high performance liquid chromatography

[0076] LC liquid chromatography

[0077] LCMS liquid chromatography mass spectrometry M molar mM millimolar Me methyl MHz megahertz min. minute(s) mins minute(s) MS mass spectrometry nM nanomolar Pd(dba)2 bis(dibenzylideneacetone)palladium(0)

[0078] Ret Time or Rt retention time sat. saturated

[0079] SFC supercritical fluid chromatography

[0080] THF tetrahydrofuran

[0081] UTAR Universal Attenuated Total Reflectance wt% weight %

[0082] The FT-IR spectra were recorded with a Perkin Elmer Infrared spectrophotometer by using UATR technique.

[0083] Preparation of Dicyclohexylphosphino Ferrocene

[0084] To a solution of ferrocene (100 g, 0.537 mmol, 1.0 eq) in dry THF (500 mL) was added tert-butyl lithium (1.0 M solution in pentane) (537.6 mL, 0.537 mmol, 1.0 eq) at 0- 5 °C under an inert atmosphere. The reaction mixture was stirred for 30 min at 0-5 °C. The reaction mixture was warmed to room temperature and w-pentane (1.0 L) was added followed by the addition of dicyclohexyl phosphine (68.81 g, 0.295 mmol, 0.55 eq). The reaction mixture was stirred for 1.0 h to 1.5 h at room temperature and then treated with degassed methanol (50.0 mL, 0.5 vol) under an inert atmosphere. The reaction mixture was diluted with tert-butyl methyl ether (500 mL, 5.0 vol). The solids were filtered to remove inorganics. The filter bed was washed with tert-butyl methyl ether (1.0 L, 10.0 vol). The filtrate was subjected to vacuum distillation and the residue was purified by methanol (1.50 L, 15.0 vol) followed by ^-heptane (300 mL, 3.0 vol). The wet solid was further dried to afford 50.0 g (52%) of (dicyclohexylphosphino)ferrocene) with 98.2% HPLC purity. *H NMR (400 MHz, CDC13): 8 1.01-1.34 (m, 10 H), 1.62-1.80 (m, 10 H), 1.91-1.94 (m, 2 H), 4.14-4.16 (m, 7 H), 4.32-4.37 (m, 2 H);31P NMR (CDCI3, 162 MHz): 5 - 7.44;13C NMR (CDCI3, 100 MHz): 5 26.36, 27.26, 30.07, 33.25, 33.36, 69.09, 71.34, 71.44, 75.99, 76.15; Mass (DIP) (m / z is 382.30): observed peak 383.1 (M++H); HRMS (Mol.F: C22H3iFeP) (ESI positive) [M++H]: calculated 383.1513, found 383.1584.

[0085] Table 1 :FT-IR Peaks of Dicyclohexylphosphino Ferrocene

[0086] Preparation of (l'-(Dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl)ferrocene)

[0087] To a solution of degassed 1,4-dioxane (1.0 L, 20.0 vol) were added 2- bromonapthalene (406.23 g, 1.961 mmol 15.0 eq), (dicyclohexylphosphino)ferrocene) (50.0 g, 0.130 mmol, 1.0 eq), sodium tert-butoxide (125.68 g, 10.0 eq), and palladium acetate (1.76 g, 0.0026 mmol, 0.02 eq) at 25-30 °C. The reaction mixture was heated to reflux and maintained at reflux for 5 h. After 5 h, the reaction mixture was cooled to 25- 30 °C and diluted with tert-butyl methyl ether (1.50 L, 30.0 vol). The reaction mixture was filtered to remove inorganic solids. The filter cake was washed with tert-butyl methyl ether (1.0 L, 30.0 vol). The filtrates were subjected to vacuum distillation. The residue was purified by methanol (2.0 L, 40.0 vol), ^-Heptane (750 mL, 15.0 vol) and DCM / w-heptane (187.5 mL / 562.5 mL, 3.75 / 11.25 vol). The wet solid was dried to afford 77.5 g (58.6%) of (l'-(dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl)ferrocene) with 93.28% HPLC purity. *H NMR (400 MHz, CDC13): 8 1.72 (d, J= 8.0 Hz, 2 H), 1.89 (d, J= 10.4 Hz, 2 H), 4.34 (s, 2 H), 4.44 (s, 2 H), 7.21-7.28 (m, 10 H), 7.34-7.40 (m, 10 H), 7.45-7.49 (m, 10 H), 7.69 (d, J= 8.0 Hz, 5 H);31P NMR (CDCI3, 162 MHz): 5 - 10.88;13C NMR (CDCI3, 100 MHz): 5 26.35, 27.73, 27.93, 31.31, 35.08, 76.27, 87.66, 125.4, 126.3, 127.39, 127.88, 130.93, 131.16, 131.94, 132.75, 133.45; Mass (DIP) (m / z is 1013.07): observed peak 1014.3 (M++H); HRMS (ESI positive) [M++H]: (Mol.F: C72H6iFeP): calculated. 1013.3860, found 1013.3936

[0088] Table 2: FT-IR Peaks of (l'-(Dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl) ferrocene)

[0089] Preparation of 3-chloro-4-(pyridin-3-yl)-l,2,5-thiadiazole with (T- (dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl)ferrocene) ligand

[0090] 3-Pyridineboronic acid pinacol ester (100 g, 487.63 mmol, 1 equiv.) was taken in a round bottom flask and dissolved in toluene (1.5 L, 15 vol.). The solution was degassed with argon gas for 20 minutes. (l'-(Dicyclohexylphosphino)-l, 2,3,4, 5-pentakis(2- naphthyl)ferrocene) (27.2 g, 26.65 mmol. 0.055 equiv.) and Pd(dba)2 (35 g, 60.86 mmol. 0.125 equiv.) were added to the solution. The reaction mixture was degassed with argon gas for 15 minutes. To this mixture, a degassed solution of K3PO4 (207 g, 975.17 mmol.

[0091] 2 equiv.) in H2O (500 mL, 5 vol.) was added followed by the addition of 3,4- di chlorothiadi azole (226 g, 1457.97 mmol. 3 equiv.). The reaction mixture was stirred at 60-65 °C for 12 h. Reaction progress was monitored by HPLC. After completion of the reaction, the mixture was filtered through a pad of celite. The organic layer was separated, 2 vol (200 mL) of water was added to the organic layer and then treated with concentrated HC1 (800 mL, 8 vol.). The mixture was stirred for 2 h. The mixture was diluted with an excess amount of water (1.4 L, 14 vol.), and the aqueous layer was separated. The aqueous layer containing 3-chloro-4-(pyridin-3-yl)-l,2,5-thiadiazole, HC1 salt was washed with DCM (2 x 500 mL). The pH of the aqueous layer was adjusted between 11 -12 by the addition of saturated ISfeCCL solution and stirred for 1 h at room temperature. The solids were filtered and washed with water (300 mL, 3 vol.) to afford 3- chloro-4-(pyridin-3-yl)-l,2,5-thiadiazole (56 g, yield: 58%) as a pale brown solid. 'H NMR (400 MHz, DMSO) 5 9.06 (s, 1H), 8.75 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.0, 4.8 Hz, 1H).;13C NMR (100 MHz, DMSO) 5 155.12, 150.85, 148.81, 142.91, 135.90, 126.49, 123.62.; HRMS (ESI+): Calculated for C7H5C1N3S 197.9893; found 197.9898.

[0092] The preparation of 3-chloro-4-(pyridin-3-yl)-l,2,5-thiadiazole was carried out with different ligands: (l'-(dicyclohexylphosphino)-l,2,3,4,5-pentakis(aryl)ferrocene), where the aryl group is phenyl, 3,5-dimethyl phenyl, 3-methyl phenyl, 4-methoxy phenyl, 4-trifluoromethyl phenyl, 2-substituted 9,9-dimethyl-97 / -fluorene, 3-substituted 9,9- dimethyl-97 / -fluorene, 2-substituted dibenzo[Z>, t / ] furan, 3-substituted dibenzo[Z>, t / ]furan and 2-naphthyl. The reaction conversions of 50%, 48%, 56%, 59%, 45%, 51%, 29%, 41%, 32% and 65% were respectively observed.

[0093] Applicants have discovered a new synthesis process for the preparation of 3- chloro-4-(pyridin-3-yl)-l,2,5-thiadiazole. The new synthesis process provides 3-chloro- 4-(pyridin-3-yl)-l,2,5-thiadiazole at a high yield. The new synthesis process does not require the use of reagents or synthesis adjuvants requiring special procedures and / or equipment. The new synthesis process is adaptable to large scale manufacturing.

Claims

CLAIMSWhat is claimed is:

1. A process for preparing a compound of Formula (I):comprising the step of reacting a compound of Formula (II) and a compound of Formula (III):in the presence of a catalyst and a ligand to provide said compound of Formula (I); wherein: each R is independently hydrogen or C1-4 alkyl; or two R are joined together to form a bridge selected from -C(CH3)2C(CH3)2-, -C(CH2CH3)2C(CH2CH3)2- -(CH2)3- and -CH2C(CH3)2CH2-; said catalyst is tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), (l-methylallyl)palladium(II) chloride dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(cinnamyl) chloride dimer, and (l,l-bis(diphenylphosphino)ferrocene) dichloro palladium(II); and said ligand is (l'-(dicyclohexylphosphino)-l,2,3,4,5-pentakis(2-naphthyl)ferrocene), (T- (dicyclohexylphosphino)-l,2,3,4,5-pentakis(aryl)ferrocene), where said aryl group is phenyl, 3,5-dimethyl phenyl, 3-methyl phenyl, 4-methoxy phenyl, 4-trifluoromethyl phenyl, 2-substituted 9,9-dimethyl-9J7-fluorene, 3-substituted 9,9-dimethyl-9J7- fluorene, 2-substituted dibenzo[Z>, t / ] furan, or 3-substituted dibenzo[Z>, t / ]furan.

2. The process according to claim 1 wherein the compound of Formula (II) is3. The process according to claim 1 wherein the level of said catalyst is in the range of from 2 to 12 % equivalents.

4. The process according to claim 1 wherein the level of said ligand is in the range of from 2 to 6 % equivalents.

5. The process according to claim 1 wherein the level of said catalyst is in the range of from 2 to 12 % equivalents; and the level of said ligand is in the range of from 2 to 6 % equivalents.

6. The process according to claim 1 wherein said process is conducted in a solvent mixture in the range of from 2: 1 to 4: 1 toluene and water (volume ratio).

7. A compound of Formula (IV) having the structure:

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