Synthesis of 5-(1-cyanocyclopropyl)-3-ethylsulfanyl-pyridine-2-carbonitrile

Abstract

A process for the preparation of compound of formula (I) is provided.

Description

[0001] SYNTHESIS OF 5-(1-CYANOCYCLOPROPYL)-3-ETHYLSULFANYL-PYRIDINE-2-CARBONITRILE

[0002] The present invention relates to the synthesis of 5-(1-cyanocyclopropyl)-3-ethylsulfanyl-pyridine-2-carbonitrile as intermediate for preparation of insecticidally active compounds.

[0003] A compound of formula (I), first described in WO2022074214, is a potentially useful intermediate for the synthesis of insecticidally active compounds containing 1-(3-pyridyl)cyclopropanecarbonitrile moiety. Such compounds have been disclosed widely, for example in WO2023072945, WO2022253841 , WO2022049144, WO2021204577, W02020090585 and W02020083662.

[0004] The currently reported route to a compound of formula (I) is depicted in Scheme 1. It starts with a selective displacement of nitro group with thiolate anion in 5-bromo-3-nitro-pyridine-2-carbonitrile as described in WO2016026848. In the second step cyanocyclopropyl group is installed by reacting with 5-amino-2,3- dihydrothiophene-4-carbonitrile in the presence of base as described in WO2022074214.

[0005] This is an adequate approach for a small-scale preparation however there are several major disadvantages for a large-scale preparation. The listed starting material is not available on a large commercial scale and has to be prepared in at least three steps (for example as described in W02003062209 and Org. Synth. 1964, 44, 34). Even more importantly the cyanocyclopropanation on this substrate is only modestly yielding (46% reported) and also involves synthesis of thiophene reagent.

[0006] Alternatively, the compound of formula (I) could be prepared using standard functional group manipulations from the corresponding acid as shown in scheme 2. This acid could be prepared in two steps from 3,5- dichloropyridine-2-carboxylic acid as described in WO2021105399 (first step) and WO2022074214 (second step). This is a more convenient approach however it does not solve the issue of too many steps spent on functional group manipulations. Such steps inevitably generate waste while not increasing molecular complexity.

[0007] The present invention describes a new strategy forthe preparation of compound of formula (I) featuring a direct coupling between a readily available 3,5-dichloropyridine-2-carbonitrile and cyano acetate of formula (II) (Scheme 3). Surprisingly high selectivity could be achieved when the reaction was conducted in polar aprotic solvents leading to a compound of formula (III). This compound could be isolated if desired, but more conveniently would undergo the second SnAr reaction with ethanethiolate anion to yield a compound of formula (IV). In the next step a compound of formula (IV) was decarboxylated to yield a compound of formula (V). Any of the isomeric compound formed in the first step could be fully removed at this stage. Finally, a compound of formula (V) was cyclopropanated using an appropriate alkylating agent to yield a compound of formula (I).

[0008] Scheme 3

[0009] The present invention provides a process for preparation of compound of formula (I) wherein the process comprises

[0010] Step A) reacting 3,5-dichloropyridine-2-carbonitrile with a cyanoacetate of formula (II) wherein R is alkyl or benzyl, preferably R is methyl or ethyl; in the presence of an appropriate base and in an appropriate solvent to produce a compound of formula (III) wherein R is as defined for a compound of formula (II);

[0011] Step B) reacting said compound of formula (III) wherein R is as defined for a compound of formula (II); with an alkali metal ethanethiolate in an appropriate solvent to produce a compound of formula (IV) wherein R is as defined for a compound of formula (II);

[0012] Step C) hydrolyzing and decarboxylating the compound of formula (IV) wherein R is as defined for a compound of formula (II); in the presence of an appropriate acid in an appropriate solvent to produce a compound of formula (V)

[0013] Step D) reacting the compound of formula (V) with an alkylating agent of formula (VI) wherein X and Y are independently selected from chloro or bromo; in the presence of an appropriate base and an appropriate additive (such as a phase transfer catalyst) in an appropriate solvent to produce the compound of formula (I).

[0014] Embodiments of the present invention are set out below.

[0015] In one embodiment of the invention step (A) comprises:

[0016] Reacting 3,5-dichloropyridine-2-carbonitrile with a compound of formula (II) in the presence of an appropriate base in an appropriate solvent (or diluent). The ratio of the compound of formula (I I) used, compared to 3,5- dichloropyridine-2-carbonitrile, is in the range from 3:1 to 1 :1 , preferably between 1 .5:1 and 1 :1 , more preferably between 1 .2:1 and 1 :1 . As used herein the term “ratio” refers to molar ratio

[0017] Examples of suitable and preferred bases for step A are alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, alkali metal phosphates such as potassium triphosphate and alkali metal alkoxides such as sodium ethylate. Preferably the base is potassium carbonate or sodium carbonate. The ratio of a base used, compared to a compound of formula (II), is from 3:1 to 2:1 , more preferably between 2.5:1 and 2:1. As used herein the term “ratio” refers to molar ratio.

[0018] Examples of suitable and preferred solvents (or diluents) for step A are polar aprotic solvents.

[0019] Examples include but are not limited to: acetonitrile, butyronitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidine, sulfolane, dimethylsulfoxide and dioxane.

[0020] Preferably the reaction of step A) is carried out at a temperature between 50 and 120°C, more preferably between 70 and 100°C.

[0021] In one embodiment, step (B) comprises:

[0022] Reacting a compound of formula (III) with an alkali metal salt of ethanethiol in the presence of an appropriate base in an appropriate solvent (or diluent). The ratio of an alkali metal salt of ethanethiol to a compound of formula (III) is in the range from 3:1 to 1 :1 , preferably between 1 .5:1 and 1 :1 . As used herein the term “ratio” refers to molar ratio.

[0023] Examples of suitable and preferred bases for step (B) are alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, alkali metal phosphates such as potassium triphosphate and alkali metal alkoxides such as sodium ethylate. Preferably the base is a potassium carbonate or sodium carbonate. The ratio of a base used, compared to a compound of formula (II), is from 2:1 to 1 :1 , more preferably between 1.5:1 and 1 :1. As used herein the term “ratio” refers to molar ratio.

[0024] Examples of suitable and preferred solvents (or diluents) for step (B) are nitriles, amides, ethers and sulfones Examples include but are not limited to: acetonitrile, butyronitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidine, sulfolane, dimethylsulfoxide, tetrahydrofuran and dioxane.

[0025] Preferably the reaction of step B) is carried out at a temperature between 20 and 100°C, more preferably between 30 and 80°C.

[0026] Optionally alkali metal salt of ethanethiol could be prepared in situ from ethanethiol and an appropriate base. Examples of suitable bases include but are not limited to sodium hydride, sodium hydroxide, sodium tert- butoxide, potassium hydroxide and potassium tert-butoxide.

[0027] Optionally steps (A) and (B) could be telescoped by adding alkali metal salt of ethanethiol to a reaction mixture of step (A) after full consumption of step (A) starting material. In this case an extra base for step (B) is not required.

[0028] In one embodiment, step (C) comprises:

[0029] A one step hydrolysis and decarboxylation of compound of formula (IV) in the presence of an appropriate acid in a mixture of an appropriate co-solvent (or diluent) and water.

[0030] Examples of suitable and preferred acids for step (C) include but are not limited to: acetic acid, propionic acid, sulfuric acid, hydrochloric acid and p-toluenesulfonic acid.

[0031] Examples of suitable and preferred co-solvents (or diluents) for step (C) are alcohols, ethers and organic acids.

[0032] Examples include but are not limited to: acetic acid, propionic acid, dioxane, ethanol and tetra hydrofuran.

[0033] Preferably the reaction of step C) is carried out at a temperature between 40 and 120°C, more preferably between 70 and 100°C.

[0034] In one embodiment, step (D) comprises:

[0035] Reacting a compound of formula (V) with an alkylating agent of formula (VI) in the presence of an appropriate base, an appropriate additive in an appropriate solvent. The ratio of compound of formula (VI) relative to a compound of formula (V) is between 3:1 and 1 :1 , more preferable between 1 .5:1 and 1 :1 . As used herein the term “ratio” refers to molar ratio

[0036] Examples of suitable and preferred bases for step (D) are alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkali metal hydroxides such as potassium hydroxide and sodium hydroxide. Preferably the base is a potassium hydroxide or sodium hydroxide. The ratio of a base used, compared to a compound of formula (V), is from 5:1 to 2:1 , more preferably between 3:1 and 2:1. As used herein the term “ratio” refers to molar ratio

[0037] Examples of suitable and preferred additives for step (D) are phase transfer catalysts such as tetrabutylammonium bromide, benzyltriethylammonium bromide and tetrabutylammonium chloride. The amount of an additive used relative to a compound of formula (V) is between 0.005 and 0.10 equivalents. More preferably between 0.01 and 0.05 equivalents. Examples of suitable and preferred solvents (or diluents) for step (D) are nitriles, amides, ethers and sulfones and water.

[0038] Examples include but are not limited to: acetonitrile, butyronitrile, dimethylformamide, dimethylacetamide, N- methylpyrrolidine, sulfolane, dimethylsulfoxide, dioxane and water.

[0039] Preferably the reaction of step D) is carried out between 0 and 60°C, more preferably between 20 and 40°C.

[0040] In one embodiment of the present invention, the process for preparation of compound of formula (I) comprises

[0041] Step A) reacting 3,5-dichloropyridine-2-carbonitrile with a cyanoacetate of formula (II) wherein R is alkyl or benzyl, preferably R is methyl or ethyl; in the presence of an appropriate base and in an appropriate solvent to produce a compound of formula (III) wherein R is as defined for a compound of formula (II);

[0042] Step B) reacting said compound of formula (III) wherein R is as defined for a compound of formula (II); with alkali metal ethanethiolate in an appropriate solvent to produce a compound of formula (IV) wherein R is as defined for a compound of formula (II);

[0043] Step C) hydrolyzing and decarboxylating the compound of formula (IV) wherein R is as defined for a compound of formula (II); in the presence of an appropriate acid in an appropriate solvent to produce a compound of formula (V)

[0044] Step D) reacting the compound of formula (V) with an alkylating agent of formula (VI) wherein X and Y are independently selected from chloro or bromo; in the presence of an appropriate base and an appropriate additive (such as a phase transfer catalyst) in an appropriate solvent to produce the compound of formula (I), wherein the molar ratio of the cyanoacetate compound of formula (II) to the 3,5-dichloropyridine-2-carbonitrile used in step A ) is 3:1 to 1 :1 ; wherein the molar ratio of the base to the cyanoacetate compound of formula (II) in step A) is from 3:1 to 2:1 ; wherein the molar ratio of the alkali metal salt of ethanethiol to a compound of formula (III) in step B) is in the range from 3:1 to 1 :1 ; wherein the molar ratio of the base to a compound of formula (II) in step B) is from 2:1 to 1 :1 ; wherein the ratio of the compound of formula (VI) to the compound of formula (V) is between 3:1 and 1 :1 ; wherein the molar ratio of the base used in step D) to the compound of formula (V) is from 5:1 to 2:1 ; and wherein the amount of the additive used relative to the compound of formula (V) is between 0.005 and 0.10 equivalents.

[0045] In another embodiment of the present invention, the process for preparation of compound of formula (I) comprises

[0046] Step A) reacting 3,5-dichloropyridine-2-carbonitrile with a cyanoacetate of formula (II) wherein R is alkyl or benzyl, preferably R is methyl or ethyl; in the presence of an appropriate base and in an appropriate solvent to produce a compound of formula (III) wherein R is as defined for a compound of formula (II);

[0047] Step B) reacting said compound of formula (III) wherein R is as defined for a compound of formula (II); with alkali metal ethanethiolate in an appropriate solvent to produce a compound of formula (IV) wherein R is as defined for a compound of formula (II);

[0048] Step C) hydrolyzing and decarboxylating the compound of formula (IV) wherein R is as defined for a compound of formula (II); in the presence of an appropriate acid in an appropriate solvent to produce a compound of formula (V)

[0049] Step D) reacting the compound of formula (V) with an alkylating agent of formula (VI) wherein X and Y are independently selected from chloro or bromo; in the presence of an appropriate base and an appropriate additive (such as a phase transfer catalyst) in an appropriate solvent to produce the compound of formula (I), wherein the reaction of step A) is carried out at a temperature between 50 and 120°C; wherein the reaction of step B is carried out at a temperature between 20 and 100°C; wherein the reaction of step C) is carried out at a temperature between 40 and 120°C; and wherein the reaction of step D) is carried out at a temperature between 0 and 60°C.

[0050] In another embodiment of the present invention, the process for preparation of compound of formula (I) comprises

[0051] Step A) reacting 3,5-dichloropyridine-2-carbonitrile with a cyanoacetate of formula (II) wherein R is alkyl or benzyl, preferably R is methyl or ethyl; in the presence of an appropriate base and in an appropriate solvent to produce a compound of formula (III) wherein R is as defined for a compound of formula (II); Step B) reacting said compound of formula (III) wherein R is as defined for a compound of formula (II); with alkali metal ethanethiolate in an appropriate solvent to produce a compound of formula (IV) wherein R is as defined for a compound of formula (II);

[0052] Step C) hydrolyzing and decarboxylating the compound of formula (IV) wherein R is as defined for a compound of formula (II); in the presence of an appropriate acid in an appropriate solvent to produce a compound of formula (V)

[0053] Step D) reacting the compound of formula (V) with an alkylating agent of formula (VI) wherein X and Y are independently selected from chloro or bromo; in the presence of an appropriate base and an appropriate additive (such as a phase transfer catalyst) in an appropriate solvent to produce the compound of formula (I), wherein the molar ratio of the cyanoacetate compound of formula (II) to the 3,5-dichloropyridine-2-carbonitrile used in step A ) is 3:1 to 1 :1 ; wherein the molar ratio of the base to the cyanoacetate compound of formula (II) in step A) is from 3:1 to 2:1 ; wherein the molar ratio of the alkali metal salt of ethanethiol to a compound of formula (III) in step B) is in the range from 3:1 to 1 :1 ; wherein the molar ratio of the base to a compound of formula (II) in step B) is from 2:1 to 1 :1 ; wherein the ratio of the compound of formula (VI) to the compound of formula (V) is between 3:1 and 1 :1 ; wherein the molar ratio of the base used in step D) to the compound of formula (V) is from 5:1 to 2:1 ; and wherein the amount of the additive used relative to the compound of formula (V) is between 0.005 and 0.10 equivalents; wherein the reaction of step A) is carried out at a temperature between 50 and 120°C; wherein the reaction of step B is carried out at a temperature between 20 and 100°C; wherein the reaction of step C) is carried out at a temperature between 40 and 120°C; wherein the reaction of step D) is carried out at a temperature between 0 and 60°C. wherein the reaction of step A) is carried out at a temperature between 50 and 120°C; wherein the reaction of step B is carried out at a temperature between 20 and 100°C; wherein the reaction of step C) is carried out at a temperature between 40 and 120°C; and wherein the reaction of step D) is carried out at a temperature between 0 and 60°C.

[0054] In another embodiment of the present invention, the process for preparation of compound of formula (I) comprises

[0055] Step A) reacting 3,5-dichloropyridine-2-carbonitrile with a cyanoacetate of formula (II) wherein R is alkyl or benzyl, preferably R is methyl or ethyl; in the presence of an appropriate base and in an appropriate solvent to produce a compound of formula (III) wherein R is as defined for a compound of formula (II); Step B) reacting said compound of formula (III) wherein R is as defined for a compound of formula (II); with alkali metal ethanethiolate in an appropriate solvent to produce a compound of formula (IV) wherein R is as defined for a compound of formula (II);

[0056] Step C) hydrolyzing and decarboxylating the compound of formula (IV) wherein R is as defined for a compound of formula (II); in the presence of an appropriate acid in an appropriate solvent to produce a compound of formula (V)

[0057] Step D) reacting the compound of formula (V) with an alkylating agent of formula (VI) wherein X and Y are independently selected from chloro or bromo; in the presence of an appropriate base and an appropriate additive (such as a phase transfer catalyst) in an appropriate solvent to produce the compound of formula (I), wherein R is selected from methyl or ethyl; wherein the molar ratio of the cyanoacetate compound of formula (II) to the 3,5-dichloropyridine-2-carbonitrile used in step A ) is 3:1 to 1 :1 ; wherein the molar ratio of the base to the cyanoacetate compound of formula (II) in step A) is from 3:1 to 2:1 ; wherein the molar ratio of the alkali metal salt of ethanethiol to a compound of formula (III) in step B) is in the range from 3:1 to 1 :1 ; wherein the molar ratio of the base to a compound of formula (II) in step B) is from 2:1 to 1 :1 ; wherein the ratio of the compound of formula (VI) to the compound of formula (V) is between 3:1 and 1 :1 ; wherein the molar ratio of the base used in step D) to the compound of formula (V) is from 5:1 to 2:1 ; and wherein the amount of the additive used relative to the compound of formula (V) is between 0.005 and 0.10 equivalents; wherein the reaction of step A) is carried out at a temperature between 50 and 120°C; wherein the reaction of step B is carried out at a temperature between 20 and 100°C; wherein the reaction of step C) is carried out at a temperature between 40 and 120°C; wherein the reaction of step D) is carried out at a temperature between 0 and 60°C. wherein the reaction of step A) is carried out at a temperature between 50 and 120°C; wherein the reaction of step B is carried out at a temperature between 20 and 100°C; wherein the reaction of step C) is carried out at a temperature between 40 and 120°C; wherein the reaction of step D) is carried out at a temperature between 0 and 60°C; wherein the base used in step A) is selected from alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates and alkali metal alkoxides; wherein the base used in step B) is selected from alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates and alkali metal alkoxides; wherein the alkali metal salt of ethanethiol used in step B) is prepared in situ from ethanethiol and an appropriate base; and wherein the base is selected from sodium hydride, sodium hydroxide, sodium tert- butoxide, potassium hydroxide and potassium tert-butoxide; wherein the acid for step C) is selected from acetic acid, propionic acid, sulfuric acid, hydrochloric acid and p- toluenesulfonic acid; wherein the base used in step D) is selected from alkali metal carbonates and alkali metal hydroxides; and wherein the additives used in step D) is a phase transfer catalyst selected from tetrabutylammonium bromide, benzyltriethylammonium bromide and tetrabutylammonium chloride.

[0058] Definitions

[0059] As used herein, the term "alkyl" in isolation or as part of a chemical group, represents straight-chain or branched hydrocarbons, preferably with 1 to 6 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1 - methylbutyl, 2-methylbutyl, 3-methylbutyl, 1 ,2-dimethylpropyl, 1 ,1 - dimethylpropyl, 2,2- dimethylpropyl, 1 -ethylpropyl, hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 1 ,2-dimethylpropyl, 1 , 3-d i methyl butyl, 1 ,4-dimethylbutyl,2,3-dimethylbutyl, 1 ,1- dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2-tnmethylpropyl, 1- ethylbutyl and 2-ethylbutyl. Alkyl groups with 1 to 4 carbon atoms are preferred, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl.

[0060] As used herein, the term “alkali metal” refers to sodium, potassium, cesium and lithium.

[0061] As used herein, the term “room temperature” or “RT” or “rt” or “ambient temperature” refer to a temperature of about 15°C to about 35°C. For example, rt can refer to a temperature of about 20°C to about 30°C. The term “room temperature” or “ambient temperature” can be used interchangeably.

[0062] As used herein the term “appropriate solvent” refers to a solvent that is suitable or fitting for a particular reaction step. The term "appropriate solvent” can be used interchangeably with the term “suitable solvent" or “preferred solvent” or “dilutent”.

[0063] As used herein the term “appropriate co-solvent” refers to a co-solvent that is suitable or fitting for a particular reaction step. The term "appropriate co-solvent” can be used interchangeably with the term “suitable cosolvent" or “preferred co-solvent”.

[0064] As used herein the term “appropriate base” refers to a base that is suitable or fitting for a particular reaction step. The term “appropriate base” can be used interchangeably with the term “base suitable for” or “preferred base”.

[0065] As used herein the term “appropriate acid” refers to an acid that is suitable or fitting for a particular reaction step. The term “appropriate acid” can be used interchangeably with the term “acid suitable for” or “preferred acid”.

[0066] As used herein the term “appropriate additive” refers to an additive that is suitable or fitting for a particular reaction step. The term “appropriate additive” can be used interchangeably with the term “additive suitable for” or “preferred additive”.

[0067] As used herein the term “telescoped” refers to a sequential one-pot synthesis with reagents added to a reactor one at a time and without work-up. Such sequential one-pot synthesis is also called a telescoping synthesis.

[0068] The telescoping process is a compelling method in chemical process development that enables the integration of two or more reactions into a one-pot operation without the isolation of intermediate product(s). A telescoped process may offer opportunities to reduce the number of unit operations and processing solvents.

[0069] As used herein, when the term “between” or “between X and Y” or “from X to Y” is used for numerical ranges (X and Y indicating numbers), it means that the end points (X and Y) of the indicated range are explicitly included in said range. For example, if a range is indicated to be “in the range between 1 .5:1 ” it means that the end points 1 .5 and 1 are included in the range; or if a range is indicated to be “from 3:1 to 1 :1 ” I means that the end points 3 and 1 are included in the range; or if a range is indicated as “a temperature between 40 and 120°C” it means that 40°C and 120°C are included in the range. EXAMPLES

[0070] The Examples which follow serve to illustrate the invention and are not meant in any way to limit the invention.

[0071] The compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by a person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates, if necessary, for example 60 ppm, 20 ppm or 2 ppm.

[0072] Compounds of formula (I) may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against diseases that are caused by fungi or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (including improved crop tolerance), improved physico-chemical properties, or increased biodegradability).

[0073] ABBREVIATIONS aq. aqueous

[0074] CDCh deuterated chloroform

[0075] DMF N,N-Dimethylformamid (or dimethylformamide)

[0076] DMSO dimethyl sulfoxide

[0077] DMSO-d6 deuterated Dimethyl sulfoxide equiv. equivalent

[0078] EtOAc ethyl acetate

[0079] HCI hydrochloric acid h / hrs hour / hours

[0080] MeCN acetonitrile

[0081] MeTHF 2-methyltetrahydrofurane min minutes

[0082] NaOH sodium hydroxide

[0083] NMP N-Methyl-2-pyrrolidone

[0084] POCh phosphorus oxychloride rt room temperature or ambient temperature

[0085] TEA triethylamine (or EtsN)

[0086] PREPARATION EXAMPLES The compounds according to the invention may be prepared using the synthetic techniques described both above and below. “Mp” means melting point in °C. Free radicals represent methyl groups.1H NMR and19F NMR measurements were recorded on a Bruker 400MHz spectrometer (or 600MHz as indicated), chemical shifts are given in ppm relevant to a TMS (1H) and CFCH (19F) standard. Spectra measured in deuterated solvents as indicated.

[0087] Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. Example 1 : Preparation of 5-(1-cvanocvclopropyl)-3-ethylsulfanyl-pyndine-2-carboxamide

[0088] To a suspension of 5-(1-cyanocyclopropyl)-3-ethylsulfanyl-pyridine-2-carboxylic acid (13.75 g, 98% assay, 54.3 mmol) in EtOAc (80 mL) was added DMF (0.17 mL, 2.2 mmol). The reaction mixture was cooled to 0°C and oxalyl chloride (5.0 mL, 57.0 mmol) was added over 30 min. The resulting suspension was allowed to warm to ambient temperature and stirred for additional 30 min (red solution). At this stage full conversion has been reached and the acid chloride was used immediately for the next stage.

[0089] To a solution of NaHCOs (5.55 g, 65.1 mmol) in water (38 mL) was added EtOAc (33 mL) and aq. NH3 (33%, 65 mL, 543 mmol). The resulting biphasic mixture was cooled to 0°C and acid chloride prepared above was dosed to it over 40 min while keeping the internal temperature below 10°C. The reaction mixture was then warmed up to ambient temperature and stirred for further 40 min.

[0090] The resulting precipitate was filtered off and kept aside (first crop). Phases of the filtrate were separated, and organic layer partially evaporated. The resulting precipitate was also filtered off and combined with the first crop. The combined solids were washed on filter with water and dried under high vacuum to constant weight to yield the title compound as a light red solid (13.32 g, 93% assay, 93% yield).

[0091] 1H NMR (400 MHz, d6-DMSO) 5 = 8.28 (d, J = 2.2 Hz, 1 H), 7.97 (br s, 1 H), 7.57 (d, J = 2.2 Hz, 1 H), 7.54 (br s, 1 H), 2.95 (q, J = 7.3 Hz, 2H), 1 .89 - 1 .81 (m, 2H), 1 .78 - 1 .67 (m, 2H), 1 .26 (t, J = 7.3 Hz, 3H).

[0092] 13C NMR (101 MHz, d6-DMSO) 6 = 166.9, 144.8, 140.6, 137.0, 134.3, 130.7, 121.5, 24.3, 18.2, 12.7, 11.5.

[0093] Example 2: Preparation of 5-(1-cvanocvclopropyl)-3-ethylsulfanyl-pyridine-2-carbonitrile

[0094] To a suspension of 5-(1-cyanocyclopropyl)-3-ethylsulfanyl-pyridine-2-carboxamide (20.0 g, 98% assay, 79.4 mmol) in EtOAc (100 mL) was added EtsN (33.4 mL, 238 mmol). The resulting mixture was heated to 50°C and POOL (11.3 mL, 119 mmol) was dosed over 1 h. After stirring for another 1 h the dark brown reaction mixture was cooled to 25°C and dosed over 45 min to 10% aq NaOH (200 mL) while keeping the internal temperature below 30°C and stirring vigorously. Phases were separated, aqueous phase extracted with EtOAc (200 mL) and combined organic phase washed with water (100 mL). Most of the solvent was evaporated under reduced pressure leaving a dark oil (ca 190 g) which was dissolved in acetone (100 mL). This solution was cooled to 0°C and water (200 mL) was dosed over 20 min. The resulting suspension was stirred for 1 h and filtered. The precipitate was washed on filter with water and dried under high vacuum to constant weight to yield the title compound (16.88 g, 96.7% assay, 90% yield) as a light brown solid.1H NMR (400 MHz, d6-DMSO) 6 = 8.50 (d, J = 1 .8 Hz, 1 H), 7.77 (d, J = 2.2 Hz, 1 H), 3.23 (q, J = 7.3 Hz, 2H), 1.97- 1.89 (m, 2H), 1.84 - 1.77 (m, 2H), 1.29 (t, J = 7.3 Hz, 3H);13C NMR (101 MHz, d6-DMSO) 6 = 145.0, 140.1 , 136.9, 132.3, 129.6, 120.9, 1 15.6, 25.8, 19.2, 13.4, 11.8.

[0095] Example 3: Preparation of ethyl 2-(5-chloro-6-cvano-3-pyridyl)-2-cvano-acetate (A) and ethyl 2-(5-chloro-2- cvano-3-pyridyl)-2-cvano-acetate (B)

[0096] To a stirred solution of 3,5-dichloropyridine-2-carbonitrile (2.00 g, 96% assay, 11.1 mmol) in dimethylacetamide (10.0 mL) was added ethylcyano acetate (1.35 g, 12.2 mmol) and K2CO3 (3.88 g, 27.8 mmol). The resulting mixture was heated to 80°C and stirred for 2h. The reaction mixture was then cooled to ambient temperature and diluted with EtOAc (25 mL) and water (25 mL). The resulting mixture was acidified with 6M aq HCI, the organic layer was separated and washed with water and brine. The combined organic layer was concentrated under reduced pressure to obtain a crude mixture of A and B. This crude material was purified by silica gel chromatography using acetone and cyclohexane (1 :9) as eluent to yield the title compound A (1.75 g, 96% assay, 60% yield) as pale-yellow liquid and B (0.300 g, 96% assay, 10% yield) as a brown liquid. compound A:1H NMR (400 MHz, CDCI3) 6 = 1.34 (t, J =7.1 Hz, 3 H), 4.32 (qd, J=7.15, 1.2 Hz, 2 H), 4.91 (s, 1 H), 8.06 (d, J=1.9 Hz, 1 H), 8.69 (d, J=2.0 Hz, 1 H);13C NMR (101 MHz, CDCI3) 6 = 13.9, 40.7, 64.8, 113.3, 114.0, 130.6, 133.9, 136.3, 137.2, 148.0, 162.7. compound B:1H NMR (400 MHz, CDCI3) 6 = 1.24 - 1.33 (m, 3 H), 4.29 (td, J=7.1 , 1.3 Hz, 2 H), 5.12 (s, 1 H), 8.02 (d, J=2.1 Hz, 1 H), 8.65 (d, J=2.2 Hz, 1 H);13C NMR (101 MHz, CDCI3) 6 = 13.9, 40.3, 65.0, 1 13.2, 114.3, 131.5, 132.0, 136.6, 136.7, 150.7, 162.2.

[0097] Example 4: Preparation of ethyl 2-cvano-2-(6-cvano-5-ethylsulfanyl-3-pyridyl)acetate (C) and ethyl 2-cyano- 2-(2-cyano-5-ethylsulfanyl-3-pyridyl)acetate (D)

[0098] To a stirred solution of 3,5-dichloropyridine-2-carbonitrile (2.00 g, 96 % assay, 11.14 mmol) in dimethylacetamide (10.0 mL) was added ethylcyano acetate (1.453 g, 12.25 mmol) and K2CO3 (3.88 g, 27.85 mmol). The resulting suspension was stirred at 80°C (full conversion of starting material). Sodium ethanethiolate (1.66 g, 15.60 mmol) was added and the reaction mixture was stirred at 80°C for further 3h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and the resulting precipitate was filtered off. The filtrate was acidified with 2M aq HCI, aqueous layer extracted with EtOAc (2x) and the combined organic layer washed with water and brine. After concentration under reduced pressure the crude material was purified by silica gel chromatography using cyclohexane and ethyl acetate as eluent to yield the title compound C (2.2 g, 97% assay, 70% yield) as a pale yellow solid and title compound D (0.320 g, 90 % purity, 9% yield) as an off white solid. compound C:1H NMR (400 MHz, CD3CN) 6 = 1.27 (t, J=7.1 Hz, 3 H), 1.37 (t, J=7.3 Hz, 3 H), 3.17 (q, J=7.4 Hz, 2 H), 4.26 (qd, J=7.1 , 1 .4 Hz, 2 H), 5.24 (s, 1 H), 7.93 (d, J=1 .9 Hz, 1 H), 8.52 (d, J=2.0 Hz, 1 H);13C NMR (101 MHz, CD3CN) 5 = 13.6, 13.7, 26.9, 41 .3, 64.3, 115.4, 116.0, 131.4, 132.6, 135.8, 141 .5, 147.1 , 164.3. compound D:1H NMR (400 MHz, CD3CN) 5 = 1.25 (t, J=7.1 Hz, 3 H), 1.35 (t, J=7.3 Hz, 3 H), 3.13 (q, J=7.4 Hz, 2 H), 4.21 - 4.32 (m, 2 H), 5.35 (s, 1 H), 7.77 - 7.81 (m, 1 H), 7.80 (d, J=2.1 Hz, 1 H), 8.54 (d, J=2.1 Hz, 1 H);13C NMR (101 MHz, CD3CN) 5 = 13.4, 13.7, 25.7, 41.4, 64.6, 114.8, 116.1 , 129.1 , 131.8, 134.0, 142.8, 148.7, 163.7.

[0099] Alternative Preparation of a mixture of compounds of formula C and D

[0100] To a solution of 3,5-dichloropyridine-2-carbonitrile (10.0 g, 96 % assay, 55.7 mmol) in NMP (40 mL) was added K3CO3(19.6 g, 139 mmol) and the resulting suspension was heated to 80°C. A solution of ethylcyano acetate (7.27 g, 61 .3 mmol) in NMP (10 mL) was dosed over 2 h while stirring vigorously. After stirring for further 3 h at this temperature (full conversion of starting material) sodium ethanethiolate (7.95 g, 82.5% assay, 78.0 mmol) was added and the reaction suspension was stirred for further 3 h. The reaction mixture was then cooled to ambient temperature and diluted with EtOAc (150 mL). The precipitate (inorganic salts) was filtered, washed on filter with EtOAc (2x50 mL) and discarded. The filtrate was acidified with 2M HCI (ca 60 mL) to pH 1-2. Phases were separated, aqueous phase extracted with EtOAc and combined organic phase washed with water and brine. The resulting solution was evaporated under reduced pressure to yield a crude material (21.57 g) as a brown oil. Quantitative NMR analysis using trimethoxybenzene as an internal standard indicates 55.9% assay for compound C (79% yield) and 12.2% assay for compound D (12% yield). This mixture of compounds of formula C and D can be used directly in the next step.

[0101] Example 5: Preparation of 5-(cvanomethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile

[0102] A solution of ethyl-2-cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl)acetate (1.00 g, 97% assay, 3.519 mmol) in a mixture of acetic acid (5 mL) and water (3 mL) was stirred at 90°C for 4 h. The reaction mixture was then cooled to 24°C and slowly poured in ice cold water (75 mL). The resulting precipitate was filtered, washed on filter with water and dried under high vacuum to constant weight to yield the title compound on (0.650 g, 98 % assay, 89% yield) as an off-white solid.1H NMR (400 MHz, DMSO-cfe) 6 = 1.31 (t, J=7.3 Hz, 3 H) 3.19 (q, J=7.3 Hz, 2 H) 4.22 (s, 2 H) 8.05 (d, J=1.7 Hz, 1 H) 8.50 (d, J=1.7 Hz, 1 H);13C NMR (101 MHz, DMSO-cfe) 6 = 13.7, 20.2, 25.7, 1 15.6, 117.8, 129.9, 132.2, 135.2, 140.4, 146.9.

[0103] Alternatively preparation of 5-(cvanomethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile by using the crude mixture obtained from the first two steps (Example 4)

[0104] To a solution of ethyl 2-cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl)acetate (17.1 g, 65% purity, 40.4 mmol) in acetic acid (85 mL) also containing ethyl 2-cyano-2-(2-cyano-5-ethylsulfanyl-3-pyridyl)acetate (14% of 17.1 g) was added water (51 mL) and the resulting reaction mixture was stirred at 95°C for 3 h. The reaction mixture was then cooled to ambient temperature and most of acetic acid was evaporated under reduced pressure. Water (170 mL) was added, and the resulting suspension stirred at 10°C for 1 h. The resulting precipitate was filtered, washed on filter with water (2x40 mL) and dried under high vacuum to yield the title compound (9.03 g, 85% purity, 93% yield) as a light brown solid. To obtain higher purity this material was suspended in MeCN (45 mL) and stirred at 80°C for 1 h. The temperature was decreased to 60°C and remaining precipitate (ca 1 .2 g) was filtered off and discarded. About 80% of MeCN was evaporated under reduced pressure followed by addition of water (91 mL) at ambient temperature. The resulting thick suspension was stirred for 16 h, filtered, the precipitate washed on filter with water (2x45 mL) and dried at 40°C under high vacuum till constant weight to yield the title compound (7.375 g, 99.7% assay, 89.5% yield) as an off-white solid.

[0105] Example 6: Preparation of isopropyl 2-(5-chloro-6-cvano-3-pyridyl)-2-cvano-acetate (E) and isopropyl 2-(5- chloro-2-cvano-3-pyridyl)-2-cvano-acetate (F)

[0106] To a stirred solution of 3,5-dichloropyridine-2-carbonitrile (2.00 g, 96% assay, 11.14 mmol) in dimethylacetamide (10 mL) was added at ambient temperature osopropyl-2-cyano acetate (1 .58 g, 12.25 mmol) and potassium carbonate (3.88 g, 27.85 mmol). The resulting suspension was heated to 80°C and stirred for 2h. After cooling to ambient temperature EtOAc (25 mL) and water (25 mL) was added followed by acidification with 6M aq. HCI. The organic layer was separated and washed with water and brine. The resulting solution was concentrated under reduced pressure to yield a crude material (3.32 g). This was purified by silica gel chromatography using ethyl acetate and cyclohexane (3:7) as eluent to yield the title compound E (1 .92 g, 98% assay, 64% yield) as pale-yellow solid and F (0.178 g, 6% yield) as a yellow gummy liquid.

[0107] Compound E:1H NMR (400 MHz, CDCb) 6 = 1 .32 (d, J=7.8 Hz, 6 H), 4.85 (s, 1 H), 5.11 (spt, J= 6.3 Hz, 1 H), 8.05 (d, J=1 .6 Hz, 1 H), 8.69 (d, J=1 .9 Hz, 1 H);13C NMR (101 MHz, CDCb) 6 = 21 .5, 40.9, 73.4, 113.4, 114.1 , 130.8, 133.8, 136.2, 137.1 , 148.0, 162.2. Compound F:1H NMR (400 MHz, CDCb) 6 ppm 1.25-1 .32 (m, 6 H), 5.04 - 5.12 (m, 1 H), 8.01 (d, J=2.2 Hz, 1 H), 8.65 (d, J=2.1 Hz, 1 H);13C NMR (101 MHz, CDCb) 6 = 21 .4, 40.6, 73.8, 113.2, 114.4, 131.5, 132.1 , 136.6, 136.7, 150.7, 161.6.

[0108] Example 7: Preparation of isopropyl 2-cvano-2-(6-cvano-5-ethylsulfanyl-3-pyridyl)acetate (G) and isopropyl 2- cvano-2-(2-cvano-5-ethylsulfanyl-3-pyridyl)acetate (H)

[0109] To a stirred solution of 3,5-dichloropyridine-2-carbonitrile (4.00 g, 96 % assay, 22.28 mmol) in dimethylacetamide (20 mL) was added isopropyl-2-cyano acetate (3.18 g, 24.52 mmol) and potassium carbonate (7.78 g, 55.72 mmol). The resulting suspension was stirred at 80°C for 2 h (full consumption of starting material). Sodium ethanethiolate (7.12 g, 79% assay, 66.86 mmol) was added and the reaction was stirred for further 7h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and the precipitate was filtered off. The filtrate was acidified with 2M aq. HCI, aqueous layer and extracted with EtOAc (2x), the combined organic layer washed with water and brine. Concentration under reduced pressure provided a crude material which was purified by silica gel chromatography using cyclohexane and ethyl acetate (0.1 % of formic acid) as an eluent to yield the title compound G (4.20 g, 96% assay, 62% yield) as a gummy liquid and the title compound H (0.50 g, 96 % assay, 7 % yield) as a gummy liquid. compound G:1H NMR (400 MHz, CD3CN) 5 = 1.21 - 1.32 (m, 6 H), 1.37 (t, J=7.3 Hz, 3 H), 3.17 (q, J=7.3 Hz, 2 H), 5.01 - 5.10 (m, 1 H), 5.21 (s, 1 H), 7.93 (d, J=2.0 Hz, 1 H), 8.53 (d, J=2.0 Hz, 1 H);13C NMR (101 MHz, CD3CN) 5 = 13.7, 21.1 , 26.9, 41.6, 72.7, 115.4, 116.0, 131.5, 132.7, 135.8, 141.4, 147.1 , 163.8. compound H:1H NMR (400 MHz, CD3CN) 5 = 1 .22 - 1 .27 (m, 3 H), 1 .29 - 1 .33 (m, 3 H), 1 .35 - 1 .41 (m, 3 H), 2.19 (s, 1 H), 3.17 (q, J=7.4 Hz, 2 H), 5.09 (dt, J=12.6, 6.2 Hz, 1 H), 5.35 (s, 1 H), 7.82 (d, J=2.2 Hz, 1 H), 8.58 (d, J=2.2 Hz, 1 H).

[0110] Example 8: Preparation of 5-(cvanomethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile

[0111] To a solution of isopropyl 2-cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl)acetate (0.700 g, 95% assay, 2.29 mmol) in acetic acid (3.5 mL) was added water (2.1 mL) and the reaction mixture was stirred at 90°C for 4 h. Most of the solvents were evaporated under reduced pressure and water (7 mL) was added to the residue. The resulting precipitate was filtered and dried under high vacuum to yield the title compound (0.439 g, 99 % assay, 94% yield) as an off-white solid. Analytical data are identical to those reported in Example 5.

[0112] Example 9: Preparation of 5-(1-cvanocvclopropyl)-3-ethylsulfanyl-pyridine-2-carbonitrile

[0113] 5-(cyanomethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile (10.00 g, 97.6% assay, 48.04 mmol) and tetrabutylammonium bromide (1.56 g, 4.80 mmol) was added to a mixture of 10% aq. NaOH (69 mL) and MeCN (10 mL). To the resulting solution was dosed 1 ,2-dibromoethane (6.4 mL, 72.0 mL) over 1 h at ambient temperature. After stirring for further 2 h the reaction mixture was acidified to pH 2 by addition of 2M aq HCI (45 mL). The resulting mixture was diluted with EtOAc (50 mL) and phases were separated. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layer was washed with water (2x50 mL). The resulting solution was evaporated under reduced pressure to yield a crude title compound (17.05 g, 63% assay, 97% yield) as a black solid. This material was purified by suspending in MeTHF (20 mL), stirring for 2 h at 0°C and filtering the resulting precipitate. The precipitate was washed on filter with cold MeTHF (15 mL) and dried under high vacuum till constant weight to yield the title compound (6.15 g, 96.7% assay, 54% yield) as an off- white solid. Analytical data are identical to those reported in Example 2.

Claims

CLAIMS1 . A process for preparation of compound of formula (I)wherein said process comprisesStep A) reacting 3,5-dichloropyridine-2-carbonitrile with a cyanoacetate of formula (II)wherein R is alkyl or benzyl; in the presence of an appropriate base and in an appropriate solvent to produce a compound of formula (III)wherein R is as defined for a compound of formula (II);Step B) reacting said compound of formula (III)wherein R is as defined for a compound of formula (II) with an alkali metal ethanethiolate in an appropriate solvent to produce a compound of formula (IV)wherein R is as defined for a compound of formula (II);Ste C) hydrolyzing and decarboxylating said compound of formula (IV)wherein R is as defined for a compound of formula (II); in the presence of an appropriate acid in an appropriate solvent to produce a compound of formula (V)Step D) reacting said compound of formula (V)with an alkylating agent of formula (VI)wherein X and Y are independently selected from chloro or bromo; in the presence of an appropriate base and an appropriate additive, in an appropriate solvent to produce said compound of formula (I).

2. A process according to claim 1 , wherein R is methyl or ethyl.

3. A process according to claim 1 or claim 2, wherein the base used in step A) is selected from alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates and alkali metal alkoxides.

4. A process according to any one of claims 1 to 3, wherein the solvent used for step A) is a polar aprotic solvent.

5. A process according to claim 4, wherein the solvent used for step A) is selected from acetonitrile, butyronitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidine, sulfolane, dimethylsulfoxide and dioxane.

6. A process according to any one of claims 1 to 5, wherein the base used in step B) is selected from alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates and alkali metal alkoxides.

7. A process according to any one of claims 1 to 6, wherein the solvent used for step B) is selected from nitriles, amides, ethers and sulfones.

8. A process according to any one of claims 1 to 7, wherein the alkali metal salt of ethanethiol used in step B) is prepared in situ from ethanethiol and an appropriate base.

9. A process according to claims 8, wherein the base is selected from sodium hydride, sodium hydroxide, sodium tert-butoxide, potassium hydroxide and potassium tert-butoxide.

10. A process according to any one of claims 1 to 5 and 7 to 9, wherein steps A) and B) are telescoped by adding an alkali metal salt of ethanethiol to the reaction mixture of step A) after full consumption of the step A) starting material.

11. A process according to any one of claims 1 to 10, wherein the acid for step C) is selected from acetic acid, propionic acid, sulfuric acid, hydrochloric acid and p-toluenesulfonic acid.

12. A process according to any one of claims 1 to 1 1 , wherein the co-solvent for step C) is selected from alcohols, ethers and organic acids.

13. A process according to any one of claims 1 to 12, wherein the base used in step D) is selected from alkali metal carbonates and alkali metal hydroxides,14. A process according to any one of claims 1 to 13, wherein the additives used in step D) is a phase transfer catalyst selected from tetrabutylammonium bromide, benzyltriethylammonium bromide and tetrabutylammonium chloride.

15. A process according to any one of claims 1 to 14, wherein the solvent used for step D) is selected from nitriles, amides, ethers, sulfones and water.

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