Process for the preparation of piperidinyl 1,2,4-oxadiazole derivatives

Abstract

The invention relates to a process for the preparation of compound of formula (I), (I) and derivatives thereof, and their uses for preparation of important intermediates for preparation of active ingredients.

Description

[0001] Process for the preparation of piperidinyl 1 ,2,4-oxadiazole derivatives

[0002] The present invention relates to novel 1 ,2,4-oxadiazole derivatives and methods for producing them, which are intermediates useful in the preparation of 3-(4-piperidyl)-1 ,2,4-oxadiazoles or their salts.

[0003] 3-(4-piperidyl)-1 ,2,4-oxadiazoles or their salts are themselves useful intermediates involved in the preparation of biologically active compounds in the agrochemical and pharmaceutical industries as described in, for example WO / 2017 / 195703, WO / 2021 / 053161 , WO / 2021 / 160680, WO / 2021 / 215393 and WO2022207462, or pharmaceuticals (e.g. WO / 2000 / 039125, 2007 / 0213314, WO / 2007 / 105049, WO / 2008 / 029924, WO / 2010 / 138487, WO / 2012 / 068106, WO / 2012 / 136492, WO / 2013 / 010453, WO / 2015 / 008230 and WO / 2020 / 021021).

[0004] It has been now found that certain novel compounds (of formulae (I) and (XVIII)) are useful in the synthesis of 5-methyl-3-(4-piperidyl)-1 ,2,4-oxadiazole of formula (II) or its salt (II’)

[0005] The preparation of 5-methyl-3-(4-piperidyl)-1 ,2,4-oxadiazole (II) or (II’) is known from WO2017 / 195703

[0006] (see Scheme A), where the starting point is from substrate (III).

[0007] Scheme A: 5-methyl-3-(4-piperidyl)-1 ,2,4-oxadiazole (II) as described in WO2017 / 195703

[0008] The process according to Scheme A has significant disadvantages. On the one hand, the cost of substrate of formula (III) would be uneconomical and unsuitable for a large-scale production because it is likely that a substrate of the formula (XII) would have been used to prepare the substrate of formula (III). Scheme B illustrates a process to prepare the substrate ofthe formula (XII) based on the disclosure in CN102070513. It involves the Michael addition of (VII) to (VI) (step B-a), followed by Dieckmann condensation of (VIII) (step B-b) and subsequent decarboxylation results in A / -benzyl-4-piperidinone (X- a) (step B-c). Then hydrogenolysis of substrate (X-a) (step B-d), and finally A / -Boc protection of the formed product (neutral (XI) or as a salt (XI’) furnishes the substrate of formula (XII).

[0009] Scheme B: Synthesis of fe / Y-butyl 4-oxopiperidine-1 -carboxylate (XII) as described in CN102070513

[0010] The proposed invention avoids the disadvantages in the prior art by relying on mild conditions to obtain the compounds of formula (II) or (II’).

[0011] Accordingly, applicant has found novel processes and intermediates for the preparation of the useful intermediates 3-(4-piperidyl)-1 ,2,4-oxadiazoles, or their salts, which rely on fewer steps, thus more sustainable (such as lower number of reaction steps, and more economical) conditions than the prior art.

[0012] The following scheme describes the reactions of the invention in brief (Scheme C).

[0013]

[0014] Scheme C: New synthetic route towards compound of formula (II) or (II’)

[0015] The use of palladium on carbon with a catalyst and molecular hydrogen gas or transfer hydrogenation conditions for preparation compound of formula (II) would be detrimental to the 1 ,2,4-oxadiazole functionality of a compound of formula (I) because the reduction of the oxadiazole heterocycle to its saturated counterpart occurs more readily than the removal of the alkyl or benzyl motif.

[0016] It has been found that commercially available and affordable A / -alky I protected piperidone are suitable starting materials. In principle, A / -dealkylation proceeds via the introduction of a certain A / -carbamate motif which can then be removed via hydrolysis of alcoholysis. The introduction of such A / -carbamate could be carried out at various stages of the process and deliver 5-methyl-3-(4-piperidyl)-1 ,2,4- oxadiazole of formula (II) efficiently. Thus, more affordable, and readily available substrate than tert- butyl 4-oxopiperidine-1 -carboxylate (XII), such as for example 1-methylpiperidin-4-one (X-b; when R1is methyl) or 1-benzylpiperidin-4-one (X-a; when R1is benzyl), are of high interest.

[0017] In a first aspect, the present invention relates to a process for the preparation of a compound of formula (I), wherein R1is Ci-C4alkyl or benzyl; comprising reacting a compound of formula (XIV) wherein R1is Ci-C4alkyl or benzyl; with acetic anhydride, acetyl chloride or ethyl acetate.

[0018] In a second aspect, the present invention relates to a process for the preparation of a compound of formula (XVIII),

[0019] (XVIII) wherein R2is Ci-C4alkyl, benzyl, phenyl or CHCICH3; comprising reacting a compound of formula (I), as defined in the first aspect, with a chloroformate compound of formula (XIX) wherein R2is Ci-C4alkyl, benzyl, phenyl or 1 -chloroethyl.

[0020] In a third aspect, the present invention relates to a process for the preparation of a compound of formula (II) or (II’), comprising

[0021] 1) reacting a compound of formula (I), as defined in the first aspect, with phosgene or triphosgene; or 2) converting a compound of formula (XVIII), as defined in in the second aspect, under hydrolytic conditions (acidic or alkaline) when R2of compound of formula (XVIII) is Ci-C4alkyl, benzyl, or phenyl, or under alcoholysis (such as with methanol or ethanol) conditions when R2of compound of formula (XVIII) is CHCICH3.

[0022] In a fourth aspect, the present invention relates to a process for the preparation of a compound of formula (XIV), wherein R1is Ci-C4alkyl or benzyl; comprising reacting a compound of formula (XIII) wherein R1is Ci-C4alkyl or benzyl; with hydroxylamine or hydroxylammonium salt, and wherein compound of formula (XIII) is prepared comprising reacting a compound of formula (X) wherein R1is Ci-C4alkyl or benzyl; with toluenesulfonylmethyl isocyanide.

[0023] In a fifth aspect, the present invention relates to a process for the preparation of a compound of formula (XVIII)

[0024] (XVIII) wherein R2is Ci-C4alkyl, benzyl, or phenyl; comprising reacting a compound of formula (XVII) wherein R2is Ci-C4alkyl, benzyl, or phenyl; with acetic anhydride, acetyl chloride or ethyl acetate.

[0025] In a sixth aspect, the present invention relates to a compound of formula (I) or (XVIII), (XVIII) wherein R1is benzyl; and wherein R2is methyl, ethyl, benzyl, phenyl, or -CHCICH3.

[0026] The route starting with a compound of formula (X) relies upon fewer steps to arrive at the compounds of formula (II) or (II’) than the prior art, which offers many advantages from a perspective of economy, time, and sustainability.

[0027] The organic solvent suitable in the present invention can comprise any suitable organic solvent well- known in the art. For example, the organic solvent can be selected among dichloromethane, 1 ,2- dichloroethane, toluene, xylenes, chlorobenzene, chloroform, tert-butyl methyl ether, ethyl acetate, tert- butanol, iso-propanol, ethanol, methanol, tetra hydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile, 2-methylpropionitrile, butyronitrile, and any combinations thereof.

[0028] The process according to the present invention use hydroxylamine or its salt (for example, in steps b) and h) as illustrated in Scheme C); preferably hydroxylamine. The term “hydroxylamine” means the free hydroxylamine of formula H2NOH, and the hydroxylamine salts can be for example hydroxylammonium chloride.

[0029] The term "Ci-C4alkyl" as used herein refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the carbon atoms having 1 to 4 carbon atoms, for example, any one of the radical methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, and fe / Y-butyl.

[0030] The term “neat” as used herein means that does not contain a co-solvent or a diluent. The term “room temperature” or “RT” or “rt” or “ambient temperature” as used herein refers 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.

[0031] In an embodiment R1, independent of compound of the formulae (I), (XIV), (XIII), (X), and independent of the first, fourth and sixth aspects, is

[0032] (A) methyl, ethyl or benzl; or

[0033] (B) methyl or benzyl; or

[0034] (C) methyl; or

[0035] (D) benzyl.

[0036] In an embodiment R2, for a compound of formula (XVIII) in any of second, third and sixth aspects and independent thereof, is

[0037] (A) methyl, ethyl, phenyl, benzl, or CHClCHs; or

[0038] (B) methyl, benzl, or CHCICH3; or

[0039] (C) methyl; or

[0040] (D) benzyl; or

[0041] (E) CHCICH3.

[0042] In an embodiment R2, for a compound of formula (XVIII) as defined in the fifth aspect, is

[0043] (A) methyl, ethyl, phenyl, or benzl; or

[0044] (B) methyl, phenyl, or benzl; or

[0045] (C) phenyl; or

[0046] (D) benzyl; or

[0047] (E) methyl.

[0048] In an embodiment R2, for a compound of formulae (XV), (XVI), (XVII) and (XIX), independent of the compound and any one of the relevant aspects, is

[0049] (F) methyl, ethyl, phenyl, or benzl; or

[0050] (G) methyl, phenyl, or benzl; or

[0051] (H) phenyl; or

[0052] (I) benzyl; or

[0053] (J) methyl.

[0054] In another embodiment of the invention, the preparation for compound of formula (XIV), as defined in the present invention, comprises reacting a compound of formula (XIII) wherein R1is Ci-C4alkyl or benzyl; with hydroxylamine or hydroxylammonium salt.

[0055] In another embodiment of the invention, the preparation for compound of formula (XIII), as defined in the present invention, comprises reacting a compound of formula (X) wherein R1is Ci-C4alkyl or benzyl; with toluenesulfonylmethyl isocyanide. ln a preferred embodiment of the invention, there is provided a process for the preparation of a compound of formula (I) from a compound of formula (X) using sequentially the step c), then step b) and finally step a) as described in Scheme C. In a preferred embodiment, R1is methyl or benzyl for the compounds of formulae (I) and (X).

[0056] In an embodiment of the third aspect, wherein the compound of formula (XVIII) is prepared according to the second aspect.

[0057] In a preferred embodiment of the invention, there is provided a process for the preparation of a compound of formula (XVIII) from a compound of formula (I), wherein R1is methyl or benzyl for the compound of formula (I), and R2is methyl, ethyl, benzyl, phenyl, or CHCICH3 for the compound of formula (XVIII).

[0058] In a further aspect of the invention, there is provided a process for the preparation of a compound of formula (XIV), as defined in the present invention, comprising reacting a compound of formula (XIII) wherein R1is Ci-C4alkyl or benzyl; with hydroxylamine or hydroxylammonium salt.

[0059] In a still further aspect of the invention, there is provided a process for preparation of a compound of formula (XIII), as defined in the present invention, comprising reacting a compound of formula (X) wherein R1is Ci-C4alkyl or benzyl; with toluenesulfonylmethyl isocyanide. In one embodiment of the invention, the preparation for compound of formula (XVII), as defined in the present invention, comprises reacting the compound of formula (XVI) wherein R2is Ci-C4alkyl, benzyl, or phenyl; with hydroxylamine or hydroxylammonium salt.

[0060] In another embodiment of the invention, the preparation for compound of formula (XVI), as defined in the present invention, comprises

[0061] 1) reacting a compound of formula (XV) wherein R2is Ci-C4alkyl, benzyl, or phenyl; with toluenesulfonylmethyl isocyanide; or

[0062] 2) reacting a compound of formula (XIII), wherein R1is Ci-C4alkyl or benzyl; with chloroformate compound of formula (XIX) wherein R2is Ci-C4alkyl, benzyl or phenyl.

[0063] In another embodiment of the invention, the preparation for compound of formula (XV), as defined in the present invention, comprises reacting the compound of formula (X) wherein R1is Ci-C4alkyl or benzyl; with chloroformate compound of formula (XIX) wherein R2is Ci-C4alkyl, benzyl or phenyl.

[0064] In a preferred embodiment of the invention, there is provided a process for the preparation of a compound of formula (XVIII) starting from either compound of formula (X) via step k) or from compound of formula (XIII) via step g), wherein R1is methyl or benzyl, and R2is methyl, ethyl, benzyl, or phenyl (as illustrated in Scheme C).

[0065] Preferred embodiments of the process for the preparation of compounds of formula (I) as shown in scheme C is further detailed:

[0066] Reaction step a): Cyclization

[0067] To obtain the compound of interest, i.e the compound of formula (I) bearing a 1 ,2,4-dioxazole motif, compounds of formula (XIV) can be subjected to a condensation reaction in the presence of an acylderivative such as acetic anhydride, acetyl chloride (1 .0-2.0 molar equivalent (or equiv.), preferably 1 .0- 1 .5 equiv.), or ethyl acetate (20-50 equiv., preferably 30-40 equiv.) to furnish compound of formula (I).

[0068] The reaction can be carried out neat, or in presence of solvent, such as ethyl acetate, acetonitrile, toluene, A / ,A / -dimethylformamide, or A / ,A / -dimethylacetamide; preferably the reaction is carried out neat. An inorganic base could be used such as sodium hydroxide, potassium hydroxide, lithium hydroxide; sodium hydroxide is preferred (1 .0-3.0 equiv., preferably 1.5-2.5 equiv.).

[0069] The temperature can vary from 10 °C to 100 °C, preferably from 20 °C to 50 °C.

[0070] The compounds of formula (I) are novel and developed specifically for the process, in line with the invention.

[0071] The compounds of formula (I) may be isolated by quenching the reaction mixture with an aqueous medium, for example, a saturated sodium bicarbonate solution or water. Then an extraction of the product could be carried out using an organic solvent as ethyl acetate, and a wash using for example water, followed by brine. Lastly, the combined organic phases may be dried and concentrated to furnish the A / -substituted piperidinyl 1 ,2,4-oxadiazoles of formula (I).

[0072] Reaction step b): Hydroxylamine condensation

[0073] To prepare the compound of formula (XIV) (the precursor to the 1 ,2,4-oxadiazole compound of formula (I)), compound of formula (XIII) is reacted with the nucleophile hydroxylamine or its salt in combination with a base (e.g. an organic base, such as triethylamine, diisopropylethylamine, DBU, DMPU, pyridine, DMAP, DABCO, or(BuOK, or an inorganic base, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide), wherein the molar equivalent ratio of the hydroxylamine is at least 1 :2, preferably in the range of 1 :4 to 1 :6 (wherein the molar equivalent of hydroxylamine to the base is preferably 1 :1). Preferably the reaction is carried out using free hydroxylamine.

[0074] Suitable solvents for the reaction step b) are ethanol, methanol, tert-buty I alcohol, / so-propyl alcohol, and binary solvents, such as ethanol:water or methanol:water. The solvent of choice is preferably a mixture of ethanol:water in a volume ratio of 10 to 25:1 , preferably 15 to 25:1 .

[0075] The reaction can be carried out preferably at temperatures ranging from 40 °C to 80 °C, preferably in ethanol: water mixture between 60°C and 80 °C.

[0076] Isolation could be achieved by concentration in vacuo of the volatiles and by trituration of the resulting solid in an organic solvent, preferably ether solvents, such as methyl fe / Y-butyl ether (MTBE).

[0077] Reaction step c): Van Leusen

[0078] The compound of formula (X) is known and disclosed in JP2013107855 or Kurihara, T; Tetrahedron Letters (1989), 30 (28), 3681-3684. Compound (XIII) may be prepared by the Van Leusen reaction from compound of formula (X). The reaction can be performed using a cyanating agent such as p- tosylmethyl isocyanide (1.0-1 .5 equiv., preferably 1.0-1 .2 equiv.) (J. Org. Chem. 1977, 42, 19, 3114- 3118) in an organic solvent (e.g.1 ,2-dimethoxyethane), or a mixture of solvents (such as 1 ,2- dimethoxyethane:ethanol), each in the presence of a base (1 .0-3.0 equiv., preferably 2.0-2.5 equiv.) (e.g. BuOK, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide).

[0079] In the instance, the process is carried out in organic solvent mixtures (for example mixture of 1 ,2- dimethoxyethane, methyl tetrahydrofuran, acetonitrile, sulpholane, or water with methanol, ethanol, isopropyl alcohol, fe / Y-butyl alcohol) at temperatures ranging from -10 °C to +80 °C, which may be elevated up to ambient temperature or to a higher temperature to complete the reaction. The reaction is preferably performed in methyl tetrahydrofuran using tert-buty I alcohol as solvent and sodium hydroxide as base (1.0-10 equiv., preferably 1.0-5.0 equiv.). The temperature preferably ranges from +10°C to +70 °C.

[0080] The compounds of formula (XIII) may be isolated by quenching the reaction mixture with an aqueous medium, (e.g. water, saturated ammonium chloride solution, or dilute hydrochloric acid solution) and by extracting the product with an organic solvent. The latter solvent may be washed with water followed by brine and dried over sodium sulfate or magnesium sulfate before being evaporated in vacuo. Further purification may be carried out by column chromatography.

[0081] Reaction step d): A / -Dealkylation

[0082] A preferred method of dealkylation (preferably of benzyl or methyl-substituted tertiary amine) is to subject the compound of formula (I) to haloformate derived electrophiles (1 .5-5.0 equiv., preferably 2.0- 4.0 equiv.). For example, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, or benzylchloroformate could be employed as demethylating or debenzylating agents and lead to compound of formula (XVIII) as described in EP0045234 or US3905981.

[0083] Haloalkyl chloroformates such as 1 -chloroethyl- chloroformate (1 .0-5.0 equiv., preferably 1 .0-3.0 equiv.) could also be utilized to dealkylate the A / -substituted piperidinyl moiety of compounds of formula (l-a, when R1is benzyl) and (l-b, when R1is methyl) to form (XVIII).

[0084] To deliver compound of formula (XVIII), when R2= Ci-C4alkyl, benzyl, phenyl, or CHCICH3, aromatic bases (e.g. pyridine, DMAP, or imidazole) are suitable for the process; preferably pyridine. An inorganic base could also be used, such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; preferably potassium carbonate (catalytic, 0.1-0.5 equiv., preferably 0.1-0.2 equiv.) is used.

[0085] Solvents useful in step d) are ethyl acetate, xylenes, acetonitrile, toluene, dichloroethane, tetra hydrofuran, or 2-methyltetrahydrofuran; preferably toluene.

[0086] The temperature can vary from +20 °C to +100 °C; preferably +60 °C to +90 °C.

[0087] Reaction step e): Carbamate hydrolysis

[0088] To access the desired target compound of formula (II) or (II’), the cleavage of the A / -carbamate moiety of compound of formula (XVIII) may be carried out via alcoholysis when R2is CHCICH3 (1.0-10 mL / mmol), and under alkaline or acidic conditions (50-200 equiv., preferably 50-100 equiv.), when R2is methyl, ethyl, benzyl or phenyl.

[0089] In the first case when R2is CHCICH3, aromatic bases such as pyridine, DMAP, or imidazole are suitable; preferably pyridine.

[0090] When R2is methyl, ethyl, benzyl or phenyl, bases as sodium hydroxide, potassium hydroxide, or lithium hydroxide are suitable for the reaction. Strong acids as HCI, or H2SO4 are preferable.

[0091] The appropriate solvents to use are water, methanol, ethanol, isopropyl alcohol, tert-buty I alcohol, or binary solvents involving aqueous and alcoholic solvents (water, and methanol, ethanol, or isopropanol); preferably water when R2is methyl, ethyl, benzyl or phenyl; and methanol when R2is CHCICH3.

[0092] The temperature may be ranging from +0 °C to +120 °C; preferably ranging from +50 °C to +100 °C.

[0093] The compounds of formula (II’) or (II) may be isolated by concentration in vacuo of the solvent and trituration of the crude using an organic solvent such as MTBE, dichloromethane or diethyl ether. Lastly concentration in vacuo of the volatiles may afford (II’); or (II) if washes of the organic medium are carried out using a basic aqueous solution of sodium bicarbonate.

[0094] Reaction step f): One-step dealkylation

[0095] The reaction from compound of formula (I) to compound of formula (II) or (II’) could be in a single step, using phosgene or triphosgene (0.3-1 .3 equiv., preferably 0.5-0.9 equiv.) as carbonyl source.

[0096] Suitable solvents are ethyl acetate, acetonitrile, toluene, chlorobenzene, and dichloromethane; preferably dichloromethane.

[0097] The temperature may be in the range from -80 °C to 50 °C; preferably ranging from -10 °C to 30 °C. The reaction mixture maybe quenched by using an HCI solution.

[0098] The compounds of formula (II’) or (II) may be recovered by diluting the reaction medium with an organic solvent and washing the organic medium using the appropriate aqueous phase (e.g., a basic aqueous solution (e.g. sodium bicarbonate) would be used for compound (II), and an acidic or neutral aqueous solution would be used for compound (II’)), and then washing with saturated brine, and thereafter drying the combined organic layers. Lastly concentration in vacuo of the latter may afford (II’), or (II).

[0099] Reaction step q): Cyclization

[0100] To obtain the compound of formula (XVIII) bearing a 1 ,2,4-dioxazole motif, compounds of formula (XVII) can be subjected to a condensation reaction in the presence of an acyl-derivative such as acetic anhydride, acetyl chloride (1 .0-2.0 equiv., preferably 1.0-1 .5 equiv.), or ethyl acetate (20-50 equiv., preferably 30-40 equiv.) to furnish compound of formula (XVIII).

[0101] The reaction can be carried out neat, or in presence of solvent, such as ethyl acetate, acetonitrile, toluene, A / ,A / -dimethylformamide, or A / ,A / -dimethylacetamide; preferably the reaction is carried out neat. An inorganic base could be used such as sodium hydroxide, potassium hydroxide, or lithium hydroxide; sodium hydroxide is preferred (1 .0-3.0 equiv., preferably 1.5-2.5 equiv.).

[0102] The temperature can vary from 10 °C to 100 °C, preferably from 20 °C to 50 °C.

[0103] The compounds of formula (XVIII) are novel and developed specifically for the process, in line with the invention.

[0104] The compounds of formula (XVIII) may be isolated by quenching the reaction mixture with an aqueous medium, for example, a saturated sodium bicarbonate solution or water. Then an extraction of the product could be carried out using an organic solvent as ethyl acetate, followed by a wash using for example water, followed by brine. Lastly, the combined organic phases may be dried and concentrated to furnish the A / -substituted piperidinyl 1 ,2,4-oxadiazoles of formula (XVIII). Reaction step h): Hydroxylamine condensation

[0105] To prepare the compound of formula (XVII) (the precursor to 1 ,2,4-oxadiazole compound of (XVIII)), compound of formula (XVI) is reacted with the nucleophile hydroxylamine or its salt, in combination with a base (e.g. an organic base such as triethylamine, diisopropylethylamine, DBU, DMPU, pyridine, DMAP, DABCO, or(BuOK, or an inorganic base, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide), wherein the molar equivalent ratio of the hydroxylamine is at least 1 :2, preferably in the range of 1 :4 to 1 :6 (wherein the molar equivalent of hydroxylamine to the base is preferably 1 :1). Preferably the reaction is carried out using free hydroxylamine.

[0106] Suitable solvents for the reaction step h) are ethanol, methanol, tert-buty I alcohol, / so-propyl alcohol, and binary solvents such as ethanol:water or methanol:water. The solvent of choice is preferably a mixture of ethanol:water in a volume ratio of 10 to 25:1 , preferably 15 to 25:1 .

[0107] The reaction can be carried out preferably at temperatures ranging from 40 °C to 80 °C, Preferably in ethanol:water mixture between 60°C and 80 °C.

[0108] Isolation could be achieved by concentration in vacuo of the volatiles and by trituration of the resulting solid in an organic solvent, preferably ether solvents such at methyl tert-butyl ether (MTBE).

[0109] Reaction step i): Van Leusen

[0110] Compound (XVI) may be prepared by the Van Leusen reaction from compound of formula (XV). The reaction can be performed using a cyanating agent such as p-tosylmethyl isocyanide (1.0-1 .5 equiv., preferably 1 .0-1 .2 equiv.) in an organic solvent (e.g.1 ,2-dimethoxyethane), or a mixture of solvents (such as 1 ,2-dimethoxyethane:ethanol) in the presence of a base (1 .0-3.0 equiv., preferably 2.0-2.5 equiv.) (e.g.(BuOK, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, or lithium hydroxide).

[0111] In the instance, the process is carried out in organic solvent mixtures (for example mixture of 1 ,2- dimethoxyethane, methyl tetrahydrofuran, acetonitrile, sulpholane, or water with methanol, ethanol, isopropyl alcohol, fert-butyl alcohol) at temperatures ranging from -10 °C to +80 °C, which may be elevated up to ambient temperature or to a higher temperature to complete the reaction. The reaction is preferably performed in methyl tetra hydrofuran using fert-butyl alcohol as solvenet and sodium hydroxide as base (1.0-10 equiv., preferably 1.0-5.0 equiv.). The temperature preferably ranges from + 10 to +70 °C.

[0112] The compounds of formula (XVI) may be isolated by quenching the reaction mixture with an aqueous medium, (e.g. water, saturated ammonium chloride solution, or dilute hydrochloric acid solution) and by extracting the product with an organic solvent. The latter solvent may be washed with water followed by brineand dried over sodium sulfate or magnesium sulfate before being evaporated in vacuo. Further purification may be carried out by column chromatography.

[0113] Reaction step i): A / -Dealkylation

[0114] A preferred method of dealkylation (preferably benzyl or methyl-substituted tertiary amine) is to subject compounds of formula (XIII) to haloformate derived electrophiles (1 .0-5.0 equiv., preferably 1.0-3.5 equiv.). For example, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, or benzylchloroformate could be employed as demethylating or debenzylating agents and lead to compound of formula (XVI).

[0115] To deliver compound of formula (XVI), when R2= Ci-C4alkyl, benzyl, or phenyl, aromatic bases (e.g. pyridine, DMAP, or imidazole) are suitable for the process; preferably pyridine. An inorganic base could also be used such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably potassium carbonate (catalytic, 0.1 -0.5 equiv., preferably 0.1 -0.2 equiv.) is used.

[0116] Solvents useful in step j) are ethyl acetate, xylenes, acetonitrile, toluene, dichloroethane, tetra hydrofuran, or 2-methyltetrahydrofuran; preferably toluene.

[0117] The temperature can vary from 20 °C to 100 °C; preferably 60 °C to 90 °C.

[0118] Reaction step k): A / -Dealkylation

[0119] A preferred method of dealkylation (preferably benzyl or methyl-substituted tertiary amine) is to subject compounds of formula (X) to haloformate derived electrophiles (1 .0-5.0 equiv., preferably 1.0-3.0 equiv.). For example, methyl chloroformate, ethyl chloroformate, phenyl chloroformate, or benzylchloroformate could be employed as demethylating or debenzylating agents and lead to compound of formula (XV)

[0120] To deliver compound of formula (XV), when R2= Ci-C4alkyl, benzyl or phenyl, aromatic bases (e.g. pyridine, DMAP, imidazole) are suitable for the process; preferably pyridine. An inorganic base could also be used such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably potassium carbonate (catalytic, 0.1 -0.5 equiv., preferably 0.1 -0.2 equiv.) is used.

[0121] Solvents useful in step k) are ethyl acetate, xylenes, acetonitrile, toluene, dichloroethane, tetra hydrofuran, 2-methyltetrahydrofuran; preferably toluene.

[0122] The temperature can vary from 20 °C to 100 °C; preferably 60 °C to 90 °C.

[0123] Preparation of a compound of formula (II) or (II’) can be carried out in separate process steps (as described in Scheme C), wherein the intermediate compounds can be isolated at each stage. Alternatively, the process can be carried out as a one-pot synthesis wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise or continuous fashion.

[0124] EXAMPLES

[0125] Abbreviations:

[0126] 2-MeTHF: 2-Methyltetrahydrofuran

[0127] DABCO: 1 ,4-diazabiclo[2.2.2]octane

[0128] DBU: 1 ,8-Diazabicyclo[5.4.0]undec-7-ene

[0129] DCM: Dichloromethane

[0130] DMA: A / ,A / -Dimethylacetamide

[0131] DMAP: A / ,A / -Dimethylaminopyridine

[0132] DMF: A / ,A / -Dimethylformaldehyde

[0133] DMPU: A / ,A / ’-Dimethylpropyleneurea

[0134] DMSO: Dimethylsulfoxide

[0135] GCMS: Gas-chromatography-mass spectrometry iPrOH: Isopropyl alcohol

[0136] LCMS: Liquid-chromatography-mass spectrometry

[0137] Rt: Retention time

[0138] NMR: Nuclear Magnetic Resonance fBME: tert-butyl methyl ether fBuOH: tert-butyl alcohol fBuOK: potassium tert-butoxide

[0139] TosMIC: 1-(isocyanomethylsulfonyl)-4-methylbenzene

[0140] UPLC: Ultra Performance Liquid Chromatography

[0141] Preparatory Examples:

[0142] “mp” means melting point in °C.1H NMR spectra were recorded on a Brucker 400 MHz spectrometer, chemical shifts are given in ppm relevant to a TMS standard. Spectra were measured in deuterated solvents as indicated. Either one of the LCMS / GCMS methods given below was used to characterize the compounds. The characteristic LCMS / GCMS values obtained for each compound were the retention time (“Rt”, recorded in minutes) and are measured in either molecular ion (M) or (M+H)+or (M-H)-.

[0143] LCMS and GCMS Methods:

[0144] GCMS method:

[0145] Spectra were recorded on SHIMADZU GCMS-QP2010 Ultra mass spectrometer equipped with an electron impact (El) ion source. Ion Source Temperature: 200 °C, Interface Temperature: 220 °C, Scan speed: 2500, Carrier Gas: Helium, Mass range: 50 to 650 Da and GC-2010 PLUS from Shimadzu, Capillary Column: SH-Rxi- 17 Sil MS, Column Length: 30 m, Internal diameter: 0.25 mm, Film Thickness: 0.25 um, Column oven Temperature: 40 °C, Combi-PAL autosampler, Injector Temperature: 250 °C, Injection Mode: Split, Split Ratio: 30:1 , Flow Control Mode: Pressure, Total Flow (mL / min): 33.0, Column Flow (mL / min): 1.0, Purge Flow (mL / min): 2.0, Runtime: 15 min, Temperature Programme: Initial temperature 40 °C for 1 min, then 40-280 °C with constant rate of 25 °C per min, Temperature hold at 280 °C for 4.4 min.

[0146] LCMS method:

[0147] Spectra were recorded on Waters (SQD2 or QDA Single quadrupole mass spectrometer) mass spectrometer equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch), Capillary: 0.8-3.00 kV, Cone range: 25 Source Temperature: 120-150 °C, Desolvation Temperature: 500-600 °C, Cone Gas Flow: 50 L / h, Desolvation Gas Flow: 1000 L / h, Mass range: 110 to 850 Da and an Acquity UPLC from Waters: Quaternary solvent manager, heated column compartment , diode-array detector. Column: Acquity UPLC HSS T3 C18, 1.8 pm, 30 x 2.1 mm, Temp: 40 °C, DAD Wavelength range (nm): 200 to 400, Solvent Gradient: A = water + 5% Acetonitrile + 0.1 % HCOOH, B= Acetonitrile + 0.05% HCOOH: gradient: 0 min 10% B; 0.-0.2 min 10-50% B; 0.2-0.6 min 50-100% B; 0.6-1 .3 min 100% B; 1.3-1 .4 min 100-10% B; 1.4-1 .6 min 10% B; Flow (mL / min) 0.6.

[0148] Example 1 : Preparation of 1-benzylpiperidine-4-carbonitrile (Xlll-a)

[0149] (Xlll-a)

[0150] To stirring mixture of sodium hydroxide (224.2 mmol) and te / Y-butanol (214.3 mmol) in 2-MeTHF (400 mmol) and heated to 60-65 °C was added a solution of 1-(isocyanomethylsulfonyl)-4-methylbenzene (TosMIC) (107.2 mmol) and 1-benzylpiperidin-4-one (X-a) (102.1 mmol) in 2-MeTHF (1800 mmol), over a period of 2.5 hours. The reaction was allowed to stir at 60-65 °C for another hour. The, the reaction was allowed to cool down to room temperature, diluted with water (140 mL), stirred, and washed with water (100 mL). The aqueous layer was re-extracted with 2-MeTHF (100 mL). The combined organic layer was concentrated under vacuum to afford (Xlll-a) as brown liquid (20.64 g, Yield: 87%). GCMS: Rt = 10.20 min, m / z 200.1H NMR (400 MHz, ACETONE-de) 6 ppm 1 .59 - 1 .75 (m, 2 H), 1 .78 - 1 .86 (m, 2 H), 2.20 (m, 2 H), 2.52 (m, 2 H), 2.69 (m, 1 H), 3.39 (s, 2 H), 7.11 - 7.17 (m, 1 H), 7.20 - 7.22 (m, 4 H).

[0151] Example 2: Preparation of 1-methylpiperidine-4-carbonitrile (Xlll-b)

[0152] (Xlll-b) To a stirred solution of 1 -methylpiperidin-4-one (X-b) (9.8 g, 86.60 mmol) in 2-MeTHF (150 mL) and te / Y-butanol (7.061 g, 95.27 mmol) was added 1 -(isocyanomethylsulfonyl)-4-methylbenzene (TosMIC) (17.75 g, 90.94 mmol) at room temperature followed by addition of potassium te / Y-butoxide (19.4 g, 173.2 mmol) in portions and heated at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum followed by trituration with a mixture of heptane / TBME. Solid obtained was filtered off and filtrate was concentrated to afford methyl 4-cyanopiperidine-1- carboxylate (Xlll-b) as brown liquid (7.77 g, Yield: 72%). GCMS: Rt = 6.12. min, m / z 124.1H NMR (400 MHz, DMSO-de) 6 ppm 1 .70-1 .78 (m, 2 H), 1 .82 - 2.03 (m, 2 H), 2.16 - 2.26 (m, 5 H), 2.39 - 2.49 (m, 2 H), 2.88 (m, 1 H).

[0153] Example 3: Preparation of 1-benzyl-A / '-hvdroxy-piperidine-4-carboxamidine (XlV-a)

[0154] To a stirred solution of 1-benzylpiperidine-4-carbonitrile (XI I l-a) (46 mmol) in EtOH (1 16 mL) was added hydroxylamine (50 mass% in H2O (186 mmol) at room temperature and heated at 80 °C in close reaction vessel for 4 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude was purified by trituration with TBME to afford 1-benzyl-A / '-hydroxy- piperidine-4-carboxamidine (XlV-a) as white solid (10.51 g, Yield: 82%). LCMS: Rt = 0.15 min, m / z 234.1H NMR (400 MHz, DMSO) 5 ppm 1 .53 - 1 .71 (m, 4 H) 1 .86 - 2.00 (m, 3 H) 2.76 - 2.87 (m, 2 H) 3.25 - 3.36 (m, 2 H) 3.40 - 3.48 (m, 2 H) 5.19 - 5.32 (m, 2H), 7.22 - 7.38 (m, 5 H) 8.70 - 8.83 (m, 1 H).

[0155] Example 4: Preparation of A / '-hvdroxy-1-methyl-piperidine-4-carboxamidine (XlV-b)

[0156] (XlV-b)

[0157] To a stirred solution of 1-methylpiperidine-4-carbonitrile (Xlll-b) (31 mmol) in EtOH (4.4 mL) was added hydroxylamine (50 mass% in H2O (68.0 mmol) at room temperature and heated at 80 °C in close reaction vessel for 4 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude was purified by trituration with TBME to afford N'- hydroxy-1-methyl-piperidine-4-carboxamidine (XlV-b) as white solid (4.15 g, Yield: 86%). LCMS: Rt = 0.30 min, m / z 158.1.1H NMR (400 MHz, DMSO-d6) 6 ppm 1.49 - 1.70 (m, 4 H), 1.78 (m, 2 H), 1 .83 - 1 .93 (m, 1 H), 2.1 1 (s, 3 H), 2.75 (m, 2 H), 5.27 (br s, 2 H), 8.80 (br s, 1 H).

[0158] Example 5: Preparation of 3-(1-benzyl-4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a)

[0159] (l-a)

[0160] To a stirring solution of A / '-hydroxy-1-benzyl-piperidine-4-carboxamidine (10.0 g, 42.0 mmol) in ethyl acetate (135.0 g, 1 .53 mol) was added powder sodium hydroxide (3.43 g, 84.0 mmol) portion wise over 1 hour at 40 °C. The reaction was allowed to stir further at 40 °C for 1 hour. Then the reaction mixture cooled down to room temperature, diluted with water and extracted using ethyl acetate. The combined organic layers were concentrated under reduced pressure and afforded the corresponding 3-(1-benzyl- 4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a) (10.4 g, Yield: 94%). LCMS: Rt = 0.38 min, m / z 182.2.1H NMR (400 MHz, CDCb) 6 ppm 1.91 - 2.10 (m, 4 H), 2.15 - 2.26 (m, 2 H), 2.57 - 2.61 (s, 3 H), 2.96 - 3.05 (m, 2 H), 3.56 - 3.65 (m, 2 H), 7.29 - 7.43 (m, 5 H).

[0161] Example 6: Preparation of 5-Methyl-3-(1-methyl-4-piperidyl)-1 ,2,4-oxadiazole (l-b)

[0162] (l-b)

[0163] To a stirred solution of A / '-hydroxy-1-methyl-piperidine-4-carboxamidine (10.5 mmol) in acetic anhydride (21.1 mmol) was heated at 95 °C for 2 hours. The reaction mixture was then cooled to room temperature, diluted with water (3 mL) and basified (pH~8) with NaHCOs (8 mL) then extracted with ethyl acetate (3 X 15 mL) combine organic layers was concentrate under reduced pressure. The aqueous layer was basified (pH=13) with 2N NaOH then extracted with DCM (3 X 15 mL) combine organic layers was concentrate under reduced pressure to afford corresponding 5-methyl-3-(1 -methyl- 4-piperidyl)-1 ,2,4-oxadiazole (l-b) (0.949 g, Yield: 49.6%). LCMS: Rt = 0.17 min, m / z 182.2.1H NMR (400 MHz, DMSO-de) 6 ppm 1 .60 - 1 .73 (m, 2 H), 1 .84 - 1 .89 (m, 2 H), 1 .99 (m, 2 H), 2.17 (s, 3 H), 2.54 (s, 3 H), 2.66 (m, 1 H), 2.77 (m, 2 H).

[0164] General Procedure A: Synthesis of 4-oxopiperidine-1 -carboxylate derivatives (XV) from compound of formula (X-a)

[0165] To a stirred solution of 1 -benzylpiperidin-4-one (X-a) (25.6 mmol) in toluene (21 mL) was added potassium carbonate (2.56 mmol) at room temperature and heated at 60 °C (2 h) followed by addition of the relevant alkyl chloroformate derivative (30.8 mmol) dropwise and continued heating for 2 h at the same temperature. The reaction mixture was then cooled to room temperature, diluted with water (30 mL) and organic layer was separated. The aqueous layer was re-extracted with toluene (2 X 30 mL) and combine organic layers was concentrate under reduced pressure. The crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford oxopiperidine- 1 -carboxylate derivative (XV).

[0166] (XV-a)

[0167] The reaction was performed on 25.6 mmol scale of (X-a) using methyl chloroformate following General Procedure A. The crude was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford methyl 4-oxopiperidine-1 -carboxylate (XV-a) as pale-yellow liquid (2.33 g, Yield: 58%). GCMS: Rt = 7.91 min, m / z 157.1H NMR (400 MHz, DMSO-d6) 6 ppm 2.37 (br t, 4 H), 3.62 (s, 3 H), 3.67 (t, 4H).

[0168] (XV-b)

[0169] The reaction was performed on 12.81 mmol scale of (X-a) using ethyl chloroformate following General Procedure A to afford Ethyl 4-oxopiperidine-1 -carboxylate (XV-b) as pale-yellow liquid (1.69 g, Yield: 77%). GCMS: Rt = 8.15 min, m / z 171.1H NMR (400 MHz, DMSO-cfe) 6 ppm 1.22 (t, J =7.09 Hz, 3 H), 2.38 (t, J =6.30 Hz, 4 H), 3.66 (t, J =6.24 Hz, 4 H), 4.09 (q, J =7.09 Hz, 2 H).

[0170] Example 9: Preparation of benzyl 4-oxopiperidine-1 -carboxylate (XV-c)

[0171] (XV-c)

[0172] The reaction was performed on 25.6 mmol scale of (X-a) using benzyl chloroformate following General Procedure A. The crude was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford benzyl 4-oxopiperidine-1 -carboxylate (XV-c) as pale-yellow liquid (3.80 g, Yield: 64%). GCMS: Rt = 11 .55 min, m / z 233.1H NMR (400 MHz, DMSO-cfe) 6 ppm 2.39 (t, J = 6.30 Hz, 4 H), 3.70 (t, J = 5.87 Hz, 4 H), 5.14 (s, 2 H), 7.32 - 7.42 (m, 5 H).

[0173] Example 10: Preparation of phenyl 4-oxopiperidine-1 -carboxylate (XV-d)

[0174] (XV-d)

[0175] The reaction was performed on 21 .81 mmol scale of (X-a) using phenyl chloroformate following General Procedure A. The crude was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford phenyl 4-oxopiperidine-1 -carboxylate (XV-d) as white solid (2.4 g, Yield: 85%). GCMS: Rt = 11.27 min, m / z 219.1H NMR (400 MHz, DMSO-d6) 5 ppm 2.42 - 2.47 (m, 4 H), 3.72-3.87 (m, 4 H), 7.14 - 7.16 (m, 1 H), 7.16 - 7.24 (m, 2 H), 7.35 - 7.42 (m, 2 H).

[0176] General Procedure B: Synthesis of 4-oxopiperidine-1 -carboxylate derivatives (XV) from compound of formula (X-b)

[0177] To a stirred solution of 1-methylpiperidin-4-one (X-b) (22.09 mmol) in toluene (10 mL) was added potassium carbonate (2.209 mmol) at room temperature. The reaction mixture was heated to 60 °C, followed by addition of the relevant chloroformate (55.24 mmol) dropwise and continued heating for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and organic layer was separated. The aqueous layer was re-extracted with toluene (2 X 30 mL) and combine organic layers was concentrate under reduced pressure. The crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford 4-oxopiperidine-1- carboxylate (XV).

[0178] Example 1 1 : Preparation of methyl 4-cyanopiperidine-1 -carboxylate (XV-a)

[0179] (XV-a)

[0180] The reaction was performed on 22.09 mmol scale of 1-methylpiperidin-4-one (X-b) using methyl chloroformate following General Procedure B. The combine organic layer was concentrated to afford methyl 4-oxopiperidine-1 -carboxylate (XV-a) as liquid (0.244 g, Yield: 7%).

[0181] Example 12: Preparation of ethyl 4-oxopiperidine-1 -carboxylate (XV-b)

[0182] (XV-b) The reaction was performed on 22.09 mmol scale of 1-methylpiperidin-4-one (X-b) using ethyl chloroformate following General Procedure B. Crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford ethyl 4-oxopiperidine-1 -carboxylate (XV-b) as liquid (1 .5349 g, Yield: 40.6 %).

[0183] Example 13: Preparation of phenyl 4-oxopiperidine-1 -carboxylate (XV-d)

[0184] (XV-d)

[0185] The reaction was performed on 8.66 mmol scale of 1-methylpiperidin-4-one (X-d) using phenyl chloroformate following General Procedure B. Crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford phenyl 4-oxopiperidine-1 -carboxylate (XV- d) as white solid (1 .1 g, Yield: 58%).

[0186] General Procedure C: Synthesis of A 4-cyanopiperidine-1 -carboxylate derivates (XVI) from compounds (XV)

[0187] To a stirred solution of 4-oxopiperidine-1 -carboxylate derivatives (XV) (6.13 mmol) in 2-MeTHF (15 mL) and te / Y-Butanol (6.74 mmol) was added 1 -(isocyanomethylsulfonyl)-4-methylbenzene (TosMIC) (6.43 mmol) at room temperature followed by addition of potassium te / Y-butoxide (12.3 mmol) in portions at 20-30 °C and then heated at 60 °C for 2 hours. The reaction mixture was then cooled to room temperature diluted with water (10 mL) and extracted with ethyl acetate. Aqueous layer was re-extracted with ethyl acetate (3 X 10 mL). The combine organic layer was concentrated under vacuum and crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford corresponding 4-cyanopiperidine-1 -carboxylate derivatives (XVI).

[0188] Example 14: Preparation of methyl 4-cyanopiperidine-1 -carboxylate (XVI-a)

[0189] The reaction was performed on 6.13 mmol scale of methyl 4-oxopiperidine-1 -carboxylate (XV-a) following General Procedure C. The crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford methyl 4-cyanopiperidine-1 -carboxylate (XVI-a) as brown liquid (0.430 g, Yield: 42%). GCMS: Rt = 8.89 min, m / z 168.1H NMR (400 MHz, CDCI3) 5 ppm 1 .75 - 1 .94 (m, 4 H), 2.83 (m, 1 H), 3.37 - 3.51 (m, 2 H), 3.65 - 3.72 (s, 3 H). Example 15: Preparation of ethyl 4-cyanopiperidine-1 -carboxylate (XVI-b)

[0190] (XVI-b)

[0191] The reaction was performed on 5.57 mmol scale of (XV-b) following General Procedure C. The crude was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford ethyl 4-cyanopiperidine-1 -carboxylate (XVI-b) as brown liquid (0.381 g, Yield: 38%). GCMS: Rt = 9.09 min, m / z 182.1H NMR (400 MHz, DMSO-cfe) 6 ppm 1.18 (t, J=7.09 Hz, 3 H), 1.60 - 1.69 (m, 2 H), 1.80 - 1 .89 (m, 2 H), 3.06 (m, 1 H), 3.22 (m, 2 H), 3.55 - 3.63 (m, 2 H), 4.04 (q, J=7.09 Hz, 2 H).

[0192] Example 16: Preparation of benzyl 4-cyanopiperidine-1 -carboxylate (XVI-c)

[0193] (XVI -c)

[0194] The reaction was performed on 3.94 mmol scale of (XV-c) following General Procedure C. The crude was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford benzyl 4-cyanopiperidine-1 -carboxylate (XVI-c) as brown liquid (0.288 g, Yield: 30%). GCMS: Rt = 12.59 min, m / z 244.1H NMR (400 MHz, DMSO-d6) 5 ppm 1.58 - 1.71 (m, 2 H), 1.85 (m, 2 H), 3.02 - 3.10 (m, 1 H), 3.19 - 3.31 (m, 2 H), 3.56 - 3.68 (m, 2 H), 5.07 (s, 2 H), 7.29 - 7.39 (m, 5H).

[0195] Example 17: Preparation of phenyl 4-cvanopiperidine-1 -carboxylate (XVI-d)

[0196] (XVI-d)

[0197] The reaction was performed on 1 .38 mmol scale of (XV-d) following General Procedure C. The crude was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford benzyl 4-cyanopiperidine-1 -carboxylate (XVI-d) as brown liquid (0.221 g, Yield: 22%). GCMS (method 1): Rt = 12.27 min, m / z 230.1H NMR (400 MHz, DMSO-d6) 6 ppm 1 .69 - 1 .85 (m, 2 H), 1 .94 (m, 2 H), 3.14 (tt, J = 8.60, 4.11 Hz, 1 H), 3.29-3.36 (m, 2 H), 3.59 - 3.88 (m, 2 H), 7.12 - 7.16 (m, 2 H), 7.19 - 7.25 (m, 1 H), 7.39 (t, J = 7.22 Hz, 2 H). General Procedure D: Synthesis of N'-l derivatives

[0198] To a stirred solution of substituted 4-cyanopiperidine-1 -carboxylate derivatives (XVI) (12.70 mmol) in EtOH (4 mL) was added hydroxylamine (50 mass% in H2O (63.29 mmol) at room temperature and then heated at 80 °C in close vial for 4 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude product was purified through trituration with TBME to afford corresponding 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1 -carboxylate derivatives (XVII).

[0199] (XVI I -a)

[0200] The reaction was performed on 12.70 mmol scale of methyl 4-cyanopiperidine-1 -carboxylate (XVI-a) following General Procedure D to afford methyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1- carboxylate (XVII-a) as white solid (2.21 g, Yield: 86.4%). LCMS: Rt = 0.22 min, m / z 202.4.1H NMR (400 MHz, DMSO-de) 6 ppm 1 .37 - 1 .53 (m, 2 H), 1.68 (m, 2 H), 2.17 (m, 1 H), 2.77 (m, 2 H), 3.57 (s, 1 H), 3.97 (m, 2 H), 5.34 (s, 2 H), 8.55 - 9.07 (br s, 1 H)

[0201] Example 19: Preparation of ethyl 4-[(Z)-N'-hvdroxycarbamimidoyl1piperidine-1 -carboxylate (XVII-b)

[0202] (XVII-b)

[0203] The reaction was performed on 7.93 mmol scale of ethyl 4-cyanopiperidine-1 -carboxylate (XVI-b) following General Procedure D to afford ethyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1 -carboxylate (XVII-b) as white solid (1 .31 g, Yield: 77%). LCMS: Rt = 0.16 min, m / z 216.5.1H NMR (400 MHz, DMSO- de) 6 ppm 1 .06 (t, 3 H), 1 .35 (m, 2 H), 1 .58 (m, 2 H), 2.08 (m, 1 H), 2.58 - 2.68 (m, 2 H), 3.91 - 4.02 (m, 4 H), 5.32 (br s, 2 H), 8.77 - 9.01 (br s, 1 H).

[0204] Example 20: Preparation of benzyl 4-[(Z)-A / '-hvdroxycarbamimidoyl1piperidine-1-carboxylate (XVII-c)

[0205] (XVI l-c)

[0206] The reaction was performed on 6.69 mmol scale of benzyl 4-cyanopiperidine-1 -carboxylate (XVI-c) following General Procedure D to afford benzyl 4-[(Z)-A / '-hydroxycarbamimidoyl]piperidine-1- carboxylate (XVII-c) as white solid (1.68 g, Yield: 90.6%). LCMS: Rt = 0.15 min, m / z 278.6.1H NMR (400 MHz, DMSO-de) 6 ppm 1 .36 - 1 .57 (m, 2 H), 1 .62 - 1 .77 (m, 2 H), 2.17 (m, 1 H), 2.65 - 2.93 (m, 2 H), 4.00 (br d, 2 H), 5.05 (s, 2 H), 5.34 (s, 2 H), 7.28 - 7.38 (m, 5 H), 8.56 - 9.07 (br s, 1 H).

[0207] Example 21 : Preparation of phenyl 4-[(Z)-A / '-hvdroxycarbamimidoyl1piperidine-1-carboxylate (XVII-d)

[0208] (XVI I -d)

[0209] To a stirred solution of phenyl-4-cyanopiperidine-1 -carboxylate (XVI-d) (2.13 mmol) in EtOH (2.5 mL) was added hydroxylamine hydrochloride (4.26 mmol) followed by addition of dropwise triethylamine (4.26 mmol) at room temperature and stirred 16 h at room temperature. The reaction mixture was concentrated and triturate with TBME (10 mL) and filtered. The solid obtained was dissolved in ethyl acetate (25 mL) and wash with water (10 mL). The organic layer was concentrated under reduced pressure to afford phenyl 4-[(Z)-A / '-hydroxycarbamimidoyl]piperidine-1-carboxylate (XVII-d) as white solid (0.170 g, Yield: 30%). LCMS: Rt = 0.78 min, m / z 264.1 .1H NMR (400 MHz, DMSO-d6) 6 ppm 1 .51 - 1 .78 (m, 4 H), 2.24 - 2.28 (m, 1 H), 2.84 - 3.06 (m, 2 H), 4.00-4.17 (m, 2 H), 5.38 (s, 2 H), 7.09 - 7.12 (m, 2 H), 7.21-7.23 (m, 1 H), 7.36 - 7.41 (m, 2 H), 8.85 (s, 1 H).

[0210] General Procedure E: Synthesis of (5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate derivatives (XVIII) from compound of formula (XVII):

[0211] A stirred solution of [(Z)-A / '-hydroxycarbamimidoyl]piperidine-1 -carboxylate carboxylate derivative (XVII) (7.08 mmol) in acetic anhydride (14.20 mmol) was heated at 95 °C for 2 hours. The reaction mixture was then concentrated under reduced pressure and crude product was purified by column chromatography to afford the corresponding Alkyl / Benzyl / Phenyl-4-(5-methyl-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carboxylate (XVIII).

[0212] Example 22: Preparation of methyl-4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-a)

[0213] (XVIII-a)

[0214] The reaction was performed on 7.08 mmol scale of methyl 4-[(Z)-A / '-hydroxycarbamimidoyl]piperidine- 1-carboxylate (XVII-a) following General Procedure E to afford methyl 4-(5-methyl-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carboxylate (XVIII-a) as pale-yellow liquid (0.986 g, Yield: 62%). LCMS: Rt = 0.89 min, m / z 226.1 .1H NMR (400 MHz, DMSO-d6) 6 ppm 1 .48 - 1 .70 (m, 2 H), 1 .90 - 2.01 (m, 2 H), 2.56 (s, 3 H), 2.80-3.00 (m, 3 H), 3.59-3.60 (s, 3 H), 4.06-4.10 (m, 4 H).

[0215] Example 23: Preparation of ethyl-4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-b)

[0216] (XVIII-b)

[0217] The reaction was performed on 10 mmol scale of ethyl 4-[(Z)- / \ / '-hydroxycarbamimidoyl]piperidine-1- carboxylate (XVII-b) following General Procedure E to afford ethyl 4-(5-methyl-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carboxylate (XVIII-b) as pale-yellow liquid (1.58 g, Yield: 63%). LCMS: Rt = 0.92 min, m / z 240.1 .1H NMR (400 MHz, CDCb) 6 ppm 1 .25 (t, 3 H), 1 .70 - 1 .86 (m, 2 H), 1 .91 - 2.06 (m, 2 H), 2.56 (s, 3 H), 2.94 (m, 3 H), 4.03 - 4.13 (m, 4 H).

[0218] Example 24: Preparation of benzyl-4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-c)

[0219] (XVIII-c)

[0220] The reaction was performed on 12 mmol scale of benzyl 4-[(Z)-N'-hydroxycarbamimidoyl]piperidine-1- carboxylate (XVII-c) following General Procedure E to afford benzyl 4-(5-methyl-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carboxylate (XVIII-c) as pale-yellow liquid (1.95 g, Yield: 52%). LCMS: Rt = 1.04 min, m / z 302.2.1H NMR (400 MHz, CDCb) 6 ppm 1.78 - 1.85 (m, 2 H), 1.94 - 2.04 (m, 2 H), 2.56 (s, 3 H),

[0221] 2.90 - 3.07 (m, 3 H), 4.19 (br s, 2 H), 5.14 (s, 2 H), 7.27 - 7.38 (m, 5 H).

[0222] Example 25: Preparation of phenyl-4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-d)

[0223] (XVIII-d)

[0224] The reaction was performed on 5.298 mmol scale of phenyl 4-[(Z)-A / '-hydroxycarbamimidoyl]piperidine- 1-carboxylate (XVII-d) following General Procedure E to afford phenyl 4-(5-methyl-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carboxylate (XVIII-d) as pale-yellow liquid (0.462 g, Yield: 30%). LCMS: Rt = 1.00 min, m / z=288.2.1H NMR (400 MHz, DMSO-cfe) 6 ppm 1.58 - 1.81 (m, 2 H), 1.99 (br s, 2 H), 2.58 (s, 3 H), 3.09 (m, 2 H), 3.20 - 3.33 (m, 1 H), 3.95-4.22 (m, 2 H), 7.10 - 7.17 (m, 2 H), 7.22 (m, 1 H), 7.35 - 7.42 (m, 2 H).

[0225] General Procedure F: Dealkylation via carbamate introduction

[0226] Procedure: To a stirring solution of 5-benzyl-3-(1-methyl-4-piperidyl)-1 ,2,4-oxadiazole (l-a) (0.377 mmol) in toluene (0.75 mL) was added chloroformate derivative (1.13 mmol) dropwise under argon at room temperature. The reaction mixture was heated to 60 °C for 2 to 10 hours. The reaction mixture was cooled to room temperature and concentrate under reduced pressure. The crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to compounds of formula (XVIII).

[0227] Example 26: Preparation of methyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-a)

[0228] (XVI I l-a)

[0229] The reaction was performed on 0.377 mmol of 3-(1-benzyl-4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a) following General Procedure F. The crude was purified by column chromatography using cyclohexane / ethyl acetate to afford methyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-b) as a pale yellow liquid (0.094 g, Yield: 87%).

[0230] Example 27: Preparation of ethyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (Xlll-b)

[0231] (Xlll-b)

[0232] The reaction was performed on 0.377 mmol of 3-(1-benzyl-4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a) following General Procedure F. The crude was purified by column chromatography using cyclohexane / ethyl acetate to afford ethyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-b) as a pale yellow liquid (0.11 g, Yield: 95%).

[0233] Example 28: Preparation of benzyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-c)

[0234] (XVIII-c)

[0235] The reaction was performed on 0.377 mmol of 3-(1-benzyl-4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a) following General Procedure F. The crude was purified by column chromatography using cyclohexane / ethyl acetate to afford benzyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-c) as a pale yellow liquid (0.13 g, Yield: 97%).

[0236] (XVIII-d)

[0237] The reaction was performed on 0.377 mmol of 3-(1-benzyl-4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a) following General Procedure F. The crude was purified by column chromatography using cyclohexane / ethyl acetate to afford phenyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-d) as a pale-yellow liquid (0.092 g, Yield: 72%).

[0238] General Procedure G: via carbamate introduction To a stirred solution of 1-methylpiperidin-4-one (l-b) (22.09 mmol) in toluene (10 mL) was added potassium carbonate (2.209 mmol) at room temperature. The reaction mixture was heated to 60 °C, followed by addition of the appropriate chloroformate source (55.24 mmol) dropwise and continued heating for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and organic layer was separated. The aqueous layer was re-extracted with toluene (2 X 30 mL) and combine organic layers was concentrate under reduced pressure. The crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to afford (5-methyl-1 ,2,4- oxadiazol-3-yl)piperidine-1-carboxylate derivatives (XVIII).

[0239] Example 30: Preparation of methyl-4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-a)

[0240] (XVIII-a)

[0241] The reaction was performed on 0.235 g (1.3 mmol) scale of 5-methyl-3-(1-methyl-4-piperidyl)-1 ,2,4- oxadiazole (l-b) using methyl chloroformate (10.4 mmol) following General Procedure G. Crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to methyl-4- (5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-a) as colorless liquid (0.0155 g, Yield: 5%,). LCMS: Rt = 0.93 min, m / z 226.1 .

[0242] Example 31 : Preparation of ethyl-4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-b)

[0243] (XVIII-b)

[0244] The reaction was performed on 0.188 g (1 mmol) scale of 5-methyl-3-(1-methyl-4-piperidyl)-1 ,2,4- oxadiazole (l-b) using ethyl chloroformate (3 mmol) following General Procedure G. Crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to Ethyl-4-(5- methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-b) as colorless liquid (0.055 g, Yield: 20%). LCMS: Rt = 0.97 min, m / z 240.1,

[0245] Example 32: Preparation of phenyl-4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-d)

[0246] (XVIII-d)

[0247] The reaction was performed on 0.235 g (1.3 mmol) scale of 5-methyl-3-(1-methyl-4-piperidyl)-1 ,2,4- oxadiazole (l-b) using phenyl chloroformate (2.59 mmol) following General Procedure G. Crude product was purified by column chromatography using cyclohexane / ethyl acetate as mobile phase to phenyl-4- (5-methyl-1 ,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (XVIII-d) as liquid (0.156 g, Yield: 42%). LCMS: Rt = 1.06 min, m / z 288.1.

[0248] General Procedure H: Synthesis of 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4-oxadiazole;chloride (II’) from compounds of formula (XVIII):

[0249] A stirred solution of (5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII) (0.993 mmol) in cone. HCI (1 14 mmol) was heated at 60°C for 8 hours. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with DCM (30 mL). The DCM layer was filtered and concentrated under reduced pressure to obtain desired 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4- oxadiazole;chloride (II’). LCMS: Rt= 0.36 min, m / z=168.1.1H NMR (400 MHz, CD3OD) 5 ppm 1.95 - 2.07 (m, 2 H), 2.26 (br dd, 2 H), 2.58 (s, 3 H), 3.12 - 3.25 (m, 3 H), 3.41 - 3.49 (m, 2 H).

[0250] Example 33: Preparation of 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4-oxadiazole;chloride (II’) from (XVIII- a}

[0251] The reaction was performed on 1.11 mmol scale of methyl-4-(5-methyl-1 ,2,4-oxadiazol-3-yl)piperidine- 1-carboxylate (XVIII-a) following General Procedure H to afford 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4- oxadiazole;chloride (II’) as off white solid (0.134 g, Yield: 60%).

[0252] Example 34: Preparation of 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4-oxadiazole;chloride (II’) from (XVIII- b}

[0253] The reaction was performed on 0.397 mmol scale of ethyl-4-(5-methyl-1 ,2,4-oxadiazol-3-yl)piperidine- 1-carboxylate (XVIII-b) following General Procedure H to afford 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4- oxadiazole;chloride (II’) as off white solid (0.145 g, Yield: 36%). Example 35: Preparation of 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4-oxadiazole;chloride (II’) from (XVIII- c)

[0254] The reaction was performed on 1.66 mmol scale benzyl-4-(5-methyl-1 ,2,4-oxadiazol-3-yl)piperidine-1- carboxylate (XVIII-c) following General Procedure H to afford 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4- oxadiazole;chloride (II’) as off white solid (0.256 g, Yield: 76%).

[0255] Example 36: Preparation of 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4-oxadiazole;chloride (II’) from (XVIII- dl

[0256] The reaction was performed on 1 .60 mmol scale of phenyl-4-(5-methyl-1 ,2,4-oxadiazol-3-yl)piperidine- 1-carboxylate (XVIII-b) following General Procedure H to afford 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4- oxadiazole;chloride (II’) as off white solid (0.109 g, Yield: 34%).

[0257] Example 37: Preparation of 5-methyl-3-(4-piperidyl)-1 ,2,4-oxadiazole (II) from compounds of formula (XVIII):

[0258] A stirred mixture of methyl 4-(5-methyl-1 ,2, 4-oxadiazol-3-yl)piperidine-1 -carboxylate (XVIII-a) (0.40 mmol) and sodium hydroxide (1.61 mmol) in methanol (0.8 mL) was heated up to 75 °C for 20 hours. The reaction was then cooled down to room temperature and diluted with ethyl acetate to be concentrated in vacuo. The crude was diluted with a mixture of ethyl acetate:methanol (3:1) (10 mL), and the precipitated solid was filtered off. The resulting filtrate was concentrated in vacuo and afforded 5-methyl-3-(4-piperidyl)-1 ,2,4-oxadiazole (II) (110 mg, Yield: 33%). LCMS: Rt= 0.36 min, m / z=168.1.1H NMR (400 MHz, CDCb) 6 ppm 2.18 - 2.39 (m, 4 H) 2.58 (s, 3 H) 3.08 - 3.18 (m, 3 H) 3.38 - 3.49 (m, 2 H).

[0259] Example 38: Preparation of 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4-oxadiazole;chloride (II’) from (I) using one-step procedure using triphosqene

[0260] To a stirring solution of bis(trichloromethyl)carbonate (0.44 mmol) in DCM (0.28 mL) at 0 °C was added pyridine (0.57 mmol). A solution of 3-(1-benzyl-4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a) in DCM (0.28 mL) was added dropwise to the reaction mixture and maintained at 0 °C for 6 hours. Then the reaction was allowed to warm up to room temperature and an aqueous solution of HCI (1 mL, 4 mmol) was added to the reaction mixture. Separation of the organic layer and concentration of the aqueous layer, followed by purification by trituration in DCM afforded compound of formula (II’) (0.182 mg, Yield: 90%).

[0261] Example 39: Preparation of 5-methyl-3-piperidin-1-ium-4-yl-1 ,2,4-oxadiazole;chloride (II’) from (I) using a-chloroethylchloroformate intermediate (XVIII-e)

[0262] To a stirring solution of 3-(1-benzyl-4-piperidyl)-5-methyl-1 ,2,4-oxadiazole (l-a) (1.47 mmol) in toluene (4.4 mL) at room temperature under argon was added a solution of chloroethyl chloroformate (1.47 mmol) in toluene (4.4 mL), followed by a slow addition of pyridine (0.15 mmol). The resulting mixture was heated up to 90 °C for 4 hours. Then the solution was cooled down to room temperature and the solvents were evaporated in vacuo to afford crude 1 -chloroethyl 4-(5-methyl-1 ,2,4-oxadiazol-3- yl)piperidine-1 -carboxylate (XVIII-e).1H NMR (400 MHz, CDCb) 6 ppm 1.84 - 1.88 (m, 3 H) 1.99 - 2.12 (m, 2 H) 2.33 - 2.45 (m, 1 H) 2.57 - 2.61 (m, 3 H) 2.94 - 3.20 (m, 3 H) 4.10 - 4.27 (m, 2 H) 6.60 - 6.67 (m, 1 H). The crude was dissolved in methanol (13.4 mL) and stirred at 60 °C for 5 min. Concentration in vacuo resulted in compound of formula (II’) (0.49 g, Yield: 93%).

[0263] Table P: Examples of compounds

Claims

Claims1 . A process for the preparation of a compound of formula (I),wherein R1is Ci-C4alkyl or benzyl; comprising reacting a compound of formula (XIV)wherein R1is Ci-C4alkyl or benzyl; with acetic anhydride, acetyl chloride or ethyl acetate.

2. The process according to claim 1 wherein the compound of formula (XIV), as defined in claim1 , is prepared comprising reacting a compound of formula (XIII)wherein R1is Ci-C4alkyl or benzyl; with hydroxylamine or hydroxylammonium salt.

3. The process according to claim 2 wherein the compound of formula (XIII), as defined in claim2, is prepared comprising reacting a compound of formula (X)wherein R1is Ci-C4alkyl or benzyl; with toluenesulfonylmethyl isocyanide.

4. A process for the preparation of a compound of formula (XVIII)(XVIII) wherein R2is Ci-C4alkyl, benzyl, phenyl or CHCICH3; comprising reacting a compound of formula (I), as defined in claim 1 , with chloroformate compound of formula (XIX)wherein R2is Ci-C4alkyl, benzyl, phenyl or 1 -chloroethyl.

5. A process for the preparation of a compound of formula (II) or (II’),comprising1) reacting a compound of formula (I), as defined in claim 1 , with phosgene or triphosgene; or2) converting a compound of formula (XVIII), as defined in claim 4, under hydrolytic conditions (acidic or alkaline) when R2of compound of formula (XVIII) is Ci-C4alkyl, benzyl, or phenyl; or under alcoholysis (such as with methanol or ethanol) conditions when R2of compound of formula (XVIII) is CHCICH3.

6. The process according to claim 5 wherein in step b) a compound of formula (XVIII) is prepared according to the process of claim 4.

7. A process for the preparation of a compound of formula (XIV)wherein R1is Ci-C4alkyl or benzyl; comprising reacting a compound of formula (XIII)wherein R1is Ci-C4alkyl or benzyl; with hydroxylamine or hydroxylammonium salt, and wherein compound of formula (XIII) is prepared comprising reacting a compound of formula (X)wherein R1is Ci-C4alkyl or benzyl; with toluenesulfonylmethyl isocyanide.

8. The process according to claims 1 to 3, and 7, wherein R1is methyl or benzyl.

9. The process according to either claim 4 or 5, wherein R2is methyl, ethyl, benzyl, phenyl or CHCICH3.

10. The process for the preparation of compound of formula (I) according to claim 1 , wherein the process is carried out with sodium hydroxide.

11. The process for the preparation of compound of formula (XIV) according to claims 2 and 7, wherein the process is carried out with hydroxylamine, at the temperature between 60 °C and 80°C, in a mixture of water and ethanol.

12. The process for the preparation of compound of formula (XIII) according to claims 3 and 7, wherein the process is carried out in an organic solvent mixture of 2-methyltetrahydrofuran and fe / Y-butyl alcohol, and in the presence of a base such as sodium hydroxide, at the temperature between 10 °C and 60°C.

13. The process for the preparation of compound of formula (XVIII) according to claims 4, wherein the process is carried out in toluene with a base selected from potassium fe / Y-butoxide, sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and pyridine (preferably potassium carbonate or pyridine), at the temperature between 20 °C and 100°C.

14. The process according to claim 5, wherein in a. step 1) the process is carried out in a solvent selected from ethyl acetate, acetonitrile, toluene, and preferably toluene, chlorobenzene, and dichloromethane, andb. step 2) the process is carried out with acidic conditions (preferably with hydrochloric acid or sulfuric acid), when R2of compound of formula (XVIII) is Ci-C4alkyl, benzyl, or phenyl; or with methanol when R2of compound of formula (XVIII) is CHCICH3.

15. A compound of formula (I) or (XVIII),(XVIII) wherein R1is benzyl; and wherein R2is methyl, ethyl, benzyl, phenyl, or -CHCICH3

Images