process

Abstract

The present invention relates to an in-situ method for synthesizing compounds from pipecolic acid, to compounds obtained and / or obtainable by said method, and to the use of said compounds in flavor compositions, for example as a cooling agent in flavor compositions.

Description

[Technical Field]

[0001] The present invention generally relates to the in situ formation of a compound of formula (V) as described herein from pipecolic acid, specifically 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one ((2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, or a racemic mixture thereof), 2-(methylthio)-1 The present invention further relates to the compounds obtained and / or obtainable by the process, the use of the compounds in flavour compositions, for example as a coolant in flavour compositions, the use of the flavour compositions in consumer products, flavour compositions comprising the compounds, and consumer products comprising the flavour compositions. [Background technology]

[0002] Background technology Pipecolic acid can be used as a starting material for the formation of various compounds. In particular, pipecolic acid can be used as a starting material for the formation of the compound represented by formula (V) as described herein. However, these methods generally require several steps, involving the isolation and purification of intermediate compounds, before carrying out the next step. Therefore, it is desirable to provide an improved or alternative method, for example, which can reduce the need to isolate and purify intermediate compounds. Summary of the Invention

[0003] overview According to a first aspect of the present invention, there is provided a process for the in-situ formation of a compound of formula (V) from pipecolic acid, wherein the in-situ process is carried out in the presence of a solvent, wherein the solvent is an organic solvent having a boiling point in the range of about 50° C. to about 160° C., water, or a mixture thereof; wherein the method includes: (a) reacting pipecolic acid with an acid chloride of formula (Ia) in the presence of a base, or reacting pipecolic acid with an acid anhydride of formula (Ib), optionally in the presence of a base, to form a compound of formula (II); (b) reacting a compound of formula (II) with a compound of formula (III) to form a compound of formula (IV); and (c) reacting a compound of formula (IV) with an ammonium source to form a compound of formula (V); wherein the structures of the compounds represented by formulae (Ia), (Ib), (II), (III), (IV) and (V) are as follows: [ka] During the ceremony, R1, R2 and R3 together with the carbon atoms to which they are attached form a hydrocarbon group optionally containing up to three heteroatoms independently selected from O, S, N and F; The phenyl group of the compounds represented by formulas (III), (IV) and (V) is substituted with n R4 substituents, where n is zero, 1, 2, 3, 4 or 5; each R4 is independently selected from halogen, cyano, nitro, C1-C6 alkyl optionally containing up to 5 halogen atoms, C2-C6 alkenyl, C1-C6 alkoxy optionally containing up to 3 halogen atoms, C1-C3 alkoxy-C1-C3-alkyl, and C3-C7 cycloalkyl; B + is the cation provided by the base; and X is a halogen.

[0004] According to a second aspect of the present invention there is provided a compound of formula (V) obtained by and / or obtainable by the method of the first aspect of the present invention, including any embodiment thereof. According to a third aspect of the present invention, there is provided the use of a compound of formula (V) according to the second aspect of the present invention, including any embodiment thereof, in a flavor composition. For example, the compound of formula (V) may be used as a cooling agent in the flavor composition.

[0005] According to a fourth aspect of the present invention there is provided a flavour composition comprising a compound of formula (V) according to the second aspect of the present invention, including any embodiment thereof. According to a fifth aspect of the present invention there is provided a consumer product comprising a flavour composition according to the fourth aspect of the present invention, including any embodiment thereof. According to a sixth aspect of the present invention there is provided the use of the flavour composition of the fourth aspect of the present invention, including any embodiment thereof, in a consumer product.

[0006] Certain embodiments of the present invention may provide one or more of the following advantages: - an in-situ process for preparing the compound of formula (V) from pipecolic acid; - Reduction in the number of purification and isolation steps; - Use of the same solvent throughout the process; - The solvent can be recycled at the end of the reaction; - the chirality of the hydrocarbon group formed by R1, R2 and R3 remains the same throughout the reaction; - the acid chloride and the compound of formula (III) can be prepared in-house and used crude and in solution, thus reducing exposure to lachrymal reagents; - Reduced hydrolysis of acid chlorides as a side reaction; - milder reaction conditions; - A reduction in the amount or number of reagents required (e.g., the carboxylic acid is deprotonated in the first reaction step, so that no additional base needs to be added in the second reaction step); - a reduction in the amount of ammonium source required for the third reaction step (e.g. due to separate addition and / or reaction temperature and / or water removal); - acceptable yield; - Acceptable selectivity.

[0007] The details, examples, and preferences provided with respect to any particular one or more of the defined aspects of the invention will be further described herein and will apply equally to all aspects of the invention. Combinations of the embodiments, examples, and preferences described herein, in all possible variations thereof, are encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

[0008] Detailed Description The present invention is based on the surprising discovery that compounds of formula (V) can be formed in situ from pipecolic acid prior to work-up and isolation.

[0009] Accordingly, provided herein is a method for the in-situ formation of a compound of formula (V) from pipecolic acid, wherein the in-situ method is carried out in the presence of a solvent, wherein the solvent is an organic solvent having a boiling point in the range of about 50° C. to about 160° C., water, or a mixture thereof, and wherein the method comprises: (a) reacting pipecolic acid with an acid chloride of formula (Ia) in the presence of a base, or reacting pipecolic acid with an acid anhydride of formula (Ib), optionally in the presence of a base, to form a compound of formula (II); [ka] (b) reacting a compound of formula (II) with a compound of formula (III) to form a compound of formula (IV); [ka]

[0010] (c) reacting a compound of formula (IV) with an ammonium source to form a compound of formula (V); [ka] During the ceremony, R1, R2 and R3 together with the carbon atoms to which they are attached form a hydrocarbon group optionally containing up to three heteroatoms independently selected from O, S, N and F; The phenyl group of the compounds represented by formulas (III), (IV) and (V) is substituted with n R4 substituents, where n is zero, 1, 2, 3, 4 or 5; each R4 is independently selected from halogen, cyano, nitro, C1-C6 alkyl optionally containing up to 5 halogen atoms, C2-C6 alkenyl, C1-C6 alkoxy optionally containing up to 3 halogen atoms, C1-C3 alkoxy-C1-C3-alkyl, and C3-C7 cycloalkyl; B + is the cation provided by the base; and X is a halogen.

[0011] As used herein, the phrase "in-situ formation of a compound of formula (V) from pipecolic acid" refers to a process in which the entire reaction is carried out in a single reaction mixture, and any intermediate compounds formed (e.g., compounds of formula (II) and (IV)) are not isolated or purified before carrying out subsequent steps to form the final product (i.e., compound of formula (V)). In other words, the conversion of pipecolic acid to a compound of formula (II), the conversion of a compound of formula (II) to a compound of formula (IV), and the conversion of a compound of formula (IV) to a compound of formula (V) are carried out in the same reaction mixture, without isolation or purification of the compound of formula (II) or the compound of formula (IV). This in-situ formation may be carried out, for example, in a flow or batch process.

[0012] It will be appreciated that while the methods described herein are in situ methods for forming a compound of formula (V) from pipecolic acid, this is not necessary to obtain a compound of formula (V), and one or more isolation or purification steps may be performed after each of steps 1, 2 and 3 described herein to obtain a compound of formula (V).

[0013] The conversion of a compound of formula (II) to a compound of formula (IV) may be concomitant with or subsequent to the conversion of pipecolic acid to a compound of formula (II). The conversion of a compound of formula (IV) to a compound of formula (V) may be simultaneous with or subsequent to the conversion of a compound of formula (II) to a compound of formula (IV).

[0014] By "concomitantly" it is meant that the reagents for each conversion step are added simultaneously to the reaction mixture so that both conversion reactions occur simultaneously in the reaction mixture.

[0015] By "subsequently," we mean that at least some of the reagents for the next step of the reaction (e.g., the acid chloride of Formula (Ia), the acid anhydride of Formula (Ib), the compound of Formula (III), and / or the ammonium source) are added to the reaction mixture after the first step of the reaction is partially or completely completed. For example, the compound of Formula (III) may be added to the reaction mixture after the complete or incomplete conversion of pipecolic acid to the compound of Formula (II). For example, the ammonium source may be added to the reaction mixture after the complete or incomplete conversion of the compound of Formula (II) to the compound of Formula (IV). If the previous conversion was incomplete, the addition of the reagents for the subsequent step may result in a period during which both conversion reactions are carried out simultaneously in the reaction mixture. However, initially, there is a period during which the previous conversion step is carried out in the absence of the subsequent conversion step. The subsequent conversions are carried out in the same reaction mixture without isolation or purification of intermediate compounds, and therefore, the subsequent conversions are in situ reactions according to the present disclosure.

[0016] Alternatively, the method for in situ formation of a compound of formula (V) as described herein above comprises: (a) reacting pipecolic acid with a compound of formula (III) in the presence of a base to form a compound of formula (VI); [ka] (b) reacting a compound of formula (VI) with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (IV); and (c) reacting a compound of formula (IV) with an ammonium source to form a compound of formula (V); Here, the structures of the compounds represented by formulae (Ia), (Ib), (III), (IV) and (V) are as shown above.

[0017] In this alternative method, the reaction with the ammonium source step 3 can optionally be carried out before the reaction with the acid chloride / anhydride. However, in the alternative, pipecolic acid must be protected with a selective amine protecting group, which must then be removed before the subsequent reaction with the acid chloride of formula (Ia) or the acid anhydride of formula (Ib).

[0018] The in-situ method described herein is carried out in the presence of a solvent, wherein the solvent is an organic solvent having a boiling point in the range of about 50°C to about 160°C, or the solvent is water, or the solvent is a mixture of an organic solvent and water. In other words, all steps of the method (including all of steps 1, 2, and 3 described herein) are carried out in the presence of a solvent, wherein the solvent is an organic solvent having a boiling point in the range of about 50°C to about 160°C, or the solvent is water, or the solvent is a mixture of an organic solvent and water. Surprisingly and advantageously, it has been found that selecting water or an organic solvent having a boiling point in the range of about 50°C to about 160°C as the solvent eliminates the need for solvent changes for each subsequent step, thereby enabling the entire method to be carried out in one step as an in-situ method. The selection of water or an organic solvent having a boiling point in the range of about 50°C to about 160°C as the solvent can help minimize the formation of impurities and by-products. In some embodiments, the solvent is an organic solvent having a boiling point in the range of about 50°C to about 160°C.

[0019] In certain embodiments, the organic solvent has a boiling point of about 60°C or higher, or about 70°C or higher, or about 80°C or higher, or about 90°C or higher, or about 100°C or higher, or about 110°C or higher. In certain embodiments, the organic solvent has a boiling point of about 150°C or less, or about 140°C or less, or about 130°C or less, or about 120°C or less. For example, the organic solvent may have a boiling point in the range of about 60°C to about 150°C, or about 70°C to about 120°C, or about 80°C to about 140°C, or about 90°C to about 130°C, or about 100°C to about 120°C.

[0020] One or more of the steps of the in-situ methods described herein (e.g., all of steps 1, 2, and 3 described herein, or all of the method steps) may be carried out at a temperature below the boiling point of the solvent, e.g., below the boiling point of an organic solvent having a boiling temperature in the range of about 50° C. to about 160° C. Alternatively, one or more of the steps of the in-situ methods described herein (e.g., all of steps 1, 2, and 3 described herein, or all of the method steps) may be carried out under reflux conditions. This may be to prevent loss of solvent from the reaction mixture during the method due to evaporation.

[0021] One or more of the in-situ method steps described herein (e.g., all of steps 1, 2, and 3 described herein, or all of the method steps) may be carried out in a closed tube or autoclave to prevent solvent loss from the reaction mixture during the reaction. This may allow, for example, temperatures higher than the boiling point of the solvent used. Thus, a solvent with a relatively low boiling point (e.g., MTBE) may be used.

[0022] One or more of the in situ method steps described herein (e.g., all of steps 1, 2, and 3, or all of the method steps described herein) may be carried out at a temperature below the temperature at which the reactants decompose. The temperature of each method step may be the same or different.

[0023] For example, it may be advantageous to select a solvent (e.g., an organic solvent having a boiling point in the range of about 50°C to about 160°C) that allows each step of the in situ method to be carried out at a temperature that maximizes the reaction rate, but is low enough to avoid decomposition of the reactants.

[0024] Organic solvents having boiling points in the range of about 50°C to about 160°C can be, for example, polar or non-polar solvents. The polarity of a solvent may be measured by determining the dielectric constant (relative permittivity) of the solvent at 0°C. Solvents with a dielectric constant of less than 15 can be considered non-polar solvents. Solvents with a dielectric constant of 15 or greater can be considered polar solvents.

[0025] Organic solvents having boiling points in the range of about 50°C to about 160°C may, for example, be immiscible with water (i.e., mixtures of organic solvents having boiling points in the range of about 50°C to about 160°C cannot be mixed with water in all proportions to form a homogeneous solution). The organic solvent having a boiling point in the range of about 50° C. to about 160° C. can be, for example, an aromatic solvent or a non-aromatic solvent.

[0026] Aromatic solvents may contain one or more heteroatoms selected from, for example, nitrogen, oxygen, sulfur, and halogens such as fluorine. Aromatic solvents may contain, for example, one or more heteroaromatic groups. Aromatic solvents may be, for example, aromatic solvents composed only of carbon and hydrogen atoms. Alkylbenzene is an example of an aromatic solvent composed only of carbon and hydrogen atoms. Alkylbenzene solvents are also examples of non-polar solvents. Alkylbenzene solvents contain a benzene group in which one or more hydrogen atoms on the benzene ring are replaced with alkyl groups. Each alkyl group may, for example, independently contain 1 to 5 carbon atoms, for example, 1 to 3 carbon atoms, for example, 1 or 2 carbon atoms. Toluene and xylene are examples of alkylbenzene solvents. Halobenzenes (benzene in which one or more hydrogen atoms are replaced with halogen atoms), such as dichlorobenzene, are examples of aromatic solvents.

[0027] Non-aromatic solvents may contain one or more heteroatoms selected from, for example, nitrogen, oxygen, sulfur, and halogens such as fluorine. Non-aromatic solvents may contain, for example, one or more non-aromatic heterocyclic groups. Methyl tetrahydrofuran, e.g., 2-methyltetrahydrofuran, is an example of a non-aromatic solvent containing a heterocyclic group. Non-aromatic solvents may be, for example, ethers. Methyl tert-butyl ether (MTBE) is an example of a non-aromatic ether solvent. Non-aromatic solvents may be, for example, non-aromatic solvents composed only of carbon and hydrogen atoms. Non-aromatic solvents composed only of carbon and hydrogen atoms may be, for example, linear (e.g., branched or straight) or cyclic. Heptane is an example of a linear linear non-aromatic solvent. Haloalkane (alkane in which one or more hydrogen atoms are replaced with halogen atoms) solvents such as dichloromethane are examples of non-aromatic solvents. Haloalkane solvents may be particularly useful, for example, when the process is carried out in a closed tube or autoclave.

[0028] In certain embodiments, the non-aromatic solvent may contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In particular, the organic solvent having a boiling point in the range of about 50° C. to about 160° C. may be an alkylbenzene solvent. For example, the organic solvent having a boiling point in the range of about 50° C. to about 160° C. may be toluene.

[0029] Step 1 - Conversion of pipecolic acid to the compound of formula (II) The in situ methods described herein may comprise reacting pipecolic acid (ai) with an acid chloride of formula (Ia) in the presence of a base, or (a-ii) with an acid anhydride of formula (Ib), optionally in the presence of a base, to form a compound of formula (II). For example, the in situ methods described herein may comprise reacting pipecolic acid with an acid chloride of formula (Ia) in the presence of a base to form a compound of formula (II).

[0030] Pipecolic acid is commercially available and has the following chemical structure: [ka]

[0031] The acid chloride represented by formula (Ia) has the following chemical structure: [ka] wherein R1, R2 and R3 together with the carbon atoms to which they are attached form a hydrocarbon group optionally containing up to three heteroatoms independently selected from O, S, N and F.

[0032] The acid chlorides of formula (Ia) may, for example, be commercially available or may be prepared by a number of synthetic routes, such as, for example, by reacting a carboxylic acid with thionyl chloride (SOCl), oxalyl chloride (COCl), phosphorus trichloride (PCl), phosphorus pentachloride (PCl), or by reacting thiolactic acid with dimethyl sulfate followed by chlorination, for example with thionyl chloride (SOCl).

[0033] The acid anhydride represented by formula (Ib) has the following chemical structure: [ka] wherein R1, R2 and R3 are as defined for the acid chloride of formula (Ia).

[0034] The acid anhydrides may, for example, be commercially available or may be prepared by a number of synthetic routes, such as, for example, by reacting an acid chloride of formula (Ia) with the corresponding carboxylic acid, or by reacting the latter with acetic anhydride.

[0035] The term "hydrocarbon group optionally containing up to three heteroatoms selected from O, S, N and F" refers to a group consisting of carbon atoms and hydrogen atom Only, and any of Oxygen atoms, sulfur atoms, nitrogen atoms and fluorine atoms Child The maximum total number of oxygen, sulfur, nitrogen and fluorine atoms is three.

[0036] R1, R2 and R3 together with the carbon atoms to which they are attached may form a hydrocarbon group optionally containing up to three heteroatoms selected from, for example, O, S and F. R1, R2 and R3 together with the carbon atoms to which they are attached may form a hydrocarbon group optionally containing up to three heteroatoms, for example, S. R1, R2 and R3, together with the carbon atoms to which they are attached, may form, for example, a hydrocarbon group containing zero heteroatoms (i.e., a hydrocarbon group containing only carbon and hydrogen atoms).

[0037] R1, R2 and R3 may, together with the carbon atoms to which they are attached, form a hydrocarbon group containing, for example, carbon and hydrogen atoms together with one or two heteroatoms independently selected from O, S, N and F. R1, R2 and R3 may, together with the carbon atoms to which they are attached, form a hydrocarbon group containing, for example, carbon and hydrogen atoms together with one or two heteroatoms independently selected from O, S and F. The carbon atom to which R, R, and R are attached may be, for example, a chiral center. In some embodiments, the carbon atom to which R, R, and R are attached is a chiral center, and the chirality remains unchanged throughout the reaction.

[0038] The "hydrocarbon group optionally containing up to three heteroatoms selected from O, S, N, and F" may contain, for example, 1 to 15 carbon atoms. For example, the "hydrocarbon group optionally containing up to three heteroatoms selected from O, S, N, and F" may contain 2 to 15 carbon atoms. For example, the "hydrocarbon group optionally containing up to three heteroatoms selected from O, S, N, and F" may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms.

[0039] R1, R2 and R3, together with the carbon atoms to which they are attached, may form, for example, 3-thiabut-2-yl, 2-methyl-3-thiabut-2-yl, 3-thiapent-2-yl, 4-thiapent-2-yl, 2-thiaprop-1-yl, 2-methyl-3-thiapent-2-yl, 3-oxo-3-thiabut-2-yl, 3-oxo-2-methyl-3-thiabut-2-yl, 3-oxo-3-thiapenta -2-yl, 4-oxo-4-thiapent-2-yl, 2-oxo-2-thiaprop-1-yl, 3-oxo-2-methyl-3-thiapent-2-yl, but-2-yl, pent-2-yl, but-3-en-2-yl, pent-3-en-2-yl, but-2-en-2-yl, pent-2-en-2-yl, but-1-en-2-yl, pent-1-en-2-yl, 2-methylbut-2-yl, 2 -methylpent-2-yl, 2-methylbut-3-en-2-yl, 3-methylbut-2-yl, 3-methylbut-3-en-2-yl, 3-methylbut-2-en-2-yl, 2,3-dimethylbut-2-yl, 2,3-dimethylpent-2-yl, 2,3-dimethylbut-3-en-2-yl, 2,3-dimethylpent-3-en-2-yl, 2-methylpent-3-en-2-yl, propa-2- yl, prop-1-yl, ethyl, cyclopropyl, 1,1-dimethylcycloprop-2-yl, 1-methylcycloprop-2-yl, 1-methylcycloprop-1-yl, 3-thiahex-5-en-2-yl, 2-methyl-3-thiahex-5-en-2-yl, 1-mercaptoeth-1-yl, 2-mercaptoprop-2-yl, 3,3,3-trifluoroprop-2-yl, 2-methyl-3,3,3-Trifluoroprop-2-yl, 1-(2-furyl)eth-1-yl, 1-(5-methylfur-2-yl)eth-1-yl, 2-(2-furyl)prop-2-yl, 1-(3-furyl)eth-1-yl, 1-(5-methylfur-3-yl)eth-1-yl, 2-(3-furyl)prop-2-yl, 1-(2-tetrahydrofuryl)eth-1-yl, 2-(2-tetrahydrofuryl)prop-2-yl, 1-(3-tetrahydrofuryl)eth-1-yl, 2-(3-tetrahydrofuryl)prop-2-yl , 1-cyclopropyleth-1-yl, 2-cyclopropylprop-2-yl, 1-cyclobutyleth-1-yl, 2-cyclobutylprop-2-yl, cyclobutyl, cyclopentyl, pent-2-en-3-yl, 1-methoxyprop-1-yl, 1-methoxyeth-1-yl, 1,1,1-trifluorobut-3-yl, 3-thiacyclobut-1-yl, 1-(N-methylamino)eth-1-yl, and 1-(N,N-dimethylamino)eth-1-yl.

[0040] R1, R2 and R3 may each, for example, independently be selected from hydrogen, alkyl (including chain alkyl groups (straight and branched) and cycloalkyl groups), alkenyl, alkoxy, alkyl-C(O)-, alkyl-S-, alkyl-S-alkyl (e.g., alkyl-S-CH2-), alkenyl-S-, alkyl-S(O)-, alkyl-S(O)2-, alkenyl-S(O)-, alkenyl-S(O)2-, -SH, CF3S-, furyl optionally substituted with alkyl (e.g., 2-furyl or 3-furyl) (e.g., furyl optionally substituted with methyl), and fluoro-alkyl.

[0041] R1, R2 and R3 can each independently represent, for example, hydrogen, linear C1-C4-alkyl, C3-C4-cycloalkyl, C2-C5-alkenyl containing one or two double bonds, C1-C3-alkoxy, C1-C4-alkyl-C(O)-, C1-C4-alkyl-S-, C1-C4-alkyl-S-C1-C4-alkyl (e.g., C1-C4-alkyl-S-CH2-), C1-C4-alkenyl-S, C1-C4-alkyl-S(O)-, C1-C4 -alkyl-S(O)2-, C1-C4-alkenyl-S(O)-, C1-C4-alkenyl-S(O)2-, -SH, CF3S-, furyl optionally substituted with C1-C4-alkyl (e.g., 2-furyl or 3-furyl) (e.g., furyl optionally substituted with methyl) and C1-C6-fluoro-alkyl (e.g., difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl).

[0042] R1 may, for example, be selected from hydrogen and C1-C4-alkyl. For example, R1 may be selected from hydrogen and methyl. R2 may be selected from, for example, hydrogen, C1-C4-alkyl, and C2-C5-alkenyl containing one or two double bonds. For example, R2 may be selected from hydrogen, C1-C2-alkyl, and C2-C3-alkenyl. For example, R2 may be methyl.

[0043] R3 may be selected from, for example, C1-C4 alkyl, C2-C5 alkenyl containing one or two double bonds, C1-C3 alkoxy, C1-C4-alkyl-C(O)-, C1-C4-alkyl-S-, C1-C4-alkyl-SCH2-, C1-C4-alkenyl-S-, C1-C4-alkyl-S(O)-, C1-C4-alkyl-S(O)2-, C1-C4-alkenyl-S(O)-, C1-C4-alkenyl-S(O)2-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl optionally substituted with methyl (e.g., 2-furyl or 3-furyl), and C1-C6-fluoro-alkyl (e.g., difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl). For example, R3 may be selected from C1-C4 alkyl, C2-C5 alkenyl containing one or two double bonds, and C1-C4-alkyl-S-. For example, R3 may be selected from C1-C2 alkyl, C2-C3 alkenyl containing one double bond, and C1-C2-alkyl-S-. For example, R3 may be selected from ethyl, ethenyl, and -SCH3.

[0044] For example, R1 may be selected from hydrogen and C1-C4-alkyl, R2 may be selected from hydrogen, C1-C4-alkyl, and C2-C5-alkenyl containing one or two double bonds, and R3 may be selected from C1-C4 alkyl, C2-C5 alkenyl containing one or two double bonds, C1-C3 alkoxy, C1-C4-alkyl-C(O)-, C1-C4-alkyl-S-, C1-C4-alkyl-SCH2-, C1-C4-alkenyl-S-, C1 It may be selected from -C4-alkyl-S(O)-, C1-C4-alkyl-S(O)2-, C1-C4-alkenyl-S(O)-, C1-C4-alkenyl-S(O)2-, -SH, CF3S-, cyclopropyl, cyclobutyl, furyl optionally substituted with methyl (e.g., 2-furyl or 3-furyl), and C1-C6-fluoro-alkyl (e.g., difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl).

[0045] For example, R1 may be selected from hydrogen and methyl, R2 may be selected from hydrogen, C1-C2-alkyl, and C2-C3-alkenyl, and R3 may be selected from C1-C4 alkyl, C2-C5 alkenyl containing one or two double bonds, C1-C3 alkoxy, C1-C4-alkyl-C(O)-, C1-C4-alkyl-S-, C1-C4-alkyl-SCH2-, C1-C4-alkenyl-S-, C1-C4-alkyl-S( 0)—, C1-C4-alkyl-S(O)2—, C1-C4-alkenyl-S(O)—, C1-C4-alkenyl-S(O)2—, —SH, CF3S—, cyclopropyl, cyclobutyl, furyl optionally substituted with methyl (e.g., 2-furyl or 3-furyl), and C1-C6-fluoro-alkyl (e.g., difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or difluoroethyl).

[0046] For example, R1 may be selected from hydrogen and methyl, R2 may be C1-C2-alkyl, and R3 may be selected from C1-C4 alkyl, C2-C5 alkenyl containing one or two double bonds, and C1-C4-alkyl-S—. For example, R1 may be selected from hydrogen and methyl, R2 may be methyl, and R3 may be ethyl, ethenyl, or -SCH3.

[0047] The acid chloride of formula (Ia) or the acid anhydride of formula (Ib) may be added to the reaction mixture either untreated or as a solution in a solvent (e.g., an organic solvent having a boiling temperature in the range of about 50°C to about 160°C). The compound of formula (III) may be added to the reaction mixture neat or as a solution in a solvent (e.g., an organic solvent having a boiling temperature in the range of about 50° C. to about 160° C.), which may help, for example, to reduce exposure to irritating compounds.

[0048] The reaction of pipecolic acid with the acid chloride of formula (Ia) or the acid anhydride of formula (Ib) can be preferably carried out in the presence of a base. The base deprotonates the carboxylic acid of pipecolic acid. Therefore, any base suitable for deprotonating pipecolic acid can be used. The base can be, for example, an inorganic base or an organic base. Examples of inorganic bases include metal phosphates, metal hydroxides, metal carbonates, metal bicarbonates, and combinations thereof. Examples of organic bases include alkylamines such as tributylamine, alkanolamines such as triethanolamine, and combinations thereof.

[0049] The base may be, for example, a metal phosphate, a metal hydroxide, a metal carbonate, a metal bicarbonate, or a combination thereof. The metal may be, for example, an alkali metal or an alkaline earth metal. B represented by formula (II) + may be, for example, a metal cation of a metal phosphate, metal hydroxide or metal carbonate. In particular, the base may be a metal hydroxide, for example selected from sodium hydroxide and potassium hydroxide.

[0050] Furthermore, the base may neutralize any acid formed as a result of the reaction of pipecolic acid with the compound of formula (Ia) or (Ib). For example, the base may neutralize HCl formed as a result of the reaction of pipecolic acid with the acid chloride of formula (Ia). Thus, at least about 2 equivalents of base may be used relative to the acid chloride of formula (Ia) (1 equivalent to deprotonate pipecolic acid and 1 equivalent to neutralize the formed acid (e.g., HCl formed when pipecolic acid is reacted with the acid chloride of formula (Ia))). For example, about 2 to about 4 equivalents, or about 2 to about 3 equivalents of base may be used relative to the acid chloride of formula (Ia). For example, at least about 1 equivalent of the acid chloride represented by formula (Ia) or the acid anhydride represented by formula (Ib) can be used relative to pipecolic acid.

[0051] The compound of formula (II) has the following chemical structure: [ka] wherein R1, R2 and R3 are as defined for the acid chloride of formula (Ia) and the acid anhydride of formula (Ib), and B + is the cation provided by the base. For example, when sodium hydroxide or potassium hydroxide is used as the base, B + Na + or K + It could be.

[0052] The reaction of pipecolic acid with the acid chloride of formula (Ia) or the acid anhydride of formula (Ib) can be carried out, for example, in the presence of a phase transfer catalyst. In particular, the reaction of pipecolic acid with the acid chloride of formula (Ia) or the acid anhydride of formula (Ib) to form the compound of formula (II) can be carried out in the presence of a phase transfer catalyst when the solvent (e.g., an organic solvent having a boiling point in the range of about 50°C to about 160°C) is a nonpolar solvent or when the solvent is a mixture of an organic solvent and water. The use of a phase transfer catalyst can, for example, increase the yield of the reaction and / or reduce hydrolysis of the acid chloride of formula (Ia) or the acid anhydride of formula (Ib).

[0053] A "phase transfer catalyst" refers to a substance that promotes the transfer of a substance from one phase to another. For example, a phase transfer catalyst can act to promote the transfer of the acid chloride represented by formula (Ia) or the acid anhydride represented by formula (Ib) to an aqueous phase when reacting with pipecolic acid, particularly when the solvent (e.g., an organic solvent having a boiling point in the range of about 50°C to about 160°C) is a nonpolar solvent.

[0054] Some solvents or bases used in in-situ reactions, for example, can also act as phase transfer catalysts. For example, partially water-soluble solvents such as methyl-tetrahydrofuran (Me-THF) can function as phase transfer catalysts. Metal phosphates or metal carbonates, for example, can act as phase transfer catalysts. When the solvent or base used in the in-situ reaction acts as a phase transfer catalyst, it may not be necessary to use an additional phase transfer catalyst. Thus, when a metal phosphate or metal carbonate is used as a base, it may not be necessary to use an additional phase transfer catalyst.

[0055] The phase transfer catalyst may be, for example, a metal halide (eg, potassium iodide or sodium iodide). The phase transfer catalyst may be, for example, a quaternary ammonium salt (NR4 + , where R is an alkyl or aryl group) or an organic phosphonium salt (PR4 + , where R is hydrogen, alkyl, aryl, or halide.

[0056] Examples of quaternary ammonium salts that may be used as phase transfer catalysts include benzyltriethylammonium salts (e.g., benzyltriethylammonium chloride), methyltricaprylammonium salts (e.g., methyltricaprylammonium dichloride), methyltributylammonium salts (e.g., methyltributylammonium chloride), methyltrioctylammonium salts (e.g., methyltrioctylammonium chloride), and tetra-n-butylammonium salts. An example of a phosphonium salt that may be used as a phase transfer catalyst is hexadecyltributylphosphonium salt (e.g., hexadecyltributylphosphonium bromide). For example, the phase transfer catalyst may be a tetra-n-butylammonium salt, such as a tetra-n-butylammonium halide, such as tetra-n-butylammonium bromide (TBAB).

[0057] The reaction of pipecolic acid with the acid chloride of formula (Ia) or the acid anhydride of formula (Ib) to form the compound of formula (II) may be carried out at any suitable pH, for example, in the pH range of about 7.0 to about 15.0, or about 8.0 to about 14.0, or about 9.0 to about 14.0, or about 10.0 to about 15.0.

[0058] The reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out, for example, at a pH of at least about 12.5. For example, the reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) may be carried out at a pH of at least about 13.0. The reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out, for example, at a pH of up to about 14.5. For example, the reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out, for example, at a pH of up to about 14.0 or up to about 13.5. For example, the reaction of pipecolic acid with an acid chloride of Formula (Ia) or an acid anhydride of Formula (Ib) to form a compound of Formula (II) may be carried out at a pH ranging from about 12.5 to about 14.5 or from about 12.5 to about 13.5. The pH of the reaction mixture may be maintained throughout the reaction of pipecolic acid with an acid chloride of Formula (Ia) or an acid anhydride of Formula (Ib) to form a compound of Formula (II). The pH of the reaction mixture may be maintained, for example, by controlling the time and the amount of base added to the reaction mixture. This may involve continuously monitoring the pH of the reaction mixture using, for example, a pH electrode. Controlling the pH of the reaction mixture during the reaction of pipecolic acid with an acid chloride of Formula (Ia) or an acid anhydride of Formula (Ib) may be useful, for example, to minimize hydrolysis of the acid chloride or anhydride.

[0059] The reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out, for example, at a temperature of at least about −10° C. For example, the reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out at a temperature of at least about −5° C. or at least about 0° C. For example, the reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out at a temperature of up to about 40° C., or up to about 35° C., or up to about 30° C., or up to about 25° C., or up to about 20° C., or up to about 15° C., or up to about 10° C. For example, the reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out at a temperature ranging from about −10° C. to about 40° C., or from about −5° C. to about 30° C., or from about 0° C. to about 20° C., or from about 0° C. to about 15° C., or from about 0° C. to about 5° C.

[0060] The reaction of pipecolic acid with the acid chloride of formula (Ia) or the acid anhydride of formula (Ib) to form the compound of formula (II) may be carried out, for example, at a temperature lower than the temperature at which pipecolic acid and / or the acid chloride of formula (Ia) or the acid anhydride of formula (Ib) decomposes.

[0061] The reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out, for example, for a time period ranging from about 30 seconds to about 5 hours. For example, the reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out, for example, for a time period ranging from about 30 seconds to about 1 hour, or from about 1 minute to about 30 minutes, or from about 1 minute to about 15 minutes, or from about 1 minute to about 5 minutes. The reaction of pipecolic acid with an acid chloride of formula (Ia) or an acid anhydride of formula (Ib) to form a compound of formula (II) may be carried out, for example, until the reaction is complete.

[0062] Step 2—Conversion of a compound of formula (II) to a compound of formula (IV) The in situ methods described herein may further comprise reacting a compound represented by formula (II) described herein with a compound represented by formula (III) to form a compound represented by formula (IV). The compound represented by formula (III) has the following chemical structure: [ka] wherein the phenyl group of the compound of formula (III) is substituted with n R4 substituents, where n is 0, 1, 2, 3, 4, or 5; Each R4 substituent (if present) is halogen (e.g., F, Cl, or Br), cyano (C≡N), nitro (-NO2), chain C1-C6-alkyl (straight or branched) optionally containing up to five halogen atoms (e.g., up to five F atoms) (e.g., CH3, CF3, or CHF2), C2-C6-alkenyl (e.g., containing one or two double bonds) (e.g., -CH=CH2), C1-C6-alkoxy (e.g., -OCH3, -OCF3, -OCHF2, -OCH2F) optionally containing up to three halogen atoms (e.g., up to three F atoms), C1-C3-alkoxy-C1-C3-alkyl (e.g., 2-methoxy-ethyl), and C3-C7-cycloalkyl (e.g., cyclopropyl or cyclobutyl), and X is halogen.

[0063] Compounds of formula (III) may, for example, be commercially available or may be prepared by Friedel-Crafts acylation of benzene or substituted benzenes using, for example, chloroacetyl chloride with an aluminum chloride catalyst, or chlorination of the corresponding acetophenone with sulfuryl chloride (SO2Cl2) or 1,3-dichloro-5,5-dimethylhydantoin or N-chlorosuccinimide.

[0064] For example, R4 may be a chain C1-C6-alkyl (linear or branched) (e.g., CH3, CF3 or CHF2) optionally containing up to five halogen atoms (e.g., up to five F atoms). For example, R4 may be methyl. For example, the phenyl group of the compound of formula (III) may be substituted with one or two R4 substituents, e.g., the phenyl group of the compound of formula (III) may be substituted with one R4 substituent which is methyl.

[0065] For example, the phenyl group of the compound of formula (III) may be substituted with five R4 substituents. For example, the phenyl group of the compound of formula (III) may be substituted with five R4 substituents, all of which are methyl. For example, X may be chlorine, bromine, or iodine. For example, X may be chlorine.

[0066] The compound of formula (III) may be added to the reaction mixture neat or as a solution in a solvent (e.g., an organic solvent having a boiling temperature in the range of about 50° C. to about 160° C.). This may help, for example, to maintain a stirrable mixture throughout the reaction of the compound of formula (II) with the compound of formula (III) to make the compound of formula (IV). The use of a solution may help, for example, to reduce exposure to irritating compounds.

[0067] For example, the reaction of a compound represented by formula (II) with a compound represented by formula (III) may be carried out at a temperature in the range of about 50°C to about 160°C, for example, about 60°C to about 150°C, for example, about 80°C to about 130°C, for example, about 90°C to about 120°C, for example, about 100°C to about 110°C.

[0068] The compound of formula (IV) has the following chemical structure: [ka] wherein R1, R2 and R3 are as defined herein for compounds of formula (Ia), (Ib) and (II), and R4 and n are as defined herein for compounds of formula (III).

[0069] The reaction of the compound of formula (II) with the compound of formula (III) to form the compound of formula (IV) may be carried out, for example, in the presence of a phase transfer catalyst. In particular, the reaction of the compound of formula (II) with the compound of formula (III) to form the compound of formula (IV) may be carried out in the presence of a phase transfer catalyst when the solvent (e.g., an organic solvent having a boiling point in the range of about 50°C to about 160°C) is a non-polar solvent.

[0070] The phase transfer catalyst may already be present in the reaction mixture in which the reaction of pipecolic acid with the acid chloride of formula (Ia) or the acid anhydride of formula (Ib) to form the compound of formula (II) was carried out in the presence of a phase transfer catalyst. Therefore, it may not be necessary to add an additional phase transfer catalyst to the reaction mixture for the reaction of the compound of formula (II) with the compound of formula (III) to form the compound of formula (IV).

[0071] The phase transfer catalyst can, for example, facilitate the migration of the compound of formula (III) to an aqueous phase where it reacts with the compound of formula (II) to form the compound of formula (IV). The compound of formula (IV) can then be transferred to an organic phase (e.g., an organic solvent having a boiling point in the range of about 50°C to about 160°C). The phase transfer catalyst may be, for example, as defined herein with respect to Step 1. For example, the phase transfer catalyst may be an ammonium salt, such as tetra-n-butylammonium bromide (TBAB).

[0072] For example, during the reaction of a compound of formula (II) with a compound of formula (III) to form a compound of formula (IV), it may not be necessary to add additional base to the reaction mixture because, for example, the carboxylic acid of compound of formula (II) may already be deprotonated.

[0073] The reaction of the compound of formula (II) with the compound of formula (III) may be carried out at a temperature and pressure to obtain a reflux temperature of the reaction mixture. For example, the reflux temperature of the reaction mixture may be different from (e.g., lower than) the reflux temperature of the solvent (e.g., an organic solvent having a boiling point in the range of about 50°C to about 160°C) due to the presence of other components in the mixture, such as water, which may result in the formation of an azeotrope.

[0074] The reaction of the compound represented by formula (II) with the compound represented by formula (III) may be carried out, for example, at a temperature lower than the temperature at which the compound represented by formula (II) and / or the compound represented by formula (III) decomposes. For example, the reaction of a compound of formula (II) with a compound of formula (III) may be carried out at a temperature of about 50°C or higher, such as about 60°C or higher, for example about 70°C or higher, for example about 80°C or higher.

[0075] For example, the reaction of a compound of formula (II) with a compound of formula (III) may be carried out at a temperature of about 160°C or less, such as about 150°C or less, for example about 140°C or less, for example about 130°C or less, for example about 120°C or less, for example about 110°C or less, for example about 100°C or less. For example, the reaction of a compound represented by formula (II) with a compound represented by formula (III) may be carried out at a temperature ranging from about 50°C to about 160°C, for example, from about 60°C to about 120°C, for example, from about 70°C to about 100°C.

[0076] The reaction of a compound of formula (II) with a compound of formula (III) may be carried out at any suitable pH, for example, provided that the carboxylic acid is deprotonated, such as a pH of about 7.0 or higher, or about 8.0 or higher, or about 9.0 or higher, or about 10.0 or higher. The reaction between a compound represented by formula (II) and a compound represented by formula (III) may be carried out, for example, at a pH of about 12.0 or higher, for example, about 12.5 or higher. The reaction between a compound represented by formula (II) and a compound represented by formula (III) may be carried out, for example, at a pH of about 14.0 or lower, for example, about 13.5 or lower. For example, the reaction between a compound represented by formula (II) and a compound represented by formula (III) may be carried out at a pH in the range of about 12.0 to about 14.0 or about 12.5 to about 13.5.

[0077] The reaction of the compound represented by formula (II) with the compound represented by formula (III) to form the compound represented by formula (IV) may be carried out, for example, for a time period ranging from about 30 seconds to about 5 hours. For example, the reaction of the compound represented by formula (II) with the compound represented by formula (III) to form the compound represented by formula (IV) may be carried out for a time period ranging from about 30 seconds to about 1 hour, or from about 1 minute to about 30 minutes, or from about 1 minute to about 15 minutes, or from about 1 minute to about 5 minutes. The reaction of the compound represented by formula (II) with the compound represented by formula (III) to form the compound represented by formula (IV) may be carried out, for example, until the reaction is complete, which can be determined, for example, by gas chromatography analysis.

[0078] When an organic solvent is used, water may be removed from the reaction mixture, for example, after the reaction of the compound represented by formula (II) with the compound represented by formula (III) to form the compound represented by formula (IV) and before the reaction of the compound represented by formula (IV) with the ammonium source to form the compound represented by formula (V). One advantage of removing water is that it increases the reaction temperature, which accelerates the reaction. For example, water may be removed from the reaction mixture after the reaction of the compound represented by formula (II) with the compound represented by formula (III) to form the compound represented by formula (IV) is complete and before the reaction of the compound represented by formula (IV) with the ammonium source to form the compound represented by formula (V). Water may be removed by any suitable method, for example, by azeotropic distillation. The product of the reaction (the compound represented by formula (IV)) may remain in the organic layer (e.g., containing an organic solvent having a boiling point in the range of about 50°C to about 160°C). This may advantageously allow step 3 to be performed at a higher temperature, for example, by refluxing at a higher temperature.

[0079] Step 3—Conversion of a compound of formula (IV) to a compound of formula (V) The in situ methods described herein further include reacting a compound represented by formula (IV), as described herein, with an ammonium source to form a compound represented by formula (V). The compound of formula (V) has the following chemical structure: [ka] wherein R1, R2, R3, R4, and n are as defined herein for compounds represented by formulas (Ia), (Ib), (II), (III), and (IV).

[0080] The compound represented by formula (V) includes, for example, 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one ((2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, or a racemic mixture), 2-(methylthio)-1-(2-(5-(p-tolyl) 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, or 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one.

[0081] The ammonium source can be, for example, any ammonium source suitable for converting a compound of formula (IV) to a compound of formula (V). The ammonium source may be, for example, an ammonium carboxylate such as ammonium acetate or ammonium formate. The ammonium source may be, for example, a mixture of ammonia and a carboxylic acid (RCOH, where R is hydrogen or an alkyl group). For example, the ammonium source may be ammonium acetate or a mixture of ammonia and acetic acid.

[0082] Suitable ammonium sources, such as ammonium acetate, are commercially available. The ammonium source may be added to the reaction mixture as a solution in water, for example. The solution may be heated before being added to the reaction mixture, for example, to keep the ammonium source dissolved at a high concentration. Adding the ammonium source in solution with water may, for example, help prevent the accumulation of unreacted ammonium source.

[0083] For example, about 5 equivalents or less of the ammonium source relative to the compound represented by formula (IV) may be used. For example, about 4 equivalents or less or about 3 equivalents or less of the ammonium source relative to the compound represented by formula (IV) may be used. For example, about 1 equivalent or more, or about 2 equivalents or more of the ammonium source relative to the compound represented by formula (IV) may be used.

[0084] The ammonium source may be added to the reaction mixture, for example, in an aqueous solution, or may be added to the reaction mixture in its natural form (i.e., not in solution), for example, as a solid. In some embodiments, the ammonium source may be added to the reaction mixture in its natural form, for example, as a solid, which may be advantageous, for example, in minimizing the amount of water introduced into the reaction.

[0085] The ammonium source may, for example, be added to the reaction mixture in portions (i.e., in separate batches as opposed to all at once). This can help make the reaction more efficient because the proportion of water in the reaction mixture due to the presence of water in the solution of the ammonium source is minimized. For example, the ammonium source may be added to the reaction mixture in at least 2, or 3, or 4 portions. For example, if the ammonium source is added to the reaction mixture, it may be added in at least 2 or at least 3 portions, e.g., 2-6 portions or 3-6 portions, or 2-4 portions or 3-4 portions. For example, if the ammonium source is added to the reaction mixture in aqueous solution, it may be added dropwise.

[0086] The reaction of the compound of Formula (IV) with the ammonium source to form the compound of Formula (V) may be carried out, for example, at a temperature and pressure to obtain a reflux temperature of the reaction mixture. The reflux temperature of the reaction mixture may be different from (e.g., lower than) the reflux temperature of the solvent (e.g., an organic solvent having a boiling point in the range of about 50°C to about 160°C) due to the presence of other components in the mixture, such as water, which may result in, for example, an azeotrope. The reaction of the compound of formula (IV) with the ammonium source to form the compound of formula (V) may be carried out, for example, at a temperature below the temperature at which the compound of formula (IV) and / or the ammonium source decomposes.

[0087] For example, the reaction of a compound of formula (IV) with an ammonium source to form a compound of formula (V) may be carried out at a temperature of about 50°C or higher, such as about 60°C or higher, for example about 70°C or higher, for example about 80°C or higher, for example about 90°C or higher, for example about 100°C or higher. For example, the reaction of the compound of formula (IV) with the ammonium source to form the compound of formula (V) may be carried out at a temperature of about 160°C or less, such as about 150°C or less, for example about 140°C or less, for example about 130°C or less, for example about 120°C or less, for example about 110°C or less.

[0088] The reaction of the compound of Formula (IV) with the ammonium source to form the compound of Formula (V) may be carried out, for example, at a pH of about 1.0 or higher, e.g., about 2.0 or higher. The reaction of the compound of Formula (IV) with the ammonium source to form the compound of Formula (V) may be carried out, for example, at a pH of about 14.0 or lower, e.g., about 12.0 or lower, or about 10.0 or lower, or about 8.0 or lower, or about 7.0 or lower, or about 6.0 or lower. For example, the reaction of the compound of Formula (IV) with the ammonium source to form the compound of Formula (V) may be carried out at a pH ranging from about 1.0 to about 14.0, or from about 1.0 to about 8.0, or from about 1.0 to about 7.0, or from about 2.0 to about 6.0. This may be due, for example, to the accumulation of an acid (e.g., acetic acid) generated during step 3 of the reaction.

[0089] The reaction of the compound represented by Formula (IV) with the ammonium source to form the compound represented by Formula (V) may be carried out, for example, for a time period ranging from about 30 minutes to about 10 hours. For example, the reaction of the compound represented by Formula (IV) with the ammonium source to form the compound represented by Formula (V) may be carried out for a time period ranging from about 1 hour to about 8 hours, or from about 2 hours to about 7 hours. The reaction of the compound represented by Formula (IV) with the ammonium source to form the compound represented by Formula (V) may be carried out, for example, until the reaction is complete, which may be determined, for example, by gas chromatography analysis.

[0090] When an organic solvent is used, water may be removed from the reaction mixture, for example, during the reaction of the compound of Formula (IV) with the ammonium source to form the compound of Formula (V). For example, water may be continuously removed from the reaction mixture during the reaction of the compound of Formula (IV) with the ammonium source to form the compound of Formula (V). For example, water may be removed using a Dean-Stark water separator. The product of the reaction (the compound of Formula (V)) may remain in the organic layer (e.g., containing an organic solvent having a boiling point in the range of about 50°C to about 160°C).

[0091] Further steps The reaction of the compound of Formula (IV) with the ammonium source to form the compound of Formula (V) may be followed, for example, by neutralizing the layer containing the compound of Formula (V) (e.g., an organic layer that may contain an organic solvent having a boiling point in the range of about 50° C. to about 160° C.) and / or washing with water. Washing with water may occur, for example, after the layer containing the compound of Formula (V) (e.g., an organic layer) has been neutralized.

[0092] For example, the compound of formula (V) can be isolated (e.g., isolated from an organic layer that may contain an organic solvent having a boiling point in the range of about 50°C to about 160°C) by any suitable method, such as crystallization. For example, the compound of formula (V) can be crystallized directly from a solvent (e.g., toluene or Me-THF) that can be used throughout the synthesis, thus providing the advantage of not needing to change solvents throughout the synthesis and crystallization steps. Alternatively, the compound of formula (V) can be crystallized by switching solvents. The compound of formula (V) can then be subjected to further purification steps.

[0093] Depending on the solvent used in the reaction, solvent switching may be advantageous to obtain olfactorily pure quality and / or higher recovery of the compound of formula (V). Suitable solvents for crystallization may be selected from, but are not limited to, ethyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, methyl isobutyl ketone, isopropanol, and mixtures such as heptane / isopropanol, heptane / ethanol, or methyl tert-butyl ether / ethyl acetate.

[0094] Use of the compound of formula (V) Further provided herein are compounds of formula (V), for example, obtained or obtainable by the methods described herein. The compound represented by formula (V) can be used, for example, in a flavor composition. In particular, the compound represented by formula (V) can be used as a cooling agent in a flavor composition. Accordingly, there is also provided herein a flavor composition comprising a compound of formula (V) as described herein.

[0095] The flavor compositions described herein may be incorporated into any consumer product that contacts a mucous membrane, for example, the consumer product may be a food product, a beverage, a chewing gum, a tobacco product, a tobacco substitute, a dental care product, a personal care product (including lip care products), or a sexual health and intimate care product. Accordingly, also provided herein are consumer products comprising the flavor compositions described herein.

[0096] The methods will now be further described with reference to the following non-limiting examples that set forth specific embodiments. Example 1: One-pot procedure for the preparation of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (compound of formula (V)) A 10 L reactor was flushed with nitrogen and charged with pipecolic acid (DL-pipecolic acid, Xiamen Synress Import and Export Co., Ltd., (800 g, 6.2 mol)) and tetrabutylammonium bromide (100 g, 0.3 mol) at room temperature. Water (1630 g), toluene (1127 g), and sodium hydroxide (32%, 1664 g, 13.3 mol) were added sequentially to the stirred solution (102 rpm). The stirring speed was increased (186 rpm), and the mixture was cooled to 5°C (Tj: -15°C). 2-Methylbutanoyl chloride (747 g, 6.2 mol) was added dropwise over 2 hours while maintaining the reaction mixture temperature between 3°C and 5°C. After the addition, the mixture was stirred for 1 hour, then the temperature was raised to 45° C. and solid 2-chloro-1-(p-tolyl)ethan-1-one (1077 g, 6.3 mol) was added portionwise over 15 minutes.

[0097] The mixture was then heated to 90°C (Tj: 110°C) for 1 hour and 15 minutes, after which GC analysis of the mixture showed complete conversion of 1-(2-methylbutanoyl)piperidine-2-carboxylic acid to 2-oxo-2-(p-tolyl)ethyl 1-(2-methylbutanoyl)piperidine-2-carboxylate. The reaction mixture was then cooled to 50°C (Tj: 50°C), stirring was stopped, and the aqueous layer was removed from the cloudy orange organic layer through the bottom valve. Toluene (607 g) was added to the mixture remaining in the reactor. The solution was stirred (160 rpm) and heated to reflux (89-114°C, Tj: 145°C) while azeotropically removing water. After all water had been removed and the reflux temperature reached the final temperature (114°C), the first portion of ammonium acetate (477 g, 6.2 mol) was added. The reaction mixture was stirred at reflux for 45 minutes, and the water generated by the reaction was azeotropically removed. Another portion of ammonium acetate (477 g, 6.2 mol) was added, and after 3 h of reaction time, the final portion of ammonium acetate (477 g, 6.2 mol) was added, and stirring at reflux was continued for 70 min until GC analysis indicated complete conversion. The reaction mixture was cooled to 50 °C, and water (500 g) and sodium hydroxide (2 M, 1000 g) were added to the stirred mixture. The pH of the mixture was then adjusted to pH 7 by adding sodium hydroxide (2 M, 2700 g). The product solution was again heated to reflux and azeotropically dried (Tj: 145 °C), and the solution was then cooled to approximately 0 °C (Tj: 0 °C) and stirring (70 rpm) was continued for 24 h. Fine crystals formed in the red mixture were removed by filtration of the cake through a 4 L Buchner funnel and then washed twice with cold methyl t-butyl ether (4 °C, 1000 ml).

[0098] The solid product was dried under vacuum to give 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (838 g, 2.5 mol, 40% yield) as a white solid. Mp: 156.3 °C. GC / MS (EI): m / z (%): 325 (10) [M+], 268 (2), 240 (100), 224 (3), 185 (10), 159 (2), 142 (1), 84 (2), 57 (4). 1 H NMR (500 MHz, DMSO-d6, 413K, mixture of stereoisomers and tautomers) δ = 11.32 (br s, 1H), 7.61(br m, 2H), 7.28 (br s, 1H), 7.14 (br m, 2H), 5.63 (br m, 1H), 4.06 (br m, 1H), 3.29 (br m, 1H), 2.76 (m, 1H), 2.31 (s, 3H), 2.23 (br m, 1H), 1.83 - 1.60 (m, 5H), 1.49 -1.33 (m, 2H), 1.09 - 1.05 (2d, J = 6.8 Hz, 3H), 0.91 -0.85 (2t, J = 7.4 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO-d6, 413 K, mixture of stereoisomers and tautomers, shifts extracted from HSQC & HMBC experiments) δ 174.4 (s), 146.8 (s), 139.6 (s), 134.3 (s), 132.1 (s), 128.1 (2d), 123.7 (2d), 110.9 (d), 47.5 ( d), 40.1 (t), 35.6 (d), 27.6 (t), 26.0 (t), 24.7 (t), 19.8 (q), 19.0 (t), 16.3 (q), 10.5 (q) ppm.

[0099] The crystalline form of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one is characterized by a powder X-ray diffraction pattern obtained using copper K-β radiation, with major peaks at 2-θ (deg) 8.93, 9.59, 11.66, 12.44, 12.95, 14.53, 15.91, 17.13, 17.89, 18.43, 19.21, 19.51, 19.90, 20.76, 22.59, 25.06, 27.03, 27.77, 28.81, 29.79, and 32.08.

[0100] Example 2: (2S)-2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one Prepared from (S)-methylbutanoyl chloride according to the disclosed procedure. [ka] The spectroscopic data are identical to those of the racemic product in Example 1.

[0101] Example 3: 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one 2-(methylthio)propanoyl chloride was prepared according to the disclosed procedure. GC / MS (EI): m / z (%): 357 (5) [M + ], 342(7), 268 (11), 240 (100), 185 (11), 159 (5), 117 (4), 89 (10). 1H NMR (500 MHz, DMSO-d6, 413K, mixture of stereoisomers and tautomers) δ 11.56 -11.06 (br m, 1H), 7.69 -7.43 (br m, 2H), 7.34 -7.24 (br m, 1H), 7.23 -7.07 (br m, 2H), 5.69 & 5.58 (2 br m, 1H), 4.04 (br m, 1H), 3.91 -3.87 (br m, 1H), 3.51 -3.13 (br m, 1H), 2.37 -2.27 (br m, 1H), 2.32 (br s, 3H), 2.09 & 2.08 (2 br s, 3H), 1.91 -1.41 (br m, 5H), 1.44 & 1.42 (2 br d, J = 6.7 Hz, 3H) ppm. 13 C NMR (125 MHz, DMSO-d6, T = 413K, mixture of stereoisomers and tautomers, shifts extracted from HSQC & HMBC experiments) δ 169.7 (s), 146.4 (s), 137.7 (s), 134.2 (s), 131.4 (s), 128.0 (2d), 123.7 (2d), 110.9 (d), 47.5 (d), 40.8 (t), 37.7 (d), 27.4 (t), 24.3 (t), 19.7 (q), 18.8 (t), 17.0 (q), 11.0 (q) ppm.

[0102] Example 4: One-pot procedure for the preparation of 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (compound of formula (V)) A 5 L reactor was flushed with nitrogen and charged with pipecolic acid (DL-pipecolic acid, Xiamen Synress Import and Export Co. Ltd., (400 g, 3.1 mol)), potassium phosphate (98%, 738 g, 3.4 mol), and potassium hydroxide (85%, 184 g, 2.8 mol) at room temperature. Water (1280 g) and 2-methyltetrahydrofuran (547 g) were added sequentially, and the mixture was cooled to 4°C. 2-Methylbutanoyl chloride (373 g, 3.1 mol) was added dropwise over 1 hour while maintaining the temperature of the reaction mixture below 15°C. Following the addition, the mixture was stirred for 1 hour, then the temperature was raised to 45°C and a mixture of solid 2-chloro-1-(p-tolyl)ethan-1-one (97%, 571 g, 3.3 mol) and tetrabutylammonium bromide (9.98 g, 0.03 mol) was added portionwise over 15 minutes.

[0103] The mixture was then heated to 76°C (Tj: 95°C) for 1 hour and 30 minutes, after which GC analysis of the mixture showed complete conversion of 1-(2-methylbutanoyl)piperidine-2-carboxylic acid to 2-oxo-2-(p-tolyl)ethyl 1-(2-methylbutanoyl)piperidine-2-carboxylate. The reaction mixture was then cooled to 60°C, stirring was stopped, and the aqueous layer was removed from the cloudy, light orange organic layer via the bottom valve. 2-Methyltetrahydrofuran (1025 g) was added to the mixture remaining in the reactor. The solution was stirred (160 rpm) and heated to reflux (85°C, Tj: 110°C), and ammonium acetate (1462 g, 18.6 mol, 98%) was added in portions with azeotropic removal of water. The reaction mixture was stirred at reflux overnight until GC analysis confirmed complete conversion and the water generated by the reaction was removed azeotropically. The reaction mixture was cooled to 60°C and washed once with water (1000 g), three times with sodium hydroxide (2M, 1000 g), and four times with water (1000 g) to pH 7. The product solution was again heated to reflux and azeotropically dried (Tj: 115°C), then the solution was cooled to 0°C (Tj: 0°C) and stirring (50 rpm) was continued for 24 hours. Fine crystals formed in the orange mixture were removed by filtration of the cake through a Buchner funnel and then washed twice with cold methyl-t-butyl ether (4°C, 400 ml).

[0104] The solid product was dried under vacuum to give 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one (390 g, 1.2 mol, 39% yield) as a white solid. Mp: 156.3 °C. GC / MS (EI): m / z (%): 325 (10) [M+], 268 (2), 240 (100), 224 (3), 185 (10), 159 (2), 142 (1), 84 (2), 57 (4). 1H NMR (500 MHz, DMSO-d6, 413K, mixture of stereoisomers and tautomers) δ = 11.32 (br s, 1H), 7.61(br m, 2H), 7.28 (br s, 1H), 7.14 (br m, 2H), 5.63 (br m, 1H), 4.06 (br m, 1H), 3.29 (br m, 1H), 2.76 (m, 1H), 2.31 (s, 3H), 2.23 (br m, 1H), 1.83 -1.60 (m, 5H), 1.49 -1.33 (m, 2H), 1.09 - 1.05 (2d, J = 6.8 Hz, 3H), 0.91 -0.85 (2t, J = 7.4 Hz, 3H) ppm. 13C NMR (125 MHz, DMSO-d6, 413K, mixture of stereoisomers and tautomers, shifts extracted from HSQC & HMBC experiments) δ 174.4 (s), 146.8 (s), 139.6 (s), 134.3 (s), 132.1 (s), 128.1 (2d), 123.7 (2d), 110.9 (d). 47.5 (d), 40.1 (t), 35.6 (d), 27.6 (t), 26.0 (t), 24.7 (t), 19.8 (q), 19.0 (t), 16.3 (q), 10.5 (q) ppm.

[0105] The above has broadly described, without limitation, certain aspects of the present invention. Variations and modifications that will be readily apparent to those skilled in the art are intended to be within the scope of the present invention as defined in the appended claims.

Claims

1. 1. A process for the in-situ formation of a compound of formula (V) from pipecolic acid, wherein the in-situ process is carried out in the presence of a solvent, wherein the solvent is an organic solvent having a boiling point in the range of about 50° C. to about 160° C., water, or a mixture thereof; wherein the method includes: (a) reacting pipecolic acid with an acid chloride of formula (Ia) in the presence of a base, or reacting pipecolic acid with an acid anhydride of formula (Ib), optionally in the presence of a base, to form a compound of formula (II); 【Chemistry 1】 (b) reacting a compound of formula (II) with a compound of formula (III) to form a compound of formula (IV); 【Chemistry 2】 (c) reacting a compound of formula (IV) with an ammonium source to form a compound of formula (V); 【Transformation 3】 During the ceremony, R 1 , R 2 and R 3 together with the carbon atom to which they are attached form a group containing only carbon and hydrogen atoms, and optionally containing up to three heteroatoms independently selected from O, S, N and F; The phenyl group of the compounds represented by formulas (III), (IV) and (V) is a group consisting of n R 4 substituted with a substituent, where n is zero, 1, 2, 3, 4, or 5; Each R 4 are independently halogen, cyano, nitro, C optionally containing up to five halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, optionally containing up to three halogen atoms 1 -C 6 Alkoxy, C 1 -C 3 Alkoxy-C 1 -C 3 -alkyl, and C 3 -C 7 cycloalkyl; B + is the cation provided by the base; and X is a halogen; The method.

2. R 1 , R 2 and R 3 together with the carbon atoms to which they are attached, 3-thiabut-2-yl, 2-methyl-3-thiabut-2-yl, 3-thiapent-2-yl, 4-thiapent-2-yl, 2-thiaprop-1-yl, 2-methyl-3-thiapent-2-yl, 3-oxo-3-thiabut-2-yl, 3-oxo-2-methyl-3-thiabut-2-yl, 3-oxo-3-thiapent-2-yl, 4-oxo -4-thiapent-2-yl, 2-oxo-2-thiaprop-1-yl, 3-oxo-2-methyl-3-thiapent-2-yl, but-2-yl, pent-2-yl, but-3-en-2-yl, pent-3-en-2-yl, but-2-en-2-yl, pent-2-en-2-yl, but-1-en-2-yl, pent-1-en-2-yl, 2-methylbut-2-yl, 2-methylpent- 2-yl, 2-methylbut-3-en-2-yl, 3-methylbut-2-yl, 3-methylbut-3-en-2-yl, 3-methylbut-2-en-2-yl, 2,3-dimethylbut-2-yl, 2,3-dimethylpent-2-yl, 2,3-dimethylbut-3-en-2-yl, 2,3-dimethylpent-3-en-2-yl, 2-methylpent-3-en-2-yl, propan-2-yl, propan-2-yl prop-1-yl, ethyl, cyclopropyl, 1,1-dimethylcycloprop-2-yl, 1-methylcycloprop-2-yl, 1-methylcycloprop-1-yl, 3-thiahex-5-en-2-yl, 2-methyl-3-thiahex-5-en-2-yl, 1-mercaptoeth-1-yl, 2-mercaptoprop-2-yl, 3,3,3-trifluoroprop-2-yl, 2-methyl-3,3,3-trifluoroprop-2-yl, 1-(2-furyl)eth-1-yl, 1-(5-methylfur-2-yl)eth-1-yl, 2-(2-furyl)prop-2-yl, 1-(3-furyl)eth-1-yl, 1-(5-methylfur-3-yl)eth-1-yl, 2-(3-furyl)prop-2-yl, 1-(2-tetrahydrofuryl)eth-1-yl, 2-(2-tetrahydrofuryl)prop-2-yl, 1-(3-tetrahydrofuryl)eth-1-yl forming a group selected from 1-cyclopropyl, 2-(3-tetrahydrofuryl)prop-2-yl, 1-cyclopropyleth-1-yl, 2-cyclopropylprop-2-yl, 1-cyclobutyleth-1-yl, 2-cyclobutylprop-2-yl, cyclobutyl, cyclopentyl, pent-2-en-3-yl, 1-methoxyprop-1-yl, 1-methoxyeth-1-yl, 1,1,1-trifluorobut-3-yl, and 3-thiacyclobut-1-yl, The method of claim 1.

3. The compound represented by formula (V) is 2-methyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)butan-1-one, 2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, 2-methyl-2-(methylthio)-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)propan-1-one, or 2,2-dimethyl-1-(2-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1-yl)but-3-en-1-one; 3. The method according to claim 1 or 2.

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