Synthesis of Capsaicin Derivatives

Abstract

The present invention relates to the synthesis of capsaicin derivatives, specifically the synthesis of 6-heptyne derivatives of capsaicin. TIFF2023518093000025.tif2443

Description

[Technical field]

[0001] The present invention relates to the synthesis of capsaicin derivatives, and in particular to the synthesis of 6-heptyne derivatives of capsaicin. [Background technology]

[0002] The 6-heptyne derivatives of capsaicin, referred to herein as capsaicyns, are valuable compounds with a variety of potential applications. Distinguished from the natural compound capsaicin by their alkyne moiety replacing the alkene moiety of capsaicin, these synthetic capsaicin derivatives have found their applications in such diverse fields as food industry, agriculture, medicine, and marine antifouling paints. Perhaps the most widely used derivative, phenylcapsaicin N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-phenyl-6-heptyneamide, has been shown to have low systemic toxicity and to be safe with respect to gene mutations and chromosomal damage (Non-Patent Document 1) and has been reviewed and deemed safe by the European Food Safety Authority (Non-Patent Document 2).

[0003] The production of capsaicins requires a multi-step chemical synthesis. For commercial products, it is very important that the synthesis is efficient and economical. Preferably, the synthesis is also sustainable and has a low environmental impact, with fewer synthetic steps and intermediates to be isolated.

[0004] The synthesis of capsaicins previously described typically relies on the coupling of the corresponding 7-substituted 6-heptynoic acid or 7-substituted 6-heptynoic acid chloride with vanillylamine.

[0005] In their US Pat. No. 5,993,336, applicants describe a six-step synthesis of capsaicins, shown in Scheme 1 for phenylcapsaicin (1a). TIFF0007655572000001.tif137117

[0006] The synthetic route disclosed in US Pat. No. 5,999,336 starts from 5-chloro-1-pentanol and achieves an overall yield of 45%. In this synthesis, as in some reported syntheses of capsaicin itself, thionyl chloride, a corrosive and reactive compound that can violently release dangerous gases when in contact with water or other reagents, is utilized in a key step.

[0007] The synthetic route provided in US Pat. No. 5,399,633 also relies on the use of thionyl chloride at a key step.

[0008] The synthetic route in Cordova et al., US Pat. No. 5,339,666 achieves a 78% yield from 6-heptynoic acid of phenylcapsaicin, but relies on palladium catalysis in the first step with a significant catalyst loading of 3%. This route is shown in Scheme 2. There is growing interest in the synthetic community to move away from the use of precious metal catalysts, as the continued need for small amounts of precious metals not only raises economic concerns, but also has significant environmental impacts (Non-Patent Document 3). The high catalyst loading reported by Cordova et al. makes the synthesis very costly to carry out on a commercial scale. Furthermore, the synthesis of 6-heptynoic acid is relatively tedious, see Non-Patent Document 4. TIFF0007655572000002.tif62110

[0009] Regarding the synthesis of capsaicin itself and capsaicin derivatives not having the 6-yne moiety, well-known synthetic routes include thionyl chloride-dependent routes via acid chlorides, as in Scheme 1 (see, for example, US Pat. No. 5,399,633), palladium-catalyzed couplings of the corresponding acids (see, for example, US Pat. No. 5,399,633) and enzymatic couplings of the corresponding acids (see, for example, US Pat. No. 5,399,633), as well as methods focused on the introduction of double bonds, such as the Wittig reaction and the Claisen ester rearrangement.

[0010] It is an object of the present invention to provide an alternative synthetic route to capsaicins, e.g., a synthetic route to phenylcapsaicins, e.g., a synthetic route for phenylcapsaicin, which is more economical, safer, more sustainable and / or more environmentally friendly and does not use precious metal catalysts than the routes previously described. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] European Patent Application Publication No. 1670310 [Patent Document 2] China Patent Application Publication No. 108947863 [Patent Document 3] International Publication No. 2015 / 144902 [Patent Document 4] US Patent Application Publication No. 2007 / 0293703 [Patent Document 5] China Patent Application Publication No. 107188818 [Patent Document 6] International Publication No. 2016 / 171538 [Non-patent literature]

[0012] [Non-Patent Document 1] Rage Paulsen et al., Toxicology Research and Application 2018, 2, 1 [Non-Patent Document 2] EFSA NDA Panel et al., EFSA Journal 2019, 17(6), e05718 [Non-Patent Document 3] Ludwig and Schindler, Chem 2017, 2, 313. [Non-Patent Document 4] Russian Chemical Bulletin 2001, 50(5), 833. Summary of the Invention

[0013] The present inventors have discovered a novel synthetic route to capsaicin, which is shown in Scheme 3.

[0014] The new route provides capsaicin in three synthetic steps from readily available raw materials. With only two isolated intermediates, the route is appealing for its shortness and simplicity. The shorter route makes it more economical and environmentally friendly than the longer route described in US Pat. No. 5,399,436, since fewer solvents and fewer reagents are required. The fewer synthetic steps also mean a more favorable output of product per unit of time and reaction volume, and fewer isolated intermediates reduce chemical exposure for operators. The synthetic route does not use any metal catalysts, making it more sustainable than the route disclosed in US Pat. No. 5,399,436. TIFF0007655572000003.tif137136

[0015] For a given synthetic route, each of R, R', Alk, LG, and LG' represents the same substituent in all compounds of that synthetic route.

[0016] In the compounds presented, R is C1-C 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12and substituted phenyl, where the phenyl ring is substituted at any one or more positions with 1 to 5 of the same or different substituents selected from the group including fluoro; chloro; bromo; iodo, cyano, nitro, trifluoromethyl, C1-C6 straight and branched alkoxy, C1-C6 sulfoxy, -S-C1-C6 alkyl, C1-C6 straight and branched alkyl, C2-C6 straight and branched alkenyl, C2-C6 straight and branched alkynyl, C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C1-C6 alkyl, and CON(C1-C6 alkyl).

[0017] R' may represent 0 to 5 identical or different substituents at one or more any position selected from the group including fluoro; chloro; bromo; iodo; hydroxy; cyano; amino; nitro; trifluoromethyl; C1-C6 straight and branched alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C6 straight and branched alkyl; C2-C6 straight and branched alkenyl; C2-C6 straight and branched alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COOH; CONH2; -NHCO(C1-C6 alkyl); COO-C1-C6 alkyl; CONH(C1-C6 alkyl); and CON(C1-C6 alkyl)2.

[0018] Alk represents a C1-C6 linear, branched or cyclic alkyl. The two Alk groups may be identical.

[0019] LG and LG' are different or the same leaving groups selected from the list including, but not limited to, perfluoroalkylsulfonates such as triflate; sulfonates such as tosylate, mesylate; fluoro; chloro; bromo; and iodo.

[0020] The present invention relates to a compound represented by the general formula 1, 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12 and substituted phenyl, wherein the substituted phenyl ring is substituted at one or more of its optional positions with from 1 to 5 identical or different substituents selected from the group including fluoro; chloro; bromo; iodo, cyano, nitro, trifluoromethyl, C1-C6 straight and branched alkoxy, C1-C6 sulfoxy, -S-C1-C6 alkyl, C1-C6 straight and branched alkyl, C2-C6 straight and branched alkenyl, C2-C6 straight and branched alkynyl, C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C1-C6 alkyl, CONH(C1-C6 alkyl), and CON(C1-C6 alkyl)2; and R' is selected from the group including fluoro; chloro; bromo; iodo, hydroxy, cyano, nitro, trifluoromethyl, C1-C6 straight and branched alkoxy, C1-C6 sulfoxy, -S-C1-C6 alkyl, C1-C6 straight and branched alkyl, C2-C6 straight and branched alkenyl, C2-C6 straight and branched alkynyl, C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COO-C1-C6 alkyl, CONH(C1-C6 alkyl), and CON(C1-C6 alkyl)2, at one or more of its optional positions. No, amino, nitro, trifluoromethyl, C1-C6 straight and branched alkoxy, C1-C6 sulfoxy, -S-C1-C6 alkyl, C1-C6 straight and branched alkyl, C2-C6 straight and branched alkenyl, C2-C6 straight and branched alkynyl, C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COOH, CONH2, -NHCO(C1-C6 alkyl), COO-C1-C6 alkyl, CONH(C The present invention relates to a method for preparing a 6-heptyne derivative of capsaicin of general formula 3, which comprises coupling a compound of general formula 3 with a benzylamine of general formula 2 or any suitable salt thereof, using 1,1'-carbonyldiimidazole (CDI), wherein R and R' for general formulas 2 and 3 are defined as for formula 1.

[0021] The present invention further provides a method for preparing the 6-heptyne derivative of capsaicin of general formula 1 above, which further comprises, prior to the steps described above, reacting a compound of general formula 4 with an alkyl malonate of general formula 5 (wherein for general formula 4, R is defined as for general formula 3) to produce said compound of general formula 3 (wherein "Alk" represents a linear, branched, or cyclic C1-C6 alkyl group; and "LG" represents any leaving group known to those skilled in the art).

[0022] The present invention also provides a method for producing a 6-heptyne derivative of capsaicin of general formula 1 above, which further comprises, prior to the above step, a step of reacting an acetylene compound of general formula 7 with a 1,3-substituted propane compound of general formula 6 (wherein for general formulas 6 and 7, LG and R are defined as for general formula 4) to produce the above compound of general formula 4 (wherein "LG" and "LG'" are different or the same leaving groups selected from the list comprising perfluoroalkylsulfonates such as triflate; sulfonates such as tosylate, mesylate; fluoro; chloro; bromo; and iodo). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Unless otherwise specified, all technical terms, notations and other scientific or technical terms used herein are intended to have the meanings that are generally understood by those skilled in the art. In some cases, terms that have generally understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein does not necessarily have to be interpreted as representing a substantial difference from what is generally understood in the art.

[0024] The term "capsaicyns" as used herein refers to 6-heptyne derivatives of capsaicin of general formula 1: [ka]

[0025] Those skilled in the art are aware that the terms "6-heptyne" and "hept-6-yne," both commonly found in chemical nomenclature, can be used interchangeably and have the same meaning. The choice to use the term "6-heptyne" and related nomenclatures such as "6-heptynoic" herein is purely for ease of reading.

[0026] The reader is advised that the nomenclature used for capsaicin derivatives in the art is inconsistent and for ease of reading, the term capsaicins is used where appropriate depending on the general group of compounds, while the established common name "phenylcapsaicin" is used when referring to N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-phenyl-6-heptynamide, and "phenylcapsaicins" is used to refer to those derivatives.

[0027] The term "derivative" as used herein refers to a molecule that differs from the parent compound in chemical structure. Examples of derivatives include, but are not limited to, homologs that additionally differ from the parent molecule's chemical structure, such as differences in the length of fatty chains; molecular fragments; structures that differ from the parent compound in one or more functional groups, for example, can be made by changing one or more functional groups of the parent; changes in the ionization state of the parent compound, such as ionizing an acid to its conjugate base; isomers, including positional, geometrical and stereoisomers; and combinations thereof.

[0028] As used herein, the term "C1-C6 alkyl" refers to straight or branched chain aliphatic radials of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, pentyl, hexyl, etc. The term "C1-C6 straight and branched chain alkoxy" refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, and tert-butoxy, etc.

[0029] As used herein, the term "solvent" refers to a liquid substance in which a compound is dissolved or partially dissolved at a given concentration sufficient to dissolve or partially dissolve the compound. The term refers to both solvent blends (i.e., multi-component solvents) and pure compounds (i.e., single-component solvents) unless the context indicates otherwise.

[0030] As used herein, the term "anhydrous solvent" refers to a solvent containing less than 0.5% water by weight, and is preferably maintained and handled under nitrogen or argon gas during the reaction.

[0031] As used herein, the term "anhydrous conditions" refers to the avoidance of any substantial amount of moisture in the reaction mixture, such as a reaction mixture containing less than 0.5% water by weight, and is not intended to mean the complete exclusion of any moisture.

[0032] As used herein, the term "base" refers to a compound that can accept a proton.

[0033] The term "simultaneously" as used herein refers to any two or more processes occurring at or near the same time, and is not to be interpreted strictly. It is not intended that the processes must be started or finished together.

[0034] As used herein, the term "quenching a reaction mixture" means to inactivate reagents and / or stop a reaction and / or initiate workup of the reaction mixture.

[0035] Phenyl rings are numbered cyclically from the ipso carbon (1) through 6, regardless of the priority of the substituents.

[0036] It will be apparent to one of skill in the art that using the disclosed methods for making the 6-heptyne derivatives of capsaicin, not only the compounds disclosed herein, but also a wide variety of derivatives, analogs, and / or salts in a variety of stereoisomers can be synthesized in accordance with the present invention.

[0037] It will further be apparent to those skilled in the art that the products obtained by any of the reactions disclosed herein may be in the form of solvates, such as hydrates, and / or may contain impurities. Those skilled in the art will be familiar with the range of different techniques for removing residual solvent. Those skilled in the art will be familiar with the range of different purification techniques.

[0038] In some embodiments, the present invention provides a compound represented by general formula 1, wherein R is hydrogen, C-C 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12 Cycloalkyl; phenoxy; phenylthio; fluoro; chloro; bromo; iodo; phenyl; and substituted phenyl; wherein the substituted phenyl is substituted at one or more arbitrary positions with 1 to 5 identical or different substituents selected from the group including fluoro; chloro; bromo; iodo; cyano; nitro; trifluoromethyl; C1-C6 straight and branched alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C6 straight and branched alkyl, alkenyl, and alkynyl; C2-C6 straight and branched alkenyl; C2-C6 straight and branched alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COO-C1-C6 alkyl; and CON(C1-C6 alkyl); and R' represents 0 to 5 identical or different substituents at one or more any position selected from the group including fluoro; chloro; bromo; iodo; hydroxy; cyano; amino; nitro; trifluoromethyl; C1-C6 straight and branched chain alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C6 straight and branched chain alkyl; alkenyl; and alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COOH, CONH2, -NHCO(C1-C6 alkyl), COO-C1-C6 alkyl, CONH(C1-C6 alkyl), and CON(C1-C6 alkyl)2). The present invention provides a synthetic route for capsaicins.

[0039] In some embodiments, the present invention provides a compound represented by general formula 1, wherein R is hydrogen, C-C 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12 a substituent selected from the group consisting of cycloalkyl; phenoxy; phenylthio; fluoro; chloro; bromo; iodo; phenyl; and substituted phenyl; wherein the substituted phenyl is substituted at any one or more positions with 1 to 5 identical or different substituents selected from the group consisting of fluoro; chloro; bromo; iodo; cyano; nitro; trifluoromethyl; C1-C6 straight and branched alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C6 straight and branched alkyl, alkenyl, and alkynyl; C2-C6 straight and branched alkenyl; C2-C6 straight and branched alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COO-C1-C6 alkyl; and CON(C1-C6 alkyl); and R' represents 0 to 5 identical or different substituents selected from the group consisting of fluoro; chloro; bromo; iodo, hydroxy, cyano, amino, nitro, trifluoromethyl, C1-C6 straight and branched chain alkoxy, C1-C6 sulfoxy, -S-C1-C6 alkyl, C1-C6 straight and branched chain alkyl, alkenyl, and alkynyl, C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, COOH, CONH2, -NHCO(C1-C6 alkyl), COO-C1-C6 alkyl, CONH(C1-C6 alkyl), and CON(C1-C6 alkyl)2 at any one or more positions. The present invention provides a synthetic route for capsaicins.

[0040] The substituted phenyl is fluoro; chloro; bromo; iodo; cyano; nitro; trifluoromethyl; C1-C6 straight and branched chain alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C 12 and CON(C1-C6 alkyl)2. Such variants are designated a1.

[0041] The substituted phenyl is fluoro; chloro; bromo; iodo; cyano; nitro; trifluoromethyl; C1-C6 straight and branched chain alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C 12 and C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl, optionally substituted at any one or more positions with one to five of the same or different substituents selected from the group consisting of: straight and branched chain alkyl, alkenyl, and alkynyl; and C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl. Such variants are designated a2.

[0042] The substituted phenyl may be substituted at any one or more positions with 1 to 5 of the same or different substituents selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, and trifluoromethyl. Such variants are designated a3.

[0043] The substituted phenyl is fluoro; chloro; bromo; iodo; C1-C 12 and C1-C6 straight or branched chain alkoxy. Such variants are designated a4.

[0044] The substituted phenyl is fluoro; chloro; bromo; iodo; C1-C 10 and C1-C6 straight or branched chain alkoxy. Such variants are designated a5.

[0045] The substituted phenyl ring may be substituted at any one or more positions with one to five of the same or different substituents selected from the group consisting of nitro; C1-C6 straight and branched chain alkyl, alkenyl, and alkynyl; and C1-C4 straight or branched chain alkoxy. Such variants are designated a6.

[0046] The substituted phenyl may be substituted at any one or more positions with 1 to 5 of the same or different substituents selected from the group consisting of C1-C6 straight and branched chain alkyl, alkenyl, and alkynyl; and C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl. Such variants are designated a7.

[0047] The substituted phenyl may have one substituent, for example at position 2, for example at position 3, for example at position 4. The phenyl ring may have two substituents, for example at positions 2 and 6, for example at positions 2 and 5, for example at positions 2 and 3, for example at positions 3 and 5, for example at positions 2 and 4, for example at positions 3 and 4. The phenyl ring may have three substituents, for example at positions 2, 3 and 6, for example at positions 2, 4 and 6, for example at positions 2, 3 and 4, for example at positions 2, 3 and 5, for example at positions 3, 4 and 5. The phenyl ring may have four substituents, for example at positions 2, 3, 4 and 6, for example at positions 2, 3, 4 and 5, for example at positions 2, 3, 5 and 6. The phenyl ring may have five substituents.

[0048] In some variants, two of the above substituents on the substituted phenyl are the same as each other. In some variants, three of the substituents are the same as each other. In some variants, four of the substituents are the same as each other. In some variants, five of the substituents are the same as each other. In other variants, all of the above substituents are different from each other.

[0049] R is as defined above, hydrogen, C1-C 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12 Such variants may be selected from the group consisting of cycloalkyl, phenoxy, phenylthio, fluoro, chloro, bromo, iodo, phenyl, and substituted phenyl. Such variants are designated b1.

[0050] R is C1-C as defined above. 18 and substituted phenyl. Such variants are designated b2.

[0051] R is as defined above, hydrogen, C1-C 10straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C8 cycloalkyl; phenoxy; phenylthio; fluoro; chloro; bromo; iodo; phenyl; and substituted phenyl. Such variants are designated b3.

[0052] R may be selected from the group consisting of C1-C6 straight and branched chain alkyl, alkenyl, and alkynyl, trifluoromethyl, C3-C6 cycloalkyl, phenoxy, phenylthio, fluoro, chloro, bromo, iodo, phenyl, and substituted phenyl, as defined above. Such variants are designated b4.

[0053] R is C1-C as defined above. 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12 Such variants may be selected from the group consisting of cycloalkyl, fluoro, chloro, bromo, iodo, phenyl, and substituted phenyl. Such variants are designated b5.

[0054] R is C1-C as defined above. 10 straight and branched chain alkyl, alkenyl, and alkynyl; C3-C8 cycloalkyl; and phenyl. Such a variant is designated b6.

[0055] Preferably, R is a substituted phenyl ring. Such a variant is designated b7.

[0056] All variants described as including substituted phenyl may include any of the substituted phenyl ring variants a1-a7, resulting in the following R groups: a1+b1, a1+b2, a1+b3, a1+b4, a1+b5, a2+b1, a2+b2, a2+b3, a2+b4, a2+b5, a3+b1, a3+b2, a3+b3, a3+b4, a3+b5, a4+b1, a4+b2, a4+b3 , a4+b4, a4+b5, a5+b1, a5+b2, a5+b3, a5+b4, a5+b5, a6+b1, a6+b2, a6+b3, a6+b4, a6+b5, a7+b1, a7+b2, a7+b3, a7+b4, a7+b5, b6, b7 For example, a1+b1 is a combination of letters and numbers, where R is hydrogen, C1-C 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12 cycloalkyl; phenoxy; phenylthio; fluoro; chloro; bromo; iodo; phenyl; and substituted phenyl (b1), where substituted phenyl is selected from the group consisting of fluoro; chloro; bromo; iodo; cyano; nitro; trifluoromethyl; C1-C6 straight and branched chain alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C6 12 and a7+b5 are each independently selected from the group consisting of C1-C6 straight and branched alkyl, alkenyl, and alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COO-C1-C6 alkyl; and CON(C1-C6 alkyl)2, optionally substituted at any one or more positions with 1 to 5 identical or different substituents. 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12(a7) refers to the variants defined above, such as (a7) which may be selected from the group consisting of or including cycloalkyl; fluoro; chloro; bromo; iodo; phenyl; and substituted phenyl, where substituted phenyl may be substituted at any one or more positions with 1 to 5 of the same or different substituents selected from the group consisting of or including C1-C6 straight and branched alkyl, alkenyl, and alkynyl; and C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl.

[0057] R' is, at any one or more positions, fluoro; chloro; bromo; iodo; hydroxy; cyano; amino; nitro; trifluoromethyl; C1-C6 straight and branched chain alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C 12 straight and branched chain alkyl, alkenyl, and alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COOH; CONH2; -NHCO(C1-C6 alkyl); COO-C1-C6 alkyl; CONH(C1-C6 alkyl); and CON(C1-C6 alkyl)2. Such variants are designated c1.

[0058] R' may represent 0-5 identical or different substituents selected from the group consisting of fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, nitro, trifluoromethyl, COOH; -NHCO(C1-C6 alkyl); and CONH2 at one or more of any position. Such variants are designated c2.

[0059] R' may represent 0 to 5 of the same or different substituents selected from the group consisting of hydroxy, methoxy, fluoro, chloro, bromo, and iodo at any one or more positions. Such variants are designated c3.

[0060] R' may represent 0 to 5 of the same or different substituents selected from the group consisting of hydroxy, methoxy, iodo, bromo, and chloro at any one or more positions. Such variants are designated c4.

[0061] Preferably, R' may represent zero substituents, meaning that the phenyl ring in which R' is depicted as a substituent is in fact unsubstituted. R' may represent one substituent, for example at the 2-position, for example at the 3-position, for example at the 4-position. R' may represent two substituents, for example at the 2- and 6-positions, for example at the 2- and 5-positions, for example at the 2- and 3-positions, for example at the 3- and 5-positions, for example at the 2- and 4-positions, for example at the 3- and 4-positions. R' may represent three substituents, for example at the 2-, 3- and 6-positions, for example at the 2-, 4- and 6-positions, for example at the 2-, 3- and 4-positions, for example at the 2-, 3- and 5-positions, for example at the 3-, 4- and 5-positions. R' may represent four substituents, for example at the 2-, 3-, 4- and 6-positions, for example at the 2-, 3-, 4- and 5-positions, for example at the 2-, 3-, 5- and 6-positions. R' may represent five substituents.

[0062] Preferably, R' represents two substituents in the 3 and 4 positions.

[0063] In some variants, two of the above substituents on the substituted phenyl are the same as each other. In some variants, three of the substituents are the same as each other. In some variants, four of the substituents are the same as each other. In some variants, five of the substituents are the same as each other. In other variants, all of the above substituents are different from each other.

[0064] In a preferred variant, R' represents the two substituents 3-methoxy and 4-hydroxy.

[0065] Each selection of possible R groups, R' groups, and substituents on the phenyl ring disclosed herein should be construed as disclosed for use in any combination with one or more of the any and all selections of possible R groups, R' groups, and substituents on the phenyl ring disclosed herein.

[0066] Thus, in some embodiments, the present invention provides synthetic routes to capsaicins of general structure 1 and R and R' listed below: <h2 style=";text-align:left;direction:ltr">a1+b1+c1, a1+b2+c1, a1+b3+c1, a1+b4+c1, a1+b5+c1, a2+b1+c1, a2+b2+c1, a2+b3+c1, a2+b4+c1, a2+b5+c1, a3+b1+c1, a3+b2+c1, a3+b3+c1, a3+b4+c 1, a3+b5+c1, a4+b1+c1, a4+b2+c1, a4+b3+c1, a4+b4+c1, a4+b5+c1, a5+b1+c1, a5+b2+c1, a5+b3+c1, a5+b4+c1, a5+b5+c1, a6+b1+c1, a6+b2+c1, a6+b3+ c1、a6+b4+c1、a6+b5+c1、a7+b1+c1、a7+b2+c1、a7+b3+c1、a7+b4+c1、a7+b5 +c1、b6+c1、b7+c1、a1+b1+c2、a1+b2+c2、a1+b3+c2、a1+b4+c2、a1+b5+c2、a2 +b1+c2,a2+b2+c2,a2+b3+c2,a2+b4+c2,a2+b5+c2,a3+b1+c2,a3+b2+c2,a3+b3+c2,a3+b4+c2,a3+b5+c2,a4+b1+c2,a4+b2+c2,a4+b3+c2,a4+b4+c2,a 4+b5+c2, a5+b1+c2, a5+b2+c2, a5+b3+c2, a5+b4+c2, a5+b5+c2, a6+b1+c2, a6+b2+c2, a6+b3+c2, a6+b4+c2, a6+b5+c2, a7+b1+c2, a7+b2+c2, a7+b3+c2 a7+b4+c2, a7+b5+c2, b6+c2, b7+c2, a1+b1+c3, a1+b2+c3, a1+b3+c3, a1+b4+c3, a1+b5+c3, a2+b1+c3, a2+b2+c3, a2+b3+c3, a2+b4+c3, a2+b5+c3, a3+b1 +c3,a3+b2+c3,a3+b3+c3,a3+b4+c3,a3+b5+c3,a4+b1+c3,a4+b2+c3,a4+b3+c3,a4+b4+c3,a4+b5+c3,a5+b1+c3,a5+b2+c3,a5+b3+c3,a5+b4+c3,a5+b4+c3,a5+b1 5+c3,a6+b1+c3,a6+b2+c3,a6+b3+c3,a6+b4+c3,a6+b5+c3,a7+b1+c3,a7+b2+c3,a7+b3+c3,a7+b4+c3,a7+b5+c3,b6+c3,b7+c3,a1+b1+c4,a1+b2+c4,a1+b3+c4, a1+b4+c4, a1+b5+c4, a2+b1+c4, a2+b2+c4, a2+b3+c4, a2+b4+c4, a2+b5+c4, a3+b1 +c4, a3+b2+c4, a3+b3+c4, a3+b4+c4, a3+b5+c4, a4+b1+c4, a4+b2+c4, a4+b3+c4, a4+b4+c4, a 4+b5+c4, a5+b1+c4, a5+b2+c4, a5+b3+c4, a5+b4+c4, a5+b5+c4, a6+b1+c4, a6+b2+c4, a6+b3+ c4, a6+b4+c4, a6+b5+c4, a7+b1+c4, a7+b2+c4, a7+b3+c4, a7+b4+c4, a7+b5+c4, b6+c4, b7+c4. , For example, a1+b1+c1 is a combination of letters and numbers, where R is hydrogen, C1-C 18 Straight and branched chain alkyl, alkenyl, and alkynyl; trifluoromethyl; C3-C 12 cycloalkyl; phenoxy; phenylthio; fluoro; chloro; bromo; iodo; phenyl; and substituted phenyl (b1), where substituted phenyl is selected from the group consisting of fluoro; chloro; bromo; iodo; cyano; nitro; trifluoromethyl; C1-C6 straight and branched chain alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C6 12 (a1), which is optionally substituted at one or more optional positions with one to five of the same or different substituents selected from the group consisting of: straight and branched chain alkyl, alkenyl, and alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COO-C1-C6 alkyl; and CON(C1-C6 alkyl)2; and R' is optionally substituted at one or more optional positions with one or more of the following substituents: fluoro; chloro; bromo; iodo; hydroxy; cyano; amino; nitro; trifluoromethyl; C1-C6 straight and branched chain alkoxy; C1-C6 sulfoxy; -S-C1-C6 alkyl; C1-C6 alkyl; 12straight and branched chain alkyl, alkenyl, and alkynyl; C1-C6 fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl; COOH; CONH2; -NHCO(C1-C6 alkyl); COO-C1-C6 alkyl; CONH(C1-C6 alkyl); and CON(C1-C6 alkyl)2, and so forth, as defined above.

[0067] In a preferred embodiment, the present invention provides synthetic routes to capsaicins of general structure 1 and R and R' as listed below: <h2 style=";text-align:left;direction:ltr">a1+b1+c1, a1+b2+c1, a1+b3+c1, a1+b4+c1, a1+b5+c1, a2+b1+c1, a2+b2+c1, a2+b3+c1, a2+b4+c1, a2+b5+c1, a3+b1+c1, a3+b2+c1, a3+b3+c1, a3+b4+c 1, a3+b5+c1, a4+b1+c1, a4+b2+c1, a4+b3+c1, a4+b4+c1, a4+b5+c1, a5+b1+c1, a5+b2+c1, a5+b3+c1, a5+b4+c1, a5+b5+c1, a6+b1+c1, a6+b2+c1, a6+b3+ c1、a6+b4+c1、a6+b5+c1、a7+b1+c1、a7+b2+c1、a7+b3+c1、a7+b4+c1、a7+b5 +c1、b6+c1、b7+c1、a1+b1+c2、a1+b2+c2、a1+b3+c2、a1+b4+c2、a1+b5+c2、a2 +b1+c2,a2+b2+c2,a2+b3+c2,a2+b4+c2,a2+b5+c2,a3+b1+c2,a3+b2+c2,a3+b3+c2,a3+b4+c2,a3+b5+c2,a4+b1+c2,a4+b2+c2,a4+b3+c2,a4+b4+c2,a 4+b5+c2, a5+b1+c2, a5+b2+c2, a5+b3+c2, a5+b4+c2, a5+b5+c2, a6+b1+c2, a6+b2+c2, a6+b3+c2, a6+b4+c2, a6+b5+c2, a7+b1+c2, a7+b2+c2, a7+b3+c2 a7+b4+c2, a7+b5+c2, b6+c2, b7+c2, a1+b1+c3, a1+b2+c3, a1+b3+c3, a1+b4+c3, a1+b5+c3, a2+b1+c3, a2+b2+c3, a2+b3+c3, a2+b4+c3, a2+b5+c3, a3+b1 +c3,a3+b2+c3,a3+b3+c3,a3+b4+c3,a3+b5+c3,a4+b1+c3,a4+b2+c3,a4+b3+c3,a4+b4+c3,a4+b5+c3,a5+b1+c3,a5+b2+c3,a5+b3+c3,a5+b4+c3,a5+b4+c3,a5+b1 5+c3,a6+b1+c3,a6+b2+c3,a6+b3+c3,a6+b4+c3,a6+b5+c3,a7+b1+c3,a7+b2+c3,a7+b3+c3,a7+b4+c3,a7+b5+c3,b6+c3,b7+c3,a1+b1+c4,a1+b2+c4,a1+b3+c4, a1+b4+c4, a1+b5+c4, a2+b1+c4, a2+b2+c4, a2+b3+c4, a2+b4+c4, a2+b5+c4, a3+b1+c4, a3+b2+c4, a3 +b3+c4, a3+b4+c4, a3+b5+c4, a4+b1+c4, a4+b2+c4, a4+b3+c4, a4+b4+c4, a4+b5+c4, a5+b1+c4, a5+b2+c4, a5+b 3+c4, a5+b4+c4, a5+b5+c4, a6+b1+c4, a6+b2+c4, a6+b3+c4, a6+b4+c4, a6+b5+c4, a7+b1+c4, a7+b2+c4, a7+b3+c4, a7+b4+c4, a7+b5+c4, b6+c4, b7+c4, where R' represents two substituents in the 3- and 4-positions, preferably R' represents the two substituents 3-methoxy and 4-hydroxy.

[0068] In a preferred embodiment, the present invention provides synthetic routes to capsaicins of general structure 1 and R and R' as listed below: <h2 style=";text-align:left;direction:ltr">a1+b1+c1, a1+b2+c1, a1+b3+c1, a1+b4+c1, a1+b5+c1, a2+b1+c1, a2+b2+c1, a2+b3+c1, a2+b4+c1, a2+b5+c1, a3+b1+c1, a3+b2+c1, a3+b3+c1, a3+b4+c 1, a3+b5+c1, a4+b1+c1, a4+b2+c1, a4+b3+c1, a4+b4+c1, a4+b5+c1, a5+b1+c1, a5+b2+c1, a5+b3+c1, a5+b4+c1, a5+b5+c1, a6+b1+c1, a6+b2+c1, a6+b3+ c1、a6+b4+c1、a6+b5+c1、a7+b1+c1、a7+b2+c1、a7+b3+c1、a7+b4+c1、a7+b5 +c1、b6+c1、b7+c1、a1+b1+c2、a1+b2+c2、a1+b3+c2、a1+b4+c2、a1+b5+c2、a2 +b1+c2,a2+b2+c2,a2+b3+c2,a2+b4+c2,a2+b5+c2,a3+b1+c2,a3+b2+c2,a3+b3+c2,a3+b4+c2,a3+b5+c2,a4+b1+c2,a4+b2+c2,a4+b3+c2,a4+b4+c2,a 4+b5+c2, a5+b1+c2, a5+b2+c2, a5+b3+c2, a5+b4+c2, a5+b5+c2, a6+b1+c2, a6+b2+c2, a6+b3+c2, a6+b4+c2, a6+b5+c2, a7+b1+c2, a7+b2+c2, a7+b3+c2 a7+b4+c2, a7+b5+c2, b6+c2, b7+c2, a1+b1+c3, a1+b2+c3, a1+b3+c3, a1+b4+c3, a1+b5+c3, a2+b1+c3, a2+b2+c3, a2+b3+c3, a2+b4+c3, a2+b5+c3, a3+b1 +c3,a3+b2+c3,a3+b3+c3,a3+b4+c3,a3+b5+c3,a4+b1+c3,a4+b2+c3,a4+b3+c3,a4+b4+c3,a4+b5+c3,a5+b1+c3,a5+b2+c3,a5+b3+c3,a5+b4+c3,a5+b4+c3,a5+b1 5+c3,a6+b1+c3,a6+b2+c3,a6+b3+c3,a6+b4+c3,a6+b5+c3,a7+b1+c3,a7+b2+c3,a7+b3+c3,a7+b4+c3,a7+b5+c3,b6+c3,b7+c3,a1+b1+c4,a1+b2+c4,a1+b3+c4, a1+b4+c4, a1+b5+c4, a2+b1+c4, a2+b2+c4, a2+b3+c4, a2+b4+c4, a2+b5+c4, a3+b1+c4, a3+b2+c4, a3+b3+c4, a3 +b4+c4, a3+b5+c4, a4+b1+c4, a4+b2+c4, a4+b3+c4, a4+b4+c4, a4+b5+c4, a5+b1+c4, a5+b2+c4, a5+b3+c4, a5+b4+c4, a5+b5 +c4, a6+b1+c4, a6+b2+c4, a6+b3+c4, a6+b4+c4, a6+b5+c4, a7+b1+c4, a7+b2+c4, a7+b3+c4, a7+b4+c4, a7+b5+c4, b6+c4, b7+c4, each combination of letters and numbers refers to a variant consisting of the substituents listed above, where R' represents two substituents at the 3- and 4-positions, preferably R' represents the two substituents 3-methoxy and 4-hydroxy.

[0069] In another preferred embodiment, the present invention provides a route for the synthesis of phenylcapsaicin having general structure 1, where R and R' are as listed below: b7+c1, b7+c2, b7+c3, b7+c4, preferably R' represents two substituents at positions 3 and 4, more preferably R' represents two substituents 3-methoxy and 4-hydroxy.

[0070] In a further preferred embodiment, the present invention provides a route for the synthesis of phenylcapsaicin having general structure 1, where R and R' are as listed below: b7+c1, b7+c2, b7+c3, b7+c4, each combination of letter and number refers to a variant of the substituents listed above, preferably R' represents two substituents at positions 3 and 4, more preferably R' represents two substituents 3-methoxy and 4-hydroxy.

[0071] Non-limiting examples of capsaicin derivatives that can be synthesized according to the present invention include: N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-phenyl-6-heptyneamide (phenylcapsaicin, 1a) N-benzyl-7-phenyl-6-heptyneamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-cyclohexyl-6-heptyneamide (1c) N-[(4-hydroxy-3-methoxyphenyl)methyl]-10-ethyl-6-dodecynamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-8,8,8-trifluoro-6-octyneamide N-(3-hexylphenyl)methyl-7-phenyl-6-heptyneamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-(3,5-diethoxyphenyl)-6-heptynamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-6-octyneamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-6-nonyneamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-nonyneamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-8,8-dimethyl-6-nonyneamide (1b) N-(3,4-dibromophenyl)methyl-7-phenyl-6-heptynamide N-[(3-ethyl-2-isopropyl-6-methylphenyl)methyl]-7-(2,6-xylyl)-6-heptynamide N-(3,5-diethoxyphenyl)methyl-7-(p-fluorophenyl)-6-heptynamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-bromo-6-heptynamide N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-cyclopentyl-6-heptyneamide Includes.

[0072] In some embodiments, the present invention provides a route to the synthesis of 6-phenyl derivatives of capsaicin (often referred to as phenylcapsaicins), where R is phenyl or substituted phenyl and R′ represents the two substituents 3-methoxy and 4-hydroxy.

[0073] In one specific embodiment, the present invention provides a route to the synthesis of phenylcapsaicin, where R is phenyl and R' represents the two substituents 3-methoxy and 4-hydroxy.

[0074] Process 3 In all embodiments, capsaicin derivative 1 is synthesized from precursor 3 and benzylamine 2. This step is referred to as step 3. Treatment with 1,1'-carbonyldiimidazole (CDI) under mild conditions gives product 1. The reaction is carried out using the method originally described by Lafrance et al. [Lafrance et al., Org. Lett. 2011, 13(9), 2322] and is believed to proceed via a carbonylimidazole intermediate. Step 3 is shown in Scheme 4.

[0075] During the development of the synthetic pathway, we found that decarboxylation of diacid 3 and subsequent conversion to the corresponding acid chloride for coupling with 2 was surprisingly challenging. This potential decarboxylation / coupling route is more similar to the previously reported thionyl chloride-dependent route, with the disadvantage that the decarboxylation requires high temperatures and is best carried out in situ, thus limiting the reaction scope. The present invention solves this problem by an elegant CDI coupling with diacid 3 that is direct and does not require a separate decarboxylation step. TIFF0007655572000005.tif36139

[0076] The reactants used in step 3 can be obtained by any method known to one of skill in the art, for example, from natural sources, commercially available, or synthesized using any route and starting materials.

[0077] The benzylamine may be the free amine or in the form of any suitable salt, such as the hydrochloride salt.

[0078] In a preferred embodiment, the benzylamine (2) is vanillylamine hydrochloride (2a). [ka]

[0079] Step 3 is carried out by the addition of compound 3 to CDI to form the putative carbonylimidazole intermediate. In some embodiments, the addition of 3 is carried out slowly, such as dropwise. The reaction may be carried out using any solvent, or a combination of two or more solvents that would be understood by one of skill in the art to be suitable for the reaction. In some embodiments, the solvent is selected from the list including, but not limited to, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), dichloromethane, acetonitrile, toluene, ethyl acetate, dimethylformamide (DMF), or any combination thereof. In some embodiments, the solvent is MTBE. The solvent may be an anhydrous solvent.

[0080] In some embodiments, the reaction of Scheme 4 is carried out at ambient temperature. In other embodiments, the reaction is carried out at elevated temperature, for example between 25°C and the boiling point of the solvent, for example between 25°C and 110°C, for example between 25°C and 75°C, for example between 30°C and 50°C, for example 40°C. In some embodiments, the same reaction temperature is maintained throughout the course of the reaction. In other embodiments, the reaction temperature is changed and / or allowed to change during the course of the reaction. In some embodiments, the reaction mixture is heated at ambient temperature, for example between 25°C and 110°C, for example between 25°C and 75°C, for example between 30°C and 50°C, for example 40°C, after a period of time.

[0081] In some embodiments, the reaction time before the addition of compound 2 or the addition to compound 2 is determined based on the time when the analysis of the reaction mixture indicates that the reaction has proceeded to completion, or the time when the analysis of the reaction mixture indicates that the reaction has stopped. Any analytical method known to those skilled in the art can be used, such as a chromatographic method, such as a thin layer chromatographic method, such as HPLC. In other embodiments, a set reaction time is used. In some embodiments, the reaction time is between 15 minutes and 3 hours, such as between 30 minutes and 2 hours, such as between 1 hour and 1 hour 45 minutes.

[0082] Compound 2 is added to a reaction mixture containing compound 3 and CDI, or a reaction mixture containing compound 3 and CDI is added to compound 2. In some embodiments, equimolar amounts of 2 and 3 are used. In other embodiments, an excess of 2 is used, for example, 1.01 to 1.5 molar equivalents, for example, 1.05 to 1.4 molar equivalents, for example, 1.1 to 1.3 equivalents, relative to the amount of 3. In yet another embodiment, an excess of 3 is used, for example, 1.01 to 1.5 molar equivalents, for example, 1.05 to 1.4 molar equivalents, for example, 1.1 to 1.3 equivalents, relative to the amount of 2.

[0083] In some embodiments, the reaction between 3 and 2 is carried out at ambient temperature. In other embodiments, the reaction is carried out at an elevated temperature, for example between 25° C. and the boiling point of the solvent, for example between 25° C. and 110° C., for example between 25° C. and 75° C., for example between 30° C. and 50° C., for example 40° C. In some embodiments, the same reaction temperature is maintained throughout the course of the reaction. In other embodiments, the reaction temperature is varied and / or allowed to vary during the course of the reaction.

[0084] In some embodiments, the reaction mixture is quenched, for example, by the addition of water, for example, at an elevated temperature after the addition of water, with continuous stirring. Workup of the reaction mixture may be performed by any method commonly used by those skilled in the art. In some embodiments, the desired product (1) is in the organic phase and is precipitated from the organic phase by methods commonly used by those skilled in the art.

[0085] In some embodiments, the reaction mixture is quenched when analysis of the reaction mixture indicates that the reaction has proceeded to completion, or when analysis of the reaction mixture indicates that the reaction has stopped. Any analytical method known to one of skill in the art can be used, such as a chromatographic method, such as a thin layer chromatographic method, such as HPLC. In other embodiments, the reaction mixture is quenched after a set reaction time, such as 2-50 hours, such as 5-40 hours, such as 10-25 hours, such as 15-20 hours, such as 15-30 hours.

[0086] In a preferred embodiment of step 3, step 3 is carried out by dropwise addition of compound 3 to CDI using MTBE as the solvent and a reaction temperature between 25° C. and 50° C. Compound 2 can be vanillylamine, preferably vanillylamine hydrochloride (2a).

[0087] Process 2 In some embodiments, compound 3 is synthesized by reacting compound 4 with a dialkyl malonate (5) under basic conditions, for example via intermediate 3′, as shown in Scheme 5. This step is referred to as Step 2. TIFF0007655572000007.tif41155

[0088] Alk in Scheme 5 represents a linear, branched, or cyclic C1-C6 alkyl group, such that compound 5 is a dialkyl malonate. In some embodiments, the Alk groups are the same as each other. In some embodiments, both Alk groups are methyl, and 5 is dimethyl malonate. In some embodiments, both Alk groups are ethyl, and 5 is diethyl malonate.

[0089] The reactants used in step 2 can be obtained by any method known to one of skill in the art, for example, from natural sources, commercially available, or synthesized using any route and starting materials.

[0090] LG in scheme 5 represents any leaving group known to those skilled in the art. In some embodiments, LG is selected from the list including, but not limited to, perfluoroalkylsulfonates such as triflate; sulfonates such as tosylate, mesylate; and fluoro; chloro; bromo; and iodo. In some embodiments, LG is selected from fluoro, chloro, bromo, iodo, triflate, tosylate and mesylate. In some embodiments, LG is chloro.

[0091] The reaction of step 2 between compound 4 and dialkyl malonate 5 can be carried out with any base commonly used by those skilled in the art for deprotection of dialkyl malonates. In some embodiments, the base is selected from the list including, but not limited to, alkoxide bases such as sodium methoxide, sodium ethoxide, sodium butoxide, sodium ethoxide in ethanol, sodium methoxide in methanol, and hydroxide bases such as sodium hydroxide base. In some embodiments, compound 5 is pretreated with a base prior to the addition of compound 4, while in other embodiments, compound 5, base and compound 4 are added simultaneously. In some embodiments, equimolar amounts of 5 and 4 are used. In other embodiments, an excess of 4 is used, for example 1.01-1.5 molar equivalents, for example 1.05-1.4 molar equivalents, for example 1.1-1.3 molar equivalents relative to the amount of 5. In yet another embodiment, an excess of 5 is used, for example 1.01-1.5 molar equivalents, 1.05-1.4 molar equivalents, 1.1-1.3 molar equivalents relative to the amount of 4.

[0092] Any solvent or combination of two or more solvents that are understood by those skilled in the art to be suitable for the reaction may be used. In some embodiments, the solvent is selected from the list including, but not limited to, methanol, ethanol, n-propanol, iso-propanol, tert-butanol, DMSO, DMF, THF, MTBE, toluene, or any combination thereof. In some embodiments, the solvent is ethanol. The solvent may be an anhydrous solvent.

[0093] In some embodiments, the reaction between 4 and 5 is carried out at ambient temperature. In other embodiments, the reaction is carried out at an elevated temperature, for example between 25° C. and the boiling point of the solvent, for example between 25° C. and 78° C., for example between 40° C. and 75° C., for example between 60° C. and 75° C., for example at 70° C. In some embodiments, the same reaction temperature is maintained during the course of the reaction. In other embodiments, the reaction temperature is changed and / or allowed to change during the course of the reaction. In some embodiments, the reaction mixture is quenched when analysis of the reaction mixture indicates that the reaction has proceeded to completion or when analysis of the reaction mixture indicates that the reaction has stopped. Any analytical method known to those skilled in the art, for example, a chromatographic method, for example, a thin layer chromatographic method, for example, HPLC, etc., can be used. In other embodiments, the reaction mixture is quenched after a set reaction time, for example, 10-70 hours, for example, 20-60 hours, for example, 30-50 hours, for example, 40-50 hours. In some embodiments, the reaction mixture is quenched, for example, at ambient temperature, for example, by addition of water.

[0094] The resulting diester intermediate 3' is then converted to the corresponding diacid compound 3.

[0095] In some embodiments, intermediate 3' is isolated prior to this transformation using standard techniques known to those of skill in the art, In preferred embodiments, intermediate 3' is not isolated.

[0096] In some embodiments, the conversion is accomplished by adding a base to compound 3', for example, by addition of an aqueous base. In some embodiments, the base is selected from the list including, but not limited to, sodium hydroxide, lithium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, barium hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the reagents are reacted until analysis of the reaction mixture indicates that the reaction has proceeded to completion or until analysis of the reaction mixture indicates that the reaction has stopped. Any analytical method known to those skilled in the art can be used, such as a chromatographic method, for example, a thin layer chromatographic method, for example, HPLC, etc. In other embodiments, the reaction mixture is quenched after a set reaction time.

[0097] The work-up of the reaction mixture may be carried out by any method commonly used by those skilled in the art, such as concentration under reduced pressure and redissolving, for example redissolving in water. In some embodiments, for example after concentration and redissolving in water, the mixture is extracted. In some embodiments, the resulting aqueous phase is added with an aqueous acid, such as HCl, until the product precipitates. In other embodiments, the aqueous phase is acidified and the product is extracted into the organic phase. In some embodiments, the product is washed. The solid product may be filtered and rinsed.

[0098] In a preferred embodiment of step 2, step 2 is carried out using diethyl or dimethyl malonate and an alkoxide base, and the diester intermediate 3' is not isolated prior to treatment with aqueous sodium hydroxide to give 3. LG can be chloro.

[0099] Process 1 In some embodiments, compound 4 is synthesized by treating compound 7 with a base and reacting it with a 1,3-substituted propane compound of the general formula LG-CH-CH-CH-LG' (6), as shown in Scheme 6, where LG and LG' represent any leaving group known to those skilled in the art. This step is referred to as step 1. In preferred embodiments, LG and LG' are different leaving groups with different leaving group capabilities. In other embodiments, LG and LG' are the same. TIFF0007655572000008.tif36108

[0100] The reactants used in step 1 can be obtained by any method known to one of skill in the art, for example, from natural sources, commercially available, or synthesized using any route and starting materials.

[0101] In some embodiments, LG and LG' are different or identical leaving groups selected from the list including, but not limited to, perfluoroalkylsulfonates such as triflate; sulfonates such as tosylate, mesylate; fluoro, chloro, bromo, and iodo. In some embodiments, LG and LG' are selected from fluoro, chloro, bromo, iodo, triflate, tosylate, and mesylate. In some embodiments, LG and LG' are both selected from chloro, bromo, and iodo. In a preferred embodiment, LG and LG' are chloro and bromo, respectively, and thus 6 is 1-bromo-3-chloropropane.

[0102] In some embodiments, the base is selected from the list including, but not limited to, sodium hydride (NaH), n-butyl lithium (n-BuLi), tert-butyl lithium (t-BuLi), lithium diisopropylamide (LDA), sodium amide (NaNH2), lithium bis(trimethylsilyl)amide (((CH3)3Si)2NLi). In some embodiments, the base is sodium hydride, such as sodium hydride in mineral oil. In some embodiments, compound 7 is pretreated with a base prior to the addition of compound 6, while in other embodiments, compound 7, base, and compound 6 are added simultaneously. In some embodiments, equimolar amounts of 7, base, and 6 are used. In other embodiments, an excess of base is used, such as 1.01 to 1.5 molar equivalents, such as 1.1 to 1.4 molar equivalents, such as 1.2 to 1.35 molar equivalents relative to the amount of 7. In some embodiments, an excess of 6 is used, for example, 1.01-1.8 molar equivalents, 1.2-1.7 molar equivalents, 1.4-1.6 molar equivalents relative to the amount of 7.

[0103] In some embodiments, particularly those for which one of skill in the art will recognize the need or advantage, anhydrous conditions are used.

[0104] Any solvent or combination of two or more solvents that are understood by those skilled in the art to be suitable for the reaction may be used. In some embodiments, the solvent is selected from the list including, but not limited to, THF, dichloromethane, N-methylpyrrolidone, MTBE, dioxane, 2-MeTHF, cyclopentyl methyl ether, DMSO, DMF, or any combination thereof. In a preferred embodiment, the solvent comprises DMSO. In some embodiments, the solvent is any mixture of THF and DMSO. The solvent may be an anhydrous solvent.

[0105] In some embodiments, the reaction is carried out at ambient temperature. In other embodiments, the reaction is carried out at a temperature below ambient temperature, for example between -78°C and -20°C. In other embodiments, the reaction is carried out at an elevated temperature, for example between 25°C and the boiling point of the solvent, for example between 25°C and 65°C, for example between 30°C and 60°C, for example between 40°C and 55°C, for example at 50°C. In some embodiments, the same reaction temperature is maintained during the course of the reaction. In other embodiments, the reaction temperature is changed and / or allowed to change during the course of the reaction. In some embodiments, the reaction mixture is quenched when analysis of the reaction mixture indicates that the reaction has proceeded to completion or when analysis of the reaction mixture indicates that the reaction has stopped. Any analytical method known to one of skill in the art can be used, for example, chromatographic methods, for example, thin layer chromatography, for example, HPLC, for example, GC, etc. In another embodiment, the reaction mixture is quenched after a set reaction time, such as from 2 to 50 hours, such as from 5 to 40 hours, such as from 10 to 25 hours, such as from 15 to 20 hours, such as from 15 to 30 hours.

[0106] In some embodiments, the reaction mixture is quenched, e.g., at ambient temperature, by the addition of an acid, e.g., by the addition of water, e.g., by the addition of an aqueous coumarin solution, e.g., by the addition of an aqueous weak acid, hi some embodiments, the reaction is selected from the list including, but not limited to, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydrochloric acid, perchloric acid, and chloric acid.

[0107] The work-up of the reaction mixture may be performed by any method commonly used by those skilled in the art, such as by quenching with an aqueous acid solution followed by separation of the two layers and / or by extraction of the organic phase. In some embodiments, the solvent is evaporated from the organic phase to obtain a crude product. In some embodiments, the organic phase or the crude product is purified, such as by any method commonly used by those skilled in the art. In some embodiments, the purification method is distillation. In some embodiments, the purification method is distillation under reduced pressure, such as at 0.1-50 mmHg, such as at 30-50 mmHg, such as at 30-40 mmHg, such as at 10-40 mmHg, such as at 0.1-20 mmHg, such as at 1-10 mmHg, such as at 2-3 mmHg.

[0108] In a preferred embodiment of step 1, LG and LG' are both halogens, the base is sodium hydride, and the solvent comprises DMSO. LG and LG' may be chloro and bromo, respectively.

[0109] In some embodiments, compound 1 is synthesized using step 3 using reactants (3 and 2) obtained in any manner known to one of skill in the art, for example, obtained from natural sources, commercially available, synthesized using any route and starting materials, etc. Preferably, step 3 is carried out by dropwise addition of compound 3 to CDI using MTBE as the solvent and a reaction temperature between 25° C. and 50° C., followed by addition of benzylamine 2.

[0110] In another embodiment, compound 1 is synthesized using steps 2 and 3 as illustrated in Scheme 7, using reactants (4 and 5) obtained in any manner known to one of skill in the art, for example, obtained from natural sources, commercially available, or synthesized using any route and starting materials. Preferably, step 2 is carried out using diethyl or dimethyl malonate and an alkoxide base, the diester intermediate 3' is not isolated prior to treatment with aqueous sodium hydroxide to give 3, and step 3 is carried out by dropwise addition of compound 3 to CDI using MTBE as the solvent and a reaction temperature between 25° C. and 50° C., followed by addition of benzylamine 2. TIFF0007655572000009.tif38151

[0111] In yet another embodiment, compound 1 is synthesized using steps 1, 2, and 3 as illustrated in Scheme 8. Preferably, in step 1, LG and LG' are both halogens, the base is sodium hydride, and the solvent comprises DMSO and THF; step 2 is carried out using diethyl or dimethyl malonate and an alkoxide base, and the diester intermediate 3' is not isolated prior to treatment with aqueous sodium hydroxide to give 3; and step 3 is carried out by dropwise addition of compound 3 to CDI using MTBE as the solvent and a reaction temperature between 25° C. and 50° C., followed by addition of benzylamine 2. TIFF0007655572000010.tif78151

[0112] In some embodiments, the present invention provides a synthetic route to capsaicins having an intact vanillyl ring of general formula 1V, as shown in Scheme 9. In some embodiments, compound 2 is vanillylamine, such as vanillylamine hydrochloride (2a). In some embodiments, only step 3 is performed. In other embodiments, steps 2 and 3 are performed. In still other embodiments, all of steps 1-3 are performed.

[0113] Preferably, in step 1 (if performed), LG and LG' are both halogens, the base is sodium hydride, and the solvent comprises DMSO and THF; step 2 (if performed) is performed using diethyl or dimethyl malonate and an alkoxide base, and the diester intermediate 3' is not isolated prior to treatment with aqueous sodium hydroxide to give 3; and step 3 is carried out by dropwise addition of compound 3 to CDI using MTBE as the solvent and a reaction temperature between 25° C. and 50° C., followed by addition of benzylamine 2. TIFF0007655572000011.tif123155

[0114] In some embodiments, the present invention provides a synthetic route to phenylcapsaicins of general formula 1P, as shown in Scheme 10. In such embodiments, compound 2 is vanillylamine, e.g., vanillylamine hydrochloride (2a), where the substituent Ar is a phenyl ring or a substituted phenyl ring as described above. In some embodiments, only step 3 is performed. In other embodiments, steps 2 and 3 are performed. In still other embodiments, all of steps 1-3 are performed. Preferably, in step 1 (if performed), LG and LG' are both halogens, the base is sodium hydride, and the solvent comprises DMSO and THF; and in step 2 (if performed), diethyl malonate or dimethyl malonate is used. and an alkoxide base, the diester intermediate 3' is not isolated prior to treatment with aqueous sodium hydroxide to give 3; and step 3 is carried out by dropwise addition of compound 3 to CDI using MTBE as the solvent and a reaction temperature between 25° C. and 50° C., followed by addition of benzylamine 2. TIFF0007655572000012.tif124155

[0115] In specific embodiments, the present invention provides a synthetic route to phenylcapsaicin (1a), as shown in Scheme 11. In such embodiments, compound 2 is vanillylamine hydrochloride 2a, where the substituent Ph is an unsubstituted phenyl ring. In some embodiments, only step 3 is performed. In other embodiments, steps 2 and 3 are performed. In yet other embodiments, all of steps 1-3 are performed.

[0116] Preferably, in step 1 (if performed), LG and LG' are both halogens, the base is sodium hydride, and the solvent comprises DMSO and THF; step 2 (if performed) is performed using diethyl or dimethyl malonate and an alkoxide base, and the diester intermediate 3' is not isolated prior to treatment with aqueous sodium hydroxide to give 3; and step 3 is carried out by dropwise addition of compound 3 to CDI using MTBE as the solvent and a reaction temperature between 25° C. and 50° C., followed by addition of benzylamine 2. TIFF0007655572000013.tif115155

[0117] Crystallization All capsaicin derivatives synthesized according to the present invention can be purified after their synthesis. In some embodiments, the capsaicin derivative is a solid compound. In such embodiments, the capsaicin derivative may be crystallized. In some embodiments, phenylcapsaicin (1a) is crystallized by adding water to a MTBE solution of 1a, such as a solution of 1a obtained directly from step 3, optionally after washing the organic phase with water. The concentration of the solution can be 0.05-1 g / mL, such as 0.05-0.5 g / mL, such as 1-0.4 g / mL, such as 0.5-1 g / mL, such as 0.7-0.9 g / mL. The crystallization is carried out by adding 0.25-1 volume of water relative to the volume of the solvent, such as 0.3-0.8, such as 0.4-0.7 volume of water relative to the volume of the solvent, and stirring for 2-24 hours, such as overnight, such as 3-6 hours, such as 5 hours, while cooling the temperature to a range of -5-5°C, to obtain crystals of 1a. The crystals may be isolated, for example, by filtration, optionally rinsed with MTBE, and dried, for example air-dried.

[0118] In a specific embodiment, 1a is crystallized by adding water to a solution of 1a obtained directly from step 3 after washing the organic phase with water, by adding water and stirring for 5 hours while cooling the temperature to the range of −5° C. to 5° C. It is clear to one skilled in the art that the crystallization method described for 1a or similar methods can also be used for other capsaicin derivatives.

[0119] The present invention is not limited to the embodiments and examples shown. While various embodiments of the present disclosure have been described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications and changes to the embodiments described herein, as well as variations and substitutions of the embodiments, will be apparent to those skilled in the art without departing from the scope of the present invention. It is understood that various alternatives to the embodiments described herein may be employed in carrying out the disclosure. Moreover, the appended claims are intended to cover such modifications and variations that fall within the true scope of the present invention.

[0120] All embodiments of the present disclosure may be combined in any manner with any one or more of the other embodiments described herein.

[0121] It should be understood that each component, compound, or parameter disclosed herein should be construed as disclosed for use alone or in combination with one or more of any and all components, compounds, or parameters disclosed herein. Furthermore, each amount / value or amount / value range for each component, compound, or parameter described herein should also be construed as disclosed in combination with each amount / value or amount / value range disclosed for any other component(s), compound(s), or parameter(s) disclosed herein, and any combination of amount / values ​​or amount / value ranges for two or more components, compounds, or parameters disclosed herein should therefore be understood to be disclosed in combination with each other for purposes of this specification. Any or all features described herein are not mutually exclusive.

[0122] It should be understood that each lower limit of each range disclosed herein should be interpreted as being disclosed in combination with each upper limit of each range disclosed herein for the same component, compound, or parameter. Thus, a disclosure of two ranges should be interpreted as a disclosure of four ranges derived by combining each lower limit of each range with each upper limit of each range. A disclosure of three ranges should be interpreted as a disclosure of nine ranges derived by combining each lower limit of each range with each upper limit of each range, etc. Furthermore, a specific amount / value of a component, compound, or parameter disclosed in the specification or in the examples should be interpreted as a disclosure of either a lower or upper limit of a range, and thus can be combined with any other lower or upper limit or range or specific amount / value for the same component, compound, or parameter disclosed elsewhere in this application to form a range for that component, compound, or parameter. EXAMPLES

[0123] Phenylcapsaicin (1a) was synthesized according to the route shown in Scheme 12. The reaction was monitored by HPLC on a reversed-phase (Phenomenex phenyl-C6) column using 80% methanol at pH 2 (0.1% TFA) as the mobile phase at 1.5 ml / min and analyzed at 240 nm. The products were identified by MS and / or NMR analysis. TIFF0007655572000014.tif164126

[0124] Example 1. Preparation of (5-chloropent-1-yn-1-yl)benzene (4a) (Step 1) Sodium hydride (60% in mineral oil) (50 g, 1.25 mol) was suspended in THF (960 mL) and phenylacetylene (7a) (98 g, 0.96 mol), DMSO (150 g, 1.92 mol) was added, followed by 1-bromo-3-chloropropane (6a) (227 g, 1.44 mmol), and the resulting mixture was heated at 50 °C for 20 h. After the reaction, the mixture was cooled and quenched with 500 mL of 0.5 M HCl (aq), whereupon stirring was stopped and the two layers were separated. 260 mL of heptane was added to the organic phase, and the resulting mixture was extracted with 350 mL of water. The solvent was evaporated from the resulting organic phase to give 266 g of crude product. The crude product was purified by distillation under reduced pressure (2-3 mmHg) to separate the first fraction boiling at 30-40 °C, which contained the excess starting material. The main fraction boiling at 90-100 °C contained the product and a small amount of compound 4a-1, which has a boiling point slightly lower than 3. It is therefore difficult to remove and its presence is tolerated since it does not react in later steps and is completely removed after hydrolysis. The yield of 4a was 146 g (85%) with 1.5% of 4a-1 (by HPLC area) after distillation. 1 H NMR(DMSO-d6) δ 7.43-7.38 (m, 2H), 7.35-7.32 (m, 3H), 3.76 (t, 2H, J=6.4 Hz), 2.58 (t, 2H, J=7.0 Hz), 1.98 (p, 2H, J=6.7 Hz); 13 C NMR(CDCl3) δ 131.2, 128.4, 127.9, 123.0, 88.7, 81.1, 44.1, 31.0, 16,2.

[0125] Example 2. Preparation of 2-(5-phenylpent-4-yn-1-yl)malonic acid (3a) (Step 2) Compound 3a was synthesized via intermediate 3'a (shown in Scheme 13 containing only ethyl groups, but which contains a combination of ethyl and methyl groups by transesterification), which was not isolated.

[0126] Diethyl malonate (5a) (184 g, 1.15 mol) and 4a (137 g, 0.767 mol) were dissolved in ethanol (430 mL) whereupon sodium methoxylate (203 g 25% solution in methanol, 0.939 mol) was added. The mixture was heated at 70° C. for 48 h. After cooling, the mixture was quenched with 290 mL water and 333 g 28% (aqueous) sodium hydroxide solution was added and the reaction mixture was stirred at 30° C. until HPLC analysis showed complete conversion of the ester to the malonic acid derivative 3a.

[0127] The reaction mixture was concentrated under vacuum to a semi-crystalline mass and dissolved in 550 mL of water. The mixture was extracted with two 300 mL portions of methyl tert-butyl ether. 365 g of 30% HCl was slowly added to the resulting aqueous phase, whereupon the product precipitated. After stirring at 25° C. for 2 h, the product was filtered and rinsed with 70 mL of heptane, followed by 70 mL of water. The resulting product, 3a, was air-dried to give 164 g of light brown crystals (87% yield). 1 H NMR(DMSO-d6) δ 7.38-7.34 (m, 2H), 7.33-7.28 (m, 3H), 3.31 (t, 1H, J=7.6 Hz), 2.43 (t, 2H, J=6.9 Hz), 1.90-1.84 (m, 2H), 1.59-1.51 (m, 2H); 13 C NMR(DMSO-d6) δ 171.1, 131.4, 128.7, 128.1, 123.4, 90.3, 81.0, 51.4, 28.0, 26.3, 18.7. HRMS(ESI) calculated for C14H15O4+ [M+H]+ 247.0970, found 247.0968.

[0128] Example 3. Preparation of phenylcapsaicin (1a) (Step 3) Malonic acid 3a (130 g, 0.528 mol) was dissolved in 375 mL MTBE and added dropwise to a suspension of carbonyldiimidazole (103 g, 0.635 mol) in 375 mL MTBE under gas evolution, the resulting mixture was stirred at 25 °C for 30 min and finally heated to 40 °C for 1 h to complete the reaction. Vanillylamine hydrochloride (2a) (120 g, 0.633 mol) was added to the mixture and stirring was continued at 45 °C for 20 h, immediately after which 500 mL of water was added and the mixture was stirred at 40 °C until two clean phases were formed. The lower aqueous layer was separated and the organic phase was extracted again with 500 mL of water at 40 °C. After separation, 300 mL of water was added followed by 15 mL of HCl (30% in water) and the layers were separated.

[0129] Example 4. Crystallization of phenylcapsaicin (1a) To the organic phase from Example 3, 300 mL of water was added again and the mixture was stirred for 5 h with cooling at 3° C. to give the precipitated product. The crystals were isolated by filtration, rinsed on the filter with 130 mL of cold MTBE, and air-dried to give 1a as a white crystalline material. The resulting solid was dissolved in 375 mL of MTBE whereupon the solvent was evaporated to give 145 g (81% yield) of 1a as a light brown syrup. 1 H NMR(DMSO-d6) δ 8.87 (s, 1H), 8.26 (t, 1H, J=5.7 Hz), 7.40-7.36 (m, 2H), 7.35-7.31 (m, 3H), 6.83 (d, 1H, J=1.7 Hz), 6.73 (d, 1H, J=7.9 Hz), 6.67 (dd, 1H, J=7.9, 1.7 Hz), 4.19 (d, 2H, J=5.7 Hz), 3.73 (s, 3H), 2.43 (t, 2H, J=7.0 Hz), 2.20 (t, 2H, J=7.2 Hz), 1.74-1.66 (m, 2H), 1.59-1.51 (m, 2H); 13C NMR(DMSO-d6) δ 172.0, 147.5, 145.5, 131.3, 130.6, 128.6, 128.0, 123.4, 119.8, 115.3, 111.6, 90.5, 80.8, 55.5, 42.0, 35.0, 27.9, 24.8, 18.5.HRMS(ESI)C 12 H 24 No.3 + [M+H] + The theoretical value is 338.1756, and the actual value is 338.1759.

[0130] Capsaicins 1b and 1c were synthesized according to the route shown in Scheme 13. The products were identified by MS and / or NMR analysis. TIFF0007655572000015.tif202157

[0131] Example 5. Preparation of 7-chloro-2,2-dimethyl-3-heptyne (4b) (Step 1) 3,3-Dimethyl-1-butyne (7b) (3 g, 36.5 mmol) was dissolved in 27 mL of anhydrous THF and the resulting mixture was cooled to -15 °C. Butyllithium 1.6 M in hexane (22.83 mL, 36.5 mmol) was added dropwise over 40 min whereupon the mixture was brought to 20 °C for 2 h. 1-Chloro-3-iodopropane (6b) (6.35 g, 31.0 mmol) was added and the mixture was stirred at 20 °C for 3 days whereupon 21 mL of water was added. The lower aqueous phase was removed and a mixture of 10 mL of water and 1 mL of 25% HCl was added to the organic phase. The lower aqueous phase was removed and the solvent was evaporated from the organic phase under reduced pressure to give a yellow oil (4b) (4.68 g, 29.5 mmol) in 95% yield. 1 H NMR(CDCl3) δ 3.63 (t, 2H, J=6.5 Hz), 2.31 (t, 2H, J=6.8 Hz), 1.91 (p, 2H, J=6.6 Hz), 1.18 (s, 9H); 13 C NMR(CDCl3) δ 90.1, 76.3, 43.8, 31.9, 31.3, 27.3, 16.2.

[0132] Example 6. (3b) Preparation of (6,6-dimethyl-4-heptynyl)malonic acid (Step 2) 7-Chloro-2,2-dimethyl-3-heptyne (4b) (4.12 g, 26.0 mmol), diethyl malonate (5a) (6.24 g, 38.9 mmol), ethanol (12.6 ml) and 25% sodium methanolate (7.01 g, 32.5 mmol) were mixed. The mixture was heated at 70° C. for 3 days. After cooling, the mixture was quenched with 5.7 mL of water, 11.95 g of 28% (aqueous) sodium hydroxide solution was added and the reaction mixture was stirred at 30° C. for 24 hours. The reaction mixture was concentrated under vacuum to a semi-crystalline mass and redissolved in 16 mL of water. The mixture was extracted twice with 10 mL portions of toluene. 16 g of 25% HCl was added to the resulting aqueous phase and the resulting mixture was extracted twice with 25 mL portions of MTBE. The MTBE portions were combined and the solvent was evaporated under reduced pressure to give an off-white solid (3b) (5.26 g, 23.3 mmol) in 90% yield. 1 H NMR(DMSO-d6) δ 3.21 (t, 1H, J=7.3 Hz), 2.09 (t, 2H, J=7.2 Hz), 1.78-1.72 (m, 2H), 1.41-1.34 (m, 2H), 1.12 (s, 9H); 13 C NMR(DMSO-d6) δ 171.2, 89.6, 78.4, 51.6, 31.6, 28.1, 27.4, 26.8, 18.2. HRMS(ESI) C 12 H 17 O4 - [MH] - Theoretical value for is 225.1127, theoretical value is 225.1126.

[0133] Example 7. (1b) Preparation of N-[(4-hydroxy-3-methoxyphenyl)methyl]-8,8-dimethyl-6-nonyneamine (Step 3) (6,6-Dimethyl-4-heptynyl)malonic acid (3b) (1.0 g, 4.4 mmol) was dissolved in 5 mL of MTBE and added dropwise to a suspension of carbonyldiimidazole (0.86 g, 5.3 mmol) in 5 mL of MTBE under gas evolution, and the resulting mixture was heated at 40 °C for 1 h. The resulting solution was added to a suspension of vanillylamine hydrochloride (2a) (1.01 g, 5.3 mmol) and stirring was continued at 50 °C for 22 h, immediately after which 10 mL of water was added and the mixture was stirred at 40 °C until two clean phases were formed. The lower aqueous layer was separated and the organic phase was washed with a mixture of 10 mL of water and 1 mL of 25% HCl. The organic phase was extracted with a solution of 0.26 g of sodium hydroxide and 10 mL of water, followed by washing with a further 5 mL of water. The two aqueous phases were combined and 0.6 mL of 37% HCl (aq) and 10 mL of MTBE were added. The resulting aqueous phase was removed and the organic phase was washed with 5 mL of water. The solvent was removed from the organic phase under reduced pressure to give a yellow oil (1b) (0.70 g, 2.2 mmol) in 50% yield. 1 H NMR(CDCl3) δ 6.86 (d, 1H, J=8.0 Hz), 6.79 (d, 1H, J=2.0 Hz), 6.74 (dd, 1H, J=8.0, 2.0 Hz), 4.34 (d, 2H, J=5.6 Hz), 3.86 (s, 3H), 2.22 (t, 2H, J=7.5 Hz), 2.15 (t, 2H, J=7.1 Hz), 1.77-1.70 (m, 2H), 1.54-1.46 (m, 2H), 1.16 (s, 9H); 13 C NMR(CDCl3) δ 172.7, 146.7, 145.1, 130.2, 120.8, 114.4, 110.7, 89.4, 77.8, 55.9, 43.6, 36.2, 31.4, 28.6, 27.3, 24.9, 18.4. HRMS(ESI) C 19 H 28 No.3 + [M+H] + The theoretical value is 318.2069, and the measured value is 318.2068.

[0134] Example 8. Preparation of 5-chloro-1-cyclohexyl-1-pentyne (4c) (Step 1) Cyclohexylacetylene (7c) (2.46 g, 22.7 mmol) was dissolved in 22 mL of anhydrous THF and the resulting mixture was cooled to -15 °C. Butyllithium 1.6 M in hexane (14.19 mL, 22.7 mmol) was added dropwise over 30 min whereupon the mixture was brought to 20 °C for 2 h. 1-Chloro-3-iodopropane (6b) (3.95 g, 19.3 mmol) was added and the mixture was stirred at 20 °C for 3 days whereupon 17 mL of water was added. The lower aqueous phase was removed and a mixture of 10 mL of water and 1 mL of 25% HCl was added to the organic phase. The lower aqueous phase was removed and the solvent was evaporated from the organic phase under reduced pressure to give a yellow oil (4c) (3.35 g, 18.2 mmol) in 94% yield. 1 H NMR(CDCl3) δ 3.63 (t, 2H, J=6.5 Hz), 2.35-2.27 (m, 3H), 1.91 (p, 2H, J=6.6 Hz), 1.78-1.72 (m, 2H), 1.70-1.62 (m, 2H), 1.51-1.47 (m, 1H), 1.41-1.33 (m, 2H), 1.32-1.23 (m, 3H); 13 C NMR(CDCl3) δ 85.7, 77.8, 43.8, 33.1, 31.9, 29.1, 25.9, 24.9, 16.2.

[0135] Example 9. Preparation of (5-cyclohexyl-4-pentynyl)malonic acid (3c) (Step 2) 5-Chloro-1-cyclohexyl-1-pentyne (4c) (1.97 g, 10.7 mmol), diethyl malonate (5a) (2.56 g, 16.0 mmol), ethanol (6.0 ml) and 25% sodium methanolate (2.88 g, 13.3 mmol) were mixed. The mixture was heated at 70° C. for 2 days. After cooling, the mixture was quenched with 2.7 mL of water, 4.77 g of 28% (aqueous) sodium hydroxide solution was added and the reaction mixture was stirred at 30° C. for 24 hours. The reaction mixture was concentrated under vacuum to a semi-crystalline mass and redissolved in 40 mL of water. The mixture was extracted twice with 25 mL portions of toluene. 6.5 g of 25% HCl was added to the resulting aqueous phase and the resulting mixture was extracted twice with 25 mL portions of MTBE. The MTBE portions were combined and the solvent was evaporated under reduced pressure to give an off-white solid (3c) (2.01 g, 8.0 mmol) in 75% yield. 1 H NMR(CDCl3) δ 3.48 (t, 1H, J=7.4 Hz), 2.33-2.28 (1H, m), 2.23 (dt, 2H, J=6.9, 2.2 Hz), 2.09-2.03 (m; 2H), 1.79-1.73 (m, 2H), 1.70-1.64 (m, 2H), 1.62-1.55 (m, 2H), 1.52-1.46 (m, 1H), 1.42-1.34 (m, 2H), 1.30-1.24 (m, 3H). 13 C NMR(CDCl3) δ 174.6, 85.7, 78.5, 51.1, 33.0, 29.1, 27.8, 26.6, 25.9, 24.9, 18.4. HRMS(ESI) C 14 H 19 O4 - [MH] - The theoretical value is 251.1283 and the actual value is 251.1286.

[0136] Example 10. Preparation of N-[(4-hydroxy-3-methoxyphenyl)methyl]-7-cyclohexyl-6-heptynamide (1c) (Step 3) (5-Cyclohexyl-4-pentynyl)malonic acid (3c) (1.0 g, 4.0 mmol) was dissolved in 5 mL of MTBE and added dropwise to a suspension of carbonyldiimidazole (0.77 g, 4.8 mmol) in 5 mL of MTBE under gas evolution, and the resulting mixture was heated at 40 °C for 1 h. The resulting solution was added to a suspension of vanillylamine hydrochloride (2a) (0.90 g, 4.8 mmol) and stirring was continued at 50 °C for 22 h, whereupon 10 mL of water was added and the mixture was stirred at 40 °C until two clean phases were formed. The lower aqueous layer was separated and the organic phase was washed with a mixture of 10 mL of water and 0.5 mL of 25% HCl. The organic phase was extracted with a solution of 0.19 g of sodium hydroxide and 10 mL of water, followed by washing with a further 5 mL of water. The two aqueous phases were combined and 0.43 mL of 37% HCl (aq) and 10 mL of MTBE were added. The resulting aqueous phase was removed and the organic phase was washed with 5 mL of water. The solvent was removed from the organic phase under reduced pressure to give a yellow oil (1c) (0.68 g, 2.0 mmol) in 50% yield. 1 H NMR(CDCl3) δ 6.84 (d, 1H, J=8.0 Hz), 6.79 (d, 1H, J=2.0 Hz), 6.74 (dd, 1H, J=8.0, 2.0 Hz), 4.34 (d, 2H, J=5.5 Hz), 3.86 (s, 3H), 2.26-2.15 (m, 5H), 1.78-1.62 (m, 6H), 1.55-1.47 (m, 3H), 1.36-1.21 (m, 5H); 13 C NMR(CDCl3) δ 172.7, 146.7, 145.1, 130.2, 120.8, 114.4, 110.7, 85.2, 79.3, 55.9, 43.5, 36.2, 33.1, 29.1, 28.6, 25.9, 25.0, 24.9, 18.5. HRMS(ESI) C 21 H 30 No.3 + [M+H] + Theoretical value is 344.2226, measured value is 344.2226.

[0137] Explanation example Illustrative Example: Preparation of IN-(4-hydroxy-3-methoxy)-nondec-6-ynamide Sodium hydride (60% in mineral oil) is suspended in THF and dodecylacetylene, DMSO is added, followed by 1-bromo-3-chloropropane (6a), and the resulting mixture is heated at 50° C. for 20 hours. After the reaction, the mixture is cooled and quenched with 0.5 M HCl (aq), whereupon stirring is stopped and the two layers are separated. Heptane is added to the organic phase, and the resulting mixture is extracted with water. The solvent from the resulting organic phase is evaporated to obtain the crude product. The crude product is purified by short path distillation under reduced pressure.

[0138] The isolated intermediate and diethyl malonate (5a) are dissolved in ethanol whereupon sodium methoxide (25% solution in methanol) is added. The mixture is heated at 70° C. for 48 h. After cooling, the mixture is quenched with water, 28% (aqueous) sodium hydroxide solution is added, and the reaction mixture is stirred at 30° C. until HPLC analysis indicates complete conversion of the ester to the malonic acid derivative 3. The reaction mixture is concentrated under vacuum to a semi-crystalline mass and redissolved in water. The mixture is extracted twice with toluene. 30% HCl is slowly added to the resulting aqueous phase whereupon the product precipitates. After stirring for 2 h at 25° C., the product is filtered and rinsed with heptane and water. The resulting malonic acid intermediate is air-dried.

[0139] The malonic acid intermediate is dissolved in MTBE and added dropwise to a suspension of carbonyldiimidazole in MTBE, stirred at 25°C for 30 minutes, and finally heated at 40°C for 1 hour to complete the reaction. Vanillylamine hydrochloride is added to the mixture and stirring is continued at 45°C for 20 hours, whereupon water is added and the mixture is stirred at 40°C until two phases are formed. The lower aqueous layer is separated and the organic phase is extracted again with water at 40°C. After separation, 300 mL of water is added, followed by 15 mL of HCl (30% aqueous solution) and the layers are separated. 300 mL of water is added to the resulting organic phase and the layers are separated. 20 g of magnesium sulfate is added to the resulting organic phase. The mixture is stirred, filtered and the solvent is evaporated from the resulting filtrate to give N-(4-dodecylbenzyl)-7-phenylhept-6-ynamine.

[0140] Illustrative Example II. Preparation of N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-ynamine Sodium hydride (60% in mineral oil) is suspended in THF and 3-methyl-1-butyne, DMSO is added, followed by 1-bromo-3-chloropropane (6a), and the resulting mixture is heated at 50° C. for 20 hours. After the reaction, the mixture is cooled and quenched with 0.5 M HCl (aq), whereupon stirring is stopped and the two layers are separated. Heptane is added to the organic phase, and the resulting mixture is extracted with water. The solvent from the resulting organic phase is evaporated to obtain the crude product. The crude product is purified by distillation under reduced pressure.

[0141] The isolated intermediate and diethyl malonate (5a) are dissolved in ethanol whereupon sodium methoxide (25% solution in methanol) is added. The mixture is heated at 70° C. for 48 h. After cooling, the mixture is quenched with water, 28% (aqueous) sodium hydroxide solution is added, and the reaction mixture is stirred at 30° C. until HPLC analysis indicates complete conversion of the ester to the malonic acid derivative 3. The reaction mixture is concentrated under vacuum to a semi-crystalline mass and redissolved in water. The mixture is extracted twice with toluene. 30% HCl is slowly added to the resulting aqueous phase whereupon the product precipitates. After stirring for 2 h at 25° C., the product is filtered and rinsed with heptane and water. The resulting malonic acid intermediate is air-dried.

[0142] The malonic acid intermediate is dissolved in MTBE and added dropwise to a suspension of carbonyldiimidazole in MTBE, stirred at 25°C for 30 minutes, and finally heated at 40°C for 1 hour to complete the reaction. Vanillylamine hydrochloride is added to the mixture and stirring is continued at 45°C for 20 hours, whereupon water is added and the mixture is stirred at 40°C until two phases are formed. The lower aqueous layer is separated and the organic phase is extracted again with water at 40°C. After separation, 300 mL of water is added, followed by 15 mL of HCl (30% aqueous solution) and the layers are separated. 300 mL of water is added to the resulting organic phase and the layers are separated. 20 g of magnesium sulfate is added to the resulting organic phase. The mixture is stirred, filtered and the solvent is evaporated from the resulting filtrate to give N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-ynamine.

[0143] Illustrative Example III. Preparation of N-(3-fluoro-4-methoxybenzyl)-7-phenylhept-6-ynamine Sodium hydride (60% in mineral oil) is suspended in THF and phenylacetylene, DMSO is added, followed by 1-bromo-3-chloropropane (6a), and the resulting mixture is heated at 50° C. for 20 hours. After the reaction, the mixture is cooled and quenched with 0.5 M HCl (aq), whereupon stirring is stopped and the two layers are separated. Heptane is added to the organic phase, and the resulting mixture is extracted with water. The solvent from the resulting organic phase is evaporated to obtain the crude product. The crude product is purified by distillation under reduced pressure.

[0144] The isolated intermediate and diethyl malonate (5a) are dissolved in ethanol whereupon sodium methoxide (25% solution in methanol) is added. The mixture is heated at 70° C. for 48 h. After cooling, the mixture is quenched with water, 28% (aqueous) sodium hydroxide solution is added, and the reaction mixture is stirred at 30° C. until HPLC analysis indicates complete conversion of the ester to the malonic acid derivative 3. The reaction mixture is concentrated under vacuum to a semi-crystalline mass and redissolved in water. The mixture is extracted twice with toluene. 30% HCl is slowly added to the resulting aqueous phase whereupon the product precipitates. After stirring for 2 h at 25° C., the product is filtered and rinsed with heptane and water. The resulting malonic acid intermediate is air-dried.

[0145] The malonic acid intermediate is dissolved in MTBE and added dropwise to a suspension of carbonyldiimidazole in MTBE, stirred at 25° C. for 30 minutes, and finally heated at 40° C. for 1 hour to complete the reaction. 3-Fluoro-4-methoxybenzylamine is added to the mixture and stirring is continued at 45° C. for 20 hours, whereupon water is added and the mixture is stirred at 40° C. until two phases are formed. The lower aqueous layer is separated and the organic phase is extracted again with water at 40° C. After separation, 300 mL of water is added, followed by 15 mL of HCl (30% aqueous solution) and the layers are separated. 300 mL of water is added to the resulting organic phase and the layers are separated. 20 g of magnesium sulfate is added to the resulting organic phase. The mixture is stirred, filtered and the solvent is evaporated from the resulting filtrate to give N-(3-fluoro-4-methoxybenzyl)-7-phenylhept-6-ynamine.

Claims

1. General formula 1: 【Chemistry 1】 (In the formula, R is C 1 -C 18 linear or branched alkyl of C2-C18, linear or branched alkenyl of C2-C18, linear or branched alkynyl of C2-C18, trifluoromethyl, 3 -C 12 Cycloalkyl, phenoxy, phenylthio, fluoro, chloro, bromo, iodo, phenyl, and substituted phenyl, where the substituted phenyl is fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, C 1 -C 6 linear or branched alkoxy, -(S=O)-C 1 -C 6 Alkyl, -S-C 1 -C6 alkyl, C 1 -C 6 linear or branched alkyl of C 2 -C 6 linear or branched alkenyl of C 2 -C 6 straight or branched chain alkynyl of C 1 -C 6 fluoroalkyl, C 1 -C 6 chloroalkyl, C 1 -C 6 bromoalkyl, C 1 -C 6 iodoalkyl, COO—C 1 -C 6 Alkyl, CONH(C 1 -C 6 alkyl), and CON(C 1 -C 6 Alkyl) 2 and R′ is fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, nitro, trifluoromethyl, C 1 -C 6 linear or branched alkoxy, -(S=O)-C 1 -C 6 Alkyl, -S-C 1 -C6 alkyl, C 1 -C 6 linear or branched alkyl of C 2 -C 6 linear or branched alkenyl of C 2 -C 6 straight or branched chain alkynyl of C 1 -C 6 fluoroalkyl, C 1 -C 6 chloroalkyl, C 1 -C 6 bromoalkyl, C 1 -C 6 iodoalkyl, COOH, CONH 2 , -NHCO(C 1 -C 6 alkyl), COO-C 1 -C 6 Alkyl, CONH(C 1 -C 6 alkyl), and CON(C 1 -C 6 Alkyl) 2 represents 0 to 5 identical or different substituents selected from the group comprising:

2. A method for producing a 6-heptyne derivative of capsaicin comprising the steps of: coupling a compound of general formula 3 with a benzylamine of general formula 2 or any suitable salt thereof, using 1,1'-carbonyldiimidazole (CDI), where R and R' for general formulas 2 and 3 are defined as for formula 1; 【Chemistry 2】 The method includes:

2. 2. The method of claim 1, wherein R' represents 0 to 5 of the same or different substituents selected from the group including hydroxy, methoxy, fluoro, chloro, bromo, and iodo at any one or more positions.

3. R is C 1 -C 18 3. The method of claim 1 or 2, wherein the alkyl group is selected from the group consisting of C2-C18 straight or branched chain alkyl, C2-C18 straight or branched chain alkenyl, C2-C18 straight or branched chain alkynyl, phenyl, and substituted phenyl.

4. R is fluoro, chloro, bromo, iodo, C 1 -C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl, and C 1 -C 6 The method according to any one of claims 1 to 3, wherein the substituted phenyl is substituted at any one or more positions with 1 to 5 identical or different substituents selected from the group comprising straight or branched chain alkoxy.

5. The method of claim 4 , wherein the substituted phenyl is mono-, di-, or tri-substituted.

6. Prior to the process of claim 1, reacting a compound of general formula 4 with an alkyl malonate of general formula 5, where R for general formula 4 is defined as for formula 3, to produce said compound of general formula 3. 【Chemistry 3】 (wherein "Alk" is a linear, branched, or cyclic C 1 -C 6 represents an alkyl group; and "LG" represents any leaving group known to those of skill in the art. The method of any one of claims 1 to 5, further comprising:

7. The method of claim 6, wherein LG represents chloro.

8. Before the step of claim 6, reacting an ethynyl compound of general formula 7 with a 1,3-substituted propane compound of general formula 6 (wherein for general formulas 6 and 7, LG and R are defined as for formula 4) to produce said compound of general formula 4. 【Chemistry 4】 where "LG" and "LG'" are different or the same leaving groups selected from the list including perfluoroalkylsulfonate, sulfonate, fluoro, chloro, bromo, and iodo. The method of claim 6, further comprising:

9. 9. The method of claim 8, wherein LG and LG' are both selected from the list comprising chloro, bromo, and iodo; triflate; tosylate and mesylate.

10. The 6-heptyne derivatives of capsaicin have the general formula 1V: 【Chemistry 5】 The method according to any one of claims 1 to 9, wherein the compound is

11. The 6-heptyne derivatives of capsaicin have the general formula 1P: 【Chemistry 6】 wherein Ar is phenyl or substituted phenyl as defined in any of claims 1, 4, or 5. The method according to any one of claims 1 to 9, wherein the compound is

12. The method according to any one of claims 1 to 3 and 6 to 11, wherein the 6-heptyne derivative of capsaicin is phenylcapsaicin (1a). 【Chemistry 7】

13. The method of claim 12, wherein the following route is used: 【Chemistry 8】

14. 14. The process of claim 12 or 13, further comprising the step of crystallizing 1a by adding 0.25 to 1 volume of water to volume of solvent to a 0.05 to 1 g / mL solution of 1a in MTBE and stirring at a temperature ranging from -5°C to 5°C for 2 to 24 hours.

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