WO2018018113A1

WO2018018113A1 - Method for producing spilanthol and analogues, thus produced spilanthol and analogues

Info

Publication number: WO2018018113A1
Application number: PCT/BR2017/000085
Authority: WO
Inventors: Julio Cesar PASTRE; Isabella Gonçalves ALONSO
Original assignee: Universidade Estadual De Campinas - Unicamp
Priority date: 2016-07-29
Filing date: 2017-07-28
Publication date: 2018-02-01
Also published as: BR102016017871A2; BR102016017871B1

Abstract

The present invention relates to methods for producing spilanthol and spilanthol analogues, as well as the resultant spilanthol 1 and analogues thereof. Spilanthol and spilanthol analogues according to the present invention exhibit high purity, besides being produced by a method with a reduced number of steps.

Description

OBSCRIPTION PROCESS OF SPILANTOL AND ANALOGS, SPILANTOL AND

LQGQS OBTAINED

Field of Invention

[1] The invention described herein is in the field of chemistry / chemical engineering, particularly applied to the field of organic synthesis, and describes processes for obtaining spilanthol as well as spilanthol thus obtained.

± nw Fundamentals:

[2] Spilanthes acmella is a plant in South America, mainly in northern Brazil, commonly known as jarabu. The extract of this plant is widely used in the treatment of toothaches and throat and is also used in cooking _*

[3] Spilanthol - N-isobutyl-2E, 6Z, SE-decatrenamide has the structural formula (1) below and is an alkylamide present in Spilanthes acmella and some other trees around the world and is primarily responsible for its effects. biological activities.

Formula (1}

[4] Most studies on the evaluation of spilanthol biological activities known by the state of the art were carried out with the crude extract of the plants containing it, with the most commonly reported activities being analgesic, antinociceptive, antioxidant, anti-inflammatory, antifungal, alarial, bacteriostatic and larvicidal against mosquitoes such as aedes aegypti.

[5] Spilanthes acmella extract is also used. in the cosmetics and food industry. Despite being the major constituent, other compounds present may generate responses that are not necessarily due to spilanthol.

[6] In 1903 _/ Gerber, E. (Arch. Pharm. Einhei Í). 1903, 241, 270) named spilanthol as the main component of the crude extract of Spilanthes Olereceae. In 1927, Asano and Kanemat.su (J. Pharm. Soc. Japan 1927, 47, 521-525) isolated spilanthol for the first time from the species Spilanthes Acmella. In 1963 Crombie et al. (J. Chem. Soc. 1963, Mo. 949, 4970-4976) first synthesized (2E, 6.Ζ ·, BE.) ^••• N-isobutyl-decatrienamidâ and proved the structure of spilanthol.

[7] Because it is used in a variety of areas and is very difficult to insulate, this compound has a high value.

[8] Thus, organic synthesis provides a good alternative for producing spilanthol more cheaply and also for exploiting the biological activities of its analogues.

State of the Art:

[9] Some prior art documents had described obtaining spilanthol and its analogues. However, none of them resemble the invention proposed herein.

[10] In addition to the synthesis proposed by Crombie et al. , other obtaining processes have been described in the state of the art, but have low overall yields or large number of steps, and do not describe purity of the formed compound and whether other isomers were obtained.

[11] Most recently, a series of patent applications on obtaining spilanthol was filed by Takasago International Corporation, namely WO 2009/091040., US2010 / 0184863, US2011 / 0105773, WO2011 / 007807 and

U32012 / Q116116.

[12] The synthetic route described in US2012 / D116116 leads to nine-step spilanthol yielding 30% overall yield, yielding a product of 96.8% purity. However, this product is composed of 3 isomers, being only 79% spilanthol.

[13] Document SP2236489 discloses some synthetic routes for obtaining spilanthol, all of which lead to a lower purity product and utilize a greater number of steps.

[14] US20140227200 discloses a long process for obtaining spilanthol which comprises 7 steps wherein the product obtained is of low purity (79) and in. whereas the presence of other isomers is indicated, however, such isomers are not quantified.

[15] U52012G 116116 discloses a process for obtaining very long spilanthol which comprises 9 steps, wherein the final product obtained is a mixture of isomers with a maximum spilantol purity of 76.5%,

[16] In view of these documents, the technical advantages achieved with the processes for obtaining spilantol and its analogs of the present invention, which make it possible to obtain spilantol and derivatives thereof, are noted. higher purity in a process with a smaller number of eta to s.

[17] Therefore, an objective of this invention is to develop a new and shorter synthetic route to obtain the spilanthol and its analogues, being inexpensive and efficient, leading to a finer product when compared to the routes used by the prior art.

Brief description of the invention:

[18] The invention proposed herein describes processes for obtaining spilanthol as well as spilanthol thus obtained.

[19 _. The processes comprise the following steps: (1) synthesis of the phosphonate ester; (2) Sonogashira reaction; (3) triple bond serial reduction; (4) oxidation of alcohol to its aldehyde; and (5) Horner-Wadsworth-SSmmons (HWE) reaction: obtaining a final product, spilanthol and the like, with. higher purity.

Brief description of the figures:

[20] For a complete and complete view of the object of this invention, reference figures are given as follows.

Figure 1 - Total synthesis of spilanthol (1).

Figure 2 - Synthesis of phosphonate ester (3).

Figure 3 - Expansion of the 1 H NMR spectra of alcohol (11a and 1b).

Figure 4 - Semi-Reduction. (E) -oct-6 ~ én-4-in-l-ol Z-selective

(11) for formation of {AZ, 6 ') - octa-4,6-dien-1-ol (7).

Figure 5 - Sern oxidation and HWE definition.

Figure 6 - Route to obtain (2 E, SE) -N-isobutyldec ~ 2. _r 8 - dien-b-enamide (21) from the

-occ-6-en-4-yn ^- 1-ol (11).

Figure 7 - 1 H NMR Spectrum ^. H of spilanthol (1).

Figure 8 - NMR Spectrum espilantol ⁱ⁵ C (1).

Figure 9 - 1 H NMR Spectrum of (2E, BE) —A;

2,8-dien-6-enamide (21).

Figure 10 - ¹³ C NMR Spectrum of (2E, BE) -ft'-isobutyldeca- , 80-enen-6-enaittida (21).

Detailed Description of the Invention

[21] The present invention relates to the processes for obtaining spilanthol as well as the spilanthol thus obtained.

[22] The processes comprise the steps of (Figure 1):

A) phosphonate ester synthesis (3);

B) Sonogashira reaction;

C) reduction of. triple bond;

D) alcohol oxidation to the respective aldehyde; and

E) Horner-Wadsworth-'Emmons (HWE) reaction.

Process of obtaining d espílanto1

Step A) - Phosphonate Ester Synthesis (3)

[23] The process for obtaining spilanthol (11 is initiated by obtaining the phosphonate fragment (3), which contains the N-isobutylamid functionality).

[24] On. A first route (Figure 2) was carried out a reaction for antide formation (4), according to a process known from the state of the art, using chloroacetyl chloride (5) and overutilization (6) and obtaining a yield of 84%. %, followed by a Michaelis-Arbuzov reaction with triethylphosphide forming the phosphonate (3) quantitatively. An alternative to obtain this compound is the coupling of isobutylamine (6) and the carboxylic acid (20) was made according to a process known in the prior art.

[25] This route leads to the formation of phosphonoacetamide ⁽ 3) in one step and with 91% yield and does not use triethylphosphite., A toxic, controlled and difficult to access reagent.

Step B) ^■■ Sonogashira Reaction: [26] Then, to obtain the desired diene portion (E, Z), a palladium and copper catalyzed Sonogashira reaction was performed, followed by a diastereosseous triple bond semi-reduction.

[27] Sonogas 1a cross coupling is used to form a C-C bond between a terminal alkyne, preferably pent-4-yn-1-ol, and an axyl or alkenyl halide. It is usually catalyzed by palladium and copper,

[28] Several parameters can be changed in response Sonogasbira such as the catalyst and its amount, the base, the temperature, ^the: reaction time and solvent.

[29] In a preferred embodiment of this invention, the best condition for the Sonogashira reaction is achieved using DF as solvent, DIPA as base,

as a catalyst at room temperature for 2 h with the addition of 10 mol% PPlv? and as alkenyl halide 1-bromoprop-1-ene (12) was used as a mixture of isomers (60: 0 E / Z), as such compound has. much lower cost than pure E-isomer. Under these reaction conditions the highest isomerization is obtained: leading to the exclusive formation of the product with the desired E geometry.

[30] In Figure 4, some examples are shown of expansion of the NMR ^spectra: K ^L obtained from the reaction. This region was used to calculate the E / 2 ratio obtained in the reaction. Signals between 6.11 and 6.02 ppm represent hydrogen at position 7 of the E isomer (dg, J-15, and 6.8 Hz), while peaks between 5.94 and 5.84 ppm represent hydrogen at position 7 for Z isomer (dq, J-10.8 and 6.8 Hz ⁾ - Hydrogen at position 6 of the two isomers is in the region between 5.49 _and 5.42 ppm, overlapping when Both compounds are present. With these data, it was concluded that the spectrum A represents a reaction with slight excess formation of product Z, while the spectrum B represents a higher formation of the isomer E. The spectrum C shows the almost exclusive formation of the isomer. AND.

Step C) - Triple bond reduction;

[31] On. Then, triple bond semi-reduction was performed.

[32] An amalgam of Zn (Cu / Ag) was used to reduce the previously obtained alkyne, leading to formation of the desired double bond with Z geometry. Initially, the conditions proposed by Hansen et al. , which obtained 86% yield and 9.0 min for the same substrate, but the reported results were not reproducible.

[33] Total conversion of alcohol (β) -oct-6-en-4-β-ol (11) was observed after 18 h of reaction and 54% yield (Figure 5).

[34] Steps D) and E) - oxidation of the alcohol (AZ, 6β-octa-4,6-dimen-1-ol (7) to the aldehyde (42,6.E) -octa-, (2) and Horner-Wadsworth-Emmons (HWE) reaction:

[35] The next step is the oxidation of alcohol (7) to its aldehyde (2).

[36] Any methodology for oxidation of primary alcohol to aldehyde, preferably Swern oxidation or using chromium reagents such as PCC or PDC may be used. Due to the instability and volatility of the aldehyde it was not possible to isolate it.

[37] Thus, the route continued using Swern oxidation. and immediately using the reaction crude in the reaction Horner-ads orth-E mons. The two steps led to the formation of spiantol (1) with 631 yield (Figure 6).

[38] Therefore, the best condition for the process of obtaining total spiiantol (1) (Figure 1) has 5 steps and an overall yield of 17% when using vinyl halide as a 60:40 E / Z mixture. and 25% when the material with geometry E was used, leading to the product with high purity when compared to the syntheses described in the state of the art.

[39] The process of obtaining in its preferred embodiment comprises a batch process.

[40] Step] Phosphonate Ester Synthesis (3)

[41] Preferably, the synthesis of the phosphonate ester (3) is carried out by coupling reaction of isobutyamine (6) and carboxylic acid (20) with DCC (or EDC} and catalytic DMAP, yielding 91% yield.

[42] In a preferred embodiment, phosphonate ester synthesis (3) was performed in dieloromethane as a solvent and at room temperature for 12 hours.

Step B) Sonogashira Reaction

[43] Alcohol (11) was obtained by a Sonogashira reaction between vinyl halide (12) and alkyne (13) in DMF using palladium catalyst, a copper oil catalyst and a base.

[44] Vinyl halide (12) may have tran geometry or a mixture of isomers, vinyl iodide may also be used as a replacement for vinyl bromide.

[45] Palladium catalyst may be chosen from the group consisting of any palladium (0) source or which causes the formation of palladium (0) in the reaction medium, such as: PMPPhs), Pd (PPhi) ₂ C1 ₂ , Pd (OAc} ₂ , Pd (dba) ₂ , Pd (TFA) 2, PdCla, Pd (acac) _2f , and Pd (PPh ₃ ) 4 is preferred. or Pd (PPh ₃ j ₂ CI- ₂ . Even more preferably, Pd (PPhj) is used.

[46] The use of the catalyst is optional and can be chosen from any copper I source, complexed or not, such as: Cul, CuBr, CuCl, Cu _? O, CuBr. DM5, CuBr.Ph ₃ P, etc. Preferably, Cul is used.

[47] The reaction time may range from 1 to 20 hours, preferably from 2 to 5 hours and the temperature may range from 20 ° C to 150 ° C. Preferably between 25 ° C and 60 ° C.

[48] As solvent, any organic solvent may be used, for example alcohols, ethers, nitriias, arias, sulfoxides, halides, preferably tetrahydrofuran.

(TKF), acid dimethylformam (DMF), ethyl ether, methanol, acetonitrile, ethanol, dimethylacetaroide (DMA), benzonitrile, trichloroacetonitrile, dimethyl sulfoxide (DSO), chloroform, dichloromethane, among others, most preferably THF and DMF.

[49] Any organic and inorganic bases may be used, for example carbonates {K ^C CC, ajCOs, Cs ^C & ⁾ , hydroxides (NaOH, ΚΟΉ, Ca (OH} ₂₎ , or primary, secondary or tertiary amines {di isoprapylamine - DIPA, piperidine, triethylamine (Et ₃ ), diisopropylethylamine

(DIPEA), tetramethylguanidine (MG), diet.ilam.ine, pyrrolidine, among others, preferably DI A and piperidin ·

[50] Optionally, PPÍ1 ₃ or any phosphine can be used as the excess ligand. [51] In a preferred embodiment (6) -oct-6-en-4-yn-1-ol (11) was obtained in 55% yield by reaction between vinyl bromide (12) and alkyne-1-ol-1-ol (13) in DMF, using 5 mole% PdPPIV as catalyst, 15 mole% Cul as co-catalyst, 10 mole% PPh ₃ and diiscpropylamine (DIPA) as base, 2h reaction and tempera environment.

Step C): Semi-reduction of the 1 trip1a connection

[52] Next, a selective Z-half reduction is performed, where zinc powder was reacted with copper acetate (Cu (OAc) ₂ and silver nitrate (AgNO;)) for amalgam formation. (E) -oct-β-en-4-in-1-o1 (11) in the presence of amalgam in a water and methanol solution is reduced leading to the formation of (AZ, 6E) -octa-4,6 dien-1-ol (7).

[53] Any methodology that leads to Z-selective semi-reduction may be used, such as using the Lindlar catalyst.

[54] The addition of T SC1 is optional and the reaction time may vary between 1 and 60 hours, preferably between 5 and 20 hours, and the temperature poete range between 20 ° C and 60 ^Q C and preferenciai temperatures between 25 ° C and 40 ° C.

[55] In a preferred embodiment, a reduction with Zn amalgam (Cu / Ag), with addition of MSCl, and with a methanol / water (1: 1; v / v) mixture as solvent at room temperature was used. 18 hours, obtaining (4Z, 6E} -octa-4,6-dien-X-ol (7) alcohol in 54% yield.

Step D): Oxidation of Alcohol to Aldehyde

[56] Oxidation of the alcohol (4Z, 6E) -octa-4, β-dien-1-ol (7) was then oxidized to the aldehyde (4Z, 6E) -octa-4,6-yenal (2) . [57] Any methodology for oxidizing primary alcohol to aldehyde may be used, for example DMSO-activated oxidation (Swern, Parikh-Doering, Pfitzner-Mof ^" att), chromium reagent oxidation (Collins, PCC and PDC reagent). ), hypervalent iodine oxidation (Dess-Martin periodinane), among others, preferably Swern oxidation or PCC.

[58] The methodology used for oxidation was Swern oxidation, and due to the volatility and instability of aldehyde (4Z, € E) -oc a-4,6-dienal (2), it was not isolated, but it is possible to perform your isolation.

Step E) j Hornad-Δadsworth-Ei; imons (; H E) reaction

[59] In this last step, the aldehyde _(4Z? 6E) octahydro-dienal 4 _F 6 ^■■ (2) in the presence of the phosphonate ester (3) and a base leads to the formation of espilantol (1).

[60] The reaction time may range from 1 to 5 hours, preferably from 1 to 3 ^: hours and the temperature may range from 0 ° C to 60 ° C, preferably from 0 ° C to 25 ° C.

[61] Any organic solvent may be used, for example ethers (THF, ethyl ether, dioxane), alcohols (methanol, ethanol), nitriles (acetonitrile), aroids (DMF, DMA), chlorinated solvents (chloroform, dichloromethane ), among others, preferably THF is used.

[62] Any base may be used, for example: t-BuO, NaH, n-BuLI, NaHMDS, LiHMDS, KHMDS, LDA, DBU, NaOH, OH, among others, preferably NaH is used.

[63] Variations may be used using lithium chloride (LiCl) and zinc triflate (ZnOTf ₃ ).

[64] Preferably, the Horner-Wads reaction ortho- Emmons (HWE) between (4Z, 6E) -octa-4,6-dia (2) and the phosphonate ester (3) use THF LEATHER solvent and Nafi as the base at a reaction time of 90 minutes. 63% yield was obtained for both steps (oxidation and HWE).

[651 From vinyl bromide with exclusively trans geometry the Sonogashira reaction with pent-4-in-1-ol alkyne (13, using piperidine as a base) was performed. The mildest possible conditions (room temperature, h, 5 mol% Pd (PPh ₃ ) * & 15 mol% Cul), obtaining 81% d yield. This leads to an overall yield of 25% for obtaining spilanthol (1).

Synthesis of spilanthol analogs

[66] 2 E {0 acetylenic analogue IF) -N-isobutilde.ca- ^'2 _i R 8 dien-6-enamide (21) was synthesized in 4 steps. As described above, with an overall yield of 23%. The modification made was the substitution of the double bond Z for a. triple

[67] Studies indicate that spilanthol has a variety of biological activities, such as anti-inflammatory activity, so the development of a synthetic route that enables large quantities of this compost to be obtained with high purity is of utmost importance for the study of its properties, since most state of the art tests are made with crude extract.

[68] In this patent application it was possible to develop a synthetic route for spilanthol with. only 5 steps, reaching a high purity product (> 98% HPLC) and without the presence of other isomers (> 95: 5% by PME of ^{: 1} H). When vinyl bromide (12) with. For double bonding with geometry E, the overall yield was 25%. Similarly, when using vinous bromide (12 ^' }, consisting of the mixture of isomers (E / Z 60:40) and having a much lower commercial value, it was possible to obtain spilanthol of the same purity and overall yield of 171.

1691 The obtained spilanthol has the following characterization: Transparent / yellowish oil R _f 0.31 (SiQ ₃ , hexanes / EtOAc 70:30). NMR ¾ {Ct> Cl _3, 600 MBZ) 5 (ppm): 6.82 (dt, J ^"15.3, 6.6 Hz, 1 H), 6.28 íãááq, J" 14.7, 11, 1.5 Hz, 1 H), 5.96 (dd, J = 10.9 Hz, 1 H), 5.80 (dt, J = 15.2, 1.5 Hz, 1 R) , 5.69 (q, 14.1, 6.8 Hz, 1H), 5.59 (bs, 1H), 5.25 (dt, J = 10.5: 7.4 Hz, 1 H), 3.14 (dd, J = 6.8 Hz, 1 H), 2.31 (dt, J = 7.4 Hz, 2 H !, 2.25 (dtd, J * 6.6,

1.3 Hz, 2 H), 1.75 - 1.83 (m, 4 H), 0.92 ppm (d, J = 6.8 Hz, 6 H). ¹³ C NMR (CDCl3, 151MHz) δ (ppm): 166.0 (C), 143.4 (CH) _. , 129.9 (CH), 129.4 (CH), 127.6 (CK), 126.6 (CH), 124.1 (CH), 46.8 C Í¾, 32.0 (C¾), 28 0.5 (CH), 26.3 (CH ₂ ), 20.1 (C¾), 1.8.2 (C¾) .IV (AT, enr ¹ ) 3280, 2957, 2927, 2870, 1668, 1627, 1545, 1235 , 1159, 978, 944, 818, 618. Purity 98%. HKMS [C 14 _-3 NO ⁺ H 3 ⁺ calcd 222, 1852, observed 222, 1846.

[70] The developed route makes it possible to obtain large scale by process in. batch, allowing material to be obtained for various biological assays. With minor changes in the initially proposed process, it was possible to synthesize (2E, 8E) -N-isobutyldeea-2,8-dien-6-enamide (21), an unnatural analog of spilanthol.

[71] The analog (2E, BB) -N-isobutyldeca-2,8-dien-6-enamide: (21) obtained has the following characterization: Orange solid. Mp 91.4 - 95.6 ° C. R _f 0.36 (SiC¾, hexanes / EtOAc 70:30). m ¾ (CDCls, 600 MHz) δ (ppm): 6.84 (dt, J ^"15.2,

6.4 Hr, 1 H), 6.05 (dq, = 15.6, 6.8 Hz, 1 H), 5.84 (d, J - 15.4 Hz, 1 H), 5.64 (bs, 1 ti), 5.44 (dq, J = 15.8 ^: 1.8 Hz, 1 H; 3.15 (dd, J = 6.4 Hz, 2 H), 2.36 - 2.45 (m, 4 H), 1.76 - 1.84 (m, 1 H), 1.74 (dd, J * 6.8, 1.7 Hz, 3 H), 0.92 ppm (d, J = 6.6 Hz, 6 fl) BN ¹³ C (CDCl 3, 151 MHz) δ (ppm): 165.8 (Ct, 142.3 (CH ), 138.6 (CH), 124.6 (CH), 110.8 (CH), 86.7 (C), 80.1 (C), 46.9 (CH-) _> 31.3 (CH ₂ ), 28.5 (CH), 20.1 (CH ₃ ), 18.5 (CH ₂ ), 18.4 (C¾) IR (ATR, cm- ¹ 3291, 2959, 2914, 2870, 1666 , 1625, 1545, 1334, 1236, 1220, 950, 650. Purity 95% HRMS [C ₁₄ H ₂ iNO + H] ⁽ calculated 220.1696, observed 220, 1710.

Claims

1. Process for obtaining spilanthol, comprising the steps of:

(1) synthesis of the phosphonate ester from the coupling reaction of isobutylamine and a carboxylic acid with DCC or EDC and catalytic DMAP using dichloromethane as solvent and temperature ranging from 0 to 40 ° C, preferably 25 ° C

(2) Sonogashira reaction between 1-bromopropene. or 1-iodopropene and pent-4-yn-1-ol in solvent using palladium catalyst, copper cocatalyst and an alcohol base, wherein the reaction time ranges from 1 to 20 hours and temperature ranges from 20 ° C to 150 ° C

(3) Z-selective semi-reduction, in which the reaction time ranges from 1 to 60 hours and the temperature ranges from 2. ° C to 60 ° C.

(4): oxidation of alcohol to its aldehyde, any methodology for primary alcohol oxidation may be used, such as DMSO-activated oxidation (Swern, Parikh-Doering, Pfítzner-Moffatt), chromium reagent oxidation (reagent). Collins, PCC and PDC), hyperventilating iodine oxidation (Dess-Martin periodinane), among others, preferably ser or PCC oxidation.

(5) Horner-Wads or th-Emmons (H E) reaction, wherein the reaction time ranges from 1 to 5 hours and the temperature ranges from 0 ° C to 60 ° C.

Process according to claim 1, characterized in that, in step i 2), the vinyl halide has trans geometry or is a mixture of isomers, wherein the vinyl halide is known to be among vinyl bromide and vinyl iodide.

Process according to Claim 1, characterized in that, in step (2), the alkyne is pent-4-in-1-ol.

Process according to claim 1, characterized in that, in step (?), The palladium catalyst is selected from the group comprising PdIPFPh ₃ ) 4, Pd {PPh- ₃ ) ₂ € 1. _s , Pd (0Ac) ₂ , Pd (dba) ₂ , Pd (TFA) ₂ , PdCl ₂ , Pd (acac) _; preferably Pd (PPh ₃ } ₄ or Pd (PPh ₂ ) ₂ C1 ₂ , more preferably d (PPh3).

Process according to Claim 1, characterized in that, in step (2), the cocatalyst is optional and chosen from a copper source (I) selected from the group consisting of Cul, CuBr , CuCl, Cu ₂₀ , preferably Cul.

_./ 6. Process according co claim 1, characterized in that, in step (2), the reaction time varies preferably between 2 and 5 hours and the temperature varies preferably between 25 ° C and 60 ° C <

Process according to Claim 1, characterized in that, in step (2), the solvent is an organic solvent selected from the group consisting of alcohols, ethers, nitriles, preferably tetrahydrofuran. ., dimethylformamide (DMF), ethyl ether, methanol, acetonitrile, ethanol, dimethylacecaraide (DMA), benzonitrile, trichloroacetonitrile, diethylsulfoxide (DMSO), chloroform, dichloromethane, more preferably THF or DMF.

Process ¹ according to claim 1, characterized in that in step (2) the base is selected from the group consisting of carbonates such as KCO ₃ , Na ₂ CO ₃ , CS ₂ CO ₃ ; hydroxides such as NaOH, KOH; or primary, secondary and tertiary amines such as DIPA, piperidine, triethylamine, diisopropylethylamine (DIPEA), tetramethylguanidine (TMG), diethylamine, pyrrolidine, preferably DIPA or iperidine.

Process according to Claim 1, characterized in that, in step (3), optionally uses TM $ Cl.

Process according to Claim 1, characterized in that, in step (3), the reaction time preferably ranges from 5 to 20 hours, and the temperature preferably ranges from 25 ° C to 40 ° C.

Process according to Claim 1, characterized in that, in step (5), the solvent is a selected organic solvent from the group consisting of ethers such as THF, ethyl ether, dioxane; alcohols, such as meta-1, ethanol; ni ri 1as, such as acetonitrile; amylas such as DMF, DMA and chlorinated solvents such as chloroform-, dichloromethane); preferably THF.

Process according to Claim 1, characterized in that, in step (5), the base is selected from the group consisting of t-BuOK, NaH, n-BnLi, NaHMDS, LiHMDS, KHMDS, LDA, DBU, NaOH, KDH, preferably aH.

Process according to Claim 1, characterized in that, in step (5), the reaction time preferably ranges from 1 to 3 hours and the temperature preferably ranges from 0 ° C to 25 ° C. Ç.

Process according to claim 1, characterized by the fact that the process takes place preferably in batch.

Spilanthol is characterized in that it is obtained according to the process defined in claims 1 to 12 and has a purity of greater than 98% by HPLC analysis and no other isomers of greater than 95: 5% by NMR.

A process for obtaining spilanthol analogs which is carried out as defined in claims 1 to 12, wherein alternatively steps (4) and (5) occur prior to step (3), and wherein the double bond Z is replaced by a triple bond.

Process according to Claim 16, characterized in that, in step (1), the coupling between carboxylic acid and isobutylamine is carried out with EDC and DMAP using methyl chloride as solvent for 18 minutes. hours at room temperature.

Process according to claim 16, characterized in that in step (5) the base is Na.H, the solvent is THF, the reaction time is 90 minutes and the temperature ranges from 0 °. C - room temperature,

Spilanthol analogs (21), characterized in that they have the official nomenclature IUPAC (2E, 8E) -M-isobutyldeca-2,8-dien-6-enamide, be obtained from the process described in claims d 16 to 18 and have the following characteristics: orange solid; P. P. 91.4 - 95.6 ° C. R / 0/36 (SiO ₂ , hexanes / EtOAc 70:30); NMR (CDCl 3, 600 MHz) δ (pp j: 6.84 idt, J = 15.2, 6.4 Hz, 1H), 6.05 (dq, J = 15.6, 6.8 Hz, 1H), 5.84 (d, J '15.4 Hz, 1 H), 5.64 (bs., 1 H), 5.44 (dq, J ^"15.8, 1.8 Hz, 1 H), 3.15 (dd, J = 6, Hz, 2 H), 2.36 - 2.45 (m, 4 H), 1 76 to 1.84 (m, 1 H) _r 1.74 (dd, J-6.8, 1.7 Hz, 3 H}, 0 -92 ppm ( d, J = 6 ·, 6 Hz, 6 H); ¹³ C (CDCl ₃ , 151

MHs) δ (ppm): 165.8 (C), 142.3 (CR), 138.6 (CH), 124.6 (C11), 110.8 (CH), 86.7 (C), 80 , 1 C), 46.9 (CH ₂ ), 31.3 (C¾), 28.5 (CK), 20.1 (CH.3), 18.5 (CH ₂ ), 18.4 (C¾) ; IR (AT, cm- ¹ ) 3291, 2959, 2914, 2870, 1666, 1625, 1545, 1334, 1236, 1220, 950, 650; Puresa 95¾ HRMS [C _L4 H NO ÷ H] * calculated 220, 1696 , observed 220.1710.