Preparation and purification of synthetic capsaicin
The present invention provides methods for synthesizing the trans isomer of capsaicin and/or capsaicin-like compounds by utilizing a process wherein the trans geometry is set from the beginning of the synthesis reaction and carried through the entire synthesis process.
1 . A method for preparing trans-capsaicin, comprising:
a) alkylating 3-methyl butyne with halovaleric acid or to obtain 8-methyl-6-nonynoic acid;
b) reducing said 8-methyl-6-nonynoic acid to obtain trans-8-methyl-6-nonenoic acid;
c) activating said 8-methyl-6-nonenoic acid to obtain an acid halide or activated acid derivatives; and
d) acylating 4-hydroxy-3-methoxybenzylamine hydrochloride with said acid halide to obtain trans-capsaicin.
2 . The method of claim 1 , wherein step a) comprises alkylating 3-methyl butyne with ω-haloalkanic acid to obtain ω-alkynoic acid analogues.
3 . The method of claim 1 , wherein step a) comprises the steps of:
i) mixing anhydrous tetrahydrofuran with hexamethylphosphoramide and cooling said mixture to about −78° C. to about −60° C.;
ii) adding to said mixture of step i) 3-methyl butyne followed by a dropwise addition of a base at a temperature from about −78° C. to about −65° C. to obtain a second mixture;
iii) warming said second mixture up to about −30° C. while stirring; and
iv) adding dropwise a halovaleric acid in anhydrous tetrahydrofuran at a temperature of about −30° C., said halovaleric acid added in a sufficient amount to convert said 3-methyl butyne to said 8-methyl-6-nonynoic acid, then gradually warming to room temperature and stirring to obtain a reaction mixture.
4 . The method of claim 2 , further comprising:
i) adding 3M hydrochloric acid to said reaction mixture and extracting said reaction mixture with ethyl acetate;
i) adding 3M hydrochloric acid to said reaction mixture and extracting said reaction mixture with ethyl acetate;
ii) washing said extracted reaction mixture with brine to yield a crude product.
5 . The method of claim 3 , further comprising:
i) purifying said crude product; and
ii) removing solvents under vacuum to provide a step a) intermediate product.
6 . The method of claim 5 , wherein said crude product is purified by column chromatography.
7 . The method of claim 5 , wherein said crude product is purified by acid-base extraction.
8 . The method of claim 5 , wherein said crude product is purified by vacuum distillation.
9 . The method of claim 5 , wherein said step a) intermediate product is 8-methyl-6-nonynoic acid.
10 . The method of claim 3 , wherein said halovaleric acid is selected from the group consisting of bromovaleric acid, chlorovaleric acid, fluorovaleric acid, iodovaleric acid and astatinovaleric acid, 1-mesyloxyvaleric acid, 1-tosyloxyvaleric acid.
11 . The method of claim 10 , wherein said halovaleric acid is bromovaleric acid.
12 . The method of claim 3 , wherein 1,2-dimethyl-3,4,5,6-tetrahydro-(1H) pyrimidinone is substituted for hexamethylphosphoramide in step i).
13 . The method of claim 4 , wherein said base is selected form the group consisting of n-BuLi, sec-BuLi, t-BuLi, lithium di(isopropyl) amide, sodium hydride, sodium amide, lithium amide, methyl lithium, methyl magnesium bromide, ethyl magnesium bromide, alkyl or aryl magnesium halides or mixture thereof.
14 . The method of claim 13 , wherein said base is n-butyllithium.
15 . The method of claim 1 , wherein step b) comprises the steps of:
i) dissolving said 8-methyl-6-nonynoic acid in a mixture of anhydrous tetrahydrofuran and t-butyl alcohol to obtain a solution and cooling said solution to about −55° C. to about −40° C.;
ii) condensing ammonia to said solution to a temperature of about −50° C. to about −33° C.
iii) adding sodium piece-wise and stirring at a temperature from about −45° C. to about −30° C. and stirring for a sufficient period of time to dissolve said sodium, and
iv) adding ammonium chloride, warming to room temperature an allowing the ammonia to evaporate to obtain a reaction mixture.
16 . The method of claim 15 , wherein additional lithium is added after step iii).
17 . The method of claim 15 , wherein step iii) comprises adding lithium at a temperature from about −65° C. to about −45° C. and stirring for a sufficient period of time to dissolve said lithium.
18 . The method of claim 15 , further comprising:
i) adding water to said reaction mixture;
ii) acidifying said reaction mixture with 6N hydrochloric acid to a pH of about 2 to about 3;
iii) extracting said reaction mixture with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate; and
iv) filtering and removing solvents under vacuum to obtain a step b) intermediate product.
19 . The method of claim 18 , wherein said step b) intermediate product is trans-8-methyl-nonenoic acid.
20 . The method of claim 17 , wherein step ii) is omitted.
21 . The method of claim 15 , wherein lower alkyl amines are substituted for said ammonium of step ii).
22 . The method of claim 15 , wherein sodium is substituted for said lithium of step iii).
23 . The method of claim 15 , wherein secondary butyl alcohol (sec-BuOH), ethyl alcohol (EtOH), or other alkyl alcohols are substituted for said t-butyl alcohol of step i).
24 . The method of claim 15 , wherein lithium and liquid ammonia or sodium and liquid ammonia are substituted for said lithium, said tetrahydrofuran and said liquid ammonia.
25 . The method of claim 17 , further comprising the steps of:
i) stirring said reaction mixture overnight to evaporate ammonia;
ii) adding additional anhydrous tetrahydrofuran and ammonium chloride, stirring said mixture for a sufficient time to neutralize excess lithium;
iii) adding ice-water portionwise;
iv) extracting said mixture with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate; and
v) filtering and removing solvents under vacuum to produce a step b) intermediate product.
26 . The method of claim 17 , further comprising the steps of:
i) cooling the reaction mixture and quenching with ice-water;
ii) acidifying said mixture with 6N hydrochloric acid added portion-wise to a pH of about 2 to about 3;
iii) extracting said mixture with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate;
iv) filtering and concentrating under vacuum at a temperature of about 30° C. to obtain a crude product.
27 . The method of claim 26 , further comprising the step of purifying said product by flash column chromatography to obtain a step b) intermediate product.
28 . The method of claim 26 , further comprising the step of purifying said crude product by vacuum distillation.
29 . The method of claim 1 , wherein step c) comprises the steps of:
i) adding dropwise a thionyl halide to said 8-methyl-nonenoic acid at room temperature to form a solution;
ii) heating said solution at about 50° C. to about 75° C. for a sufficient period of time to convert said 8-methyl-6-nonenoic acid to said acid halide; and
iii) removing excess thionyl halide under vacuum to obtain a step c) intermediate product.
30 . The method of claim 29 , wherein said thionyl halide is thionyl bromide.
31 . The method of claim 29 , wherein said thionyl halide is thionyl chloride.
32 . The method of claim 29 , wherein said step c) intermediate product is an acid halide.
33 . The method of claim 32 , wherein said acid halide is acid bromide.
34 . The method of claim 32 , wherein said acid halide is acid chloride.
35 . The method of claim 32 , wherein said acid halide is an activated carboxylic acid.
36 . The method of claim 35 , wherein said activated carboxylic acid is an imidazolide.
37 . The method of claim 35 , wherein said activated carboxylic acid is an carbodiimide.
38 . The method of claim 1 , wherein step d) comprises the steps of:
i) mixing 4-hydroxy-3-methoxy benzylamine hydrochloride and dimethylformamide;
ii) adding portion-wise at room temperature to said mixture of step i) aqueous sodium hydroxide and stirring to obtain a reaction mixture;
iii) adding acid halide in anhydrous ether at a temperature of about 0° C. to about 10° C. for a sufficient period of time to convert said acid halide to an amide; and thereafter
iv) gradually warming said mixture to room temperature and stirring.
39 . The method of claim 38 , further comprising the steps of:
i) adding water to said mixture and extracting said mixture with ethyl acetate to obtain an ethyl acetate extract;
ii) washing said extract with 1N hydrochloric acid and, thereafter, washing with sodium bicarbonate;
iii) washing said solution with brine and drying over anhydrous sodium sulfate;
iv) filtering and removing solvents under vacuum to obtain a crude trans capsaicin product.
40 . The method of claim 39 , further comprising the steps of:
i) purifying said crude product by column chromatography to obtain trans-capsaicin product.
41 . The method of claim 38 , wherein potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or an alkyl amine is substituted for said aqueous sodium hydroxide of step ii).
42 . The method of claim 38 , wherein 4-hydroxy-3-methoxy benzylamine is substituted for said 4-hydroxy-3-methoxy benzylamine hydrochloride of step i).
43 . The method of claim 41 , wherein said alkyl amine is selected from the group consisting of triethylamine, Hunig's base, 4-dimethylaminopyridine and pyridine.
44 . The method of claim 38 , wherein tetrahydrofuran, 2-dimethoxyethane, acetonitrile, dichloromethane, chloroform, or methyl ethyl ketone is substituted for said dimethylformamide in step i).
45 . A method of purifying the trans-capsaicin product of claim 35 , comprising the steps of:
i) dissolving said crude trans-capsaicin product in a mixture of ether/hexane and heating said mixture to about 40° C. to about 45° C.;
ii) cooling said mixture to room temperature or bellow room temperature; and
iii) filtering said mixture to provide a purified trans-capsaicin product.
46 . The method of claim 45 , wherein step iii) comprises filtering said mixture and washing said mixture with a mixture of ether/hexane and drying under vacuum to obtain a purified trans-capsaicin product.
47 . The method of claim 1 , further comprising purifying said trans-capsaicin using a semi-preparative HPLC.
48 . The method of claim 39 , further comprising purifying said crude trans-capsaicin product using a semi-preparative HPLC.
49 . The method of claim 40 , further comprising purifying said trans-capsaicin product using a semi-preparative HPLC.
50 . The method of claim 47 , wherein the purification using the semi-preparative HPLC provides for a resulting ultra-purified trans-capsaicin having a purity of about 97% or greater capsaicin.
51 . The method of claim 47 , wherein the purification using the semi-preparative HPLC provides for a resulting ultra-purified trans-capsaicin having a purity of about 98% or greater capsaicin.
52 . The method of claim 47 , wherein the purification using the semi-preparative HPLC provides for a resulting ultra-purified trans-capsaicin having a purity of about 99% or greater capsaicin.
53 . The trans-capsaicin product produced by the method of claim 47 .
54 - 62 . (canceled)