CN100500142C - Preparation and purification of synthetic capsaicin - Google Patents

Abstract

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.

Description

The preparation of synthetic capsaicin and purification

Technical field

The present invention relates to the preparation and the purification process of the capsaicin of synthetic method preparation.

Background technology

Capsaicin is to come from the pungent that Solanaceae belongs to (solanaceae family) (Fructus Capsici) plant, owing to indicate the painful minor diameter afferent nerve fiber C-fiber and the selectively acting of A-δ fiber to being considered to, it is used as test instrument for a long time.According to the research in animal, it seems that capsaicin be the depolarization (depolarization) that has caused the C-fibrous membrane by the cationic channel of opening permeable calcium and sodium.Recently, a kind of receptor that is used for the capsaicin effect is cloned.Capsaicin can obtain by the fruit with alcohol extraction Fructus Capsici shrub or multicolored Fructus Capsici (capsicum annum) at an easy rate.The chemical name of capsaicin is N-(4-hydroxyl-3-methoxy-benzyl)-8-methyl ninth of the ten Heavenly Stems-trans-6-alkene amide (enamide).Capsaicin is in fact water insoluble, but can be dissolved in arbitrarily in alcohol, ether, benzene and the chloroform.In treatment, capsaicin has been used as the local analgesia agent.Can be from Steve Weiss ﹠amp; Co., 315 East 68 ^ThStreet, NewYork, NY 10021 buys capsaicin with capsaicin USP, also can be by the synthetic preparation of disclosed method.＂ Synthesis and Local AnestheticProperties of N-substituted 3 referring to people such as Michalska, 4-Dimethoxyphenethylamine Derivatives ＂, Diss Pharm.Pharmacol., the 24th volume (1972) 17-25 pages or leaves (chemical abstracts CA77:19271a), it discloses amyl group and the N-hexyl-3 that is reduced to secondary amine separately, 4-dimethoxy benzene yl acetamide.Capsaicin (USP) contains usually 110% the total capsaicin alkaloid of being no less than corresponding to 63% pure capsaicin.The USP capsaicin is trans capsaicin (55-60%), and contains the parent Dihydrocapsaicin and fall Dihydrocapsaicin.

Though detailed mechanism does not know that also the instrumentality of capsaicin comprises: (i) in peripheral organization, activate nociceptor; (ii) making the final mistake of exterior injury sensor quick is one or more stimulus object forms; The cellular degeneration that (iii) makes responsive A-δ and C-fiber import body into; (iv) activate the neuronal protein enzyme; (v) block the aixs cylinder transmission; And (vi) under the situation that does not influence non-nociceptor fiber numerical value, reduce the absolute figure of nociceptor fiber.

The existing report of method that is used for synthetic capsaicin and analog thereof, for example, the ＂ Amides of Vegetable Origin Part VI Synthesis of Capsaicin of Crombie etc., ＂ Journalof the Chemical Society, 1025-1027 page or leaf (1955) described clear and definite capsaicin, the active principle N-in the Fructus Capsici (4-hydroxyl-3-methoxy-benzyl)-8-methyl the ninth of the ten Heavenly Stems-trans-6-alkene amide synthetic.Authorize on January 15th, 1985 among people's such as LaHann the USP 4,493,848 and described the phenyl that N-[(replaces) methyl]-the saturated alkenyl amide compositions of cis-list and synthesize the method for compositions that this is used for injecting drug use, oral and local application.USP 5,094,782 people such as mandate on March 10th, 1992 Chen has described from synthetic capsaicin (nonanoyl vanillylamide) and the synthetic nonanoyl vanillylamide succinate of succinic anhydride.

In addition, other list of references has been reported and has been utilized Wei Tixi (witting) reaction as the committed step of introducing two keys.Yet witig reaction always helps the cis-form olefin product.Like this, the other step that need comprise fractional recrystallization is with the cis-product isomerization and be separated into trans product.

The alternative approach that is used for synthetic capsaicin utilizes the Clarkson ester to reset as the means that optionally form the two key transisomers of alkene (alkene).Though be not better than witig reaction because not forming the cis product, be to use the Clarkson ester to reset and produced the wherein too short elementary product of carbochain.Like this, after the Clarkson step before forming end product, must make described chain elongated with the benzylamine coupling.

The method that is provided for the transisomer of synthetic capsaicin is favourable, so that the complete synthesis of transisomer is provided, does not need the synthetic required other step of capsaicin described in the prior art.

Also have, it is favourable by the method for the synthetic capsaicin of method preparation described herein that purification is provided.

It is to begin just to determine and be applied in the fact of carrying out simple four step method from synthetic reaction that the present invention partly relates to trans geometry.In addition, the present invention partly relate to the trans capsaicin of synthetic method preparation can be with 99.0% or the fact of higher purity purification.

Summary of the invention

An object of the present invention is to provide a kind of method that is used for the transisomer of complete synthesis capsaicin or capsaicin compounds.

Another object of the present invention provides a kind of method that is used for purification capsaicin of the present invention or capsaicin compounds.

Consistent with top purpose and other purpose, in some embodiment preferred of the present invention, provide method according to four step method synthetic capsaicin transisomers.

At some in other the embodiment, the method for preparing trans capsaicin is provided, it comprises: a) with halogen valeric acid and/or ω-halogenated-chain acid alkylation 3-methyl butine, to obtain 8-methyl-6-n-heptylacetylene acid and/or to have the acetylenic acid analog (wherein n=4-8) of following chemical formula:

B) reduction described 8-methyl-6-n-heptylacetylene acid trans to obtain-8-methyl-nonenoic acid; C) the described 8-methyl-nonenoic acid of activation is to obtain the derivant of acid chloride or activatory acid; And d) with described acid chloride acidylate 4-hydroxyl-3-methoxybenzylamine hydrochloride to obtain trans capsaicin.

In other the embodiment, provide the method for preparing trans capsaicin at some, wherein: step a) may further comprise the steps: i) mix anhydrous tetrahydro furan (THF) and hexamethyl phosphoramide (HMPA) and this mixture is cooled to-78 ℃ to-60 ℃ approximately approximately; Ii) to step I) mixture in add 3-methyl butine, next at-78 ℃ to dripping alkali to obtain second mixture under-65 ℃ the temperature approximately; Iii) second mixture is warmed to-30 ℃ and stirring (preferred about 30 minutes) approximately; Iv) under about-30 ℃ temperature, drip the anhydrous tetrahydrofuran solution of halogen valeric acid, the addition of this halogen valeric acid is enough to described 3-methyl butine is changed into 8-methyl-6-n-heptylacetylene acid, be warmed to room temperature and stirring (preferred a whole night) then gradually, to obtain reactant mixture.

In certain embodiments, provide the method for the thick intermediate product that obtains step a), it further may further comprise the steps: i) in reactant mixture, add hydrochloric acid (HCl) (HCL of preferred 3M), and with ethyl acetate extraction this reactant mixture; Ii) the reactant mixture that is extracted with the salt water washing is to make crude product.

In another embodiment of the invention, a) method of thick intermediate product of purification step is provided, it may further comprise the steps: i) use the silica gel purification crude product by column chromatography, and adopt the described crude product of mixture eluting of ethyl acetate/hexane; Ii) under vacuum, remove and desolvate so that the intermediate product of step a) to be provided.

At some in other the embodiment, the method for preparing trans capsaicin is provided, wherein step b) may further comprise the steps: i) described 8-methyl-6-n-heptylacetylene acid is dissolved in the mixture of the anhydrous tetrahydro furan and the tert-butyl alcohol (t-BuOH) obtaining solution, and this solution is cooled to-55 ℃ to-40 ℃ approximately approximately; Ii) condensation ammonia (NH in this solution ₃) so that temperature reaches-50 ℃ to-33 ℃ approximately; Iii) approximately-45 ℃ add sodium to-30 ℃ the temperature approximately blocks ofly and drip and stir the sufficiently long time to dissolve described sodium (preferred about 30 minutes to about 2 hours) and iv) to add ammonium chloride (NH ₄Cl), be warmed to room temperature and make NH ₃Evaporate a whole night to obtain reactant mixture.In other the embodiment, wherein omitted described step I i at some).In other the embodiment, wherein use low-grade alkylamine step of replacing described ammonia ii) at some.At some in other the embodiment, wherein lithium has substituted the described sodium of step I in ii).In other the embodiment, wherein sec-butyl alcohol (sec-BuOH), ethanol (EtOH) or other alkylol are replaced described step I at some) the tert-butyl alcohol.In other the embodiment, wherein lithium and liquefied ammonia or sodium and liquefied ammonia replace described sodium, described oxolane and described liquefied ammonia at some.

At some in other the embodiment, the method for preparing trans capsaicin is provided, and wherein the reactions steps of step b) iii) further is included in approximately-65 ℃ to add lithium and stir the sufficiently long time to dissolve described lithium (preferred about 30 minutes to about 2 hours) under-45 ℃ the temperature approximately blocks ofly.

In other the embodiment, provide the method for preparing trans capsaicin at some, wherein step b) further may further comprise the steps: i) stir described reactant mixture a whole night with vaporized ammonia; Ii) add other anhydrous tetrahydro furan and ammonium chloride, stir the sufficiently long time of described mixture with the excessive lithium that neutralizes (preferred 30 minutes); Iii) piecemeal adds frozen water; Iv) use the described mixture of ethyl acetate extraction, with the salt water washing and pass through anhydrous sodium sulfate drying; V) filter and under vacuum, remove and desolvate, with preparation process b) intermediate product.

In other the embodiment, provide the method for preparing trans capsaicin at some, wherein step b) further may further comprise the steps: i) reaction mixture is also used the frozen water quenching; Ii) with a part of hydrochloric acid that adds of a part described reactant mixture being acidified to pH is 2 to 3; Iii) use the described reactant mixture of ethyl acetate extraction, with the salt water washing and pass through anhydrous sodium sulfate drying; Iv) filter and under 30 ℃ temperature, concentrate in a vacuum, obtain crude product.In other the embodiment, wherein step b) further comprises the midbody product that obtains step b) by the described product of flash column chromatography purification at some.In other the embodiment, wherein step b) further comprises the step by the described crude product of vacuum distilling purification at some.

In certain embodiments, provide the method for the thick intermediate product that is used to obtain step b), it further may further comprise the steps: i) add entry in reactant mixture; Ii) using HCl (preferred 6N HCL) that this reactant mixture is acidified to pH is about 2 to about 3; Iii) with this reactant mixture of ethyl acetate extraction, with the salt water washing and by anhydrous sodium sulfate (Na ₂SO ₄) drying; V) filter and under vacuum, remove and desolvate, to obtain the thick intermediate product of step b).

In another embodiment of the invention, purification step b is provided) the method for thick intermediate product, this method may further comprise the steps: i) use this product of silica gel purification by quick (flash) column chromatography, and with the mixture eluting of ethyl acetate/hexane, to obtain the intermediate product of step b).

In other the embodiment, provide the method for preparing trans capsaicin at some, wherein step c) may further comprise the steps: i) at room temperature drip thionyl halide to form solution in 8-methyl-6-nonenoic acid; Ii) heat the sufficiently long time of this solution down described 8-methyl-6-nonenoic acid is converted into acyl halide (preferred about 1 hour) at about 50 ℃ to about 75 ℃; Iii) under vacuum, under about 40 ℃ to about 45 ℃, remove excessive thionyl halide to obtain the intermediate product of step c).In other the embodiment, wherein said thionylhalides is a thionyl bromide at some.In other the embodiment, wherein said acyl halide is activated carboxylic acid at some.In other the embodiment, wherein said activated carboxylic acid is an acylimidazole at some.In other the embodiment, wherein said activated carboxylic acid is a carbodiimide at some.

In other the embodiment, provide the method for preparing trans capsaicin at some, wherein step d) further may further comprise the steps: i) mix 4-hydroxyl-3-methoxybenzylamine hydrochloride and dimethyl formamide (DMF); Ii) at room temperature to step I) mixture in piecemeal add aqueous NaOH (preferred 5N NaOH) and stir (preferred about 30 minutes); Iii) in about 0 ℃ of sufficiently long time of acyl halide that drips to about 10 ℃ temperature in the absolute ether, acyl halide is transformed into amide (preferred about 20 minutes to about 1 hour); Iv) gradually this mixture be warmed to room temperature and stir (preferred a whole night) thereafter.At some in other the embodiment, wherein potassium hydroxide, Lithium hydrate, sodium carbonate, potassium carbonate or alkylamine replace step I i) described in aqueous NaOH.At some in other the embodiment, wherein 4-hydroxyl-3-methoxybenzylamine replaces step I) described in 4-hydroxyl-3-methoxybenzylamine hydrochloride.

In certain embodiments, provide the method for the rough trans capsaicin that obtains step d), it further may further comprise the steps: i) in this mixture, add entry, and with ethyl acetate extraction this mixture to obtain the extract of ethyl acetate; Ii) use HCl (preferred 1N HLC) to wash described extract, thereafter, with sodium bicarbonate (NaHCO ₃) washing; Iii) use this solution of salt water washing, and by anhydrous sodium sulfate (Na ₂SO ₄) drying; Iv) filter and under vacuum, remove and desolvate to obtain crude product.

In another embodiment of the invention, purification step d is provided) in the method for rough trans capsaicin, it may further comprise the steps: use the silica gel purification crude product by column chromatography, and with the mixture eluting of ethyl acetate/hexane, to obtain rough trans capsaicin product.

At some in other the embodiment, the method for the other trans capsaicin product of purification is provided, it may further comprise the steps: i) rough trans capsaicin product is dissolved in the mixture of ether/hexane, and with this mixture heated to about 40 ℃ to about 45 ℃; Ii) with the mixture cool to room temperature, stir about is 2 hours simultaneously; The trans capsaicin product of this mixture to provide purification to cross iii) is provided.In other the embodiment, wherein step I ii) comprises the described mixture of filtration at some, and described mixture washs with the mixture of ether/hexane, and dry to obtain purified trans capsaicin product under vacuum.

At some in other the embodiment, provide by HPLC (high performance liquid chromatography) (HPLC), with the method for semipreparative HPLC purification capsaicin.

In certain embodiments of the invention, further relate to the method for purification rough trans capsaicin product of the present invention, or be further purified the method for the trans capsaicin product of the present invention that previous purification crosses.It is about 97% or higher, preferred about 98% or higher that preferred this purification provides purity, more preferably from about 99% or higher hyperpure trans capsaicin product.Such purification is also referred to as half preparation purification of " semi-finished product purification " or capsaicin in this article.Use semipreparative HPLC to carry out according to the half-finished purification of capsaicin of the present invention.In some preferred embodiment, this capsaicin before being further purified by semipreparative HPLC by purification in advance.

In certain embodiments, the invention still further relates to the hyperpure capsaicin product for preparing according to the present invention, wherein said capsaicin product contain purity surpass about 97%, preferably surpass about 98%, more preferably surpass about 99% capsaicin.

, provide to be used in other the embodiment at some in the lenitive position of human or animal's needs alleviating pain, the main capsaicin compositions of forming by trans capsaicin.The suitable medium thing that preferred this capsaicin compositions comprises ultrapure capsaicin of the present invention and is used for administration (for example, by injection or infiltration).

At some in other the embodiment, the compositions that comprises trans capsaicin or trans capsaicin compounds is provided, to be used for various and the treatment pain associated conditions, for example, nociceptive pain (passing the pain of complete neuron passage), neuropathic pain (by to the caused pain of the injury of neuromechanism), pain (neuroma and continuous neuroma) from nerve injury, from neuralgic pain (coming from the pain of sacred disease and/or neural inflammation), pain (being derived from the pain of muscle disease and/or inflammation) from myalgia, the pain relevant with painful trigger point, pain from the tumor in the soft tissue, with neurotransmitter imbalance syndrome (the neurotransmitter molecule that is associated with signal transmission in normal nerve is quantity/qualitative destruction) and with plastic surgery lack of proper care relevant pain, for example foot, knee joint, buttocks, spine, shoulder, elbow, hands, the disease of head and neck.Preferred described trans capsaicin or trans capsaicin compounds are hyperpure.

For invention described herein is more fully understood, provide to give a definition:

The term of Shi Yonging " trans capsaicin " had both comprised the transisomer by the capsaicin of method preparation of the present invention herein, comprised the transisomer of capsaicin compounds again.

The term of Shi Yonging " receptor of capsaicin " is included in herein vanillon class (vanilloid) receptor subtype of describing in detail-1 (VR1) herein, but does not mean that and be confined to VR1, and can refer to receptor subtype VR1 and VR2 especially usually.

The specific embodiment

Method disclosed herein can be used for synthesis of trans capsaicin or trans capsaicin compounds.

In some other embodiments of the present invention, trans capsaicin is synthetic by following chemical reaction:

In the first step of synthesis of trans capsaicin, preferably by synthetic first intermediate of alkylated reaction.In a preferred embodiment, preferably 8-methyl-6-n-heptylacetylene acid of synthetic first intermediate of institute.8-methyl-6-n-heptylacetylene acid is synthetic by using halogen valeric acid such as bromine valeric acid, chloro pentane acid, fluorine valeric acid, iodine valeric acid, astatine valeric acid, 1-mesyloxy valeric acid and 1-tosyloxy valeric acid alkylation 3-methyl-butine.

Preferred described alkylated reaction is in the presence of suitable alkali such as n-BuLi, for example hexamethyl phosphoramide and oxolane drive by adding solvent.In some other embodiment of the present invention, the alkali that can use other during the alkylated reaction step is s-butyl lithium (sec-BuLi), tert-butyl lithium (t-BuLi), lithium diisopropylamine (LDA), sodium hydride (NaH), Sodamide. (NaNH for example ₂), Lithamide. (LiNH ₂), lithium methide (MeLi), methyl-magnesium-bromide (MeMgBr), ethylmagnesium bromide (EtMgBr), halogenated alkyl or aryl magnesium and their mixture replacing butyl lithium.

In other the embodiment, hexamethyl phosphoramide can be by 1 at some, 2-dimethyl-3,4,5, and the 6-tetrahydrochysene-(1H) pyrimidone substitutes.

In other the embodiment, in the alkylated reaction step, can preferably use other solvent, for example ether at some.

Crude product from first step in synthetic is preferably by the column chromatography purification.

In other the embodiment, the intermediate of first step can extract purification by Acid-Base at some.

At some in other the embodiment, the intermediate of first step can come purification by vacuum distillation method or vacuum topping method or the crystallizing process under low temperature.

In second step of synthesis of trans capsaicin, preferably synthesize second intermediate by reducing described first intermediate.In a preferred embodiment, synthetic second intermediate of institute 8-methyl-6-nonenoic acid preferably.

Preferred described reduction reaction is by lithium, the tert-butyl alcohol, NH ₃/ THF promotes.Yet, at some in other the embodiment, preferably in described reduction reaction, can use sodium in diisobutyl alanate (DIBAL-H), the liquefied ammonia, have the lithium of the amine of low alkyl, to obtain required product.The percentage yield of required product can change according to the reagent of selecting to be used to finish reduction step.

In other the embodiment, the tert-butyl alcohol can for example sec-butyl alcohol (sec-BuOH), ethanol (EtOH) be replaced by other alkylol at some.

In the third step of synthesis of trans capsaicin, preferably synthesize the 3rd intermediate by activate second intermediate with thionyl halide such as thionyl chloride.In a preferred embodiment, synthetic the 3rd intermediate of institute is acyl halide preferably, for example has the acid chloride of following chemical formula:

R wherein ₂Be to be selected from following group: chlorine, bromine, acylimidazole (imidazolide), carbodiimide and other split-off group (cleaving group), for example mix esters.

In other the preferred embodiment, can preferably use oxalyl chloride, phosphorus pentachloride, Phosphorous chloride. and chlorosulfuric acid to replace thionyl halide at some.

In other the embodiment, the activation of carboxylic acid can realize by forming mixed ester with isobutyl chlorocarbonate, acylimidazole and carbodiimide at some.

At some in other the embodiment, activation can be by 1, and 3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), DCC and I-hydroxybenzotriazole (HOBt) or 1-hydroxyl-combination, EDCI and the HOAt of 7-azepine benzotriazole (HOAt) or the combination of HOBt or carbonyl dimidazoles (CDI), thiocarbonyl imidazoles replace thionyl halide to realize.

In the 4th step of synthesis of trans capsaicin, last trans capsaicin product is by synthetic with acyl halide acyl group benzyl amine derivative.In a preferred embodiment, this benzyl amine derivative is 4-hydroxyl-3-methoxybenzylamine hydrochloride.

In certain embodiments, this 4-hydroxyl-3-methoxybenzylamine HCl salt can be reacted by 4-hydroxyl-3-methoxybenzylamine and acid chloride and replace.

In certain embodiments, the acylation reaction of acyl halide is by being driven by aqueous NaOH (NaOH) in dimethyl formamide (DMF) and ether (EtzO).

In other preferred embodiment, preferably can use other alkali, for example triethylamine, Hunig alkali, 4-dimethylaminopyridine (DMAP) and pyridine replace sodium hydroxide as potassium hydroxide (KOH), Lithium hydrate (LiOH), sodium carbonate, potassium carbonate, alkylamine.

In other the embodiment, preferably can use other solvent such as oxolane, 1 at some, 2-dimethoxy-ethane (DME), acetonitrile, methyl ethyl ketone (MEK), dichloromethane and chloroform replace dimethyl formamide/ether.

In certain embodiments, the 5th and last step come the trans capsaicin product of purification last (slightly) by recrystallization.Preferably, recrystallization comprises the described trans capsaicin product of purification, and it may further comprise the steps: (i) rough trans capsaicin product is dissolved in ether/hexanes mixtures, and this mixture heated is arrived about 40 ℃-Yue 45 ℃; Ii) when stirring with this mixture cool to room temperature; Iii) filter this mixture so that the trans capsaicin product of purification to be provided.As an alternative, last (slightly), trans capsaicin product can be by using the column chromatography purification of silica gel, and the mixture eluting by for example ethyl acetate/hexane is to obtain the trans capsaicin product of purification.

In addition, perhaps as the alternative of above-mentioned the 5th and final step, last trans capsaicin product is by semipreparative HPLC purification, with provide purity be about 97% higher, preferred 98% or higher, more preferably from about 99% or higher hyperpure trans capsaicin.

In certain embodiments, this semipreparative HPLC system is for example adsorption chromatography system, ion exchange chromatography system, size exclusion chromatography or the like.Preferred described HPLC system is the adsorption chromatography system, as the reversed phase chromatography system.

In certain embodiments, the last purification step of the present invention comprises by using isocratic elution (for example, isoconcentration mobile phase) or gradient elution (for example, gradient mobile phase) to carry out semipreparative HPLC.In isocratic elution, use mobile phase eluting chemical compound (for example capsaicin and impurity) with constant composition.Chemical compound moves by pillar when beginning to react, and wherein every kind of chemical compound moves with different speed, thereby causes compound separation.In gradient elution, the change that this chemical compound can be formed along with mobile phase and concentration by increasing organic solvent and/or intensity and eluting.

The mobile phase that is used for the present invention for example comprises usually, acetonitrile, diox, ethanol, isopropyl alcohol, hexane, EtOAc, methanol, oxolane, water and their combination or the like.Most preferably this mobile phase comprises methanol.

The HPLC post that partly prepares that uses according to the present invention includes but not limited to, for example SymmetryC18, Cogent HPS C18, Zorbax SB-C18 StableBond, Hichrom C18, Genesis 300 C18, OmniSphere C18, HxSil C18 etc.

In certain preferred aspects, the trans capsaicin by the inventive method preparation has about 97% or higher, about 98% or higher or about 99% or higher purity.

In certain embodiments, the invention further relates to contain and have an appointment 97% or higher, about 98% or higher or about 99% or the trans capsaicin chemical compound of more highly purified capsaicin.This capsaicin is also referred to as ultrapure capsaicin in this article.

In certain embodiments, the invention further relates to impurity content is about 3% or lower, about 2% or lower or about 1% or the trans capsaicin chemical compound of lower ultrapure capsaicin.

Preferably being suitable for preparing by the trans capsaicin of method of the present invention preparation can be to human or animal's dispersion position administration injectable or the permeable compositions with treatment pain.

Except as otherwise herein provided, term used herein " trans capsaicin " is included in the capsaicin at identical pharmacology position and the transisomer of capsaicin compounds with " trans capsaicin compounds ", for example, as the vanillon receptoroid hypotype-1 of capsaicin.Capsaicin compounds with similar physiologic properties, for example, the triggering C fibrous membrane of depolarization is known by opening the cationic channel that can permeate calcium and sodium.For example, authorized Brand (Procter on March 14th, 1989; Gamble Co.) USP 4,812,446 has described other capsaicin compounds and their preparation method.Authorized the USP4 of LaHann on January 3rd, 1984,424,205 have quoted the analog of capsaicin class as proof.People such as Ton have discussed the pharmacotoxicological effect of capsaicin and analog thereof in Brit.J.Pharm.10:175-182 (1955).

In the place by method synthetic capsaicin compounds of the present invention, this trans capsaicin compounds preferably can provide and the identical physiologic properties of trans capsaicin known in the art.

Suitable trans capsaicin compounds preferably includes, but is not limited to high peppery element, acetaminol, curcumin, anandamide, piperine, piperyline, piperettine, piperoleinA, piperolein B, piperanine and their combination in any or mixture.

Because transisomer is the vehicle of the VR-1 mechanism of generally acknowledging, being particularly suitable for treatment by synthetic trans capsaicin of the inventive method and trans capsaicin compounds can alleviate imbalance or pain by activating this vanillon receptoroid.Synthetic method of the present invention has caused the capsaicin product of mainly being made up of trans capsaicin.Capsaicin product prepared in accordance with the present invention comprises and is less than 1% cis capsaicin.

Vanillon has partly constituted the primary structure composition of trans capsaicin and trans capsaicin compounds, therefore, the reactive site of these trans-compounds of suggestion is called vanillon receptoroid (Szallasi 1994 Gen.Pharmac.25:223-243) more widely.On the contrary, though the cis-isomer of capsaicin has activity by a lot of mechanism, yet VR-1 still is considered to not comprise the main influence of this reagent.

VR-1 is via vanillon class such as capsaicin and the activatory Ca of resin toxin (resiniferatoxin) ²⁺Permeable non-selective cationic channel.When representing with mammalian cell people's vanillon receptoroid be surpass under 42 ℃ the temperature and pH be lower than 5.5 times activatory by capsaicin.The activation of all these effectors can partly or entirely be blocked by the effect of capsaicin antagonist capsazepine.

VR-1 finds along the whole length of the main sensory neuron with somata I Dorsal root and nervi trigeminus maincenter.These neurons have little extremely medium sized diameter and form unmyelinated C fiber.The positive neuron of VR-1 with C-fiber can be divided into two subclass: Toplink with non-Toplink.In the neuropeptide of finding in the vanillon sensitive neuron, Substance P and CGRP are characterized best.The capsaicin sensitive neuron behavior ground of non-Toplink has P2X ₃Intersection between purinoceptor and purinoceptor and vanillon receptoroid is lost quick.The neuronic subclass of knotty neuroganglion also comprises VR-1.Can believe VR-1 for various deleterious stimulations, comprise that heat, acid and some phytotoxins have played the effect that receptor is shared.In addition, in the process of inflammation, the endogenous substance that is discharged by activatory immunocyte can also aim at the VR-1 target, except nociception, and (CGRP-mediated) local vascular diastole that its activation has also caused CGRP-to reconcile.In gastrointestinal tract, can believe that this mechanism has main effect in mucus (mucousal) protection.Comparatively speaking, VR-1 is at main neuronic maincenter end, that is, the effect of the dorsal horn of spinal cord and the interior living activator of this receptor is unknown.

Vanillon class such as trans capsaicin have the effect of two stages to responsive peripheral nerve, be initial irritability stage (being shown as pain and/or nerve inflammation), next be commonly referred to as the quick unmanageable state (Szallasi 2000 Trends Neurosci.25:491-497) that continues that loses.

Trans capsaicin compositions of the present invention can be by providing pain relief at specific position, and be used for treating the various diseases relevant with pain.The embodiment of the disease that will treat includes but not limited to that the compositions and methods of the invention can be used to handle the various diseases relevant with pain.The embodiment of the disease that will handle includes but not limited to: nociceptive pain (passing the pain of complete neuron passage), neuropathic pain (by to the caused pain of the injury of neuromechanism), pain (neuroma and continuous neuroma) from nerve injury, from neuralgic pain (coming from the pain of sacred disease and/or neural inflammation), pain (being derived from the pain of muscle disease and/or inflammation) from myalgia, the pain relevant with painful trigger point, pain from the tumor in the soft tissue, with neurotransmitter imbalance syndrome (the neurotransmitter molecule that is associated with signal transmission in normal nerve is quantity/qualitative destruction) and with plastic surgery lack of proper care relevant pain, for example foot, knee joint, buttocks, spine, shoulder, elbow, hands, the disease of head and neck.

In certain embodiments, the invention further relates to the pharmaceutical composition that comprises according to the capsaicin (for example, hyperpure capsaicin) of the present invention's preparation.Preferably said composition comprises according to the capsaicin (for example, hyperpure capsaicin) of the present invention preparation and is suitable for vehicle to human or animal's administration.Preferably this capsaicin is incorporated in the described vehicle.More preferably this vehicle is suitable for human or animal's infiltration or drug administration by injection.

In certain embodiments, capsaicin is dissolved in other vehicle that is suitable for preparing injectable or permeable solution usually, for example in oil, propylene glycol or other solvent.The acceptable vehicle of suitable pharmacology preferably includes aqueous vehicles, non-aqueous vehicle, antimicrobial, isotonic agent, buffer agent, antioxidant, suspension and dispersant, emulsifying agent, sequestering agent or chelating agen and their combination in any or mixture.The example of aqueous vehicles preferably include sodium chloride injection, antibacterial restrain property sodium chloride injection, ringer's inj, etc. open glucose injection, sterile water for injection, antibacterial and restrain property sterile water for injection, glucose lactate ringer's inj and their combination in any or mixture.Non-aqueous parenteral injecting drug use vehicle preferably includes nonvolatile oil, cottonseed oil, Semen Maydis oil, Oleum sesami, Oleum Arachidis hypogaeae semen and their combination in any or the mixture of plant origin.Acceptable other pharmacology's vehicle also preferably include be used for can with miscible vehicle ethanol, Polyethylene Glycol, glycerol and propylene glycol of water and sodium hydroxide, hydrochloric acid, citric acid or the lactic acid that is used to reconcile pH, and their combination in any or mixture.Can use above-mentioned vectorial combination in any.Be preferred for vehicle of the present invention and comprise about 20% PEG300, the sucrose of about 10mM histidine and about 5% in water, to be used for injection.

As alternatively or additionally, below one or more reagent can also be included in the compositions of the present invention:

The antimicrobial that is used for described compositions, comprise the concentrate of restraining antibacterial or restraining fungus, preferably include phenol, cresol, mercurial, benzyl alcohol, methaform, ethyl and propyl group metagin, thiomersalate, phenylmethane ammonium chloride (benzalkoniumchloride), the benzene first and second oxychlorination ammoniums (benzethonium chloride) and their mixture;

The isotonic agent that is used for the present composition preferably includes sodium chloride, glucose and their combination in any or mixture;

The buffer agent that is used for compositions of the present invention preferably includes acetate, phosphate, citrate and their combination in any or mixture;

The antioxidant that is used for compositions of the present invention preferably includes ascorbic acid, sodium bisulfate and their combination in any or mixture;

The suspension and the dispersant that are used for compositions of the present invention preferably include sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, polyvinyl pyrrolidone and their combination in any or mixture;

The emulsifying agent that is used for compositions of the present invention preferably includes Spheron MD 30/70 (Tween 80).

Be used for metallic sequestering agent of the present invention or chelating agen and preferably include ethylenediaminetetraacetic acid.

Preferably, when the capsaicin of single dose by administration individually or when not having under the local anesthesia administration, then the capsaicin of this dosage can be preferably makes up with the acceptable vehicle of pharmacology that is used to inject or permeate.

According to the acceptable vehicle of selected pharmacology, in certain embodiments, the capsaicin of single dose can be with aqueous solution or the suspension administration that is used to inject or permeate.

The following examples are for example understood various aspects of the present invention.In any case they should not be considered to be yet and limit claim by any way.

Step 1: with bromine valeric acid alkylation 3-methyl-butine

The first step of synthesis of trans capsaicin relates to by synthesizing first intermediate as (8-methyl-6-n-heptylacetylene acid) with halogen valeric acid such as bromine valeric acid alkylation 3-methyl-butine.The first intermediate composition is successfully synthetic by following example I (a)-(e) in laboratory:

Example I (a)

8-methyl-6-n-heptylacetylene acid is to add anhydrous tetrahydro furan (15ml) in three mouthfuls of RB flasks by 50ml under thermometer, magnetic stirring apparatus and logical nitrogen/denitrogen gas are housed and hexamethyl phosphoramide (3.8ml) prepares in two reactions that separate (reaction 1 and reaction 2).Mixture is cooled to-78 ℃ to-75 ℃ approximately approximately.Add methyl butine (1g) then, next at about-78 n-BuLis (Rxn 1=1 equivalent and Rxn 2=2 equivalent) that drip 2.5M to the temperature of a ℃ pact-65 ℃.Mixture in two reactions all is warmed to-30 ℃ approximately gradually, and under this temperature stir about 30 minutes.Approximately under-30 ℃ in about 10 to about 15 minutes Dropwise 5-bromine valeric acid (1.33g is in the THF of 3ml) solution.Then, reaction 1 and the mixture that reacts 2 are warmed to room temperature gradually, and stir a whole night.

Then this reactant mixture (rxn1 and 2) is heated.The 3M HC1 of about 50ml is joined in the solution of the solution of reaction 1 and reaction 2.(2 * 100ml) extract described solution and use the salt water washing to use ethyl acetate then.This extract has produced about 1.1g crude product from reacting 1, produced about 0.8g crude product 2 from reacting.

Use about 50g silica gel purification to react 1 crude product by column chromatography, and with the mixture eluting of 2: 1 hexane/ethyl acetate.Gleanings is mixed.Under vacuum, remove and desolvate with the midbody product (8-methyl-6-n-heptylacetylene acid) of producing step 1.The midbody product that is produced is lurid oil.The intermediate weight that is produced is about 0.55g (productive rate=46%).

Example I (b)

8-methyl-6-n-heptylacetylene acid is by adding hexamethyl phosphoramide (30ml) in three mouthfuls of BR flasks of the 500ml that mechanical agitator, addition funnel and thermometer are housed and anhydrous tetrahydro furan (120ml) prepares under nitrogen.Mixture is cooled to-78 ℃ to-70 ℃ approximately approximately.Add 3-methyl-butine 7.9gm (11.8ml) at about-75 ℃ then, next in about 20 minutes, drip the n-BuLi (46ml) of 2.5M.Mixture is warmed to-30 ℃ of whiles of pact stir about 45 minutes.Approximately under-30 ℃-Yue 25 ℃ in about 20 minutes dripping bromine valeric acid (10.4g is in the anhydrous THF of about 20ml) solution.Then this mixture is heated gradually to room temperature and stir a whole night.The TLC of reactant mixture demonstrates does not have raw material to exist.

HC1 (100ml) and the water (100ml) of 3M are joined in this mixture.Temperature is increased to about 3 ℃.(3 * 200ml) extract this mixture to use ethyl acetate then.Extract is made up and uses the salt water washing.By the anhydrous sodium sulfate drying organic layer, filter and under about 35 ℃ of vacuum, remove and desolvate, to produce the rough end product of step 1, this product is light orange/xanchromatic oil.By column chromatography with silica gel (about 250g) this rough end product of purification and with 1: 2 ethyl acetate/hexane mixture eluting.Mix this gleanings, and under vacuum, remove and desolvate, obtain the intermediate of the step 2 of light yellow oil.Its weight is about 6.7g (71% productive rate).

Example I (c)

Under logical nitrogen/denitrogen gas with hexamethyl phosphoramide (60ml) and anhydrous tetrahydro furan (240ml; The BHT polymerization inhibitor that contains 250ppm) joins in 3 mouthfuls of BR flasks of the 1L that mechanical agitator, addition funnel and thermometer are housed.Cooling solution is to-70 ℃.3-methyl-butine of 15.7gm (23.6ml) is joined in this solution.Next, under being lower than approximately-50 ℃, in about 25 minutes, drip 2.5M n-BuLi (92ml).Then this solution is warmed to gradually-30 ℃ and stirred 50 minutes.Approximately-30 ℃ to approximately under-25 ℃ in about 30 minutes the Dropwise 5-solution of bromine valeric acid (20.8g) in anhydrous tetrahydro furan (40ml).Heat this mixture to room temperature gradually and stir a whole night.The TLC of reactant mixture has shown more purified reaction.

Reactant mixture is cooled to 5 ℃ to 10 ℃.3M HCl (100ml) and water (150ml) are joined in this solution.(3 * 200ml) extract formed mixture with ethyl acetate.The TLC of acetic acid ethyl ester extract shows that twice ethyl acetate extraction is just enough.Two kinds of acetic acid ethyl ester extracts are mixed, wash and pass through anhydrous Na with saline (350ml) ₂SO ₄Dry also filtration.Under vacuum, remove and desolvate to produce the midbody product of about 25.8g.

Use this rough midbody product of about 300g silica gel purification by column chromatography, and with the mixture eluting of 1: 2 ethyl acetate/hexane.

Mix the gleanings that contains required product.Under vacuum, remove and desolvate, obtained about 15g intermediate (89% productive rate).Described intermediate is lurid oil.

Example I (d)

Under logical nitrogen/denitrogen gas, anhydrous tetrahydro furan (200ml) and hexamethyl phosphoramide (46ml) are added in three mouthfuls of BR flasks of the 1L that mechanical agitator, addition funnel and thermometer are housed.Cooling solution is to-70 ℃.Add 3-methyl-butine (18.1ml), produced limpid solution.Under-70 ℃, in about 25 minutes, drip the 2.5M n-BuLi in the hexane (90.7ml).This solution is warmed to-30 ℃ gradually, and stirred 1 hour down at about-25 ℃ to about 40 ℃.At-30 ℃ down in about 10 minutes in Dropwise 5-bromine valeric acid (16g is in the anhydrous THF of 40ml).Mixture is heated gradually to room temperature, and under nitrogen, stir a whole night.The TLC of reactant mixture show the reaction finished.

Reactant mixture is cooled to about 10 ℃, and with 3N HCl (80ml) acidified reaction mixture so that pH is about 3.Add entry (200ml).(2 * 300ml) extract this solution with ethyl acetate.With the organic layer mixing and with saline (200ml) washing, pass through anhydrous Na ₂SO ₄Dry also filtration.Under about 35 ℃ of vacuum, remove and desolvate, obtain lurid oil (weight 18.7g).Use this product of silica gel (about 350g) purification by column chromatography, and with the mixture eluting of 1: 2 ethyl acetate/hexane.

Mix the gleanings that contains required product.Under vacuum drying the whole night after, removing under vacuum desolvates has obtained lurid oil (wt.=14.5g).

Example I (e)

Oxolane (240ml, poly-by the BHT resistance) and hexamethyl phosphoramide (60ml) under covering, nitrogen are added in three mouthfuls of BR flasks of the 1L that mechanical agitator, addition funnel and thermometer are housed.This mixture is cooled to-70 ℃.Add 3-methyl-butine (15.6g) then, next be lower than under-50 ℃ the internal temperature and drip n-BuLi (92ml).In the time of 1hr, this mixture is warmed to-30 ℃ gradually then.Keeping internal temperature to be lower than the solution of adding 5-bromine valeric acid (20.7g) in oxolane (40ml) in-30 ℃.This mixture is warmed to room temperature gradually and stirs a whole night.TLC at the reactant mixture in this stage shows that whole bromine valeric acids consumes and reacts and finish.

Reactant mixture is cooled to 5-10 ℃, adds 3M HCl (100ml) and water (150ml) then, so that internal temperature did not rise 15 ℃.(2 * 200ml) extract and concentrate by this organic layer of dried over sodium sulfate with under vacuum, have obtained the rough midbody product of step 1 to use ethyl acetate then.Use this thick midbody product of silica gel/substrate purification of 10: 1 by the flash chromatography method, and with the mixture eluting of 1: 2 ethyl acetate/hexane.Mix described product fraction and concentrated midbody product (8-methyl-6-n-heptylacetylene acid), under vacuum, this midbody product is dried to constant weight then so that step 1 to be provided.The midbody product of being produced is lurid oil.The weight of gained intermediate is 15g (productive rate=89%).The spectroscopic data of the midbody product of step 1 is as follows: ¹H NMR (CDCl ₃) δ 2.56-2.48 (and m, 1H), 2.38 (t, 2H), 2.18 (dt, 2H), 1.75 (br q, 2H), 1.53 (br q, 2H), 1.13 (d, 6H); MS167 (M '-1); GC:100%.

Example I (f)

Under argon feeding/discharge, anhydrous THF (5L, poly-by the BHT of 250ppm resistance) and HMPA (1.3L) joined be equipped with mechanical agitator, thermometer, addition funnel and the four-hole round-bottomed flask of 22L in.Formed mixture is cooled to-60 ℃, and adds 3-methyl isophthalic acid-butine (509mL).Be no more than then add under-60 ℃ the temperature n-BuLi (2.5M, 502ml).Reactant mixture is warmed to gradually is no more than-30 ℃ and kept about one hour.5-bromine valeric acid (450g) solution of anhydrous THF (900mL contains the BHT of 250ppm) is being no more than by addition funnel under-30 ℃ the temperature and adding.This reactant mixture is heated to room temperature gradually and stirs a whole night.Monitor this reaction by TLC.

With ice bath reactant mixture is cooled to≤10 ℃, and in the quenching of≤30 ℃ of following waters (10L) piecemeal.Use cold this water-bearing layer of 6N HCl acidify to be about 2-3 to pH, with twice of ethyl acetate extraction (10L, 6L).Mix the extract of ethyl acetate and wash with saline (10L).Passing through anhydrous Na ₂SO ₄After the drying, filter this ethyl acetate solution, and under about 45 ℃ of vacuum, be concentrated into drying, obtained crude product.

Use normal phase place the Biotage chromatograph, with ethyl acetate/hexane (1: 2) as this crude product of eluent purification.Mix the gleanings that contains required product, and under vacuum, remove and desolvate, produced the product of 237g (77% productive rate) light yellow oil.

Example I (g)

8-methyl-6-n-heptylacetylene acid (1.4g) is dissolved among the MTBE (10ml).Alkalize this solution to pH be 10-11, and with MTBE extracting twice (2 * 8ml).Use cold 6N HCl that aqueous layer is acidified to pH and be about 2-3, and extract (2 * 8ml) with MTBE.Mix the extract of MTBE and use saline (4ml) washing.Use anhydrous Na ₂SO ₄Dry this organic layer, filtration also is concentrated into drying under vacuum, obtained product.

The reduction of step 2:8-methyl-6-n-heptylacetylene acid

Second step of synthesis of trans capsaicin relates to by reduction 8-methyl-6-n-heptylacetylene acid and synthesizes second intermediate (8-methyl-6-nonenoic acid).8-methyl-6-n-heptylacetylene acid is under lab successfully reductive by following examples II (a)-(g):

Example II (a)

Under logical nitrogen/denitrogen gas, be equipped with in three mouthfuls of RB flasks of 250ml of thermometer, magnetic stirring apparatus and condenser, 8-methyl-6-n-heptylacetylene acid is being dissolved in the anhydrous tetrahydro furan (30ml) and the tert-butyl alcohol (0.42ml).Solution is cooled to-40 ℃.Approximately-40 ℃ to approximately under-50 ℃ with ammonia condensing in flask.Add sodium one by one.Adding the sodium sheet makes solution become navy blue.Stirred this solution about 30 minutes down at about-40 ℃ to about-45 ℃.Add NH ₄Cl (1.7g) (about 32mmol), and this mixture is warmed to room temperature gradually.Make ammonia evaporate a whole night.The TLC of reactant mixture shows about 30% to about 40% product productive rate.

This reactant mixture is studied (worked-up).Add cold water (100ml) and temperature is increased to about 24 ℃ from about 18 ℃.Then with this solution of 6N HCl acidify to pH be about 3.With ethyl acetate (2 * 80ml) extraction solutions.Ethyl acetate layer is mixed, use the salt water washing, pass through anhydrous Na ₂SO ₄Dry also filtration.Under vacuum, remove and desolvate.Obtained the midbody product of light yellow oil.

Example II (b)

Under logical nitrogen/denitrogen gas, 8-methyl-6-n-heptylacetylene acid, anhydrous tetrahydro furan and the tert-butyl alcohol are joined in three mouthfuls of RB flasks of 250ml that magnetic stirring apparatus, acetone-dry-ice condenser and thermometer are being housed.Solution is cooled to-50 ℃ approximately.Under-40 ℃ with ammonia condensing in reaction flask.The thin slice that adds sodium in about 10 minutes one by one.This solution was warmed to approximately-33 ℃ and stir about 2 hours.The TLC of reactant mixture shows about 30% to about 40% product productive rate.Add other sodium (about 0.3g).Evaporate NH gradually ₃Reactant mixture is warmed to room temperature gradually and stirs a whole night.

Add NH ₄Cl (1g) also stirred this solution about 30 minutes.The water quenching is also with ethyl acetate (2 * 60ml) extractions then.Acetic acid ethyl ester extract is mixed and use the salt water washing, pass through anhydrous Na ₂SO ₄Dry also filtration removes under vacuum and desolvates.Obtained the midbody product of light yellow oil.

Example II (c)

Under logical nitrogen/denitrogen gas, 8-methyl-6-n-heptylacetylene acid is joined in three mouthfuls of RB flasks of 250ml that mechanical agitator, condenser and thermometer are housed.Solution is cooled to-40 ℃ approximately.In this flask, add the ammonia of condensation, stir the mixture until having obtained solution.Add sodium one by one up to having obtained blue mixture.Add NH ₄Cl also stirs gained mixture a whole night with evaporation NH ₃

Add entry (100ml) and ethyl acetate (60ml).Then with this solution of 6N HCl acidify to its pH be about 3.Extract the water-bearing layer with the organic layer separation and with ethyl acetate (60ml).Ethyl acetate layer is mixed, with the salt water washing and pass through anhydrous Na ₂SO ₄Dry.

Example II (d)

With anhydrous tetrahydro furan (200ml does not contain polymerization inhibitor) and anhydrous tertiary butanol (7ml) dilution 8-methyl-6-n-heptylacetylene acid (10g; About 10ml).This mixture is cooled to-50 ℃ approximately.(about 300-400ml) condenses in this mixture with ammonia.

In 30 minutes, add lithium (3-4g) one by one.Show at the TLC that adds 30 minutes afterreaction mixture of lithium and not have raw material.Under argon, stir this reactant mixture a whole night then to remove NH ₃Evaporant.Further TLC shows some by-products of existence.

Add anhydrous tetrahydro furan (about 200ml), next add NH ₄Cl (about 30g).Stirred the mixture 30 minutes.Frozen water (about 400ml) piecemeal is joined in this mixture.(3 * 300ml) extract this mixture to use ethyl acetate then.The TLC of reactant mixture shows that twice extraction is just enough.

Two kinds of extracts of beginning are mixed,, pass through anhydrous Na with saline (200ml) washing ₂SO ₄Drying and filtration.Under about 35 ℃ of vacuum, remove then and desolvate, produced the midbody product of the yellow oil of about 7.8g like this.

Example II (e)

Under argon feeding/discharge, 8-methyl-6-n-heptylacetylene acid (4g), anhydrous tetrahydro furan (120ml does not contain polymerization inhibitor) and the tert-butyl alcohol (2.8ml) are joined in three mouthfuls of RB flasks of 1L that condenser, thermometer and magnetic stirring apparatus are housed.This solution is cooled to-55 ℃ to-45 ℃ approximately approximately.With NH ₃(about 150-200ml) condenses in the reaction flask.Under about-45 ℃, add lithium (0.1-0.15g/ea.) at-60 ℃ one by one, and stir the navy blue disappearance before a slice lithium under adding of this mixture.TLC after adding the 0.4g lithium shows about 40% to about 50% conversion ratio.Add other lithium (0.75g) then, and observe end by TLC.This reactant mixture is stirred in addition one hour (temperature-45 ℃ to-42 ℃).Add NH partially in about-45 ℃ of extremely about-42 ℃ of next parts ₄Cl (2g).Gradually mixture is warmed to room temperature.The TLC of this reactant mixture shows the product of pure (clean).

This reactant mixture is cooled to about 5 ℃ and with frozen water (200ml) quenching.Temperature is elevated to about 25 ℃.Use then 6N HCl (adding about 50ml partially) souring soln 25 ℃ of next parts to its pH be about 2-about 3.(2 * 300ml) extract this mixture to use ethyl acetate then.Ethyl acetate layer is mixed,, pass through anhydrous Na with saline (200ml) washing ₂SO ₄Dry also filtration.The mixture of concentrate drying under about 30 ℃ of vacuum has obtained the midbody product (wt.=3.8g) of light yellow oil.

Use this midbody product of silica gel (about 100 to about 110g) purification by flash column chromatography, and with the mixture eluting of 1: 3 ethyl acetate/hexane.

The gleanings that will contain required product mixes.Under vacuum, remove and desolvate, obtained lurid midbody product (wt.=3.7g).

Example II (f)

Under argon feeding/discharge, 8-methyl-6-n-heptylacetylene acid (4g), anhydrous tetrahydro furan (120ml does not contain polymerization inhibitor) and the tert-butyl alcohol (2.8ml) are joined in three mouthfuls of RB flasks of 1L that condenser, thermometer and magnetic stirring apparatus are housed.This solution is cooled to-55 ℃ to-45 ℃ approximately approximately.With NH ₃(about 150-200ml) condenses in the flask.Under about-65 ℃ to about-50 ℃, add lithium (about 4-5g) in about 1 hour 40 minutes.Then at-35 ℃ of following about 30 minutes of formed mixture of stirring and by the TLC monitoring, until the disappearance of observing raw material.

Use NH ₄Cl (about 20g) piecemeal disappears up to blueness to this solution quenching.Gradually this mixing is warmed to room temperature and stirs a whole night.

Piecemeal adds frozen water (about 400ml) and makes its pH reach about 2-about 3 with the formed solution of 6N HCl (about 150ml) acidify.(2 * 400ml) extract this mixture with ethyl acetate.(300ml) washs this extract with saline, passes through anhydrous Na ₂SO ₄Drying is filtered and is concentrated under vacuum, obtains lurid oil (wt.=14.2g).Use silica gel (about 300-350g) purification with column chromatography, and with this crude product of mixture eluting of 1: 2 ethyl acetate/hexane.

Mix this gleanings and remove under vacuum and desolvate, dry this product is to obtain the midbody product of 12.2g (86% productive rate) under vacuum.

Example II (g)

Under argon, oxolane (200ml does not contain polymerization inhibitor), acid (14g) and the tert-butyl alcohol (7.7g) are joined in three mouthfuls of RB flasks of 1L that mechanical agitator, addition funnel and thermometer are housed.With dry ice/acetone batch formed solution is cooled to-50 ℃.(about 200ml) condenses in the reactant mixture with ammonia.It is lasting up to blueness that piecemeal adds lithium in this flask then.Be lower than-35 ℃ and stirring down these reactant mixtures and by the TLC monitoring, until the conversion fully of observing raw material.Come this reaction of quenching by adding 20g ammonium chloride at-40 ℃.Gas chromatogram has confirmed only to have synthesized trans (E) isomer.

Be warmed to room temperature and in the time at 10hr after the vaporized ammonia, adding frozen water (400ml), then with this mixture of 6N HCl acidify to pH be 2-3.(2 * 400ml) extract this mixture to use ethyl acetate then.Blended Organic substance with saline (300ml) washing and by sodium sulfate (100g) drying, is filtered and concentrates under vacuum, obtain second midbody product.This second midbody product is lurid oil, on silicagel column with flash chromatography to its purification, obtain the yellow oil (86% productive rate) of pure trans 8-methyl-6-nonenoic acid of 12.2g.The spectroscopic data of second midbody product is as follows: ¹H NMR (CDC1 ₃) δ 5.43-5.29 (and m, 2H), 2.35 (t, 2H), 2.22 (m, 1H), 2.02 (m, 2H), 1.65 (m, 2H), 1.41 (m, 2H), 0.95 (d, 6H).MS169(M ^--1)。

Example II (h)

Under argon, 8-methyl-6-n-heptylacetylene acid (225g), anhydrous tetrahydro furan (2.7L does not contain polymerization inhibitor) and the tert-butyl alcohol (154ml) are joined in the four-hole RB flask of the 22L that condenser, thermometer and mechanical agitator are housed.This mixture is cooled to-55 ℃ to-45 ℃ approximately approximately.(about 4L) condenses in the flask with ammonia.The temperature next part that is being no more than-33 ℃ adds lithium (about 30-35g) partially, stirs to be no less than 30 minutes under the maintenance navy blue.Piecemeal adds NH ₄Cl (143g).Gradually formed mixture is warmed to room temperature and makes the ammonia evaporation.

Piecemeal adds frozen water (3L).Use 6N HCl that formed mixture is acidified to pH≤3, and (2 * 4.5L) extract this mixture with ethyl acetate.Organic layer is mixed, with saline (5L) washing, by dried over sodium sulfate and filtration.Under vacuum, remove to desolvate and obtain crude product.

By this crude product of Biotage column chromatography (ethyl acetate/hexane 1: 3) purification, obtained the product of 214g (94%) light yellow oil.Gas chromatogram has confirmed that the ratio of trans/cis (E/Z) is about 94: 3 to about 94: 5.

The activation of step 3:8-methyl-6-nonenoic acid

The third step of synthesis of trans capsaicin relates to by activation 8-methyl-6-nonenoic acid and synthesizes the 3rd intermediate (acyl halide).8-methyl-6-nonenoic acid successfully is converted into into acyl halide by following examples III (a)-(c) in laboratory.

EXAMPLE III (a)

8-methyl-6-nonenoic acid is joined in three mouthfuls of RB flasks of the 50ml that condenser, addition funnel, thermometer and magnetic stirring apparatus are housed.Thionyl chloride (SOCl at room temperature about 25 minutes ₂) 3.9ml.Heated this solution about 1 hour with water-bath down at about 50 ℃ to about 60 ℃ then.To about 45 ℃ of vacuum, remove excessive thionyl chloride at about 40 ℃, obtained about 3g the 3rd midbody product (acid chloride; The oil of sundown).

EXAMPLE III (b)

8-methyl-6-nonenoic acid (12g) is joined in three mouthfuls of RB flasks of the 100ml that magnetic stirring apparatus, addition funnel, condenser and thermometer are housed.Thionyl chloride (15.5ml) in 30 minutes under room temperature, nitrogen.Heat this solution then about 1 hour so that temperature reaches about 60 ℃ from about 50 ℃, or produce about 74 ℃ of brown solution.To about 42 ℃ of following vacuum, remove excessive thionyl chloride at about 40 ℃, obtain the brown oil of about 13.4g.Dry this midbody product 1 hour under 40 ℃ of vacuum then.

EXAMPLE III (c)

8-methyl-6-nonenoic acid (12g) is joined in three mouthfuls of RB flasks of the 100ml that magnetic stirring apparatus, addition funnel, condenser and thermometer are housed.Thionyl chloride (25.2ml) in 30 minutes time then.In the time of 1hr, this reactant mixture is heated to about 65-74 ℃ subsequently.Under vacuum, remove excessive thionyl chloride, obtain rough acid chloride product.Should be used for the 4th synthesis step by rough acid chloride product then, and not be further purified to produce trans capsaicin.

EXAMPLE III (d)

Handle 8-methyl-6-nonenoic acid (200g) with thionyl chloride (419g).Then at about 70 ℃ of about 1hr of following reacting by heating mixture.Under vacuum, remove unnecessary thionyl chloride, obtain the 249g crude product.Then rough acid chloride product is used for the 4th synthesis step, is not further purified.

Step 4: benzyl amine derivative is coupled to acyl halide

The 4th step of synthesis of trans capsaicin relates to the end product by coupling benzyl amine derivative synthesis of trans capsaicin to the acyl halide.Benzyl amine derivative is under lab by following examples IV (a)-(c) and successfully be coupled on the acyl halide.

EXAMPLE IV (a)

Under nitrogen, 4-hydroxyl-3-methoxybenzylamine HCl salt (3.35g) and dimethyl formamide (10ml) are joined in three mouthfuls of RB flasks of the 100ml that addition funnel, thermometer and magnetic stirring apparatus are housed.At room temperature piecemeal adds 5N NaOH (7ml).Stirred this mixture 30 minutes down at 35 ℃.Then this mixture is cooled to about 0 ℃ to about 5 ℃.Be added dropwise to acid chloride (in step 3, producing) in the absolute ether (30ml) at about 0 ℃ in following 20 minutes to about 5 ℃ or 10 ℃.Add other 5ml anhydrous dimethyl formamide.Gradually this mixture is warmed to room temperature and under nitrogen, stirs a whole night.

Add entry (150ml).(1 * 100ml and 1 * 50ml) extracts this mixture with ethyl acetate.With 1N HC1 (2 * 60ml), next use saturated NaHCO ₃(2 * 100ml) and the extract of salt water washing ethyl acetate.Pass through anhydrous Na then ₂SO ₄Dry this extract and filtration.Remove to about 40 ℃ of vacuum at about 35 ℃ and to desolvate, obtain condensed light orange/peach residue (wt.=3.4g).

Use this crude product of silica gel purification of the about 160g of about 150-by column chromatography, and with the mixture eluting of 1: 1 ethyl acetate/hexane.

Mixing concentrates under about 40 ℃ of vacuum from the gleanings of column type purification, and dry under vacuum, has obtained the white solid product that 3.1g needs.

EXAMPLE IV (b)

Under nitrogen, 4-hydroxyl-3-methoxybenzylamine hydrochloride (13.4g) and dimethyl formamide (40ml) are joined in three mouthfuls of RB flasks of the 500ml that mechanical agitator, addition funnel and thermometer are housed.This mixture is cooled to about 10 ℃.The NaOH (28ml) that adds 5N with the ice-water bath piecemeal.Stir this solution 30 minutes down at about 20 ℃, be cooled to 5 ℃ then.Under 5 ℃, drip the acid chloride (120ml) (temperature is lifted to about 7 ℃) in the absolute ether in about 1 hour.Gradually this solution is warmed to room temperature and stirs a whole night.

Add entry (400ml), (1 * 400ml and 2 * 200ml) extracts formed mixture to use ethyl acetate then.The TLC of extract shows that twice ethyl acetate extraction is just enough.(2 * 200ml and 1 * 100ml) washs this acetic acid ethyl ester extract with 1NHC1.Use saturated NaHCO then ₃(2 * 200ml and 200ml), salt water washing organic layer pass through anhydrous Na ₂SO ₄Drying and filtration.Under vacuum, remove and desolvate and with this residue of ether (* 2) co-evaporated, produced the residue crude product (wt.=20.2g) of about 21g light brown viscous.Dry this residue (wt.=20.2g) a whole night under vacuum.

Use the described product of about 600g silica gel purification by column chromatography, and use i) mixture (2L) of 2: 3 ethyl acetate/hexane; Ii) the mixture of 1: 1 ethyl acetate/hexane (3L) and iii) 3: 2 mixture (3L) eluting of ethyl acetate/hexane to obtain crude compound.

The mixed collection thing removes under about 40 ℃ of vacuum and desolvates.With this product of ether (x2) coevaporation, and under vacuum dry a whole night, obtained the white solid product (wt.=14.1g, 65% productive rate) that needs.HPLC96% purity.

Also the gleanings of compound (overlap) is mixed to be incorporated in to remove under the vacuum and desolvate, obtain the product of 2.4g than low-purity.But also the by-product (1.4g) of separation and sign ester.

In other embodiments of the present invention, adding NaHCO ₃The back is detected on the test tube scale by the crude product purification that the NaOH with 2N handles.Can find that the salt that produces is dissolvable in water in the ethyl acetate.Find in addition, marquis when in reactant mixture, adding acid chloride, control reaction temperature (about 5-10 ℃) is better.

EXAMPLE IV (c)

Under nitrogen, 4-hydroxyl-3-emilium tosylate hydrochlorate (13.4g) and dimethyl formamide (40ml) are joined in three mouthfuls of RB flasks of the 500ml that mechanical agitator, addition funnel and thermometer are housed.With solution be cooled to about 10 ℃ and Dropwise 5 N sodium hydroxide 28ml so that internal temperature remain on below 20 ℃.Stir this solution 30 minutes at 20 ℃, be cooled to 5 ℃ then.In case cool down, in 1 hour time, add the solution of acid chloride (13.3g) in ether (120ml), keeping internal temperature simultaneously is 3-7 ℃.Stirred this reactant mixture 12 hours at 20 ℃ then.

Water (400ml) and ethyl acetate (2 * 200ml) washing reaction mixture.With the HCl of 1N (2 * 200ml), saturated sodium bicarbonate (2 * 200ml) and the blended Organic substance of saturated sodium-chloride (200ml) washing right, after pass through dried over sodium sulfate.Under vacuum, remove and desolvate, produced peach solid, use mixture (2: 3 to 3: the 2) purification of silica gel and ethyl acetate/hexane by flash chromatography.Pure fraction is mixed, and weight is corresponding to the 14.1g of 65% productive rate (HPLC=96% scope % purity).

, handle in other the embodiment at some,, obtained the product of high-purity and high-recovery thus so can in the 4th step, preferably avoid flash chromatography because crude product is a direct crystallization.

The use ether/hexane (1: 2,150ml) trans capsaicin recrystallization under 40-45 ℃ to obtaining by method described above.In 2 hours time period with this mixture cool to room temperature.Filter the precipitate of white and be dried constant weight (weight=12.7g (productive rate=91%)).The spectroscopic data of trans capsaicin product is as follows: ¹H NMR (CDCl ₃) δ 6.86-6.75 (and m, 3H), 5.82 (br s, 2H), 5.35-5.32 (m, 2H), 4.34-4.32 (d, 2H), 3.86 (s, 3H), 2.22-2.17 (m, 3H), 2.00-1.95 (m, 2H), 1.75-1.65 (m, 2H), 1.45-1.35 (m, 2H), 0.95 (d, 6H); MS=306 (M+1).C ₁₈H ₂₇NO ₃Analysis; C, 70.79; H, 8.91; N, 4.59; Find: C, 70.94, H, 8.94, N, 4.75.

The HPLC purity of synthetic trans capsaicin (area %) is 98%.

EXAMPLE IV (d)

Under argon, 4-hydroxyl-3-methoxybenzylamine hydrochloride (245g) and dimethyl formamide (700ml) are joined in the four-hole RB flask of the 12L that mechanical agitator, addition funnel and thermometer are housed.Then this suspended substance is cooled to 10 ℃, and at the sodium hydroxide (494ml) that is lower than Dropwise 5 N under 20 ℃ the temperature.This solution is cooled to about 10 ℃ and stirred 30 minutes, is cooled to about 5 ℃ then.Drip the solution of acid chloride (249g) in ether (1.7L) down at about 5 ℃.Gradually reactant mixture is warmed to room temperature and stirs a whole night.

This reactant mixture is separated in 1N HCl (5L) and ethyl acetate (5L).Separately aqueous layer is also with ethyl acetate (5L) extraction.Mix organic layer, with the HCl (5L) of 1N, saturated sodium bicarbonate (3 * 5L) and saline (5L) washing, pass through dried over sodium sulfate and filtration then.Under vacuum, remove and desolvate to obtain crude product.By this crude product being carried out purification, obtain the required product of 237g (66% productive rate) from twice recrystallization of ether/hexane (1: 2).HPLC has confirmed that the ratio of trans/cis (E/Z) is about 98: 0.9.

By the recrystallization purifying capsaicin

EXAMPLE V (a)

With thick capsaicin (1g; HPLC 91%) be dissolved in the mixture (15ml) of 1: 2 ether/hexane.With this mixture heated to about 40 ℃ to about 42 ℃ to dissolve this solid.When stirring with this mixture cool to room temperature gradually.Obtained cream-coloured granule.At room temperature stirred this suspended substance about 2 hours.Cross filter solid, obtain cream-coloured solid (wt.=0.74g).

EXAMPLE V (b)

In about 40 ℃ to about 45 ℃ mixture (150ml) that capsaicin (14g) are dissolved in 1: 2 ether/hexane.With solution cool to room temperature gradually.Formed white precipitate.At room temperature stirred this mixture then about 2 hours.Filter suspended substance, with the mixture washing of 1: 2 ether/hexane and under the room temperature vacuum about 2 hours of drying, so that white solid (wt.=12.7g to be provided; 91% response rate).

EXAMPLE V (c)

With ether/hexane (1: 2,2.5L) join in the thick capsaicin (337g).Formed mixture was cooled to about 10 ℃ and stir about 2 hours.Cross filter solid, with ether/hexane (1: 2) washing and recrystallization once more from ether/hexane (1: 2) in a similar manner, obtain 237g HPLC purity and be 98%, the E/Z ratio is 98: 0.9 required capsaicin.

Capsaicin partly prepare purification

Example VI (a)

In example VI (a), pass through HPLC purification 10g capsaicin.These conditions are methanol under 10ml/ minute flow rate (57: 43).Employed pillar is WatersSymmetry Prep C18 (300 * 19mm, 7 μ), and sequence number T22981A 04.

Material used in the A.HPLC method is as follows:

1. install

The Gilson HPLC system of band UV detector

Gilson UV/Vis detector models #119 sequence number 109H7D083

Gilson Dynamic agitator model #811C sequence number 369H7T264

Gilson interface type number #506 sequence number 369J7PA383

Gilson liquid processor model #215 sequence number 259G7272

Gilson Valvemate model 610 sequence number 339H7A109

2. chemicals

Methanol lot number 43080313, EM Science, HPLC level

Water lot number 43010, EM Science, HPLC level

Acetonitrile lot number 42165226, EM Science, HPLC level

TEA lot number CE619, Burdick and Jackson

TFA lot number X07476 JT Baker

B. the test procedure that is used for the HPLC method is as follows:

1. the preparation of sample

It with 1mL HPLC level dissolve with methanol 500mg purity 95.4% capsaicin sample.The concentration of the prepared sample that is used for purification is about 500mg/mL.

2. the condition that is used for the HPLC of purification

Symmetry Prep C18 300 * 19mm-7 micron that purification uses is as follows:

Mobile phase: 57% methanol/43% water

Flow rate: 10.0mL/min

Running time: 100 minutes

Injection volume: 400 μ L

Wavelength: 281nm

3. be used to the HPLC condition analyzed

Use Synergi Hydro RP, 80A, the post of 250 * 4.6mm and 4 microns carries out following purity check:

Mobile phase: gradient

A: water+0.1%TEA+0.1%TFA

B: acetonitrile

Time %A %B

0 100 0

10 52 48

30 52 48

40 0 100

50 0 100

Flow rate: 1ml/min

Running time: 50 minutes

Volume injected: 10 μ L

Wavelength: 281nm

C. result

This partly prepares purification process and is proved to be extremely successful.The final purity of capsaicin is 99.86%.Reclaimed about 7.29g capsaicin.When using the 1g raw material to carry out feasibility study, the actual amount of handled rough raw material is about 9 grams.Total response rate is about 81%.

Example VI (b)

In example VI (b), be further purified capsaicin with the anti-phase HPLC method that partly prepares.

A. used material is as follows in this HPLC method:

1.HPLC system and solvent

A. with the Hitachi HPLC system of UV detector

Intelligent pump type L-7100 sequence number 1158-047

Diode array detector model L-7455 sequence number 1005-030

Autosampler model L-7255 sequence number 1128-005

Interface D-7000 sequence number 1127-021

Degasser (ERC) N/A sequence number 102899N0880

B.HPLC post (Waters):

Analytical column: Symmetry C18,250 * 4.6mm5 μ sequence number W20801D041

Semipreparative post: Symmetry C18,300 * 29mm7 μ sequence number T20101N07

C.HPLC solvent (EM Science)

The MeOH:HPLC level, lot number 42213232

H ₂The O:HPLC level, lot number 42347

B. the test procedure that is used for the HPLC method is as follows:

1. the HPLC method of developing for purification:

For being further purified the exploitation of carrying out extensive analysis HPLC method.The common HPLC condition of being estimated is summarized as follows:

Flow rate: 1.0mg/ml

Detector: UV=281nm

Temperature: RT

Sample solution concentration: 2mg/ml is at ACN/H ₂Among the O (1: 1)

Employed HPLC post and mobile phase are summarised in the following table:

In the middle of all methods of being developed, the Symmetry C18 (250 * 4.6mm, 5 μ) that the grade in the water is opened 52% MeOH is preferred.The time of staying of falling Dihydrocapsaicin (impurity) is 60.1 minutes, and the capsaicin eluting is 69.1 minutes.Because only buying the long semipreparative HPLC post of 30cm from the market, so the mobile phase that changes this method a little is to adapt to variation.

2. the capsaicin that contains 1.7% impurity by semipreparative HPLC purification

A. the preparation of sample

The thick capsaicin that will have 1.7% impurity is dissolved among the HPLC level MeOH of about 20mL.

The b.HPLC condition

Post: Symmetry C18 (300 * 19mm, 7 μ)

Mobile phase: A=H ₂O; B=MeOH

Eluting: wait a 57-58%MeOH

Temperature: RT

Flow rate: 9.5ml/min

Volume injected: 400-450 μ l

Detector: 281nm (UV)

C. result

By estimating the chromatogram of thick capsaicin, though found also to observe the back eluting impurity of trace, falling Dihydrocapsaicin is major impurity.Owing to fall Dihydrocapsaicin and capsaicin all is to be no earlier than 60 minutes eluting, therefore use the composite injection means that the purification cycle is shortened to 45 minutes, thereby also reduced solvent loss.

In the process of purification, collect fraction and come analysis confirmation purity more than 99.0% by analyzing HPLC.Concentrate all purification fraction and by making its drying at 55-60 ℃ of rotary evaporation.

This purification process is proved to be success.Handle final purity and surpassed 99.9% 9.85 gram capsaicin.The overall recovery of purification is 80%.

The chemical compound title	Capsaicin
		Weight (g)	9.58
The purification response rate	80％
		HPLC purity	>99.9％
NMR analyzes, mass spectrum	Consistent with structure
		Drying loss (105 ℃, 4 hours)	0.1％

Example VII A

Comparative Examples

At first, propose to be used for four step method of synthesis of trans capsaicin, this method comprises: a) form dianion; B) this dianion of alkylation; C) reduce this dianion; And d) is coupled to benzyl amine derivative to obtain trans capsaicin.This four step method is as follows:

In the first step detects, attempt at first using 2-iodopropane, and use LDA, NaH and LiNH as alkylating reagent ₂Form the alkene anion as alkali.Only reclaimed the 6-heptynoic acid of beginning.These results suggest remove HI from isopropyl iodide (E2) be distinctive, rather than desirable nucleophilic displacement of fluorine forms required isopropyl alkynes.

With 2-N-Propyl Bromide and isopropyl mesylate as alkylating reagent and with NaH and n-BuLi/AlCl ₃Further detect the alkylation of 6-heptynoic acid as alkali.Do not observe the product of hope under these conditions.

In other alkylation detects, detected the formation of dianion.Particularly, under the condition that the isopropyl halogenation thing similar in appearance to the front reacts, handle 6-heptynoic acid (2g) with LDA (3 equivalent).Handle this reactant mixture with benzyl bromide a-bromotoluene then.Confirmed the formation of product.

Yet, in other method, detected the functional alkylation of orthoester-protected and ensuing this alkynes of carboxylic acid group of 6-heptynoic acid.Respectively with n-BuLi and ethylmagnesium chloride as alkali, with the ortho esters of 300mg6-heptynoic acid, with the alkylation of benzyl bromide a-bromotoluene as model reaction.

Using the ratio of the product/starting compound of n-BuLi alkali production is 7: 2.Using ethylmagnesium chloride to produce a spot of product/feed ratio is 1: 2 product.

In other detection, use samarium means of samarium iodide (SmI respectively ₂) and ethylmagnesium bromide in the scale of 300mg with the Ge Liya of isopropyl iodate thing alkylation ortho esters, the alkylation of samarium media.All not observing product from each reaction forms.

In other detection, by witig reaction and ensuing isomerization synthesis of trans 8-methyl-6-nonenoic acid.By with the rough capsaicin of ether/hexane (1: 3) crystallization purifying (the sticking oil of 1.4g, about 84% trans and 12% cis-isomer), obtained the 0.4g beige solid.HPLC has shown 91.5% purity and the trans/cis ratio of 91.5/6.7.This cis-isomer has shown lower crystallization, and has obtained mixture (0.3g) from condensed residue.

In other detection, detected the ortho esters of under the Ge Liya condition, using isopropyl bromide alkylation 6-heptynoic acid, but generated the product of wishing.

In the description in front, the present invention has been described with reference to concrete exemplary embodiment and their embodiment.Yet, do not departing under the wideer spirit and scope of the present invention obviously, can as listed in the following claim, carry out various modifications and changes.Correspondingly, description and accompanying drawing should be considered to indicative rather than restrictive.

Claims (45)

1. method that is used to prepare trans capsaicin, it comprises:

A) with halogen valeric acid alkylation 3-methyl butine to obtain 8-methyl-6-n-heptylacetylene acid:

I) mix anhydrous tetrahydro furan and hexamethyl phosphoramide, and described mixture is cooled to-78 ℃ to-60 ℃;

Ii) to step I) described mixture in add 3-methyl butine, next under-78 ℃ to-65 ℃ temperature dropping alkali to obtain second mixture;

Iii) simultaneously described second mixture is warmed to-30 ℃ in stirring; With

Iv) drip the anhydrous tetrahydrofuran solution of halogen valeric acid under-30 ℃ temperature, described halogen valeric acid little by little is warmed to room temperature and stirring then to be enough to described 3-methyl butine is changed into the amount adding of described 8-methyl-6-n-heptylacetylene acid, obtains reactant mixture;

B) reduction described 8-methyl-6-n-heptylacetylene acid is to obtain trans 8-methyl-6-nonenoic acid:

I) described 8-methyl-6-n-heptylacetylene acid is dissolved in the mixture of the anhydrous tetrahydro furan and the tert-butyl alcohol to obtain solution, cools off described solution to-55 ℃ to-40 ℃;

Ii) condensation ammonia to temperature is-50 ℃ to-33 ℃ in described solution;

Iii) under-45 ℃ to-30 ℃ temperature, add sodium one by one, and stir the sufficiently long time with dissolve described sodium and

Iv) add ammonium chloride, be warmed to room temperature and make the ammonia evaporation, obtain reactant mixture;

C) activation described 8-methyl-6-nonenoic acid is to obtain acyl halide or activatory acid:

I) at room temperature in described 8-methyl-6-nonenoic acid, drip thionyl halide to form solution;

Ii) heat the sufficiently long time of described solution down, described 8-methyl-6-nonenoic acid is converted into acyl halide at 50 ℃ to 75 ℃; With

Iii) under vacuum, remove excessive thionyl halide, obtain the midbody product of step c); And

D) with described acyl halide acidylate 4-hydroxyl-3-methoxybenzylamine hydrochloride to obtain trans capsaicin:

I) mix 4-hydroxyl-3-methoxybenzylamine hydrochloride and dimethyl formamide;

Ii) at room temperature to step I) described mixture in piecemeal add aqueous NaOH and stir, obtain reactant mixture;

Iii) under 0 ℃ to 10 ℃ temperature, add the sufficiently long time of anhydrous ether solution of acyl halide, make described acyl halide be transformed into amide; Thereafter

Iv) gradually described mixture is warmed to room temperature and stirring.

2. the process of claim 1 wherein that step a) comprises with the ω-ω-acetylenic acid analog of halogenated-chain acid alkylation 3-methyl butine to obtain following formula (I):

N=4-8 wherein.

3. the process of claim 1 wherein that step a) further comprises:

I) in described reactant mixture, add hydrochloric acid, and with the described reactant mixture of ethyl acetate extraction; With

Ii) use the described reactant mixture of salt water washing to produce crude product through extracting.

4. the method for claim 3, wherein step a) further comprises:

I) the described crude product of purification; With

Ii) under vacuum, remove and desolvate, the midbody product of step a) is provided.

5. the method for claim 4, wherein said crude product is by the column chromatography purification.

6. the method for claim 4, wherein said crude product is by the Acid-Base abstraction purification.

7. the method for claim 4, wherein said crude product is by the vacuum distilling purification.

8. the method for claim 4, the intermediate product of wherein said step a) is 8-methyl-6-n-heptylacetylene acid.

9. the process of claim 1 wherein that described halogen valeric acid is selected from following group: bromine valeric acid, chloro pentane acid, fluorine valeric acid, iodine valeric acid, astatine valeric acid, 1-mesyloxy valeric acid and 1-tosyloxy valeric acid.

10. the method for claim 9, wherein said halogen valeric acid is the bromine valeric acid.

11. the process of claim 1 wherein 1,2-dimethyl-3,4,5, the pyrimidone alternative steps i of 6-tetrahydrochysene-(1H)) in hexamethyl phosphoramide.

12. the process of claim 1 wherein that described alkali is selected from following group: n-BuLi, s-butyl lithium, tert-butyl lithium, two (isopropyl) Lithamide., sodium hydride, Sodamide., Lithamide., lithium methide, methyl-magnesium-bromide, ethylmagnesium bromide, alkyl or aryl magnesium halide or their mixture.

13. the method for claim 12, wherein said alkali is n-BuLi.

14. the process of claim 1 wherein and add extra sodium after iii) in step b).

15. the process of claim 1 wherein that step b) iii) is included in-65 ℃ and adds lithium to-45 ℃ temperature, and stir the sufficiently long time to dissolve described lithium.

16. the process of claim 1 wherein that step b) further comprises:

I) in described reactant mixture, add entry;

Ii) with hydrochloric acid described reactant mixture being acidified to pH is 2 to 3;

Iii) use the described reactant mixture of ethyl acetate extraction, with the salt water washing and pass through anhydrous sodium sulfate drying; With

Iv) filter and under vacuum, remove and desolvate, obtain the midbody product of step b).

17. the method for claim 16, the midbody product of wherein said step b) are trans-8-methyl-nonenoic acids.

18. the method for claim 15 is wherein omitted step b) ii).

19. the process of claim 1 wherein lithium alternative steps b) described sodium in iii).

20. the process of claim 1 wherein the tert-butyl alcohol of sec-butyl alcohol (second month in a season-BuOH), ethanol (EtOH) or other alkylol replace described step b) i).

21. the process of claim 1 wherein that lithium and liquefied ammonia or sodium and liquefied ammonia replace described sodium, described oxolane and the described liquefied ammonia of step b).

22. the method for claim 15, wherein step b) further may further comprise the steps:

I) stir described reactant mixture a whole night to evaporate described ammonia;

Ii) add extra anhydrous tetrahydro furan and ammonium chloride, stir the sufficiently long time of described mixture with the excessive lithium that neutralizes;

Iii) piecemeal adds frozen water;

Iv) use the described mixture of ethyl acetate extraction, with the salt water washing and pass through anhydrous sodium sulfate drying; With

V) filter and under vacuum, remove and desolvate, produce the midbody product of step b).

23. the method for claim 15, wherein step b) further may further comprise the steps:

I) reaction mixture is also used the frozen water quenching;

Ii) with a part of hydrochloric acid that adds of a part described reactant mixture being acidified to pH is 2 to 3;

Iii) use the described reactant mixture of ethyl acetate extraction, with the salt water washing and pass through anhydrous sodium sulfate drying;

Iv) filter and under 30 ℃ temperature, concentrate in a vacuum, obtain crude product.

24. the method for claim 23, wherein step b) further comprises the midbody product that obtains step b) by the described product of flash column chromatography purification.

25. the method for claim 23, wherein step b) further comprises the step by the described crude product of vacuum distilling purification.

26. the process of claim 1 wherein that described thionylhalides is a thionyl bromide.

27. the process of claim 1 wherein that described thionylhalides is a thionyl chloride.

28. the process of claim 1 wherein that the midbody product of described step c) is an acyl halide.

29. the method for claim 28, wherein said acyl halide is an acid bromide RCOBr.

30. the method for claim 28, wherein said acyl halide is an acid chloride.

31. the method for claim 28, wherein said acyl halide are activated carboxylic acids, it is selected from following group: acylimidazole and carbodiimide.

32. the process of claim 1 wherein that step d) further may further comprise the steps:

I) in described mixture, add entry and, obtain acetic acid ethyl ester extract with the described mixture of ethyl acetate extraction;

Ii) use the described extract of salt acid elution, wash with sodium bicarbonate thereafter;

Iii) use the described solution of salt water washing, and pass through anhydrous sodium sulfate drying;

Iv) filter and under vacuum, remove and desolvate, obtain rough trans capsaicin product.

33. the process of claim 1 wherein that step d) further may further comprise the steps:

I) by the described crude product of column chromatography purification, obtain trans capsaicin product.

34. the process of claim 1 wherein that potassium hydroxide, Lithium hydrate, sodium carbonate, potassium carbonate or alkylamine replace the aqueous NaOH of step d) described in ii).

35. the process of claim 1 wherein that 4-hydroxyl-3-methoxybenzylamine replaces step d) i) described in 4-hydroxyl-3-methoxybenzylamine hydrochloride.

36. the method for claim 34, wherein said alkylamine are selected from following group: triethylamine, Hunig alkali, 4-dimethylaminopyridine and pyridine.

37. the process of claim 1 wherein that oxolane, 2-dimethoxy-ethane, acetonitrile, dichloromethane, chloroform or methyl ethyl ketone replace step d) i) in described dimethyl formamide.

38. the method for the trans capsaicin product in the purification claim 1, it may further comprise the steps:

I) described rough trans capsaicin product is dissolved in the mixture of ether/hexane, and heats described mixture to 40 ℃ to 45 ℃;

Ii) with described mixture cool to room temperature or below the room temperature; With

Iii) filter described mixture so that purified trans capsaicin product to be provided.

39. the method for claim 38, wherein step I ii) comprises the described mixture of filtration, and described mixture washs with the mixture of ether/hexane, and dry to obtain purified trans capsaicin product under vacuum.

40. the method for claim 1, it further comprises the described trans capsaicin of the semipreparative HPLC purification of use.

41. the method for claim 32, it further comprises the described rough trans capsaicin product of the semipreparative HPLC purification of use.

42. the method for claim 33, it further comprises the described trans capsaicin product of the semipreparative HPLC purification of use.

43. the method for claim 40 wherein uses the purification partly prepare HPLC to provide to contain 97% or the trans capsaicin of desired ultrapureization of high-purity capsaicin more.

44. the method for claim 40 wherein uses the purification partly prepare HPLC to provide to contain 98% or the trans capsaicin of desired ultrapureization of high-purity capsaicin more.

45. the method for claim 40 wherein uses the purification partly prepare HPLC to provide to contain 99% or the trans capsaicin of desired ultrapureization of high-purity capsaicin more.