CN102952072B - Horned artemisia ester alkali analog and preparation method thereof and the application in analgesic - Google Patents

Abstract

The present invention relates to the analog of the natural product horned artemisia ester alkali containing cyclobutane dimer skeleton of novel structure, including compound of Formula I and Compounds of formula II and officinal salt thereof, and their preparation method and they purposes in analgesic.Formula I is wherein: R₁For hydrogen or various alkyl substituent or various acyl substituent or various aryl, such as methyl, ethyl, propyl group, butyl, pi-allyl, benzyl, Cvclopropvlmethvl, cyclobutylmethyl, acetyl group, benzoyl, phenyl etc.；R₂And R₃Each represent hydrogen or methyl, or R₂And R₃Jointly represent methylene.Formula II is wherein: R₄For hydrogen or various alkyl substituent or various acyl substituent or various aryl, such as methyl, ethyl, propyl group, butyl, pi-allyl, benzyl, Cvclopropvlmethvl, cyclobutylmethyl, acetyl group, benzoyl, phenyl etc.；N represents 04.This compounds has good analgesic activity.

Description

Horned artemisia ester alkali analog and preparation method thereof and the application in analgesic

Technical field

The present invention relates to novel structure, the analog with the natural product horned artemisia ester alkali of notable anti-injury activity and pharmaceutical salts thereof, Their preparation method and they purposes in analgesic.

Background technology

Pain (pain) is the offending reaction of one that damage tissue or potential damage are produced by body, is the physiology of a kind of complexity Mental activity, is one of the most modal symptom.It includes that noxious stimulation acts on the pain caused by body and feels, with And the pain reaction-somatic movement of noxious stimulation is reacted and/or internal organs vegetative reaction by body, and it is often accompanied by strong emotion Color.

A kind of warning that the pain sensation can come to harm as body, causes a series of egodefense of body to react.But then, pain Pain also has its limitation, such as cancer as alarm, often as patient perceptions to pain, reaches an advanced stage, meanwhile, and some The most long-term the having an intense pain that have an intense pain can become a kind of torment to body, causes the injury on patients ' psychological, impact to suffer from The quality of life of person.Therefore, analgesia is the vital task that medical personnel faces all the time.

Drug therapy is the measure that analgesia is indispensable.The analgesic of Clinical practice mainly has NSAID (non-steroidal anti-inflammatory drug) at present And opioid drug two class (NSAIDs).Although NSAID (non-steroidal anti-inflammatory drug) such as aspirin, ibuprofen, indomethacin etc. are the most extensively For treating acute and chronic pain, but its analgesic effect is more weak, and has stimulation to gastrointestinal tract, to side effect such as ulcer.Treatment The medium main force to severe pain is undoubtedly opioid drug, and wherein morphine has a very important status, 1806 from Ah Being separated in sheet, 1833 for clinic, the most history of more than 200 year.But some the serious poison due to it Side effect, uses especially continuously and is easily generated tolerance and addiction, find toxic and side effects little analgesic few, additive all the time It it is the target of medicament research and development person.Although by the structural modification of morphine, simplify transformation the replacement of a series of morphine had been developed Product, such as Pethidine etc., but they yet suffer from additive and other toxic and side effects in various degree so that their clinical practice It is very restricted.Therefore, the non-addicted analgesics that exploitation toxic and side effects is few is still that drug research focus.

Natural product plays very important effect in drug discovery process, the medicine applied the most clinically about 70% Derive from the derivant of natural product or natural product, by biologically active native structural modification is developed medicine with being transformed into One important channel, and success rate is the highest.Opium kind analgesics is main by natural product morphine with to its chemical modification and knot just Analog composition obtained by structure transformation.Herba Incarvilleae sinensis (Incarvillea sinensis LAM) is one of main source of Herba speranskiae tuberculatae, is referred to as " Cornu Caprae seu Ovis Herba speranskiae tuberculatae ", has effect of expelling wind and removing dampness, reducing swelling and alleviating pain.1999, trip day natural product chemistry man was the beautifulst bright etc. A kind of novel bimolecular monoterpene alkaloid with Tetramethylene. dimeric structure, named Herba Incarvilleae sinensis ester has been isolated from the herb of Herba Incarvilleae sinensis Alkali (Incarvillateine is abbreviated as INCA).They find that this natural product shows in the formalin-induced model of mice Go out to be better than the analgesic activities of morphine, and its mechanism of action is different from morphine, the most also find at conditioned place preference (Conditioned Place Preference, CPP) experiment small mouse, to its dependence effect that is a cup too low, has certain suspicion on the contrary Dislike tendency.Therefore, horned artemisia ester alkali has become the important lead compound developing novel non-narcotic analgesics thing.To horned artemisia ester alkali It is chemically modified or structure of modification is expected to find low toxicity, the novel non-narcotic analgesics of safety.

The structure of horned artemisia ester alkali is as follows:

Summary of the invention

It is an object of the invention to provide the compound with good analgesic effect-natural product horned artemisia ester alkali that a class formation is brand-new (Incarvillateine) analog, containing Tetramethylene. dimeric structure.

Another object of the present invention is to provide the preparation method and application of above-claimed cpd.

According to the first aspect of the invention, it is provided that compounds of formula I, or its stereoisomer:

Wherein:

R₁Represent hydrogen or various alkyl substituent or various acyl substituent or various aryl, as methyl, ethyl, propyl group, butyl, Pi-allyl, benzyl, Cvclopropvlmethvl, cyclobutylmethyl, acetyl group, benzoyl, phenyl etc.；

R₂And R₃Each represent hydrogen or methyl, or R₂And R₃Jointly represent methylene.

According to the second aspect of the invention, it is provided that compounds of formula II:

Wherein:

R₄Represent hydrogen or various alkyl substituent or various acyl substituent or various aryl, as methyl, ethyl, propyl group, butyl, Pi-allyl, benzyl, Cvclopropvlmethvl, cyclobutylmethyl, acetyl group, benzoyl, phenyl etc.；N represents 0-4.

According to the third aspect of the present invention, it is provided that the preparation method of compound of Formula I, synthetic route is as follows:

Reaction reagent and condition stub:

A:lewis acid, aqueous sodium hypochlorite solution, solvent, 0 DEG C.Lewis acid in this condition can be Indium-111 chloride, tri-chlorination Cerium or their hydrate；Dichloromethane or chloroform and water form two-phase solvent.

B: hydrogen peroxide, sodium hydrate aqueous solution, solvent, 0 DEG C.Solvent is alcohol, can be methanol or ethanol.

C: acid, lithium chloride, oxolane, 0 DEG C.Acid in this condition can be various inorganic acid or organic acid, preferably Trifluoroacetic acid.

D: para-methylbenzenepyridinsulfonate sulfonate, 3,4-dihydropyran, dichloromethane.Reaction is at room temperature carried out.

E:Favorskii reacts.Feldalat NM, ether, 0 DEG C.

F: sodium azide, solvent, 60-90 DEG C.In this condition, solvent can be polar non-proton organic solvent, can be that dimethyl is sub- Sulfone, DMF, oxolane, acetonitrile etc., preferably DMF；Reaction temperature is 60-90 DEG C, During with boiling point solvent in this range, it is heated to reflux, preferably 70 DEG C.

G: triphenylphosphine, water, oxolane, backflow.Intramolecular amideization reaction is directly there is after Staudinger reaction.

H: catalytic hydrogenation.Catalyst in this reaction can be heterogeneous catalysis, as palladium/carbon, platinum dioxide, platinum oxide, Raney Ni, it is also possible to be homogeneous catalyst, such as Wilkinson catalyst；The pressure of hydrogen is 4atm, and solvent is alcohol.

I: alkali, R₁X, oxolane, 0 DEG C-room temperature.In this reaction, alkali can be sodium hydride, it is also possible to is Feldalat NM, tertiary fourth Potassium alcoholate, butyl lithium etc..

J: Lithium Aluminium Hydride, oxolane.Reaction temperature is room temperature.

K: acid, solvent.In this reaction, acid can be strong acid or strong acid in hydrochloric acid, acetic acid, p-methyl benzenesulfonic acid, boric acid etc., it is possible to To be para-methylbenzenepyridinsulfonate sulfonate, the lewis such as stannum dichloride acid；Solvent proton solvent, such as methanol, ethanol, oxolane and water As mixed solvent.

L: esterification has three kinds of methods:

Method 1: With At solvent in the presence of reagent and catalyst Middle reaction, wherein condensation reagent can be N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3-diformazan Aminopropyl)-3-ethyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride etc., it is also possible to for triphenyl Phosphine and carbon tetrachloride, iodate 1-methyl-2-chloropyridine, catalyst is DMAP or pyridine, solvent be dichloromethane, Oxolane or acetonitrile, reaction temperature is 25-60 DEG C；

Method 2: With React in a solvent in the presence of agent, its Middle catalyst is DMAP or pyridine, solvent be dichloromethane, 1,2-dichloroethanes, pyridine or oxolane, instead Temperature is answered to be 25-85 DEG C；

Method 3: With In the presence of agent the most anti- Should, wherein catalyst is DMAP or pyridine, and solvent is dichloromethane, oxolane, normal heptane or acetonitrile, instead Answering temperature is room temperature.

Method for optimizing 3, the wherein preferred DMAP of catalyst, the preferred acetonitrile of solvent.

M: sodium/anthracene, oxolane ,-40 DEG C.

In the synthetic route of compound of Formula I, R₁、R₂And R₃As defined above, X is Br, I, OMs, OTs, Preferably I and OTs.

According to the fourth aspect of the present invention, it is provided that the preparation method of Compounds of formula II, synthetic route is as follows:

Reaction reagent and condition stub:

A: alkali, Wittig reagent, oxolane.In this condition, alkali can be sodium hydride, butyl lithium, tert-butyl lithium, pregnancy Base two silica-based amido potassium, potassium tert-butoxide etc.；Reaction temperature is-78 DEG C-room temperature, depending on different Wittig reagent.

B: catalytic hydrogenation or hydrolysis.The condition of catalytic hydrogenation be catalyst can be heterogeneous catalysis, such as palladium/carbon, dioxy Change platinum, platinum oxide, Raney Ni, it is also possible to be homogeneous catalyst, such as Wilkinson catalyst；The pressure of hydrogen is 4atm, Solvent is alcohol.The condition of hydrolysis be acid can be the hydrochloric acid of trace, trifluoroacetic acid or trichloroacetic acid, solvent is proton solvent, The mixed solvent constituted such as methanol, ethanol, or oxolane and water.

C: reduction reaction.Reducing agent is sodium borohydride, lithium borohydride or diisobutyl aluminium hydride, and solvent is methanol, ether or four Hydrogen furan, reaction temperature be-20 DEG C to room temperature.

D: esterification.Condensation reagent can be N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3- Dimethylamino-propyl)-3-ethyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride etc., it is also possible to it is three Phenylphosphine and carbon tetrachloride, iodate 1-methyl-2-chloropyridine, preferably 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride； Catalyst is DMAP；Solvent is dichloromethane, oxolane or acetonitrile, preferably dichloromethane；Reaction temperature is 25-60 DEG C, preferably 25 DEG C.

E: trifluoroacetic acid, dichloromethane, reacts under room temperature.

F: reduction amination.Reducing agent can be sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or palladium/ Carbon and hydrogen, preferably sodium triacetoxyborohydride；Aldehyde can be various fatty aldehyde, as formaldehyde, acetaldehyde, propionic aldehyde, acrylic aldehyde, Benzaldehyde etc.；Acid as catalyst, can with formic acid, acetic acid, or lewis acid such as zinc chloride；Solvent can be acetonitrile, tetrahydrochysene Furan, Isosorbide-5-Nitrae-dioxane, dichloromethane, methanol etc., preferably acetonitrile.

G: sodium/anthracene, oxolane ,-40 DEG C.

In the synthetic route of Compounds of formula II, R₄As defined above with n, R₅Represent methoxyl group or methyl carbonate or Ethyl carbonate, m represents 0-3.

Reagent in the present invention can be not required to process further from commercially available, when solvent for use needs Non-aqueous processing, be ability The known method that different solvents is carried out Non-aqueous processing in territory, it is not necessary to do other additional process.Conventional in the art lazy Property gas all can realize the present invention.In an embodiment of the present invention, described noble gas is nitrogen or argon.

In an embodiment of the present invention, " concentrate " and refer generally to use under water pump reduced pressure Rotary Evaporators solvent evaporated.The present invention Device used by method is the conventional equipment of this area.In the present invention, the purification of thick product can be adopted according to the character of target product Carry out with separation method well known in the art, such as recrystallization, distillation or column chromatography etc..

Formula above I, the compound of II and salt form thereof, the salt of especially HX (X represents halogen atom) form has good town Pain activity, can as analgesic or as analgesic bioactive substance for analgesic composition.

Detailed description of the invention

In order to further describe the present invention, some embodiments are given below, but these embodiments are merely illustrative, not to this Invention protection domain constitute any restriction, it will be apparent to a skilled person that according to the present invention spirit done replacement, Amendment etc. each falls within protection scope of the present invention.

Embodiment 1

Take 500mL there-necked flask, R-carvone (3g, 20mmol) be dissolved in 150mL dichloromethane, Add CeCl₃·H₂Water (100mL) solution of O (8.2g, 22mmol), mechanical agitation, with dripping at 0 DEG C The NaClO aqueous solution (8%, 160mL) that liquid funnel is added dropwise over, 0 DEG C continue stirring 3 hours until Thin layer chromatography detection raw material disappears.Dilute, is slow added into saturated Na₂S₂O₃Aqueous solution cancellation is reacted, and dichloromethane extracts Take three times, merge organic facies, by saturated NaCl solution washing, anhydrous Na₂SO₄It is dried, is concentrated to give pale yellow oily liquid Body is directly used in next step reaction.

Thick for above-mentioned gained product is dissolved in 25mL methanol, the H being added dropwise over respectively under ice bath₂O₂Aqueous solution (35%, 10mL) With NaOH aqueous solution (2.0M, 5mL), after reacting 30 minutes at 0 DEG C, it is warmed to room temperature reaction 3 hours.Dilute, ice bath Under be slow added into saturated Na₂S₂O₃Aqueous solution cancellation is reacted, and dichloromethane extracts three times, merges organic facies, uses saturated NaCl Solution washing, anhydrous Na₂SO₄It is dried, is concentrated to give pale yellow oily liquid body and is directly used in next step reaction.

Above-mentioned gained crude product and LiCl (8.5g, 0.2mmol) are dissolved in 80mL oxolane, at 0 DEG C, are slowly added to trifluoro second Acid (4.6mL, 60mmol) is reacted 2 hours afterwards, is added dropwise over saturated NaHCO with Dropping funnel₃Aqueous solution is until no longer there being gas Bubble produces.Ether extracts three times, merges organic facies, by saturated NaCl solution washing, anhydrous Na₂SO₄It is dried, after concentration Pillar layer separation obtains colourless oil liquid 2.5g, three step gross production rates 52%.

Taking above-mentioned products therefrom (2.25g, 9.5mmol) and 3,4-dihydropyran (3mL, 33.3mmol) is dissolved in 10mL dichloromethane Alkane, adds PPTS (238mg, 0.95mmol), reacts 24 hours under room temperature.Add saturated NaHCO₃Aqueous solution cancellation is reacted, Ethyl acetate extracts three times, gained organic facies saturated NaCl solution washing, anhydrous Na₂SO₄It is dried, column chromatography after concentration Isolated colourless oil liquid 2.7g, productivity 89%.

Take above-mentioned products therefrom (2.5g, 7.8mmol) to be dissolved in 30mL ether, at 0 DEG C, add the methanol of freshly prepd NaOMe Solution (1.0M, 37.5mL), reacts 1 hour.Add saturated NH₄Cl aqueous solution cancellation, ethyl acetate extracts three times, gained Organic facies saturated NaCl solution washing, anhydrous Na₂SO₄Being dried, after concentration, pillar layer separation obtains compound 1, colourless Oily liquids, 2.4g, productivity 97%.

¹H NMR (400MHz, CDCl₃, 1:1mixture of epimeric acetals, data for both epimeric acetals given) δ 5.20 (s, 1H), 5.19 (s, 1H), 4.96 (s, 1H), 4.95 (s, 1H), 4.65 (m, 1H), 4.57 (m, 1H), 4.20 (t, J=4.0 Hz, 1H), 4.09 (t, J=4.3Hz, 1H), 4.04 (d, J=12.0Hz, 2H), 4.00 (d, J=12.0Hz, 2H), 3.70-3.56 (m, 1H), 3.53 (brs, 6H), 3.46 (m, 2H), 3.38 (dt, J=10.8,6.8Hz, 1H), 3.28 (dt, J=11.0,6.6Hz, 1H), 2.84 (dd, J=10.0,8.0Hz, 1H), 2.80 (dd, J=10.0,8.0Hz, 1H), 2.60-2.50 (m, 2H), 1.06 (dd, J= 13.1,6.6Hz, 1H), 1.98-1.91 (m, 2H), 1.83-1.73 (m, 3H), 1.68-1.60 (m, 3H), 1.57-1.45 (m, 8H), 1.08 (d, J=7.0Hz, 3H), 0.98 (d, J=7.0Hz, 3H).

¹³C NMR (100MHz, CDCl₃, 1:1mixture ofepimeric acetals, data for both epimeric acetals given) δ 174.5 (2 × C), 145.60,145.55,115.0,114.7,100.2,94.7,81.4,76.6,62.6,61.7,53.5 (2 × C), 51.2 (2 × C), 48.4,48.3,42.4,42.2,42.03,41.98,38.9,36.1,30.9,30.7,25.5,25.4,19.7,19.1,14.0, 13.9.

Embodiment 2

Compound 2: be dissolved in DMF (30mL) by compound 1 (1.6g, 5.0mmol), adds NaN₃(650mg, 10mmol).Mixture is heated to 70 DEG C and reacts 15 hours.Concentrate, add water dilute Releasing residue, be then extracted with ethyl acetate three times, gained organic facies is washed with saturated NaCl aqueous solution Wash, anhydrous Na₂SO₄It is dried, is concentrated to give yellow oily liquid and is directly used in next step reaction.

Above-mentioned products therefrom is dissolved in 30mL oxolane, add triphenylphosphine (1.6g, 6.0mmol) and water (0.9mL, 50 mmol).It is heated to reflux 12 hours.After concentration, pillar layer separation obtains compound 2, white solid, 1.2g, two step gross production rates 90%.

¹H NMR (400MHz, CDCl₃, 1:1mixture of epimeric acetals, data for both epimeric acetals given) δ 6.83 (brs, 2H), 4.89 (brs, 3H), 4.86 (s, 1H), 4.73 (m, 1H), 4.58 (m, 1H), 4.12 (m, 1H), 4.03 (m, 1H), 3.90-3.84 (m, 4H), 3.71 (m, 1H), 3.67 (m, 1H), 3.51-3.47 (m, 2H), 3.28 (dd, J=18.3,9.3Hz, 1H), 3.19 (dd, J=18.3,9.6Hz, 1H), 2.57 (t, J=9.9Hz, 1H), 2.52 (t, J=9.6Hz, 1H), 2.24 (m, 2H), 2.17 (ddd, J=13.6,8.2,2.0Hz, 1H), 2.07 (dd, J=13.7,7.8Hz, 1H), 1.94 (m, 1H), 1.85-1.76 (m, 3H), 1.74-1.65 (m, 2H), 1.62-0.51 (m, 8H), 1.29 (d, J=6.8Hz, 3H), 1.18 (d, J=6.8Hz, 3H).

¹³C NMR (100MHz, CDCl₃, 1:1mixture of epimeric acetals, data for both epimeric acetals given) δ 174.5 (2 × C), 143.7 (2 × C), 113.7,113.4,100.3,94.6,81.4,76.5,62.7,61.6,56.0,55.9,53.54,53.50, 51.2 (2 × C), 42.9,42.7,42.2,41.9,38.5,35.6,30.9,30.6,25.4,25.3,19.7,19.1,13.95,13.87.

Embodiment 3

Compound 3: compound 2 (5.7g, 21.6mmol) is dissolved in 70mL methanol, in argon shield Lower addition palladium/carbon (10%, 1.1g, 1.1mmol).Fill hydrogen exchange argon and be placed on hydrogenation instrument (4atm H₂Reaction 15 hours in).With filtered off through Celite palladium/carbon, after concentrated filtrate, pillar layer separation obtains chemical combination Thing 3, white solid, 3.86g, productivity 67%.

¹H NMR (400MHz, CDCl₃, 1:1mixture of epimeric acetals, data for both epimeric acetals given) δ 6.62 (brs, 2H), 4.69 (m, 1H), 4.56 (m, 1H), 4.09 (m, 1H), 4.00 (m, 1H), 3.90-3.83 (m, 2H), 3.50-3.45 (m, 2H), 3.06-2.98 (m, 3H), 2.74-2.66 (m, 1H), 2.64-2.55 (m, 1H), 2.44 (m, 2H), 2.15-2.01 (m, 5H), 1.89-1.75 (m, 4H), 1.73-1.64 (m, 2H), 1.59-1.48 (m, 9H), 1.41-1.34 (m, 1H), 1.27 (d, J=6.9Hz, 3H), 1.14 (d, J=6.9Hz, 3H), 0.89 (d, J=6.9Hz, 3H), 0.88 (d, J=6.9Hz, 3H).

Compound 4: above-mentioned reaction can get the stereoisomeric compounds 4 of compound 3 simultaneously, white is solid Body, 1.88g, productivity 33%.

¹H NMR (400MHz, CDCl₃, 1.3:1mixture of epimeric acetals, data for both epimeric acetals given) δ 5.87 (brs, 1.6H), 4.72 (m, 1H), 4.58 (m, 0.8H), 4.06 (m, 1H), 3.97-3.95 (m, 0.8H), 3.93-3.86 (m, 1.9H), 3.52-3.48 (m, 1.9H), 3.20-3.15 (m, 1.7H), 2.95 (m, 1.7H), 2.53 (t, J=10.3Hz, 1H), 2.48 (t, J =10.0Hz, 0.8H), 2.27-2.07 (m, 5.7H), 1.85-1.78 (m, 1.9H), 1.75-1.68 (m, 2.7H), 1.59-1.48 (m, 10H), 1.34 (d, J=6.7Hz, 3H), 1.23 (d, J=6.7Hz, 2.5H), 0.98 (d, J=6.9Hz, 5.4H).

Embodiment 4

Compound 5: compound 3 (209mg, 0.78mmol) is dissolved in 1mL oxolane, argon It is cooled to 0 DEG C under gas shielded, adds sodium hydride (60%in oil, 47mg, 1.2mmol), stir 15 Add iodopropane after minute, be warmed to room temperature and continue to react 24 hours.Add saturated under ice bath NH₄Cl aqueous solution cancellation is reacted, and ethyl acetate extracts three times, gained organic facies saturated NaCl solution washing, anhydrous Na₂SO₄ Being dried, after concentration, pillar layer separation obtains colourless oil liquid, 148mg, productivity 61%.

Above-mentioned products therefrom is dissolved in 2mL oxolane, at 0 DEG C, adds LiAlH₄(72.8mg, 1.9mmol), under room temperature React 1 hour.Reactant mixture is cooled to 0 DEG C, adds several NaOH solution cancellation, filter solid, and use acetic acid second Ester washs.Next step reaction it is directly used in after concentrating gained filtrate.

Above-mentioned gained crude product is dissolved in 1mL methanol, adds PTSA (91mg, 0.5mmol), react 4 hours under room temperature.Dense Contracting, adds 0.2N NaOH solution dilution residue, and dichloromethane extracts, gained organic facies anhydrous Na₂SO₄It is dried, concentrates Rear pillar layer separation obtains compound 5, white solid, 92mg, two step productivity 91%.

¹H NMR (400MHz, CDCl₃) δ 4.29 (m, 1H), 2.76-2.72 (m, 1H), 2.60-2.57 (m, 1H), 2.46-2.38 (m, 1H), 2.28-2.24 (t, J=7.5Hz, 2H), 2.09-2.06 (m, 1H), 1.92-1.89 (m, 1H), 1.85-1.77 (m, 2H), 1.68 (t, J=11.5Hz, 1H), 1.61-1.47 (m, 5H), 1.01 (d, J=7.3Hz, 3H), 0.88 (t, J=7.3Hz, 3H), 0.85 (d, J= 4.0Hz, 3H).

Embodiment 5

Compound 6: preparation method is with embodiment 4.With compound 3 as initiation material, to toluene sulphur Acid N-butyl is alkylating agent, and experience three-step reaction obtains compound 6 with the gross production rate of 90%, oil Shape liquid, 102mg.

¹H NMR (400MHz, CDCl₃) δ 4.28 (t, J=6.4,1.6Hz, 1H), 2.74 (ddd, J=11.2,5.6,1.6Hz, 1H), 2.58 (ddd, J=11.2,4.4,1.6Hz, 1H), 2.42 (td, J=12.8,6.4Hz, 1H), 2.29 (dd, J=8.8,6.8Hz, 2H), 2.07 (m, 1H), 1.90 (m .1H), 1.79 (td, J=12.8,6.4Hz, 2H), 1.68 (t, J=11.2Hz, 1H), 1.55 (t, J= 11.6Hz, 1H), 1.52-1.44 (m, 3H), 1.34-1.22 (m, 3H), 1.01 (d, J=7.6Hz, 3H), 0.91 (t, J=7.6Hz, 3H), 0.87 (d, J=6.8Hz, 3H)；

¹³C NMR (100MHz, CDCl₃) δ 72.5,58.1,55.16,55.10,44.8,42.2,37.6,32.3,29.5,27.9,20.5, 17.1,14.0,13.7；

HRMS(ESI)calcd for C₁₄H₂₈NO[M+H]⁺226.2171；found 226.2167.

Embodiment 6

Compound 7: preparation method is with embodiment 4.With compound 4 as initiation material, iodomethane is alkylating agent, Experience three-step reaction obtains compound 7, white solid, 170mg with the gross production rate of 93%.

¹H NMR (400MHz, CDCl₃) δ 4.19 (m, 1H), 3.73 (m, 1H), 2.81 (d, J=12.0Hz, 1H), 2.65 (ddd, J= 11.0,3.0,1.2Hz, 1H), 2.22 (s, 3H), 2.10-2.01 (m, 2H), 1.92 (ddd, J=14.6,6.6,1.2Hz, 1H), 1.84 (td, J=6.6,3.2Hz, 1H), 1.77 (m, 1H), 1.72 (ddd, J=14.6,8.0,2.5Hz, 1H), 1.48 (t, J=11.0Hz, 1H), 1.47 (m, 1H), 1.40-1.32 (m, 1H), 0.98 (d, J=6.8Hz, 3H), 0.80 (d, J=6.3Hz, 3H)；

¹³C NMR (100MHz, CDCl₃) δ 74.9,63.4,55.4,46.8,43.6,42.1,39.4,38.8,34.5,17.7,11.8.

Embodiment 7

Compound 8: preparation method is with embodiment 4.With compound 2 as initiation material, iodomethane is alkylating agent, Experience three-step reaction obtains compound 7,130mg with the gross production rate of 81%.

¹H NMR (400MHz, CDCl₃) δ 4.85 (s, 1H), 4.81 (s, 1H), 4.22 (m, 1H), 3.00 (d, J=12.3Hz, 1H), 2.78 (q, J=6.6Hz, 1H), 2.72 (d, J=12.3Hz, 1H), 2.44 (dd, J=11.8,4.4Hz, 1H), 2.37 (dd, J=11.8,4.8Hz, 1H), 2.24 (dt, J=13.8,6.3Hz, 1H), 2.24 (s, 3H), 1.89 (dt, J=13.6,5.2 Hz, 1H), 1.91-1.82 (m, 1H), 1.70 (dd, J=13.8,2.8Hz, 1H), 1.68 (dd, J=13.8,2.8Hz, 1H), 0.98 (d, J=6.6Hz, 3H)；

¹³C NMR (100MHz, CDCl₃) δ 145.9,109.6,74.1,61.4,56.8,46.3,45.0,40.4,40.1,38.4,12.6.

Embodiment 8

Compound 9: by compound 5 (72mg, 0.34mmol), DMAP (4.2mg, 0.034mmol) He 3,3 '-dimethoxy-4 ', 4 '-two p-methyl benzenesulfonic acid ester group-α- Soil former times acid two pivalic acid acid anhydrides (147.4mg, 0.17mmol) are dissolved in 1mL acetonitrile In, react 3 days under room temperature.Add 20mL CH₂Cl₂Dilution, uses NaOH Reaction system PH is adjusted to 11～12 by solution (0.2N).Aqueous phase CH₂Cl₂ Extraction, merges organic facies and uses anhydrous Na₂SO₄It is dried, through post color after concentration Spectrum isolated white powdery solids, 104mg, productivity 56%.

Above-mentioned product (87mg, 0.083mmol) is dissolved in 5mL oxolane, under argon shield, is cooled to-40 DEG C, add new The tetrahydrofuran solution (0.49mL, 0.25mmol) of the Na/Anthracene of preparation, reacts 3 hours until raw material disappears at-40 DEG C Lose.Add saturated NaHCO₃Cancellation.Extract with dichloromethane, merge organic facies and use anhydrous Na₂SO₄It is dried, warp after concentration Pillar layer separation obtains compound 8 white solid, 54mg, productivity 84%.

¹H NMR (400MHz, CDCl₃) δ 6.80-6.76 (m, 6H, 4.89 (m, 2H), 4.33 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.84 (m, 2H), 2.66 (m, 2H), 2.54 (m, 2H), 2.29-2.16 (m, 4H), 2.16-2.07 (m, 1H), 1.96 (m, 3H), 1.83 (m, 3H), 1.76-1.67 (m, 2H), 1.64-1.56 (m, 3H), 1.53-1.42 (m, 4H), 1.04 (m, 1H), 0.83 (t, J= 7.4Hz, 6H), 0.79 (d, J=7.4Hz, 3H), 0.74 (d, J=6.8Hz, 3H), 0.58 (d, J=7.2Hz, 3H), 0.66-0.46 (m, 1H).

¹³C NMR (100MHz, CDCl₃) δ 171.9,171.7,146.7,146.6,145.2,145.1,130.7,130.5,120.4,119.9, 114.49,114.45,110.9,110.8,76.6,76.4,60.7 (2 × C), 55.8,55.7,55.5 (2 × C), 55.2,55.1,47.9,47.3, 45.63,45.58,41.8,41.2,40.52,40.49,37.92,37.86,30.0,29.9,29.8,29.3,19.53,19.50,17.1,16.9, 14.8,14.4,12.0 (2 × C).

Embodiment 9

Compound 10: preparation method is with embodiment 8.By compound 6 and 3,3 '-diformazan Epoxide-4,4 '-two p-methyl benzenesulfonic acid ester group-α-soil former times acid two pivalic acid acid anhydrides are condensed it Obtain after rear removing p-toluenesulfonyl protection group, white, amorphous solid, two Step gross production rate 64%.

¹H NMR (400MHz, CDCl₃) δ 6.87-6.78 (m, 6H), 5.72 (brs, 2H), 4.94-4.84 (m, 2H), 4.39-4.29 (m, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.87-3.80 (m, 2H), 2.62 (m, 2H), 2.51 (m, 2H), 2.23 (m, 4H), 2.18-2.10 (m, 1H), 1.97 (m, 3H), 1.87-1.78 (m, 3H), 1.76-1.52 (m, 5H), 1.43 (m, 5H), 1.31-1.22 (m, 5H), 1.06 (m, 1H), 0.88 (t, J=7.3Hz, 6H), 0.81 (d, J=7.3Hz, 3H), 0.75 (d, J=6.9Hz, 3H), 0.70 (d, J=6.8Hz, 3H), 0.60 (d, J=7.3Hz, 3H), 0.58-0.53 (m, 1H)；

¹³C NMR (100MHz, CDCl₃) δ 171.9,171.7,146.7,146.6,145.2,145.1,130.6,130.4,120.3,119.8, 114.54,114.50,110.8,110.7,76.6,76.4,58.6 (2 × C), 55.7 (2 × C), 55.5 (2 × C), 55.2,55.1,47.9,47.2, 45.7,45.6,42.0,41.7,40.5 (2 × C), 37.9,37.8,29.99,29.95,29.8,29.2,28.5,28.4,20.7 (2 × C), 17.1, 16.9,14.8,14.4,13.9 (2 × C)；

Embodiment 10

Compound 11: preparation method is with embodiment 8.By compound 7 and 3,3 '-two Methoxyl group-4,4 '-two p-methyl benzenesulfonic acid ester group-α-soil former times acid two pivalic acid acid anhydride condensation Obtain after removing p-toluenesulfonyl protection group afterwards, white powdery solids, Two step gross production rates 88%.

¹H NMR (400MHz, CDCl₃) δ 6.85 (brs, 2H), 6.75-6.70 (m, 6H), 4.77 (m, 1H), 4.65 (m, 1H), 4.29 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.79-3.71 (m, 2H), 2.76 (t, J=12.7Hz, 2H), 2.59 (t, J=12.2Hz, 2H), 2.15 (s, 3H), 2.14 (s, 3H), 2.02 (dd, J=12.2,4.6Hz, 2H), 1.97 (dd, J=11.9,4.6Hz, 2H), 1.74 (dd, J=14.8,6.2Hz, 1H), 1.60 (m, 1H), 1.49-1.20 (m, 9H), 1.07-1.01 (m, 1H), 0.76 (d, J=6.5Hz, 3H), 0.70 (d, J=5.2Hz, 3H), 0.66 (d, J=6.3Hz, 3H), 0.48 (d, J=6.6Hz, 3H)；

¹³C NMR (100MHz, CDCl₃) δ 171.8,171.7,146.8,146.5,145.3,145.1,130.6 (2 × C), 120.3,120.1, 114.8,114.5,110.84,110.77,79.0,78.6,63.04,62.97,55.72,55.66,54.8,54.6,47.8,47.5,46.6, 46.5,44.1,44.0,41.70,41.66,41.4,41.2,37.3 (2 × C), 37.0,36.5,34.2,34.0,17.54,17.51,11.8,11.3.

Embodiment 11

Compound 12: preparation method is with embodiment 8.By compound 8 and 3,3 '-diformazan Epoxide-4,4 '-two p-methyl benzenesulfonic acid ester group-α-soil former times acid two pivalic acid acid anhydrides are condensed it Obtain after rear removing p-toluenesulfonyl protection group, white, amorphous solid, two Step gross production rate 43%.

¹H NMR (400MHz, CDCl₃) δ 6.84-6.78 (m, 6H), 5.68 (brs, 2H), 4.86 (m, 2H), 4.82 (s, 1H), 4.81 (s, 1H), 4.80 (m, 2H), 4.38-4.29 (m, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 3.81 (m, 2H), 2.94 (d, J=12.2Hz, 2H), 2.68 (t, J=11.9Hz, 2H), 2.55 (m, 1H), 2.39-2.26 (m, 5H), 2.20 (brs, 6H), 2.11 (dt, J=14.4, 6.2Hz, 1H), 1.90 (dd, J=14.4,6.2Hz, 1H), 1.86 (dd, J=14.4,7.8Hz, 1H), 1.82-1.66 (m, 3H), 1.31 (dd, J=14.4,8.0Hz, 1H), 0.88-0.75 (m, 1H), 0.79 (d, J=6.7Hz, 3H), 0.51 (d, J=5.5Hz, 3H)；

¹³C NMR (100MHz, CDCl₃) δ 171.8,171.7,146.55,146.47,145.02,144.96,144.81,144.75,130.9, 130.8,120.5,120.0,114.4 (2 × C), 110.8,110.6,110.2,110.1,77.7,77.4,61.0 (2 × C), 56.14,56.08, 55.9 (2 × C), 48.0,47.4,46.0 (2 × C), 45.2 (2 × C), 41.7,41.3,40.0 (2 × C), 38.70,38.66,35.7,35.1,12.8, 12.3.

Embodiment 12

Compound 13: NaH (60%in oil, 500mg, 12.5mmol) is added Enter in 10mL oxolane, ice bath cooling under argon shield, add phosphono Guanidine-acetic acid triethyl (2.2mL, 12.5mmol), removes ice bath, under room temperature React 1 hour.Again being cooled with an ice bath by reactant mixture to 0 DEG C, N-Boc-piperidones (997mg, 5mmol) is dissolved in 1mL It is slowly added dropwise after in oxolane into reaction system, removes ice bath, react 18 hours under room temperature until reaction is complete.Add saturated NH₄Cl solution cancellation, ethyl acetate extracts three times.Merge organic facies, use saturated NaHCO successively₃Solution, saturated NaCl Solution washs, anhydrous Na₂SO₄It is dried.Through pillar layer separation white solid 1.3g, productivity 97% after concentration.

Above-mentioned products therefrom (639mg, 2.4mmol) is dissolved in 6mL methanol, under argon, adds Pd/C (10w%, 200mg). Fill three hydrogen exchange argon, at hydrogenation instrument (4atm H₂In), reaction is overnight.Reactant liquor kieselguhr filters, and ethyl acetate is washed. Filtrate obtains white solid, 722mg, productivity 100% through pillar layer separation after concentrating.

Above-mentioned products therefrom (506mg, 1.9mmol) is dissolved in 10mL ether, is cooled to-20 DEG C, add diisobutyl hydrogenation Aluminum (1.0M, 5mL, 5mmol), reacts 10 minutes and disappears to raw material.Pour saturated sodium potassium tartrate solution into, under room temperature, stir 3 Hour to reaction mixture clarify, aqueous phase with ether extract three times, merge organic facies, with saturated NaCl solution washing, anhydrous Na₂SO₄It is dried.White solid, 368mg, productivity 86% is obtained through pillar layer separation after concentration.

By above-mentioned products therefrom (367mg, 1.6mmol), 3,3 '-dimethoxy-4 ', 4 '-two p-methyl benzenesulfonic acid ester group-α-soil former times acid (522mg, 0.75mmol) and DMAP (183mg, 1.5mmol) add in 5mL dichloromethane, stir 10 minutes under room temperature Until solid is completely dissolved, adds EDCI (432mg, 2.3mmol), react overnight under room temperature.It is subsequently adding saturated NaHCO₃ Solution dilutes, and aqueous phase is extracted with ethyl acetate three times, merges organic facies, washs by saturated NaCl solution, anhydrous Na₂SO₄Dry Dry.White unsetting solid, 707mg, productivity 84% is obtained through pillar layer separation after concentration.

Above-mentioned products therefrom (655mg, 0.58mmol) is dissolved in 3mL dichloromethane, adds 1mL trifluoroacetic acid, reaction 15 minutes.Concentrate, dchloromethane, add saturated Na₂CO₃Solution produces to bubble-free, aqueous phase CH₂Cl₂Extraction three Time, merge organic facies, use anhydrous Na₂SO₄It is dried.During after concentration, residual oil thing is dissolved in 40mL acetonitrile, ice bath is cooled to 0 DEG C, It is sequentially added into NaCNBH₃(443mg, 7.0mmol) and formalin solution (1.5mL), remove and react overnight under ice bath, room temperature Until raw material disappears, add 1.5mL AcOH cancellation.NaOH solution with 10% modulates PH=11～12, and dichloromethane extracts Take, gained organic facies anhydrous K₂CO₃It is dried.Obtain white unsetting solid, 332mg through pillar layer separation after concentration, produce Rate 60%.

Above-mentioned product (301mg, 0.32mmol) is dissolved in 80mL oxolane, under argon shield, is cooled to-40 DEG C, add The tetrahydrofuran solution (2.9mL, 1.44mmol) of freshly prepd Na/Anthracene, reacts 1 hour until raw material disappears at-40 DEG C Lose.Add saturated NaHCO₃Cancellation.Extract with dichloromethane, gained organic facies anhydrous Na₂SO₄It is dried, through post after concentration Chromatographic isolation obtains compound 13, white solid, 205mg, productivity 100%.

¹H NMR (400MHz, MeOD) δ 6.89 (s, 2H), 6.75 (m, 4H), 4.32 (dd, J=10.4,7.6Hz, 2H), 3.91-3.74 (m, 4H), 3.87 (s, 6H), 3.82 (dd, J=10.4,7.6Hz, 2H), 2.83 (d, J=11.2Hz, 4H), 2.30. (s, 6H), 1.99 (t, J=13.0Hz, 4H), 1.49 (q, J=13.2Hz, 4H), 1.17 (m, 4H), 1.09 (t, J=13.0Hz, 4H), 0.90 (m, 2H)；

¹³C NMR (100MHz, MeOD) δ 173.9,148.8,146.9,132.0,121.3,116.2,112.7,63.1,56.5,56.2, 48.9,46.0,42.8,35.9,32.2,32.1.

Embodiment 13

Compound 14: preparation method is with embodiment 8.With N-Boc-piperidones as initiation material, Experience Wittig reaction, hydrolysis alkene ether becomes aldehyde, reduction reaction, esterification, removes uncle Butoxy carbonyl, reduction amination and removing p-toluenesulfonyl 7 step reaction obtain.In vain Color solid, 210mg, 7 step gross production rates 43%.

¹H NMR (400MHz, DMSO-d₆) δ 8.84 (brs 2H), 6.85 (s, 2H), 6.67 (m, 4H), 4.23 (dd, J=10.4,7.6 Hz, 2H), 3.75 (dd, J=10.4,7.6Hz, 2H), 3.73 (s, 6H), 3.53 (m, 4H), 2.60 (d, J=10.8Hz, 4H), 2.08 (s, 6H), 1.66 (t, J=10.8Hz, 4H), 1.22 (m, 4H), 1.10 (m, 2H), 0.90 (m, J=12.0,3.2Hz, 4H)；

¹³C NMR (100MHz, DMSO-d₆) δ 171.6,147.3,145.6,129.8,119.8,115.1,112.1,68.2,55.6,54.6, 46.8,46.1,40.8,34.0,28.2,28.1.

Biological activity test example:

Embodiment horned artemisia ester alkali analog being prepared as its corresponding hydrochlorate and carries out analgesic test in Mice Body, result is as shown in table 1:

Test mice: male ICR mouse

Method of testing: hot plate method in mice, hot plate temperature is set as 55 DEG C, and thermostimulation deadline is 60s, licks metapedes with mice Or the incubation period of hopping response is threshold of pain index.Intraperitoneal injection, each compound amount is 40 μm ol/kg.With hydrochloric acid Coffee is as positive control drug, and consumption is 10mg/kg, about 27 μm ol/kg.

Evaluation of result:

Calculate maximum analgesic effect percentage rate (MPE%) as follows, evaluation analgesia intensity:

Table 1: the analgesic activities result of representative horned artemisia ester alkali analog

Data represent meansigma methods ± SEM；Vehicle represents the solvent for dissolved compound and positive drug, for DMSO (dimethyl Sulfoxide)+saline (normal saline) 1: 99；* P ＜ 0.01 compared with Vehicle controls group is represented；* represents and Vehicle controls group Compare P ＜ 0.001.

Conclusion (of pressure testing):

Above result of the test shows, in hot plate method animal pain models, each embodiment horned artemisia ester alkali analog all demonstrates stronger Analgesic activities.Wherein the activity of INCAD-4 and INCAD-6 is better than natural product horned artemisia ester alkali (INCA), especially INCAD-6 is under the dosage of 40 μm ol/kg, suitable when its analgesic effect and morphine 27 μm ol/kg.

Claims (9)

1. the synthetic route of preparation compound of Formula I:

Wherein R₁For hydrogen or methyl, ethyl, propyl group, butyl, pi-allyl, benzyl, Cvclopropvlmethvl, cyclobutylmethyl, Acetyl group, benzoyl or phenyl；R₂And R₃Each represent hydrogen or methyl, and R₂And R₃It is asynchronously hydrogen, methyl, or R₂And R₃Common expression=CH₂；X is Br, I, OMs, OTs；

A:lewis acid, aqueous sodium hypochlorite solution, solvent, 0 DEG C, the lewis acid in this condition is Indium-111 chloride, cerous chloride Or their hydrate, the two-phase solvent that described solvent is dichloromethane or chloroform and water is formed；

B: hydrogen peroxide, sodium hydrate aqueous solution, solvent, 0 DEG C, solvent is alcohol；

C: acid, lithium chloride, oxolane, 0 DEG C, the acid in this condition is various inorganic acid or organic acid；

D: para-methylbenzenepyridinsulfonate sulfonate, 3,4-dihydropyran, dichloromethane, reaction temperature is room temperature；

E: Feldalat NM, ether, 0 DEG C；

F: sodium azide, solvent, 60-90 DEG C, in this condition, solvent is polar non-proton organic solvent, and reaction temperature is 60-90 DEG C, during with boiling point solvent in this range, it is heated to reflux,；

G: triphenylphosphine, water, oxolane, backflow；

H: catalytic hydrogenation, the catalyst in this reaction is heterogeneous catalysis or homogeneous catalyst, and the pressure of hydrogen is 4atm, solvent is alcohol；

I: alkali, R₁X, oxolane, 0 DEG C-room temperature, in this reaction, alkali is sodium hydride, Feldalat NM, potassium tert-butoxide, butyl Lithium；

J: Lithium Aluminium Hydride, oxolane, reaction temperature is room temperature；

K: acid, solvent, in this reaction, acid is middle strong acid, strong acid or lewis acid, and solvent is proton solvent；

L: esterification has three kinds of methods:

Method 1:WithMolten in the presence of reagent and catalyst Reacting in agent, wherein condensation reagent is N, N'-dicyclohexylcarbodiimide, N, N'-DIC, 1-(3-diformazan Aminopropyl)-3-ethyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, triphenylphosphine, tetrachloro Changing carbon or iodate 1-methyl-2-chloropyridine, catalyst is DMAP or pyridine, and solvent is dichloromethane, tetrahydrochysene furan Muttering or acetonitrile, reaction temperature is 25-60 DEG C；

Method 2:WithReact in a solvent in the presence of agent, Wherein catalyst is DMAP or pyridine, solvent be dichloromethane, 1,2-dichloroethanes, pyridine or oxolane, Reaction temperature is 25-85 DEG C；

Method 3:WithIn the presence of agent in a solvent Reaction, wherein catalyst is DMAP or pyridine, and solvent is dichloromethane, oxolane, normal heptane or acetonitrile, Reaction temperature is room temperature；

M: sodium/anthracene, oxolane ,-40 DEG C.

2. the synthetic route of claim 1, wherein X is I or OTs.

3. the synthetic route of claim 1, wherein the alcohol in step b is methanol or ethanol.

4. the synthetic route of claim 1, wherein the acid in step c is trifluoroacetic acid.

5. the synthetic route of claim 1, wherein the polar non-proton organic solvent in step f is dimethyl sulfoxide, N, N-diformazan Base Methanamide, oxolane or acetonitrile；Reaction temperature is 70 DEG C.

6. the synthetic route of claim 5, wherein the polar non-proton organic solvent in step f is DMF.

7. the synthetic route of claim 1, wherein the heterogeneous catalysis in step h be palladium/carbon, platinum dioxide, platinum oxide or Raney Ni；Homogeneous catalyst is Wilkinson catalyst.

8. the synthetic route of claim 1, wherein the middle strong acid in step k or strong acid be hydrochloric acid, acetic acid, p-methyl benzenesulfonic acid or Boric acid, lewis acid is para-methylbenzenepyridinsulfonate sulfonate or stannum dichloride；Proton solvent is methanol, ethanol or oxolane and water work For mixed solvent.

9. the synthetic route of claim 1, wherein the method for esterification is method 3, and the catalyst in method 3 is 4-diformazan ammonia Yl pyridines, solvent is acetonitrile.