CN103992212A - Synthesis method for cis-benvitimod, and applications of cis-benvitimod - Google Patents

Synthesis method for cis-benvitimod, and applications of cis-benvitimod Download PDF

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CN103992212A
CN103992212A CN201410233095.1A CN201410233095A CN103992212A CN 103992212 A CN103992212 A CN 103992212A CN 201410233095 A CN201410233095 A CN 201410233095A CN 103992212 A CN103992212 A CN 103992212A
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dimethoxy
reaction
isopropyl
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moral
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CN103992212B (en
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杜曼
张越
刘婷婷
徐世霞
宋海文
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Hebei University of Science and Technology
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    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
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Abstract

The invention discloses a synthesis method for cis-benvitimod, and applications of cis-benvitimod. The synthesis method comprises the following steps: by taking 3,5-dihydroxy-4-isopropylbenzoic acid as a raw material, sequentially performing methylation, reduction, oxidization, condensation, decarboxylation and demethylation to finally synthesize cis-benvitimod, the purity of the prepared high-purity product cis-benvitimod achieves 95-99%, and the cis-benvitimod can be used for detecting the content of cis-benvitimod as a standard substance in the synthesis of trans-benvitimod; according to the synthesis method, the defects that the cis-benvitimod is low in content, instable in properties and difficult to separate in the prior art can be overcome, a method for analyzing and detecting important impurities in the preparation process of the trans-benvitimod preparation process can be established. The synthesis method is applicable to synthesis of cis-benvitimod, the prepared product is used for detecting the content of cis-benvitimod as a standard substance in the synthesis process of trans-benvitimod.

Description

Cis benzene alkene is synthetic method and the not application of moral of cis benzene alkene of moral not
Technical field
The invention belongs to pharmacy field, relate to a kind of synthetic and application of diphenylethylene compounds, specifically not synthetic method and the not application of moral of cis benzene alkene of moral of a kind of cis benzene alkene.
Background technology
The toxicity of impurity, especially heredity toxicity in the former medicine of chemical synthetic drug and preparation are the important factors that affects drug safety.Impurity majority in medicine has potential biological activity, and the untoward reaction that medicine produces in clinical use is except outside the Pass the pharmacologically active with medicine itself has, also with medicine in the impurity that exists have much relations.Some impurity can interact with medicine, directly affects drug safety and validity, even produces toxic action.The control of impurity of the drug is for the usefulness that guarantees medicine, and the untoward reaction that reduces medicine plays critical effect.The research of impurity is the importance of drug research, and it through whole drug research all the time.Can the impurity in medicine obtain rationally, effectively control, and is directly connected to quality controllability and the security of medicine.
Benzene alkene not moral (Benvitimod) is anti-inflammation drugs of new generation, can be used for treating multiple great autoimmune disorder, as psoriasis, eczema, send out colitis and multiple anaphylactic disease dense.Benzene alkene not moral is diphenylethylene compounds, comprise cis-trans-isomer, trans benzene alkene not moral has stronger physiologically active, and physicochemical property are stable, and cis benzene alkene not moral be mainly the not by product in moral building-up process of trans benzene alkene, traditional synthetic benzene alkene not moral method as cis-isomeride impurity in Wittig reaction be inevitable.
As the trans benzene alkene major impurity of moral in synthetic not, no matter be to carry out drug testing, or the monitoring in reaction process, cis benzene the alkene synthetic and establishment of analytical procedure of moral does not have very important meaning.Traditional benzene alkene not in moral synthetic method the content of this impurity very low, and cis-compound character is extremely unstable, easily changes into transconfiguration, so according to synthetic method before, this cis-compound is difficult to separate.Its synthetic method was not reported in document before.Therefore the route of synthesis of moral is not most important, to find a cis benzene alkene.
The synthetic method of cis-stilbene compounds, in the prior art, has had a lot of reports, still, the method reaction raw materials of synthesizing cis product and reagent source difficulty in prior art, the catalyzer using is more expensive, and cost is higher, operational difficulty, is unfavorable for scale operation, for example:
1. Gaukroger K, John A. Hadfield. Novel syntheses of cis and trans isomers of combretastatin A-4[J] .J. Org. Chem, 2001, (66): 8135-8138, take the styryl bromine that replaces and the phenylo boric acid of replacement is raw material, Suzuki linked reaction under palladium catalysis, obtains cis-compound, reaction process as shown in the formula:
The method productive rate selectivity high and structure is good, but reaction raw materials source difficulty, catalyzer is more expensive, has limited the use of the method.
2. Felix N, Ngassa, Erick A, Lindsey, Brandon E, Haines.The first Cu-and amine-free Sonogashira-type cross-coupling in the C-6-alkynylation of protected 2 '-deoxyadenosine [J]. Tetrahedron Letters, 2009, (65): 4085-4091, adopts the easy catalyzed dose of Pd/CaCO of the phenylacetylene replacing 3, Fe 2(CO) 9, Pd (OAc) 2deng catalytic reduction, produce cis-compound.Reaction process as shown in the formula:
The method advantage is alkynes stereospecificity reduction under catalyst action, has overcome the cis-trans isomerization in Wittig reaction, but because reaction needed is at-78 ℃, be unfavorable for operation, and reagent source difficulty, price is higher, increase cost, be unfavorable for scale operation.
3. Belluci G, Chiappe C, Moro G Lo. Crown ether catalyzed stereospecific synthesis of Z-and E-stilbenes by Wittig reaction in a solid-liquid two-phases system[J] .Tetrahedron Letters, 1996, (37): 4225-4228, adopts Pd (PPh 3) 4as catalyzer, organic zinc reagent and halogenide coupling generate cis-compound, reaction process as shown in the formula:
The advantage of the method is that selectivity is good, obtains cis yield high; Weak point is operational difficulty, and catalyzer is expensive.
4. Wang Zhi is new, Zhang Xuejing, all Yue, Zou Yongshun, trans-Resveratrol synthetic. Chinese pharmacy, 2005,14 (4); 204-208, has reported trans-compound has been dissolved in DMSO, is made into certain density solution, under 365nm uv irradiating, reacts, and is converted to cis-compound, and reaction process is shown in following formula:
But the method requires stricter to solution concentration preparation, reaction times.
Summary of the invention
The technical problem to be solved in the present invention, be to provide the not synthetic method of moral of a kind of cis benzene alkene, with 3,5-dihydroxyl-4-isopropyl acid is raw material, through the final synthesizing cis benzene of Hypermethylation, reduction, oxidation, condensation, decarboxylation and demethylating reaction alkene moral not, prepared cis benzene alkene not moral purity reaches 95-99% successively;
Another object of the present invention, is to provide the not a kind of application of moral of aforesaid method institute preparing cis benzene alkene, it can trans benzene alkene not in moral synthetic as standard substance, for detection of the cis benzene alkene content of moral not; Overcome in prior art that moral content is not low, character is unstable is difficult to separated shortcoming because of cis benzene alkene, and set up trans benzene alkene not analysis and the detection method of a kind of important impurity in moral preparation process.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
A kind of cis benzene alkene is the synthetic method of moral not, it is with 3,5-dihydroxyl-4-isopropyl acid is raw material, successively through methylation reaction synthetic 3,5-dimethoxy-4 '-isopropyl acid ester, reduction reaction synthetic 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, oxidizing reaction is synthesized 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde, condensation reaction synthetic 3, the acid of 5-dimethoxy-4 '-isopropyl toluylene, decarboxylic reaction synthesizes 3,5-dimethoxy-4 '-isopropyl toluylene, finally by crossing not moral of demethylating reaction synthesizing cis benzene alkene.
As a kind of restriction of the present invention, the reaction scheme of above-mentioned synthetic method is as follows:
。
As the further restriction of above-mentioned restriction, described synthetic method is carried out according to following steps order:
(1) methylation reaction
3,5-dihydroxyl-4-isopropyl acid, Anhydrous potassium carbonate are mixed with mol ratio 1:3～5, join in DMF, at room temperature stir; Then, at cryosel, bathe cooling under, slowly drip methyl iodide; After dropwising, rise to room temperature, reaction 2-3h; Add after completion of the reaction water and stir, ethyl acetate extraction, concentrated, obtain 3,5-dimethoxy-4 '-isopropyl acid ester, yield is 90-95%, purity is 95-99%; Wherein:
The mol ratio of 3,5-dihydroxyl-4-isopropyl acid and methyl iodide is 1:3～5;
The weightmeasurement ratio of 3,5-dihydroxyl-4-isopropyl acid and DMF is 1:20～30g/mL;
(2) reduction reaction
By tetrahydrofuran (THF), mol ratio, be 1:4～6 3,5-dimethoxy-4 '-isopropyl acid ester and sodium borohydride mixed at room temperature stir, and are heated to reflux, slowly drip methyl alcohol, after reaction 4～6h, add water 3～5L and stir, ethyl acetate extraction, washing, revolve to steam and obtain white solid except desolventizing, 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, yield is 94-98%, and purity is 95-99%; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropyl acid ester, methyl alcohol and tetrahydrofuran (THF) is 1:1～3:10～20g/mL/mL;
(3) oxidizing reaction
By 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, DMSO and acetic anhydride mix and blend, after room temperature reaction 2-3h, add water and stir, ethyl acetate extraction, washing, dry, concentrated 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde, yield is 90-95%, purity is 95-99%; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, DMSO and acetic anhydride is 1:10～15:2～3g/mL/mL;
It is oxygenant that the present invention adopts DMSO, and reaction conditions is gentle, and operational safety is simple, and yield is higher.
The present invention has adopted multiple oxygenant to test, and still, adopts PCC, the CrO3/ vitriol oil and Collins reagent, because toxicity is larger, and harm environment and experimenter, and in reaction process, sticky wall is serious, and not exclusively, aftertreatment is very difficult in reaction; While adopting potassium bichromate as oxygenant, because oxidisability is stronger, formed corresponding aldehyde product is less, is directly oxidized to acid; While adopting activated manganese dioxide, aluminum isopropylate as oxygenant, yield is lower, and aftertreatment is more difficult; As can be seen here, be not that the oxygenants that alcohol can be oxidized to aldehyde all in prior art can both be for the present invention, and its consumption is also very large on reaction result impact, adopt 3, the weightmeasurement ratio of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol, DMSO and acetic anhydride is 1:10～15:2～3g/mL/mL, exceed ratio upper limit DMSO and acetic anhydride excessive, in last handling process, be difficult to except clean, increase the difficulty of aftertreatment, waste reagent, exceed ratio lower limit and can produce the incomplete phenomenon of reaction, and yield is lower.
(4) condensation reaction
By mol ratio, be 1:1 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and toluylic acid mix, add in acetic anhydride, stirring and dissolving, adds sodium-acetate, be heated to 135 ℃, after reaction 6-8h, be down to that to add rare acid for adjusting pH after room temperature be 2-3, ethyl acetate extraction, concentrated, adding saturated sodium bicarbonate solution adjusting pH is 7～8, stirs after 2-3h dichloromethane extraction, it is 2～3 that water adds dilute hydrochloric acid tune pH, filter yellow solid, 3, the acid of 5-dimethoxy-4 '-isopropyl toluylene, yield is 94-98%, and purity is 80-85%; Wherein:
The mol ratio of 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and sodium-acetate is 1:2～4;
The weight/volume of 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and acetic anhydride is 1:20～30g/mL;
This step is committed step of the present invention, and the ratio of cis-product controlled well is particularly crucial, and reaction conditions provided by the present invention maximizes the content of cis-product, and guarantees that yield is higher.
In prior art, mostly adopting toluene is solvent, adds a small amount of acetic anhydride, back flow reaction at 110 ℃, but adopting toluene is solvent, and yield is lower is 60-90%, and in the present invention, adopting acetic anhydride is solvent, and yield can reach more than 94%.
It is basic catalyst that the present invention adopts sodium acetate, anhydrous, and aftertreatment is simple, and yield is higher.
The present invention has adopted multiple basic catalyst to test, and still, while adopting triethylamine as basic catalyst, yield is lower; Adopt Anhydrous potassium carbonate and anhydrous potassium fluoride, in reaction process, sticky wall is serious, and reaction solution is the glutinous colloidal liquid of black, and aftertreatment is very difficult; While adopting Glacial acetic acid potassium to be basic catalyst, although aftertreatment is relatively simple, yield is lower; As can be seen here, be not that basic catalysts all in prior art can both be for the present invention, and its consumption is also very large on reaction result impact, adopt 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and sodium-acetate mol ratio be 1:2-4, when the weightmeasurement ratio of 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and acetic anhydride is 1g:20～30mL, react completely, yield is higher.Exceed ratio upper limit acetic anhydride excessive, in last handling process, being difficult to except clean, increases the difficulty of aftertreatment, waste reagent; Exceed the reaction of ratio lower limit not exclusively, yield is lower.
(5) decarboxylic reaction
By mol ratio, be 1:6～8 3, the acid of 5-dimethoxy-4 '-isopropyl toluylene and copper powder join in quinoline, and 180 ℃ are reacted after 3-5h, be down to room temperature, add ethyl acetate and stir, filter, filtrate is washed to water layer colourless with dilute hydrochloric acid, water is used ethyl acetate reversed phase extraction again, merges organic layer, saturated common salt water washing is to neutral, be spin-dried for, obtain 3,5-dimethoxy-4 '-isopropyl toluylene, yield is 90-95%, and purity is 75-80%; Wherein:
The acid of 3,5-dimethoxy-4 '-isopropyl toluylene is 1:15～20g/mL with the weight/volume of quinoline;
The cis-product of controlling well is not converted into stable trans product, is the key of this step, and the control of therefore reacting the factors such as mol ratio, temperature, reaction times and aftertreatment is extremely important.
Traditional decarboxylation method used be 210-230 ℃ of reaction, but high temperature easily aggravates the not reversion of moral of cis benzene alkene, finally take trans benzene alkene not moral as main, therefore, the present invention is using on the basis of preferably decarboxylation reagent copper powder and quinoline, the strict temperature of reaction of controlling, finally make cis benzene alkene not the content of moral be 75-80%.
It is decarboxylation reagent that the present invention adopts copper powder and quinoline, and aftertreatment is simple, and yield is higher.
The present invention has adopted multiple decarboxylation reagent to test, and still, adopts acetic acid and sulfuric acid back flow reaction at 110 ℃, and yield is lower; Adopt sodium-chlor and DMSO decarboxylation at 180 ℃, or when DMSO and under reflux conditions decarboxylation of water, during aftertreatment, DMSO is difficult to steam except clean, and yield is not high yet; Adopt decarboxylation under 60% sulfuric acid reflux conditions, yield is lower; Adopt concentrated hydrochloric acid decarboxylation at ambient temperature, mild conditions is difficult to decarboxylation, and yield is lower; Adopt tosic acid and water to react at 100 ℃, toxicity is larger, and yield is not high yet; Adopt lithium chloride, DMSO and water to react at 130 ℃, lithium chloride is expensive, and cost is higher, and DMSO is difficult to remove during aftertreatment; As can be seen here, be not that decarboxylation reagent all in prior art can both be for the present invention, and its consumption is also very large on reaction result impact, adopt 3, the mol ratio of the acid of 5-dimethoxy-4 '-isopropyl toluylene and copper powder is 1:6-8,3, the acid of 5-dimethoxy-4 '-isopropyl toluylene is 1g:15-20mL with the weight/volume of quinoline, exceed ratio upper limit copper powder and quinoline excessive, aftertreatment is difficult to be removed totally, increases the difficulty of aftertreatment, waste reagent, exceed ratio lower limit and react not exclusively, yield is lower.
(6) demethylating reaction
3,5-dimethoxy-4 '-isopropyl toluylene is placed in to toluene, in ice bath, stirs, be cooled to 0 ℃, after dissolving, slowly add DMA, add aluminum trichloride (anhydrous) in batches, stir after 0.5h, rise to room temperature, be heated to, after 100 ℃ of reaction 2-3h, be cooled to 60 ℃, separate while hot toluene layer, in water, add dilute hydrochloric acid stirring and adjusting pH value for 2-3, ethyl acetate extraction, washing, concentrated, obtain not moral of target product cis benzene alkene, yield is 92-98%, purity 70-80%, after separation, yield is 65-75%, and purity is 95-99%; Wherein:
The weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene is for being 1:15～20g/mL;
The mol ratio of 3,5-dimethoxy-4 '-isopropyl toluylene and DMA, aluminum trichloride (anhydrous) is 1:5～7:5～7.
Common demethyl method is back flow reaction at 110 ℃, excess Temperature, the easily not reversion of moral of aggravation cis benzene alkene, moral is not as main finally to take trans benzene alkene, and therefore, the present invention is selecting preferably demethylation reagent N, on the basis of accelerine and aluminum trichloride (anhydrous), strict proportioning and the temperature of reaction of controlling between reactant, finally make cis benzene alkene not the content of moral be 70-80%, after separation, purity is up to 95-99%.
The present invention adopts DMA, aluminum trichloride (anhydrous) to be demethylation reagent, and simple to operate, yield is higher.
The present invention has adopted multiple demethylation reagent to test, still, employing must hydrochloride and pyridine hydrobromide salt as demethylation reagent, toxicity is larger, harm environment and experimenter, and temperature of reaction is higher, product configuration is transconfiguration substantially; Adopt BBr 3/ methylene dichloride is during as demethylation reagent, due to BBr 3highly volatile, must ℃ dropping in low temperature-70～80, severe reaction conditions, operational difficulty; While adopting trimethyl silane as demethylation reagent, because trimethyl silane easily volatilizees, be difficult for storage, operate more difficultly, and yield is lower; While adopting dense HI solution as demethylation reagent, increase cost, and yield is not high yet; While adopting 40%HBr/ acetic acid as demethylation reagent, yield is lower; While adopting lauryl mercaptan sodium/DMF as demethylation reagent, need be 190 ℃ of reactions, temperature of reaction is higher, and product is transconfiguration substantially; As can be seen here, be not that demethylation reagents all in prior art can both be for the present invention, and its consumption is also very large on reaction result impact, adopt the weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene for being 1g:15-20mL; 3,5-dimethoxy-4 '-isopropyl toluylene is 1:5～7:5～7 with the mol ratio of reacting of DMA, aluminum trichloride (anhydrous).Exceeding the ratio upper limit increases the difficulty of aftertreatment, and waste reagent, exceeds ratio lower limit and reacts not exclusively, and yield is lower.
The present invention also provides the not a kind of application of moral of above-mentioned synthetic method institute's preparing cis benzene alkene, it can trans benzene alkene not in moral synthetic as standard substance, for detection of the cis benzene alkene content of moral not.
As a kind of restriction of the present invention, the detection cis benzene alkene not content of moral is the method that adopts HPLC: chromatographic column is Nucleosil 5 C18; Column temperature is 20 ℃; Detection wavelength is 318nm; Acetonitrile and water that moving phase is 50: 50 by volume ratio form; Flow velocity is 0.6mL/min, and sample size is 5 μ L.
Owing to having adopted above-mentioned technical scheme, compared with prior art, obtained technical progress is in the present invention:
The present invention is with 3,5-dihydroxyl-4-isopropyl acid for raw material, and through the final synthesizing cis benzene of Hypermethylation, reduction, oxidation, condensation, decarboxylation and demethylating reaction alkene moral not, prepared cis benzene alkene not moral purity reaches 95-99% successively; The high purity product of preparing, can trans benzene alkene not in moral synthetic as standard substance, for detection of the cis benzene alkene content of moral not.Synthetic method of the present invention has overcome in prior art that moral content is not low, character is unstable is difficult to separated shortcoming because of cis benzene alkene, and has set up trans benzene alkene not analysis and the detection method of a kind of important impurity in moral preparation process.
The present invention is applicable to not moral synthetic of cis benzene alkene, products made thereby for trans benzene alkene not moral building-up process as standard substance, for the cis benzene alkene content detection of moral not.
The present invention is described in further detail below in conjunction with Figure of description and specific embodiment.
Accompanying drawing explanation
Fig. 1 is cis benzene alkene moral not in the embodiment of the present invention 1 1hNMR figure;
Fig. 2 is trans benzene alkene moral not in the embodiment of the present invention 1 1hNMR figure;
Fig. 3 is the cis benzene alkene HPLC figure of moral not in the embodiment of the present invention 1;
Fig. 4 is the trans benzene alkene HPLC figure of moral not in the embodiment of the present invention 1;
Fig. 5 is along the anti-benzene alkene HPLC figure of moral mixture not in the embodiment of the present invention 1.
Embodiment
1 one kinds of cis benzene alkene of embodiment are synthetic method and the not application of moral of institute's preparing cis benzene alkene of moral not
This cis benzene alkene is the synthetic method of moral not, according to following route, reacts:
Concrete preparation process is carried out according to following steps order:
(1) methylation reaction
By 195.12g(1mol) 3,5-dihydroxyl-4-isopropyl acid, 414.57g(3mol) Anhydrous potassium carbonate adds the DMF of 5000ml after mixing, at room temperature stir, then at cryosel, bathe cooling under, the slow 425.85g(3mol that drips) methyl iodide, after dropwising, rise to room temperature, reaction 2h, adds after completion of the reaction water and stirs, ethyl acetate extraction, concentrated, obtain 3,5-dimethoxy-4 '-isopropyl acid ester; Yield is 93%, and purity is 99%.
(2) reduction reaction
By the tetrahydrofuran (THF) of 3000ml and 240g(1mol) 3,5-dimethoxy-4 '-isopropyl acid ester, 151.40g(4mol) sodium borohydride mixed at room temperature stir, be heated to reflux, slowly drip the methyl alcohol of 400ml, after reaction 4h, adding 3L water stirs, ethyl acetate extraction, washing, revolves to steam and obtains white solid except desolventizing, obtain 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol; Yield is 96%, and purity is 99%.
(3) oxidizing reaction
By 212g(1mol) 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, the DMSO of 800ml and the acetic anhydride mix and blend of 500ml, after room temperature reaction 2h, add water and stir, ethyl acetate extraction, washing, dry, concentrated 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde; Yield is 94%, and purity is 99%.
(4) condensation reaction
By 209.18g(1mol) 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and 136.15g(1mol) the mixture of toluylic acid add in the acetic anhydride of 5000ml, stirring and dissolving, add 246.09g sodium-acetate, be heated to 135 ℃, after reaction 6h, be down to that to add rare acid for adjusting pH after room temperature be 2, ethyl acetate extraction, concentrated, adding saturated sodium bicarbonate solution adjusting pH is 7, stirs after 2h dichloromethane extraction, it is 2 that water adds dilute hydrochloric acid tune pH, filter yellow solid, obtain the acid of 3,5-dimethoxy-4 '-isopropyl toluylene; Yield is 96%, and purity is 80%.
(5) decarboxylic reaction
By 327g(1mol) 3,5-dimethoxy-4 '-isopropyl toluylene acid and 384g(6mol) copper powder join in the quinoline of 5000ml, 180 ℃ reaction 3h after, be down to room temperature, adding ethyl acetate stirs, filter, filtrate is washed to water layer colourless with dilute hydrochloric acid, and water is used ethyl acetate reversed phase extraction again, merge organic layer, saturated common salt water washing, to neutral, is spin-dried for and obtains 3,5-dimethoxy-4 '-isopropyl toluylene; Yield is 92%, and purity is 77%.
(6) demethylating reaction
By 282.32g(1mol) 3,5-dimethoxy-4 '-isopropyl toluylene is placed in the toluene of 4000ml, in ice bath, stir, be cooled to 0 ℃, after dissolving, slowly add 605.9g(5mol) DMA, add 666.7g(5mol in batches) aluminum trichloride (anhydrous), stir after 0.5h, rise to room temperature, be heated to, after 100 ℃ of reaction 2h, be cooled to 60 ℃, separate while hot toluene layer, to adding dilute hydrochloric acid stirring and adjusting pH value in water, be 2, ethyl acetate extraction, washing, concentrated, obtain not moral of cis benzene alkene; Crude product yield is 95%, and purity is 74%.After through column chromatography, carry out separation, adopt 300-400 object silica gel, separated cis benzene alkene is moral sterling not, yield is 68%, purity is 98.5%.Prepared cis benzene alkene not moral nuclear-magnetism figure as shown in Figure 1, nuclear magnetic data is as follows:
1H?NMR?(CDCl 3,?500?Hz,?δ:?ppm),?7.255?(m,?5H),?6.558?(d,?1H),?6.402?(d,?1H),?6.218?(s,?2H),?4.872?(s,?2H),?3.423?(m,?1H),?1.359?(q,?6H)。Coupling constant j=12.
Trans benzene alkene not moral nuclear-magnetism figure as shown in Figure 2, nuclear magnetic data is as follows:
1H?NMR?(CDCl 3,?500?Hz,?δ:?ppm),?7.477?(d,?2H),?7.360?(t,?2H),?6.969?(q,?2H),?6.501?(s,?1H),?4.722?(s,?2H),?3.486?(m,?1H),?1.380?(t,?6H)。Coupling constant j=16.
Cis benzene alkene is the HPLC condition of moral sterling not: chromatographic column is Nucleosil 5 C18; Column temperature is 20 ℃; Detection wavelength is 318nm; Acetonitrile and water that moving phase is 50: 50 by volume ratio form; Flow velocity is 0.6mL/min, and sample size is 5 μ L; Cis benzene alkene not moral is that 18.423min goes out peak in retention time, and content is 96.39%, sees accompanying drawing 3.Trans benzene alkene not moral is that 17.630min goes out peak in retention time, and content is 99.8%, sees accompanying drawing 4.After both mix, trans benzene alkene not moral is that 17.664min goes out peak in retention time, and cis benzene alkene not moral is that 18.458min goes out peak in retention time, sees accompanying drawing 5.
The cis benzene alkene that detection is prepared not moral stability and probe into its storage requirement, carried out the experiment of following study on the stability:
1, the stability experiment carrying out according to pharmacopeia (Chinese Pharmacopoeia 2010 editions)
Note: the value in upper table is the not content of moral (%) of cis benzene alkene.
2, illumination condition experiment
Note: the value in upper table is the not content of moral (%) of cis benzene alkene.
3, temperature condition experiment
Note: the value in upper table is the not content of moral (%) of cis benzene alkene, and stores under lucifuge condition.
4, permanent stability experiment
Note: the value in upper table is the not content of moral (%) of cis benzene alkene, and stores under lucifuge condition.
Known according to above-mentioned test, the prepared cis benzene of the present embodiment alkene not moral has stability, and the cis benzene alkene making the not storage requirement of moral should be: below 0 ℃, keep in Dark Place.
embodiment 2-6 cis benzene alkene is the synthetic method of moral not
Embodiment 2-6 is respectively the not synthetic method of moral of a kind of cis benzene alkene, and its building-up process is similar to embodiment 1, and difference is only wherein related technical parameter, shown in table specific as follows:
embodiment 7 condition tests
The present embodiment has carried out optionally screening to the technical parameter in embodiment 1-6, finds that the type of agents useful for same is very large on reacting impact with consumption.
1, oxygenant and the consumption thereof in reactions steps (3) selected, and be not the reaction that oxygenants all in prior art can both make its mild condition, and yield is higher, and particular content sees the following form:
Final determine that DMSO/ acetic anhydride is oxygenant, rear its consumption is tested, find that both proportion relations are larger to the influence factor of reacting with consumption, shown in table specific as follows:
As can be seen from the above table, adopt 3, the weightmeasurement ratio of 5-dimethoxy-4 '-isopropyl benzene methyl alcohol, DMSO and acetic anhydride is 1:10～15:2～3g/mL/mL, exceed ratio upper limit DMSO and acetic anhydride excessive, in last handling process, being difficult to except clean, increases the difficulty of aftertreatment, waste reagent, exceed ratio lower limit and can produce the incomplete phenomenon of reaction, and yield is lower.
2, basic catalyst condensation reaction being used is selected, and be not the reaction that basic catalysts all in prior art can both make its mild condition, and yield is higher, and particular content sees the following form:
As can be seen from the above table, select sodium acetate, anhydrous as the basic catalyst in condensation reaction, aftertreatment is relatively simple, and reaction yield is higher.
Final determine that sodium acetate, anhydrous is basic catalyst, rear its consumption is tested, find that both proportion relations are larger to the influence factor of reacting with consumption, shown in table specific as follows:
As can be seen from the above table, as can be seen from the above table, adopt 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and sodium-acetate mol ratio be 1:2-4, when the weightmeasurement ratio of 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and acetic anhydride is 1g:20～30mL, react completely, yield is higher.Exceed ratio upper limit acetic anhydride excessive, in last handling process, being difficult to except clean, increases the difficulty of aftertreatment, waste reagent; Exceed the reaction of ratio lower limit not exclusively, yield is lower.
Also temperature of reaction and reaction times are selected simultaneously, shown in table specific as follows:
As can be seen from the above table, the temperature of reaction of condensation reaction is selected 135 ℃ can arrive higher reaction yield, and the content of cis-product is also higher.
As can be seen from the above table, the reaction times of condensation reaction selects 6-8h can arrive higher reaction yield, and the content of cis-product is also higher.
3, decarboxylation reagent decarboxylic reaction being used is selected, and be not the reaction that decarboxylation reagent all in prior art can both make its mild condition, and yield is higher, and particular content sees the following form:
As can be seen from the above table, the reagent of decarboxylic reaction select copper powder/quinoline can arrive higher reaction yield and aftertreatment simple.
Final determine that copper powder/quinoline is decarboxylation reagent, rear its consumption is tested, find that both proportion relations are larger to the influence factor of reacting with consumption, shown in table specific as follows:
As can be seen from the above table, as can be seen from the above table, adopting the mol ratio of the acid of 3,5-dimethoxy-4 '-isopropyl toluylene and copper powder is 1:6-8,3, the acid of 5-dimethoxy-4 '-isopropyl toluylene is 1g:15-20mL with the weight/volume of quinoline, exceeds ratio upper limit copper powder and quinoline excessive, and aftertreatment is difficult to be removed totally, increase the difficulty of aftertreatment, waste reagent, exceeds ratio lower limit and reacts not exclusively, and yield is lower.
Also temperature of reaction and reaction times are selected simultaneously, shown in table specific as follows:
As can be seen from the above table, the temperature of reaction of decarboxylic reaction is selected 180 ℃ can arrive higher reaction yield, and the content of cis-product is also higher.
As can be seen from the above table, the reaction times of decarboxylic reaction selects 3-5h can arrive higher reaction yield, and the content of cis-product is also higher.
4, demethylation reagent demethylating reaction being used is selected, and be not the reaction that demethylation reagents all in prior art can both make its mild condition, and yield is higher, and particular content sees the following form:
As can be seen from the above table, demethylation reagent is selected DMA/anhydrous AlCl 3can arrive higher reaction yield, simple to operate, and the content of cis-product is also higher.
Final definite DMA/anhydrous AlCl 3for demethylation reagent, rear its consumption is tested, find that both proportion relations are larger to the influence factor of reacting with consumption, shown in table specific as follows:
As can be seen from the above table, as can be seen from the above table, adopt the weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene for being 1g:15-20mL; 3,5-dimethoxy-4 '-isopropyl toluylene is 1:5～7:5～7 with the mol ratio of reacting of DMA, aluminum trichloride (anhydrous).Exceeding the ratio upper limit increases the difficulty of aftertreatment, and waste reagent, exceeds ratio lower limit and reacts not exclusively, and yield is lower.
Also temperature of reaction and reaction times are selected simultaneously, shown in table specific as follows:
As can be seen from the above table, the temperature of reaction of demethylating reaction is selected 100 ℃ can arrive higher reaction yield, and the content of cis-product is also higher.
As can be seen from the above table, the reaction times of demethylating reaction selects 6-8h can arrive higher reaction yield, and the content of cis-product is also higher.
5, to cis benzene alkene not the HPLC method of moral carried out condition test, finally determine: chromatographic column is Nucleosil 5 C18; Column temperature is 20 ℃; Detection wavelength is 318nm; Acetonitrile and water that moving phase is 50: 50 by volume ratio form; Flow velocity is 0.6mL/min, and sample size is 5 μ L.
When preparation detects solution, if adopt methyl alcohol sample, because cis-product is very unstable in methyl alcohol, within very short time, can change into trans product, if and during by acetonitrile/water sample, cis-product is relatively stable, therefore selects acetonitrile/water to guarantee that as moving phase the result detecting is better accurately.
Concrete screening process is as follows:
As can be seen from the above table, cis-trans benzene alkene not moral HPLC separation condition is selected acetonitrile/water=50:50, and flow velocity 0.6mL/min can reach along the moral separation preferably of anti-benzene alkene.

Claims (5)

1. a cis benzene alkene synthetic method for moral not, it is characterized in that:it is with 3,5-dihydroxyl-4-isopropyl acid is raw material, successively through methylation reaction synthetic 3,5-dimethoxy-4 '-isopropyl acid ester, reduction reaction synthetic 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, synthetic 3, the 5-dimethoxy-4 '-isopropyl benzene formaldehyde of oxidizing reaction, the acid of condensation reaction synthetic 3,5-dimethoxy-4 '-isopropyl toluylene, decarboxylic reaction synthetic 3,5-dimethoxy-4 '-isopropyl toluylene, finally by crossing not moral of demethylating reaction synthesizing cis benzene alkene.
2. the cis benzene alkene according to claim 1 synthetic method of moral not, it is characterized in thatsynthetic method is reacted according to following route:
3. the cis benzene alkene according to claim 2 synthetic method of moral not, it is characterized in thatit carries out according to following steps order:
(1) methylation reaction
3,5-dihydroxyl-4-isopropyl acid, Anhydrous potassium carbonate are mixed with mol ratio 1:3～5, join in DMF, at room temperature stir; Then, at cryosel, bathe cooling under, slowly drip methyl iodide; After dropwising, rise to room temperature, reaction 2-3h; Add after completion of the reaction water and stir, ethyl acetate extraction, concentrated, obtain 3,5-dimethoxy-4 '-isopropyl acid ester; Wherein:
The mol ratio of 3,5-dihydroxyl-4-isopropyl acid and methyl iodide is 1:3～5;
The weightmeasurement ratio of 3,5-dihydroxyl-4-isopropyl acid and DMF is 1:20～30g/mL;
(2) reduction reaction
By tetrahydrofuran (THF), mol ratio, be 1:4～6 3,5-dimethoxy-4 '-isopropyl acid ester and sodium borohydride mixed at room temperature stir, be heated to reflux, slowly drip methyl alcohol, after reaction 4～6h, adding water 3～5L stirs, ethyl acetate extraction, washing, revolves to steam and obtains white solid except desolventizing, 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropyl acid ester, methyl alcohol and tetrahydrofuran (THF) is 1:1～3:10～20g/mL/mL;
(3) oxidizing reaction
By 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, DMSO and acetic anhydride mix and blend, after room temperature reaction 2-3h, add water and stir, ethyl acetate extraction, washing, dry, concentrated 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde; Wherein:
The amount ratio of 3,5-dimethoxy-4 '-isopropyl benzene methyl alcohol, DMSO and acetic anhydride is 1:10～15:2～3g/mL/mL;
(4) condensation reaction
By mol ratio, be 1:1 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and toluylic acid mix, and add in acetic anhydride, stirring and dissolving, adds sodium-acetate, is heated to 135 ℃, after reaction 6-8h, be down to that to add rare acid for adjusting pH after room temperature be 2-3, ethyl acetate extraction, concentrated, adding saturated sodium bicarbonate solution adjusting pH is 7～8, stirs after 2-3h, dichloromethane extraction, it is 2～3 that water adds dilute hydrochloric acid tune pH, filters yellow solid, 3, the acid of 5-dimethoxy-4 '-isopropyl toluylene; Wherein:
The mol ratio of 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and sodium-acetate is 1:2～4;
The weight/volume of 3,5-dimethoxy-4 '-isopropyl benzene formaldehyde and acetic anhydride is 1:20～30g/mL;
(5) decarboxylic reaction
By mol ratio, be 1:6～8 3, the acid of 5-dimethoxy-4 '-isopropyl toluylene and copper powder join in quinoline, and 180 ℃ are reacted after 3-5h, be down to room temperature, add ethyl acetate and stir, filter, filtrate is washed to water layer colourless with dilute hydrochloric acid, water is used ethyl acetate reversed phase extraction again, merge organic layer, saturated common salt water washing, to neutral, is spin-dried for, obtain 3,5-dimethoxy-4 '-isopropyl toluylene; Wherein:
The acid of 3,5-dimethoxy-4 '-isopropyl toluylene is 1:15～20g/mL with the weight/volume of quinoline;
(6) demethylating reaction
3,5-dimethoxy-4 '-isopropyl toluylene is placed in to toluene, in ice bath, stirs, be cooled to 0 ℃, after dissolving, slowly add DMA, add aluminum trichloride (anhydrous) in batches, stir after 0.5h, rise to room temperature, be heated to, after 100 ℃ of reaction 2-3h, be cooled to 60 ℃, separate while hot toluene layer, in water, add dilute hydrochloric acid stirring and adjusting pH value for 2-3, ethyl acetate extraction, washing, concentrated, obtain not moral of target product cis benzene alkene; Wherein:
The weight/volume of 3,5-dimethoxy-4 '-isopropyl toluylene and toluene is for being 1:15～20g/mL;
The mol ratio of 3,5-dimethoxy-4 '-isopropyl toluylene and DMA, aluminum trichloride (anhydrous) is 1:5～7:5～7.
4. a not application for moral of cis benzene alkene, this cis benzene alkene not moral in claim 1-3 the cis benzene alkene described in any one not moral synthetic method make, it is characterized in that:this cis benzene alkene not moral trans benzene alkene not in moral synthetic as standard substance, for detection of the cis benzene alkene content of moral not.
5. the not application of moral of cis benzene alkene according to claim 4, it is characterized in that:detect the not method of the content employing HPLC of moral of cis benzene alkene, chromatographic column is Nucleosil 5 C18; Column temperature is 20 ℃; Detection wavelength is 318nm; Acetonitrile and water that moving phase is 50: 50 by volume ratio form; Flow velocity is 0.6mL/min, and sample size is 5 μ L.
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JP2021105027A (en) * 2015-05-21 2021-07-26 ダーマバント、サイエンシーズ、ゲゼルシャフト、ミット、ベシュレンクテル、ハフツングＤｅｒｍａｖａｎｔ Ｓｃｉｅｎｃｅｓ Ｇｍｂｈ Topical pharmaceutical compositions
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RU2795144C2 (en) * 2017-11-10 2023-04-28 Дермавант Саенсиз Гмбх Method of obtaining tapinarof
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