CN103265412B - Method for preparing benvitimod from (E)-3,5-dimethoxy-4-isopropyl stilbene - Google Patents
Method for preparing benvitimod from (E)-3,5-dimethoxy-4-isopropyl stilbene Download PDFInfo
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Abstract
The invention discloses a method for preparing benvitimod from (E)-3,5-dimethoxy-4-isopropyl stilbene. According to the method, a demethylation reagent is combined with the microwave technique, and a method of the combined action of the demethylation reagent with single-power microwaves or multiple-cycle microwaves with different powers is adopted, so as to achieve the effects of reducing the reaction temperature, shortening the reaction time, reducing by-products and improving the reaction yield and purity. The method is suitable for preparing benvitimod which can be further applied to treating diseases such as inflammation, dermatosis, psoriasis, tumors and the like.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of preparation method of benzene alkene not moral, specifically a kind of method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene.
Background technology
Benzene alkene not moral, chemical name (
e)-3,5-dihydroxyl-4-isopropyl toluylenes, belonging to stilbenes compound, is the derivative with large intestine parasitic nematode symbiotic bacterium extract.Show after deliberation, (
e)-3,5-dihydroxyl-4-isopropyl toluylenes disease that neutrophil is correlated with or the disorder relevant with protein kinase, comprising inflammation, tetter, psoriasis, tumour etc. has physiologically active.(
e) structural formula of-3,5-dihydroxyl-4-isopropyl toluylenes is as follows:
Have been reported (
e)-3,5-dihydroxyl-4-isopropyl toluylene synthetic route, adopt Heck reaction, Perkin reaction, Knoevenagel reaction, grignard reaction, aldol reaction and Wittig-Horner condensation reaction etc. to synthesize, comprehensive yield and configuration are considered, with Wittig-Horner condensation route for the best.But the demethylation steps in Wittig-Horner condensation route uses pyridine hydrochloride as demethylation reagent, and synthesising reacting time is longer, desired reaction temperature is higher, and yield is low, because temperature of reaction is higher, therefore the by product generated in product is also many, affects reaction yield and purity.
P.P.Kulkarni, A.J.Kadam, R.B.Mane, etal.J.Chem.Res, report in 394 (1999) and use pyridine hydrochloride demethylation in microwave, microwave frequency is 215W, after microwave irradiation 2min, reaction solution is cooled to room temperature, then microwave irradiation again, 8 times repeatedly, microwave concurrent irradiation 16min, yield is 80 ~ 95%.But all need reaction solution to be cooled to room temperature after each microwave irradiation of this preparation method, then put back in microwave, complex operation step.
Angela Farina etc. also uses and uses pyridine hydrochloride demethyl method demethylation in microwave in document " Synthesis of hydroxystilbenes and their derivatives via Heck reaction ", microwave frequency is 215W, after microwave irradiation 2min, reaction solution is cooled to room temperature, then microwave irradiation again, 8 times repeatedly, microwave concurrent irradiation 16min, yield is 95%.But the purity of not mentioned prepared product in literary composition, and after each microwave irradiation of this method, all need reaction solution to be cooled to room temperature, then put back in microwave, same operation steps is more loaded down with trivial details.
" Demethylation of aryl methyl ethers using pyridinium p-toluenesulfonate under microwave irradiation " By Lamba, Mandeep S.; Makrandi; Jagdish K; report and use para-methylbenzenepyridinsulfonate sulfonate PPTS to carry out deprotection to arylmethyl ether under microwave and condition of no solvent; microwave power is 900W; microwave irradiation 1.5 ~ 3min; yield is 70 ~ 85%, but the microwave power that aforesaid method needs is higher, and yield is lower.
《Methylation?of?phenolic?hydroxyl?group?and?demethylation?of?anisoles》
By Sato, Nobuhiro; Endo, Hiroyuki, report the method using Iodotrimethylsilane phenol methyl ether to be carried out to demethylation under microwave condition, microwave power is 300W, and temperature is 105 ~ 114 DEG C, microwave irradiation 15min, and yield is more than 85%.But the not mentioned purity to product of above-mentioned preparation method's products therefrom, and this method temperature of reaction is higher, and the demethylation reagent trimethyl silane used not is common demethylation reagent, not easily obtains.
Se Kyung Park etc. reports and uses a kind of ionic liquid [bmim] [Br] deprotection in microwave condition in " Efficient Cleavage of Aryl Ethers Using an Ionic Liquid under Microwave Irradiation ".When protecting group is methyl, microwave power is 20W, and temperature controls at 200-220 DEG C, and the reaction times is 30min, and yield is 93%, but this method of above-mentioned reaction temperature of reaction is higher.
Summary of the invention
The technical problem to be solved in the present invention, be to provide a kind of by (E)-3,5-dimethoxy-4 '-isopropyl toluylene prepares the method for benzene alkene not moral, adopt the method that demethylation reagent combines with microwave technology, reduction temperature of reaction can be reached, Reaction time shorten, reduces the generation of by product, improves the effect of reaction yield and purity.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
A kind of method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene, the method that its adopts demethylation reagent to be combined with microwave, its chemical equation is as follows:
。
As restriction of the present invention,
1., when described demethylation reagent is aluminum chloride, microwave condition is following I or II, wherein:
I, 80 ~ 90 DEG C, 400 ~ 500W microwave, reaction 10 ~ 20min;
II, 80 ~ 90 DEG C, 200 ~ 600W microwave divides 3-5 stage to be circulation, altogether circulation 2-4 time;
2., when described demethylation reagent is pyridine hydrochloride, microwave condition is following III or IV, wherein:
III, 140 ~ 150 DEG C, under 400 ~ 500W microwave, 10 ~ 20min is reacted;
IV, 120 ~ 150 DEG C, 200 ~ 600W microwave divides 3-5 stage to be circulation, altogether circulation 2-4 time.
As further restriction, in A, II, microwave condition is:
Microwave power is P for the first time
1=500 ~ 600W, microwave irradiating time is t
1=1 ~ 2min;
Second time microwave power is P
2=400 ~ 500W, microwave irradiating time is t
2=2 ~ 3min;
Microwave power is P for the third time
3=200 ~ 400W, microwave irradiating time is t
3=2 ~ 3min;
Above three microwave treatment are circulation, altogether circulation 2-4 time;
b,in IV, microwave condition is: microwave power is P for the first time
1=200 ~ 300W, microwave irradiating time is t
1=2 ~ 3min;
Second time microwave power is P
2=500 ~ 600W, microwave irradiating time is t
2=1 ~ 2min;
Microwave power is P for the third time
3=400 ~ 500W, microwave irradiating time is t
3=2 ~ 3min;
Above three microwave treatment are circulation, altogether circulation 2-4 time.
When C, microwave condition are I, the preparation process of benzene alkene not moral is as follows:
By (E)-3 of 0.3 weight part, 5-dimethoxy-4 '-isopropyl toluylene is dissolved in the toluene of 15 parts by volume, be placed in cryostat, to stir, be cooled to-2 ~ 2 DEG C, slowly add the N of 0.81 parts by volume, accelerine, add the aluminum chloride that total amount is 0.85 weight part more in batches, it is 0 ~ 5 DEG C that adition process controls temperature of reaction, add rear stirring 5 ~ 15min completely, after rise to room temperature, be placed in microwave reactor, be warming up to 80 ~ 90 DEG C, 10 ~ 20min is reacted under 400 ~ 500W microwave, after reacting completely, add the dilute hydrochloric acid of 20 parts by volume, being adjusted to pH value is 3 ~ 5, extraction into ethyl acetate, organic phase is merged after extraction, being washed to pH value is 6 ~ 7, revolve steaming, obtain benzene alkene not moral.
In this step, the ratio of weight part and parts by volume is gram: milliliter.
When D, microwave condition are III, the preparation process of benzene alkene not moral is as follows:
(E)-3,5-dimethoxy-4 's-isopropyl toluylene of 0.3 weight part is mixed with the pyridine hydrochloride of 1.5 weight parts, is placed in microwave reactor, be warming up to 140 ~ 150 DEG C, after under 400 ~ 500W microwave, reaction 10 ~ 20min reacts completely, add the dilute hydrochloric acid of 20 parts by volume, being adjusted to pH value is 3 ~ 5, extraction into ethyl acetate, merge organic phase after extraction, being washed to pH value is 6 ~ 7, revolves steaming, postlyophilization, obtains benzene alkene not moral.
In this step, the ratio of weight part and parts by volume is gram: milliliter.
As further limiting, when (1) microwave condition is A, the preparation process of benzene alkene not moral is as follows:
(E)-3,5-dimethoxy-4 's-isopropyl toluylene of 0.3 weight part is dissolved in the toluene of 15 parts by volume, is placed in cryostat, and stirs, be cooled to-2 ~ 2 DEG C, slowly add the DMA of 0.81 parts by volume, then add the aluminum chloride that total amount is 0.85 weight part in batches, it is 0 ~ 5 DEG C that adition process controls temperature of reaction, add rear stirring 5 ~ 15min completely, after rise to room temperature, be placed in microwave reactor, carry out microwave cycle, reaction total time is 10 ~ 32min;
After reacting completely, add parts by volume dilute hydrochloric acid, being adjusted to pH value is 3 ~ 5, and extraction into ethyl acetate, merges organic phase after extraction, and being washed to pH value is 6 ~ 7, revolves steaming, obtains benzene alkene not moral.
In this step, the ratio of weight part and parts by volume is gram: milliliter.
(2), when microwave condition is B, the preparation process of benzene alkene not moral is as follows:
Mixed with the pyridine hydrochloride of 1.5 weight parts by (E)-3,5-dimethoxy-4 's-isopropyl toluylene of 0.3 weight part, be placed in microwave reactor, carry out microwave cycle, reaction total time is 10 ~ 32min; After reacting completely, add the dilute hydrochloric acid of 20 parts by volume, being adjusted to pH value is 3 ~ 5, and extraction into ethyl acetate, merges organic phase after extraction, and being washed to pH value is 6 ~ 7, revolves steaming, postlyophilization, obtains benzene alkene not moral.
In this step, the ratio of weight part and parts by volume is gram: milliliter.
As further limiting,
Described (E)-3,5-dimethoxy-4 's-isopropyl toluylene and the reaction mol ratio of DMA are 1:6; (E) the reaction mol ratio of-3,5-dimethoxy-4 's-isopropyl toluylene and aluminum chloride is 1:6.
Described (E)-3,5-dimethoxy-4 's-isopropyl toluylene is 1:5 with the reaction mass ratio of pyridine hydrochloride.
Owing to have employed above-mentioned technical scheme, compared with prior art, acquired technical progress is in the present invention:
(1) the present invention adopts the method that demethylation reagent combines with microwave technology, reaches reduction temperature of reaction, Reaction time shorten, reduces the generation of by product, improves the effect of reaction yield and purity, is more easy to suitability for industrialized production;
(2) the present invention adopts aluminum chloride to be under demethylation reagent, single power illumination, and obtained benzene alkene not moral yield is 93 ~ 96%, and purity is 97 ~ 99%; Carry out under the irradiation of different steps repeatedly circulating power, obtained benzene alkene not moral yield is 97 ~ 99%, and purity is 98 ~ 100%;
(3) the present invention adopts pyridine hydrochloride to be under demethylation reagent, single power illumination, and obtained benzene alkene not moral yield is 95 ~ 97%, and purity is 98 ~ 100%; Carry out under the irradiation of different steps repeatedly circulating power, obtained benzene alkene not moral yield is 97 ~ 99%, and purity is 98 ~ 100%.
(4) two kinds of demethylation reagents of the present invention's employing, the irradiation of different steps repeatedly circulating power, for continuous print irradiates, next one circulation is being carried out after not needing, after a stage or circulation, its temperature is down to room temperature, method more of the prior art has easy operation, saves the feature in reaction times.
As fully visible, (E) provided by the present invention-3,5-dimethoxy-4 's-isopropyl toluylene prepares the method for benzene alkene not moral, and overcome the deficiency existing for prior art, yield is greatly improved.
The present invention is applicable to prepare benzene alkene not moral, and this medicine can be applied to the diseases such as treatment inflammation, tetter, psoriasis, tumour further.
The present invention is described in further detail below in conjunction with Figure of description and specific embodiment.
Accompanying drawing explanation
Fig. 1 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 1;
Fig. 2 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 6;
Fig. 3 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 11;
Fig. 4 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 16;
Fig. 5 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 31;
Fig. 6 is the high-efficient liquid phase chromatogram of the embodiment of the present invention 32.
Embodiment
embodiment 1-5 prepares the method (be demethylation reagent with aluminum chloride, adopt single power microwave) of benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene
Embodiment 1-5 is respectively a kind of by (E)-3,5-dimethoxy-4 '-isopropyl toluylene prepares the method for benzene alkene not moral, the method that they all adopt demethylation reagent to be combined with microwave, demethylation reagent is aluminum chloride, the method of microwave is 80 ~ 90 DEG C, reacts 10 ~ 20min under 400 ~ 500W microwave.
Reference table 1, concrete preparation method is as follows:
By 0.3g(E)-3,5-dimethoxy-4 's-isopropyl toluylene is dissolved in 15mL toluene, is placed in cryostat, and stirs, 1. be cooled to temperature is-2 ~ 2 DEG C (being shown in Table 1), slowly adds 0.81mL DMA, and wherein, the reaction mol ratio of (E)-3,5-dimethoxy-4 's-isopropyl toluylene and DMA is 1:6, add 0.85g aluminum chloride more in batches, wherein, (E)-3, the reaction mol ratio of 5-dimethoxy-4 '-isopropyl toluylene and aluminum chloride is 1:6, it is that 2. temperature is 0 ~ 5 DEG C that adition process controls temperature of reaction, add rear stirring 5 ~ 15min completely, after rise to room temperature, be placed in microwave reactor, be warming up to temperature and be 3. 80 ~ 90 DEG C, 10 ~ 20min is reacted under microwave power 400 ~ 500W, after reacting completely, add 20mL dilute hydrochloric acid, being adjusted to pH value is 3 ~ 5, extraction into ethyl acetate, organic phase is merged after extraction, being washed to pH value is 6.0 ~ 7.0, revolve steaming, obtain benzene alkene not moral.
?
embodiment 6-10 prepares the method (take aluminum chloride as demethylation reagent, adopt different capacity microwave repeatedly to circulate) of benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene
Embodiment 6-10 is respectively a kind of by (E)-3,5-dimethoxy-4 '-isopropyl toluylene prepares the method for benzene alkene not moral, they are the method adopting demethylation reagent to be combined with microwave, demethylation reagent is aluminum chloride, the method of microwave is adopt different capacity repeatedly to circulate the method for irradiating, first time microwave power be P
1=500 ~ 600W, microwave irradiating time is t
1=1 ~ 2min; Second time microwave power is P
2=400 ~ 500W, microwave irradiating time is t
2=2 ~ 3min; Microwave power is P for the third time
3=200 ~ 400W, microwave irradiating time is t
3=2 ~ 3min is a circulation, circulation 2-4 time.
Reference table 2, concrete preparation method is as follows:
By 0.3g(E)-3,5-dimethoxy-4 '-isopropyl toluylene is dissolved in 15mL toluene, be placed in cryostat, to stir, 1. be cooled to temperature is-2 ~ 2 DEG C, slowly adds 0.81mL DMA, wherein, (E) the reaction mol ratio of-3,5-dimethoxy-4 's-isopropyl toluylene and DMA is 1:6; Add 0.85g aluminum chloride more in batches, wherein, (E) the reaction mol ratio of-3,5-dimethoxy-4 's-isopropyl toluylene and aluminum chloride is 1:6, and adition process controls temperature of reaction and is 2. 0 ~ 5 DEG C in temperature, add rear stirring 5 ~ 15min completely, after rise to room temperature, be placed in microwave reactor, be warming up to temperature 3. namely 80 ~ 90 DEG C, adopt different capacity repeatedly circulate irradiate method, first time microwave power be P
1=500 ~ 600W, microwave irradiating time is t
1=1 ~ 2min; Second time microwave power is P
2=400 ~ 500W, microwave irradiating time is t
2=2 ~ 3min; Microwave power is P for the third time
3=200 ~ 400W, microwave irradiating time is t
3=2 ~ 3min is a circulation, circulation 2-4 time, and reaction total time is 10 ~ 32min, after reacting completely, adds 20mL dilute hydrochloric acid, and being adjusted to pH value is 3 ~ 5, and extraction into ethyl acetate, merges organic phase after extraction, and being washed to pH value is 6 ~ 7, revolves steaming, obtains benzene alkene not moral.
embodiment 11-15 prepares the method (be demethylation reagent with pyridine hydrochloride, adopt single power microwave) of benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene
Embodiment 11-15 is respectively a kind of by (E)-3,5-dimethoxy-4 '-isopropyl toluylene prepares the method for benzene alkene not moral, the method that they all adopt demethylation reagent to be combined with microwave, demethylation reagent is pyridine hydrochloride, wherein, (E)-3,5-dimethoxy-4 's-isopropyl toluylene and the reaction mass of pyridine hydrochloride are than being 1:5, the method of microwave is 140 ~ 150 DEG C, reacts 10 ~ 20min under 400 ~ 500W microwave.
Reference table 3, concrete preparation method is as follows:
By 0.3g(E)-3,5-dimethoxy-4 's-isopropyl toluylene mixes with 1.5g pyridine hydrochloride, is placed in microwave reactor, be warming up to temperature and be 1. 140 ~ 150 DEG C, after under 400 ~ 500W microwave, reaction 10 ~ 20min reacts completely, add 20mL dilute hydrochloric acid, being adjusted to pH value is 3 ~ 5, extraction into ethyl acetate, merge organic phase after extraction, being washed to pH value is 6 ~ 7, revolves steaming, postlyophilization, obtains benzene alkene not moral.
embodiment 16-20 prepares the method (take pyridine hydrochloride as demethylation reagent, adopt different capacity microwave repeatedly to circulate) of benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene
Embodiment 16-20 is respectively a kind of by (E)-3,5-dimethoxy-4 '-isopropyl toluylene prepares the method for benzene alkene not moral, the method that they all adopt demethylation reagent to be combined with microwave, demethylation reagent is pyridine hydrochloride, the method of microwave is adopt different capacity repeatedly to circulate the method for irradiating, first time microwave power be P
1=200 ~ 300W, microwave irradiating time is t
1=2 ~ 3min; Second time microwave power is P
2=500 ~ 600W, microwave irradiating time is t
2=1 ~ 2min; Microwave power is P for the third time
3=400 ~ 500W, microwave irradiating time is t
3=2 ~ 3min is a circulation, circulation 2-4 time.
Reference table 4, concrete preparation method is as follows:
By 0.3g(E)-3,5-dimethoxy-4 '-isopropyl toluylene mixes with 1.5g pyridine hydrochloride, wherein, (E)-3,5-dimethoxy-4 '-isopropyl toluylene is 1:5 with the reaction mass ratio of pyridine hydrochloride, be placed in microwave reactor, adopt different capacity repeatedly circulate irradiate method, first time microwave power be P
1=200 ~ 300W, microwave irradiating time is t
1=2 ~ 3min; Second time microwave power is P
2=500 ~ 600W, microwave irradiating time is t
2=1 ~ 2min; Microwave power is P for the third time
3=400 ~ 500W, microwave irradiating time is t
3=2 ~ 3min, be a circulation, circulation 2-4 time, after reacting completely, adds 20mL dilute hydrochloric acid, and being adjusted to pH value is 3 ~ 5, and extraction into ethyl acetate, merges organic phase after extraction, and being washed to pH value is 6 ~ 7, revolves steaming, postlyophilization, obtains benzene alkene not moral.
embodiment 21-30 prepares the method (adopting the microwave method of different steps multiple circulation to carry out demethylation) of benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene
Embodiment 21-30 is respectively a kind of method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene, and wherein the demethylation reagent of embodiment 21-25 is aluminum chloride, and the demethylation reagent of embodiment 26-30 is pyridine hydrochloride.Particularly:
I, in () embodiment 21-25, demethylation reagent is aluminum chloride, the method for microwave is: adopt microwave power to be that 200 ~ 600W divides 3-5 stage to be circulation, altogether circulation 2-4 time, design parameter is as shown in table 5.
(ii) in embodiment 26-30, demethylation reagent is pyridine hydrochloride, and the method for microwave is: adopt microwave power to be that 200 ~ 600W divides 3-5 stage to be circulation, altogether circulation 2-4 time, design parameter is see table 6.
As can be seen from table 5 and table 6, when adopting the microwave method of the multiple circulation of different steps to carry out demethylation, the reaction times is also shorter, and yield is higher.
embodiment 31 prepares the method (demethylation reagent is aluminum chloride, without microwave treatment step) of benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene
Take (E)-3 of 0.3g, 5-dimethoxy-4 '-isopropyl toluylene, add 15ml toluene, be placed in cryostat, to stir, be cooled to 0 DEG C, slowly N is added after to be dissolved, accelerine is (with (E)-3, the mol ratio of 5-dimethoxy-4 '-isopropyl toluylene is 6:1), then stirring lower slowly (in batches) adds aluminum trichloride (anhydrous) (be 6:1 with the mol ratio of (E)-3,5-dimethoxy-4 's-isopropyl toluylene), and added-time heat release is violent, simultaneous gas generates, and has white cigarette in reaction flask.In the process system adding aluminum chloride, temperature is below 5 DEG C.
Aluminum chloride finishes rear stirring 10min, shifts out, naturally rise to room temperature from cryostat.Then move to oil bath to be heated to reflux (reflux temperature is 110 DEG C), back flow reaction 4 ~ 6h.
Add dilute hydrochloric acid after having reacted, be extracted with ethyl acetate, be washed to neutrality, be spin-dried for, obtain benzene alkene not moral 0.1358g, yield is 50.26%.
Prepare benzene alkene not moral relative to the microwave method of embodiment 1-30, the present embodiment does not use microwave method and adopts oil bath to heat demethylation, and the reaction times is longer is 4 ~ 6h, and temperature of reaction is high is about 110 DEG C; And microwave demethylation only needs 10 ~ 20min, temperature of reaction is 80 ~ 90 DEG C; As can be seen from reaction result also, yield is starkly lower than and uses microwave method demethylation, and impure more, as shown in Figure 5, products benzene alkene not moral goes out peak at 5.939min, and purity is 51.48%, the impurity of a de-methyl goes out peak at 14.889min, and an other impurity goes out peak at 45.500min.
embodiment 32 prepares the method (demethylation reagent is pyridine hydrochloride, without microwave treatment step) of benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene
Take (E)-3 of 0.3g, 5-dimethoxy-4 '-isopropyl toluylene and pyridine hydrochloride are (with (E)-3, the mass ratio of 5-dimethoxy-4 '-isopropyl toluylene is 5:1) mixing, react at temperature 180 ~ 200 DEG C respectively, add dilute hydrochloric acid after having reacted and adjust pH to acid, extraction into ethyl acetate, be washed to neutrality, be spin-dried for, obtain benzene alkene not moral 0.1414g, yield is 52.31%.
Benzene alkene not moral is prepared relative to the microwave method of embodiment 1-30, the present embodiment does not use microwave method and adopts oil bath to heat demethylation, long reaction time is 4 ~ 6h, temperature of reaction is high is 180 ~ 200 DEG C, and the reaction times adopting the method for microwave demethylation to need is 10 ~ 20min, temperature of reaction is 140 ~ 150 DEG C; As can be seen from reaction result also, yield is starkly lower than and uses microwave method demethylation, and impure more, as shown in Figure 6, products benzene alkene not moral goes out peak at 6.312min, and purity is 49.97%, impurity cis-product goes out peak at 2.085min, and another impurity goes out peak at 16.007min.
embodiment 33 adopts the condition test of the single microwave power of aluminum chloride demethylation
Adopt the method for aluminum chloride and single microwave power demethylation, because the aluminum chloride used reacts in solution system, if during the microwave reaction adopting power lower, not only rise to the required temperature of reaction time longer, also make reaction can not react completely in a long time; If during the microwave reaction adopting power higher, although it is shorter to rise to the required temperature of reaction time, the by product generated is more, and the impurities affect for product is larger; Reaction raw materials involved by the present embodiment and the chemical structure of product more special, therefore suitable microwave power is selected, temperature of reaction and reaction times are very important, on this basis, technical parameter when carrying out demethylation to selecting aluminum chloride has carried out orthogonal test, consider the impact of influence factor on raw material and product, select best reaction conditions, specifically as shown in table 7 Yu table 8.
Table 8
From table 7 and the above-mentioned testing data in table 8, the principal element affecting yield is microwave power, and preferred embodiment is: power is 400 ~ 500W, and temperature is 80 ~ 90 DEG C, and the time is 10 ~ 20min, and yield is 93 ~ 96%, and purity is 97 ~ 99%; And be 50.26% without the yield of microwave, purity is 51.48%, and therefore the improvement of the present embodiment has had very large technical progress compared with prior art.
embodiment 34 adopts the condition test of the single microwave power of pyridine hydrochloride demethylation
Adopt the method for pyridine hydrochloride and single microwave power demethylation, because the pyridine hydrochloride used is solid reagent, react again after making its at high temperature melting, therefore required temperature of reaction comparatively aluminum chloride wants high, if during the microwave reaction adopting power lower, not only rise to the required temperature of reaction time longer, also make reaction can not react completely in a long time; If during the microwave reaction adopting power higher, although it is shorter to rise to the required temperature of reaction time, the by product generated is more, and the impurities affect for product is larger; Reaction raw materials involved by the present embodiment and the chemical structure of product more special, therefore suitable microwave power is selected, temperature of reaction and reaction times are very important, on this basis, technical parameter when carrying out demethylation to selecting aluminum chloride has carried out orthogonal test, select best reaction conditions, specifically as shown in table 9 Yu table 10.
Table 10
From table 9 and the above-mentioned testing data in table 10, the principal element affecting yield is microwave power, and preferred embodiment is: power is 400 ~ 500W, and temperature is 140 ~ 150 DEG C, and the time is 10 ~ 20min, and yield is 95 ~ 97%, and purity is 98 ~ 100%; And be 52.31% without the yield of microwave, purity is 49.97%, and therefore the improvement of the present embodiment has had very large technical progress compared with prior art.
embodiment 35 adopts aluminum chloride to be the condition test that demethylation reagent repeatedly circulates stage by stage
Because demethylation reagent used is aluminum chloride, and its to react be carry out under the condition of solution, selection stage by stage with circulation time, adopt four-stage to carry out the screening of condition experiment, rise to superpower from low power respectively, high-low power alternation sum is down to low power from superpower and is tested.
(1) power from low to high time, result is as shown in table 11:
Above test-results display: adopt microwave power to test from low to high, yield is 60 ~ 80%, and purity is 60 ~ 85%, and cycle index is 2 ~ 4 times.But reaction is that after 4 circulations, yield is still lower, and this is very disadvantageous to suitability for industrialized production, adds labour intensity.
(2) high-low power is staggered when carrying out, and result is as shown in table 12:
Above test-results display: adopt microwave power height to interlock and test, cycle index is 2-4 time, and yield is 60 ~ 80%, and purity is 70 ~ 85%.When yield when initial power is superpower is low power higher than initial power.After cycle index is more than 4 times, yield is on a declining curve.This is because along with the increase of cycle index, side reaction also aggravates, and adds the generation of impurity.
(3) power from high to low time, result is see table 13:
Above test-results display: adopt microwave power to test from high to low, yield increases along with cycle index and improves, and cycle index is 2-4 time, and yield is 85 ~ 95%, and purity is 90 ~ 96%.In addition, also carried out the test of other cycle index, result shows, if circulation is less than 2 times, then reaction not exclusively; If be greater than 4 times, then by-products content increases, the purity drop of product.Because when aluminum chloride does demethylation reagent, reaction system is solution state, and superpower contributes to reaching temperature of reaction rapidly, and low power maintains temperature of reaction, therefore adopts microwave power can reach the highest yield from high to low.
The selection of power number of times stage by stage, as follows:
As seen from the above table, when being divided into 3-5 stage, yield can reach 95 ~ 99%, and purity reaches 95 ~ 100%, and number of stages is lower than 3 times, and owing to reacting completely, therefore purity is lower; Number of stages is higher than after 5 times, and the reaction times is longer, and yield and purity not obvious compared with 5 raisings, add operation steps and production cost, therefore select 3-5 stage to be the best.
In sum, when using aluminum chloride demethylation, finally determine to adopt microwave power staged reaction from high to low, 3-5 stage, circulation 2-4 time, yield and purity the highest.
embodiment 36 adopts pyridine hydrochloride to be the condition test that demethylation reagent repeatedly circulates stage by stage
?because demethylation reagent used is pyridine hydrochloride, and it reacts and carries out in the absence of a solvent, selection stage by stage with circulation time, adopt the test of four-stage to carry out conditional filtering, be increased to superpower from low power respectively, high-low power alternation sum is down to low power from superpower and is tested.
(1) power from low to high time, result is see table 14:
Above test-results display: adopt microwave power to test from low to high, yield increases along with cycle index and improves, and cycle index is 2-4 time, and yield is 80 ~ 90%, and purity is 90 ~ 95%.In addition, also carried out the test of other cycle index, result shows, if circulation is less than 2 times, then reaction not exclusively; If be greater than 4 times, then by-products content increases, the purity drop of product.This is because when adopting pyridine hydrochloride to do demethylation reagent, whole reaction system is solvent-free state, first use the vibration between low power promotion pyridine hydrochloride molecular solids, re-use superpower and improve temperature of reaction rapidly, adopt microwave power method from low to high to obtain the highest yield.
(2) high-low power is staggered when carrying out, and result is see table 15:
Above test-results display: adopt microwave power height to interlock and test, cycle index is 2-4 time, and yield is 60 ~ 80%, and purity is 70 ~ 85%.When yield when initial power is low power is superpower higher than initial power, this is because when initial power is low power, the vibration between molecular solids can be promoted, add the carrying out of fast response.After cycle index is more than 4 times, yield is on a declining curve.When high-low power interlocks, temperature of reaction reaches higher point rapidly, exacerbates the generation of side reaction, adds the generation of impurity.
(3) power from high to low time, result is see table 16:
Above test-results display: adopt microwave power to test from high to low, yield increases along with cycle index and improves, and cycle index is 2-4 time, and yield is 60 ~ 70%, and purity is 60-75%.But reaction is that after 4 circulations, yield is still lower, and this is very disadvantageous to suitability for industrialized production, adds labour intensity.
In sum, when using pyridine hydrochloride demethylation, adopt power mode from low to high to carry out staged reaction, reaction yield is higher, and selects circulation to be for 2-4 time the best; In addition, also carried out the test of other cycle index, result shows, if circulation is less than 2 times, then reaction not exclusively; If be greater than 4 times, then by-products content increases, the purity drop of product; Therefore, microwave power staged reaction from low to high is finally determined, circulation 2-4 time.
The selection of power number of times stage by stage, as follows:
As seen from the above table, when being divided into 3-5 stage, yield can reach 95 ~ 99%, and purity reaches 96 ~ 100%, and number of stages is lower than 3 times, and owing to reacting completely, therefore purity is lower; Number of stages is higher than after 5 times, and the reaction times is longer, and yield and purity not obvious compared with 5 raisings, add operation steps and production cost, therefore select 3-5 stage to be the best.
In sum, when using aluminum chloride demethylation, finally determine to adopt microwave power staged reaction from high to low, 3-5 stage, circulation 2-4 time, yield and purity the highest.
the preparation method of embodiment 37 1 kinds of benzene alkene not moral
The present embodiment provides a kind of method preparing benzene alkene not moral, and its synthetic route is as follows:
This preparation method in accordance with the following steps order carries out:
a.3,5-resorcylic acid methylation reaction:
the preparation of 3,5-dimethoxybenzoic acid ester A
3,5-resorcylic acid, Anhydrous potassium carbonate, acetone, methyl-sulfate mix, and add water after backflow 2 ~ 18h, extraction, desolventizes, obtain product A; (mol ratio of 3,5-resorcylic acids used, Anhydrous potassium carbonate, acetone, methyl-sulfate is 1:3 ~ 6:10 ~ 50:3 ~ 10)
b.isopropylation:
the preparation of 3,5-dimethoxy-4 '-isopropyl acid B
A mixes with 60 ~ 80% vitriol oils, drips Virahol, and 30 ~ 90 DEG C of reaction 5 ~ 12h, add water filtration, dry Off-white product B; (mol ratio of A used, the vitriol oil, Virahol is 1:0.1 ~ 0.5:1 ~ 3)
c.the reduction reaction of non-fluorochemical:
the preparation of 3,5-dimethoxy-4 '-isopropylbenzyl alcohol C
B and I is added after the mixing of sodium borohydride, tetrahydrofuran (THF)
2, add water after reaction 12 ~ 80h, extraction, desolventizing obtains white solid product C; (B used, sodium borohydride, tetrahydrofuran (THF), I
2mol ratio be 1:0.1 ~ 10:10 ~ 50:0.1 ~ 10)
d.chlorination:
the preparation of 3,5-dimethoxy-4 '-sec.-propyl benzyl chlorine D
C and hydrochloric acid and normal hexane join hybrid reaction in four-hole boiling flask; Separate organic phase desolventizing and obtain yellow oil D; (mol ratio of C used, hydrochloric acid, normal hexane is 1:1 ~ 20:10 ~ 100)
e.wittig-Horner condensation reaction:
the preparation of 3,5-dimethoxy-4 '-isopropyl benzyl diethyl phosphonate E
Mol ratio is the D of 1:1 ~ 6 and the product E that reduces pressure to obtain after triethyl-phosphite mixing backflow 3 ~ 20h;
f. (
e) preparation of-3,5-dimethoxy-4 's-isopropyl toluylene F
E mixes with tetrahydrofuran (THF), N
2protection, adds N ɑ H and phenyl aldehyde when-20 ~ 20 DEG C, after backflow 2 ~ 8 in impouring frozen water, extraction, desolventizes to obtain F; (mol ratio of E used, tetrahydrofuran (THF), N ɑ H, phenyl aldehyde is 1:20 ~ 100:0.1 ~ 10:0.5 ~ 10).
The preparation of g, benzene alkene not moral
G1, employing aluminum chloride are demethylation reagent
(1) method of single power illumination is adopted to prepare
0.3gF is dissolved in 15mL toluene, is placed in cryostat, and stirs, be cooled to-2 ~ 2 DEG C, slowly add 0.81mL DMA, wherein, (E) the reaction mol ratio of-3,5-dimethoxy-4 's-isopropyl toluylene and DMA is 1:6, add 0.85g aluminum chloride more in batches, wherein, (E)-3, the reaction mol ratio of 5-dimethoxy-4 '-isopropyl toluylene and aluminum chloride is 1:6, it is 0 DEG C that adition process controls temperature of reaction, add rear stirring 10min completely, after rise to room temperature, be placed in microwave reactor, be warming up to 80 DEG C, 10min is reacted under microwave power 500W, after reacting completely, add 20mL dilute hydrochloric acid, being adjusted to pH value is 4, extraction into ethyl acetate, organic phase is merged after extraction, being washed to pH value is 6.0, revolve steaming, obtain benzene alkene not moral 0.2575g, yield is 95.29%, the detected result of content as shown in Figure 1.
Products benzene alkene not moral goes out peak at 6.246min, and purity is 98.92%, and the impurity of a de-methyl goes out peak at 15.869min, and an other impurity is that raw material (E)-3,5-dimethoxy-4 's-isopropyl toluylene goes out peak at 49.212min.
(2) adopt different capacity repeatedly circulate irradiate method preparation
Be dissolved in by F in 15mL toluene, be placed in cryostat, and stir, be cooled to temperature 2 DEG C, slowly add DMA, wherein, the reaction mol ratio of F and DMA is 1:6; Add aluminum chloride more in batches, wherein, the reaction mol ratio of F and aluminum chloride is 1:6, and adition process controls temperature of reaction temperature 3 DEG C, adds rear stirring 12min completely, after rise to room temperature, be placed in microwave reactor, be warming up to temperature 87 DEG C, adopt different capacity repeatedly circulate irradiate method, first time, microwave power was 550W, and microwave irradiating time is 1.5min; Second time microwave power is 400W, and microwave irradiating time is 3min; Third time, microwave power was 350W, and microwave irradiating time is 2.3min, is a circulation, circulate 2 times, reaction total time is 13.6min, after reacting completely, add 20mL dilute hydrochloric acid, being adjusted to pH value is 3, extraction into ethyl acetate, organic phase is merged after extraction, being washed to pH value is 7, revolves steaming, obtains benzene alkene not moral 0.2667g, yield is 98.69%, and detection level result as shown in Figure 2.Products benzene alkene not moral goes out peak at 6.238min, and purity is 99.30%, does not substantially have impurity peaks to occur.
G2, employing pyridine hydrochloride are demethylation reagent
(1) method of single power illumination is adopted to prepare
0.3gF and 1.5g pyridine hydrochloride is mixed, be placed in microwave reactor, be warming up to temperature and be 1. 150 DEG C, react after 15min reacts completely under 470W microwave, add 20mL dilute hydrochloric acid, being adjusted to pH value is 3, extraction into ethyl acetate, organic phase is merged after extraction, being washed to pH value is 7, revolves steaming, postlyophilization, obtain benzene alkene not moral 0.2614g, yield is 96.73%, and as shown in Figure 3, products benzene alkene not moral goes out peak at 5.952min to detection level result, purity is 98.70%, 45.509min place a little impurity peaks.
(2) adopt different capacity repeatedly circulate irradiate method preparation
0.3gF is mixed (mass ratio of F and pyridine hydrochloride is 1:5) with pyridine hydrochloride and is placed in microwave reactor, adopt different capacity repeatedly circulate irradiate method, first time microwave power be 250W, microwave irradiating time is 2.5min; Second time microwave power is 500W, and microwave irradiating time is 2min; Third time, microwave power was 430W, and microwave irradiating time is 2.7min, is a circulation, circulates 3 times, reaction total time is 21.6min, after reacting completely, adds 20mL dilute hydrochloric acid, being adjusted to pH value is 3, and extraction into ethyl acetate, merges organic phase after extraction, being washed to pH value is 7, revolves steaming, postlyophilization, obtain benzene alkene not moral 0.2672g, yield is 98.86%, and detection level result as shown in Figure 4, products benzene alkene not moral goes out peak at 6.215min, and purity is 99.34%, does not substantially have impurity peaks to occur.
The detection of the not moral purity of the benzene alkene involved by embodiment 1-37 is all measured by high performance liquid chromatography, and liquid-phase condition is as follows:
Chromatographic column is Nucleosil 5 C18, and determined wavelength is 318nm, and moving phase is acetonitrile: water (V:V)=60:40, and flow velocity is 1mL/min, and sample size is 5 μ L.Detection time is 60min, and products benzene alkene not moral goes out peak at about 6min, and raw material (E)-3,5-dimethoxy-4 's-isopropyl toluylene goes out peak at about 50min.
The above is only preferred embodiment of the present invention, but not limitation of the invention, any those skilled in the art can utilize the technology contents of above-mentioned enlightenment to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, according to technical spirit of the present invention to simple modification, equivalent variations and remodeling done by above embodiment, still belong to the protection domain of technical solution of the present invention.
Claims (6)
1. prepared the method for benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene for one kind,
it is characterized in thatthe method that it adopts demethylation reagent to be combined with microwave, chemical equation is as follows:
；
1., when described demethylation reagent is aluminum chloride, microwave condition is following I or II, wherein:
I, 80 ~ 90 DEG C, 400 ~ 500W microwave, reaction 10 ~ 20min;
II, 80 ~ 90 DEG C, 200 ~ 600W microwave divides 3 stages to be circulation, altogether circulation 2-4 time;
Particularly, microwave power is P for the first time
1=500 ~ 600W, microwave irradiating time is t
1=1 ~ 2min;
Second time microwave power is P
2=400 ~ 500W, microwave irradiating time is t
2=2 ~ 3min;
Microwave power is P for the third time
3=200 ~ 400W, microwave irradiating time is t
3=2 ~ 3min;
Above three phases is circulation, altogether circulation 2-4 time;
2., when described demethylation reagent is pyridine hydrochloride, microwave condition is following III or IV, wherein:
III, 140 ~ 150 DEG C, under 400 ~ 500W microwave, 10 ~ 20min is reacted;
IV, 120 ~ 150 DEG C, 200 ~ 600W microwave divides 3 stages to be circulation, altogether circulation 2-4 time;
Particularly, microwave power is P for the first time
1=200 ~ 300W, microwave irradiating time is t
1=2 ~ 3min;
Second time microwave power is P
2=500 ~ 600W, microwave irradiating time is t
2=1 ~ 2min;
Microwave power is P for the third time
3=400 ~ 500W, microwave irradiating time is t
3=2 ~ 3min;
Above three phases is circulation, altogether circulation 2-4 time.
2. the method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene according to claim 1,
it is characterized in thatwhen microwave condition is I, preparation process is as follows:
By (E)-3 of 0.3 weight part, 5-dimethoxy-4 '-isopropyl toluylene is dissolved in the toluene of 15 parts by volume, be placed in cryostat, to stir, be cooled to-2 ~ 2 DEG C, slowly add the N of 0.81 parts by volume, accelerine, add the aluminum chloride that total amount is 0.85 weight part more in batches, it is 0 ~ 5 DEG C that adition process controls temperature of reaction, add rear stirring 5 ~ 15min completely, after rise to room temperature, be placed in microwave reactor, be warming up to 80 ~ 90 DEG C, 10 ~ 20min is reacted under 400 ~ 500W microwave, after reacting completely, add 20 parts by volume dilute hydrochloric acid, being adjusted to pH value is 3 ~ 5, extraction into ethyl acetate, organic phase is merged after extraction, being washed to pH value is 6 ~ 7, revolve steaming, obtain benzene alkene not moral,
The ratio of above-mentioned weight part and parts by volume is gram: milliliter.
3. the method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene according to claim 1,
it is characterized in thatwhen microwave condition is III, preparation process is as follows:
0.3 weight part (E)-3,5-dimethoxy-4 's-isopropyl toluylene is mixed with 1.5 weight part pyridine hydrochlorides, is placed in microwave reactor, be warming up to 140 ~ 150 DEG C, after under 400 ~ 500W microwave, reaction 10 ~ 20min reacts completely, add 20 parts by volume dilute hydrochloric acid, being adjusted to pH value is 3 ~ 5, extraction into ethyl acetate, merge organic phase after extraction, being washed to pH value is 6 ~ 7, revolves steaming, postlyophilization, obtains benzene alkene not moral;
The ratio of above-mentioned weight part and parts by volume is gram: milliliter.
4. the method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene according to claim 1,
it is characterized in thatwhen microwave condition is II, preparation process is as follows:
By (E)-3 of 0.3 weight part, 5-dimethoxy-4 '-isopropyl toluylene is dissolved in the toluene of 15 parts by volume, be placed in cryostat, to stir, be cooled to-2 ~ 2 DEG C, slowly add the N of 0.81 parts by volume, accelerine, add the aluminum chloride that total amount is 0.85 weight part again, it is 0 ~ 5 DEG C that adition process controls temperature of reaction, adds rear stirring 5 ~ 15min completely in batches, after rise to room temperature, be placed in microwave reactor; Then
Carry out microwave cycle, reaction total time is 10 ~ 32min;
After reacting completely, add the dilute hydrochloric acid of 20 parts by volume, being adjusted to pH value is 3 ~ 5, and extraction into ethyl acetate, merges organic phase after extraction, and being washed to pH value is 6 ~ 7, revolves steaming, obtains benzene alkene not moral;
The ratio of above-mentioned weight part and parts by volume is gram: milliliter.
5. the method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene according to claim 1,
it is characterized in thatwhen microwave condition is IV, preparation process is as follows:
(E)-3,5-dimethoxy-4 's-isopropyl toluylene of 0.3 weight part is mixed with the pyridine hydrochloride of 1.5 weight parts, is placed in microwave reactor,
Carry out microwave cycle, reaction total time is 10 ~ 32min;
After reacting completely, add the dilute hydrochloric acid of 20 parts by volume, being adjusted to pH value is 3 ~ 5, and extraction into ethyl acetate, merges organic phase after extraction, and being washed to pH value is 6 ~ 7, revolves steaming, postlyophilization, obtains benzene alkene not moral;
The ratio of above-mentioned weight part and parts by volume is gram: milliliter.
6. the method being prepared benzene alkene not moral by (E)-3,5-dimethoxy-4 's-isopropyl toluylene according to claim 3 or 5,
it is characterized in thatdescribed (E)-3,5-dimethoxy-4 's-isopropyl toluylene is 1:5 with the reaction mass ratio of pyridine hydrochloride.
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