CN100425591C - Sulfonyl diphenylethyllene endocompound and its preparation method and pharmaceutical uses - Google Patents
Sulfonyl diphenylethyllene endocompound and its preparation method and pharmaceutical uses Download PDFInfo
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- CN100425591C CN100425591C CNB200510044870XA CN200510044870A CN100425591C CN 100425591 C CN100425591 C CN 100425591C CN B200510044870X A CNB200510044870X A CN B200510044870XA CN 200510044870 A CN200510044870 A CN 200510044870A CN 100425591 C CN100425591 C CN 100425591C
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Abstract
The present invention relates to an ethene bridge compound containing sulfonyl diphenyl with a general formula (I) (disclosed in the specification). R1 in the formula represents 4-methylsulfonyl; R2 represents one of H, OH, OCOCH3, OCH3 and OCOCH=CHC6H5; R3 and R4 represent one of H, OCH3, Cl and Br; R5 represents one of H, K, Na, CH3 and CH2CH3. The present invention also relates to a method for preparing the compound, and the use of the compound for preparing medicine for inhibiting cyclooxygenase 2 and preparing a medicine for treating mammals' inflammation or pain.
Description
Technical field
The present invention relates to contain the etheno compound of alkylsulfonyl phenylbenzene; particularly relate to compound of general formula (I) and preparation method thereof; with contain one or more these compound compositions, and this compound suppresses application in the medicine with cyclooxygenase 2 relative diseases in preparation.
Background technology
NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) medicine is widely used in the treatment of rheumatism, inflammatory diseases, pain, soft tissue diseases and sport injury because it has definite anti-inflammatory, analgesic effect, also is used for the prevention of cardiovascular disorder and tumour in addition.The stomach complication is to take the modal side effect of NSAIDs medicine for a long time.Cyclooxygenase newly developed (COX-2) inhibitor can obviously reduce the generation of stomach complication in treatment inflammation, pain.
The pharmacological action of NSAIDs medicine is to hinder the result that prostaglandin(PG) (PGs) forms.The investigator supposes that the NSAIDs medicine has suppressed the necessary enzyme of this biological process.This enzyme is called as cyclooxygenase (COX), and it can change arachidonic acid into PGG through a cyclooxygenase reaction, change PGH into through peroxidase reaction then, PGH exists as the precursor of producing other various in-house ring-type prostanoid.
Arachidonic acid generates PGH through the cyclooxygenase effect
2PGH
2Produce PGD through the isomerase effect
2, PGE
2Further generating PGF
2xPGH
2Produce TXA through the thromboxane synthase effect
2And TXB
2PGH
2Produce PGI through the prostacyclin synthase effect
2, this kind of enzyme is a kind of globular proteins that has long drain water piping, and long drain water piping its activity site place just.By the essential substance of enzyme effect, be arachidonic acid, it is a kind of lipid acid, just in time is filled in this pipeline, resembles key and inserts a lock.If this pipeline is twisted or stops up, enzyme substrate can not arrive activity site, and enzyme has just lost activity so, when acetylsalicylic acid gives, causes pipeline to be twisted owing to specific Serine molecule is acetylation, thereby enzyme is lost activity.Other NSAIDs medicine has the mechanism similar with acetylsalicylic acid.
It is generally acknowledged that cyclooxygenase has two kinds of isomer, i.e. COX-1 and COX-2.The gene of these two kinds of isomerases has different karyomit(e), but their structure has 70% to be similar, and they have identical homology at activity site.COX-1 induces the prostaglandin(PG) of generation mainly to play physiology and defencive function, is called basal enzyme; COX-2 mainly expresses in scavenger cell, fibroblast, cartilage, endothelium and epidermic cell, level is extremely low under base state, in case be subjected to cytokine or endothelin to stimulate its expression amount will tens of multiplications long, produce prostaglandin(PG) and participate in inflammatory reaction, thereby be called inducible enzyme again.
The investigator has studied the inhibition of 25 kinds of NSAID (non-steroidal anti-inflammatory drug) to COX-1 and COX-2, find that the COX enzyme in the stomach mainly is COX-1, and acetylsalicylic acid and indomethacin etc. some cause the medicine of serious stomach ulcer, to the COX-2 restraining effect a little less than, oppose that mutually the COX-1 restraining effect is very strong.
The cyclooxygenase selective depressant is that a class can optionally suppress COX-2, but NSAIDs medicine to the less inhibition of COX-1, in theory, this class medicine can not influence the necessary ring-type prostate gland of synthesising physiological compound in the body, but can produce good analgesia and antiphlogistic effects.
So far, the cyclooxygenase-2 inhibitors of exploitation listing is mainly the diaryl heterocyclic compound, compound such as celecoxib (celecoxib as the pyrazoles lopps, WO9641625), the compound of furans lopps such as rofecoxib (rofecoxib, WO9613483); the compound of isoxazole lopps is as penta ground former times cloth (valdecoxib, EP 0912518, US 5861419) and Parecoxib (Parecoxib, us 6828456), the constructional feature of this class medicine all is that center ring is a heterocyclic diaryl heterogeneous ring compound, and the contraposition of 1 aromatic ring has-SO therein
2CH
3The base or-SO
2NH
2Base.And the U.S. former times cloth of chlorine (lumiracoxib) is that intermediate axle connects with the N atom.
Several extensive perspective studys have in recent years all proposed query to the risk benefit ratio of cox 2 inhibitor, on September 30th, 2004, Merck ﹠ Co., Inc. whole world Recall voluntarily rofecoxib incident caused fierce cox 2 inhibitor security battle especially: does the cardiovascular danger of cox 2 inhibitor have much actually?
Some experts that are engaged in the cox 2 inhibitor drug research think, the heart trouble risk problem that ten thousand networks exist, and other COX-2 medicine may exist too, because all cox 2 inhibitors all can suppress prostaglandin I
2(PGI
2, a kind of Cardioprotective material) generation, and ten thousand networks, celecoxib are similar with the biochemical property that cuts down ground former times cloth, therefore, unless special evidence is arranged, all may have the heart trouble risk in this class medicine.
Other experts then think, only be conceived to explain that with a kind of mechanism of action the cardiovascular danger of cox 2 inhibitor is wrong, all members of same class medicine not necessarily must have all mechanism of action, in fact, all members of which kind of medicine do not have its whole mechanism of action.
Several studies show that in addition, and the increase of the cardiovascular adverse effects that cox 2 inhibitor causes may be relevant with its abuse, comprising the patient that may not necessarily therefrom benefit.
The expert who is engaged in cox 2 inhibitor research for a long time thinks that because molecular structure, pharmacokinetics and the pharmacodynamics of medicine are different, different cox 2 inhibitors is to the difference that influences of cardiovascular danger.
Celecoxib significantly improves endothelial function, reduces the level of oxidative stress and inflammation marker, and rofecoxib and diclofenac then do not show this beneficial effect.Rofecoxib is because water-soluble better, show cell membrane destruction is arranged, infer that the membrane structure energy of rupture that rofecoxib causes allows more oxyradical enter in the cell, thereby increase the oxidative stress level, make lipoprotein easier to be oxidized, cause rofecoxib to have the detrimental action of short low-density lipoprotein (LDL) oxidation.
The portion report of publishing recently points out that it may be to cause rofecoxib to have the important factor of long term toxicity that oxidation forms the maleic anhydride derivative, and other cox 2 inhibitor does not have this newfound reactivity, as the celecoxib of Pfizer, cut down the chlorine cloth of U.S. former times of ground former times cloth and Novartis Co.,Ltd.If this hypothesis is proved to be correctly, will become other cox 2 inhibitors of explanation does not have the similar toxic favourable evidence of ten thousand networks.
Chlorine cloth of U.S. former times is structurally also inequality with other this type of medicine, does not have the sulfur-bearing position, but carboxyl is arranged, and therefore is slightly acidic, and time that its continues in synovia is longer than in blood plasma, and this may be useful to reducing some side effect.Studies show that in TARGET test, when osteoarthritis treatment, patient's the incidence rate of myocardial infarction of taking chlorine cloth of U.S. former times is lower than rofecoxib, and takes two kinds of non-steroidal anti-inflammatory drugs Naproxen Bases and compares with Ibuprofen BP/EP and do not have significant difference.Another studies show that with contrasting Naproxen Base and compares with Ibuprofen BP/EP, can obviously reduce the incidence of ulcer, but cardiovascular danger does not increase.
We infer that the intermediate axle structure of the cox 2 inhibitor medicine that gone on the market is perhaps relevant with cardiovascular side effects, and the exploitation of cyclooxygenase-2 inhibitors is based upon on the new compound skeleton basis and perhaps can be beneficial to reducing cardiovascular side effects.
Forulic acid (Fendic Acid) is a principal monomer activeconstituents in the Chinese medicinal materials water soluble extracts such as Radix Angelicae Sinensis, river Chinese herbaceous peony.Clinical its sodium salt (Soditun Fenilete) treatment hypertension commonly used, coronary heart disease, cerebral arteriosclerosis and thromboangitis obliterans.Have been found that now forulic acid has following function at least: antisepsis and anti-inflammation, atherosclerosis, anti-platelet aggregation and thrombus, antitumor, anti-mutation; Remove nitrite, oxyradical, peroxidation nitroso-group; Increase immunologic function, human body are skillful in vigor and mobility etc.Forulic acid can and be easy to for absorption of human body discharge from urine, can not accumulate in vivo, and be the high medicine of a kind of security therefore.
In the prior art, people wish it when reducing its stomach side effect when the new compound of design nonsteroidal anti-inflammatory drug, also wish to reduce the side effect of its cardiovascular aspect.But; by retrieval: based on the compound skeleton of active ingredient of Chinese herbs forulic acid; structure activity study according to cyclooxygenase-2 inhibitors; the two aromatic ring series compounds that design connects with etheno; particularly contain the etheno compound of alkylsulfonyl phenylbenzene and utilize its preparation to suppress the application of the anti-inflammatory drug of cyclooxygenase 2; in existing document, do not see as yet so far.
Summary of the invention
At the deficiencies in the prior art, the object of the present invention is to provide a kind of alkylsulfonyl diphenylethlene bridge novel cpd;
Another object of the present invention is to provide the method for the etheno compound that a kind of preparation contains the alkylsulfonyl phenylbenzene;
A further object of the present invention is to provide a kind of pharmaceutical composition that contains one or more this compounds;
Another purpose of the present invention is to provide a kind of purposes of this compound in the medicine of inhibition and cyclooxygenase 2 relative diseases that contain.
In order to finish the present invention's purpose, alkylsulfonyl diphenylethlene bridge novel cpd provided by the invention, have general formula (I) shown in structure:
Its constructional feature is as follows: two aromatic rings connect with etheno, and are positioned at the same side (being trans α-phenylcinnamic acid) of ethylenic linkage.First sulfo group or sulfahydantoin are arranged in the contraposition of one of them aromatic ring, and this is the key structure that COX-2 is produced selective inhibitory.In the contraposition of another aromatic ring, hydroxyl is arranged, be connected with hydroxy-acid group on the etheno, the 4-hydroxy styrenes can act on mutually with plurality of enzymes active centre hydrophilic radical, think that but the hydroxyl in its β-aromatic nucleus contraposition is the activity of essential group and interferases, the side chain α that is connected with aromatic ring, drug effect be agreed with and be strengthened to β-unsaturated system of gripping altogether can mutually with arachidonic acid, this structure also is the core texture of forulic acid, wish that it strengthens the selection of inhibitors effect, reduces the side effect of cardiovascular aspect simultaneously.Acetoxyl to the forulic acid skeleton has been introduced different groups with the ortho position of hydroxyl and hydroxyl, and examination is to the active influence of anti-inflammatory.
Wherein, in the above-mentioned general formula:
R
1Expression-H ,-CH
3,-COCH
3,-COCH=CHC
6H
5One of;
R
2, R
3Expression-H ,-OCH
3One of ,-Br ,-Cl;
R
4Expression-H ,-K ,-Na ,-CH
3,-CH
2CH
3One of.
R in the above-mentioned compound
1Preferred expression-H ,-CH
3,-COCH
3,-COCH=CHC
6H
5One of, R
2, R
3Preferred expression-H ,-OCH
3One of, R
4Preferred expression-H ,-K ,-Na ,-CH
3,-CH
2CH
3One of.
R in the above-mentioned compound
1Preferred expression-COCH again
3,-COCH=CHC
6H
5One of, R
2, R
3Again preferably expression-H ,-OCH
3One of, R
4Again preferably expression-H ,-K ,-Na ,-CH
2CH
3One of.
R in the above-mentioned compound
1Further preferred expression-COCH
3, R
2, R
3Further preferred expression-H ,-OCH
3One of, R
4Further preferred expression-H ,-Na ,-CH
2CH
3One of.
R in the above-mentioned compound
1Expression-COCH most preferably
3, R
2Expression-H, R
3Expression-H ,-OCH
3One of, R
4The table most preferably-H ,-CH
2CH
3One of.
Above-claimed cpd is (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid;
Above-claimed cpd is (E)-2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) vinylformic acid;
Above-claimed cpd is (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxy phenyl) ethyl propenoate;
Above-claimed cpd is (E)-2-(4-first sulfone phenyl)-3-(4-hydroxy phenyl) ethyl propenoate;
Above-claimed cpd is (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) ethyl propenoate;
Above-claimed cpd is (E)-2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) ethyl propenoate.
Be the described compound of preparation general formula of the present invention (I), the method that the present invention adopts comprises, thioanisole is reflected at deacetylate in the contraposition of thioether by Friedel-Crafts, be sulfone by oxidizing reaction with sulfide oxidation then, make acetophenone compounds become the toluylic acid compounds by the Willgerodt reaction again, last toluylic acid compounds and aromatic aldehyde obtain the target compound carboxylic acid product by claisen condensation; Again with the ethanol condensed target compound esterification products that obtains; Esterification products and diacetyl oxide or excess acetyl chloride obtain the acetyl esterification products; The salt of carboxylic acid product and sodium Metal 99.5 or potassium or alkali reaction obtain the organic salt product.
Specifically, prepare the method for the described compound of general formula of the present invention (I), form by following steps:
(A) thioanisole and Acetyl Chloride 98Min. in-10～10 ℃, are used AlCl in inert solvents such as chloroform, methylene dichloride, benzene
3Catalyzed reaction is introduced ethanoyl in the contraposition of thioether;
(B) with substituted thioethers in acetate, make catalyzer with phosphoric acid, back flow reaction obtains product oxidation products substituted benzoyl sulfone;
(C) substituted acetophenone, sulphur and morphine woods back flow reaction are decomposed with NaOH solution again, obtain substituted phenylacetic acid;
(D) substituted phenylacetic acid and substituted aroma aldehyde in the middle of the diacetyl oxide solvent, are made catalyzer with triethylamine, react down at 130～140 ℃ to obtain the target compound carboxylic acid product;
(E) target compound carboxylic acid product and ethanol are used sulphuric acid catalysis under 60～90 ℃, reflux 2～6h, and condensation obtains the target compound esterification products;
(F) esterification products and diacetyl oxide are under 100～140 ℃, and reaction obtains the acetyl esterification products; Or esterification products and Acetyl Chloride 98Min. reaction under 0～60 ℃, obtain the acetyl esterification products;
(G) carboxylic acid product is with NaOH or Na
2CO
3Basic solutions such as solution are regulated pH value 8～10, and reaction obtains the organic salt product.
The preparation process of the compound of above-mentioned general formula (I) statement also can be expressed as follows by reaction formula:
In above-mentioned reaction formula, a.b.c.d.e.f.g. is expressed as follows content respectively:
A.AlCl
3, CH
3COCl, CHCl
3B.H
2O
2, H
3PO
4, CH
3COOH c. is 2. NaOH solution d.Ac of S, morphine woods 1.
2O, triethylamine, 120～140 ℃ of e.C
2H
5OH, dense H
2SO
4, 90 ℃ of f.Ac
2O, 120～140 ℃ of g.NaOH solution
The application of the compound that the present invention relates in the medicine of preparation inhibition cyclooxygenase 2.
The application of the compound that the present invention relates in the medicine of preparation treatment inflammation in mammals or pain.
The compound that the present invention relates to also can be further used for treating the pharmaceutical composition of inflammation in mammals or pain, wherein contains the compound of the present invention and the pharmaceutically acceptable carrier for the treatment of effective dose.
Pharmaceutical research shows that the described compound of general formula of the present invention (I) has good anti-inflammatory activity, for the mice ear that dimethylbenzene causes, has the obvious suppression effect.
The compounds of this invention is the nonsteroidal anti-inflammatory drug that a class has selective inhibitory, also be a kind of cyclooxygenase 2 inhibitor, it can be used for treating rheumatic arthritis, rheumatalgia, disease and symptoms such as various inflammation and heating, in addition, because cyclooxygenase 2 ￡ high expression level and high-content in colon also can be used for treating cancers such as the colorectal carcinoma and the rectum cancer.
Select for use pharmaceutical carrier well known to those skilled in the art can make the pharmaceutical composition of the The compounds of this invention that contains effective dosage.
The compounds of this invention or its composition can be with oral methods or non-enterally administers.Oral medication can be tablet, capsule, Drug coating, non-ly through the intestines drug formulation injection and suppository etc. be arranged.These preparations prepare according to method well-known to those having ordinary skill in the art.For manufacturing tablet, capsule, the used auxiliary material of Drug coating are the auxiliary agents of conventional usefulness, for example starch, gelatin, gum arabic, silica, polyoxyethylene glycol, the used solvent of liquid dosage form for example has water, ethanol, propylene glycol, plant oil such as Semen Maydis oil, peanut oil, olive wet goods.
Containing in the preparation of The compounds of this invention also can have other auxiliary agent, for example tensio-active agent, lubricant, disintegrating agent, sanitas, correctives, pigment etc.
The dosage that contains the described compound of general formula of the present invention (I) in tablet, capsule, Drug coating, injection or suppository is that the compound amount that exists in unit dosage form is calculated.The general content of the described compound of general formula of the present invention (I) is 10-200mg in unit dosage form.
Be treatment rheumatic arthritis and other inflammation, heating, pain relieving, be 10-500mg The compounds of this invention every day that adult patient is taken, and can once take or divide and take for 2-3 time; The dosage of children taking is according to every kg body weight 5-30mg.
Embodiment
, but do not limit the scope of the invention inventing further elaboration below with reference to embodiment.
Determining instrument used herein: fusing point is used the close instrument of the Nereid WRS-1B of company limited fusing point instrument and is measured, and temperature is not calibrated; Carbon spectrum and hydrogen spectrum are measured by the super shielding of the AVANCE of Switzerland Bruker company 600,000,000 superconductors fourier transform NMR spectrometer; Infrared absorption spectra, by the U.S. NEXUS of Nicolet company 470 class Fourier transformation infrared spectrometer, pellet technique is measured; Mass spectrum is measured by the U.S. API4000 of Applied Biosystems company type mass spectrograph.
" preparation of intermediate "
The preparation of embodiment 1:4-dimethyl sulfide methyl phenyl ketone
In the four-hole bottle of 1L, add AlCl
3130.0g (0.97mol) with chloroform 650mL, ice-water bath is cooled to about 5 ℃, stirs and dripping acetyl chloride 76g (0.97mol), dropwise, maintain the temperature at 5 ℃, in the time of 1hr, stir down and drip thioanisole 100g (0.81mol), dropwise, shift out ice-water bath, at room temperature stir 2hr, impouring 1000mL water, in the mixture of dense HCl of 250mL and 500g ice, stir, separate chloroform layer, use the chloroform extraction water layer of 100mL again, the combined chloroform layer is used anhydrous sodium sulfate drying, in 100 ℃ oil bath, boil off chloroform, evaporated under reduced pressure obtains lurid liquid again, shift out oil bath after, cooling, become solid, heavy 127.0g, yield 95.0%.Solid adds ethanol 300mL recrystallization and obtains white needle 120.0g, total recovery 90.0%, m.p.79.5～81.2 ℃.(80.6～81.4 ℃ of document fusing points)
IR(KBr)(v/cm
-1)：3440.69，3323.88，2988.97，2971.21，3032.93，1668.85(υ
c＝o)，1589.79，1554.96，1490.56，1432.04，1397.01，1358.02，1287.67，1267.59，1100.99，958.42，817.01
The preparation of embodiment 2:4-first sulfone methyl phenyl ketone
In the four-hole bottle of 500mL, add 4-dimethyl sulfide methyl phenyl ketone 83.1g (0.5mol), acetate 180mL and 85% phosphatase 11 .0mL, put into 110 ℃ of oil baths, heated and stirred drips 30%H in the time of 2hr
2O
2The mixture of 130mL (1.1mol) and 85% phosphoric acid 0.7mL, after dropwising, in oil bath, stir 1hr again, in the mixture of impouring 600mL water and 300g ice, stir and separate out white solid then, cold filtration, obtain white solid, wash twice earlier with water, use washing with alcohol again twice, oven dry obtains white solid 95.0g, yield 96.0%.Obtain white rib shape crystal with ethyl alcohol recrystallization, m.p.126.2～126.5 ℃.(124～126 ℃ of document fusing points).
IR(KBr)(v/cm
-1)：3356.33，3095.29，3072.47，3017.05，3004.23，2922.78，1687.69(υ
c＝o)，574.31，1395.36，1356.83，1310.57，1296.21，1258.55，1172.40，1148.46，1089.72
The preparation of embodiment 3:4-first sulfone toluylic acid
In the four-hole bottle of 1L, add 4-first sulfone methyl phenyl ketone 80g (0.4mol), sublimed sulphur 12.8g (0.4mol) and morphine woods 56.0mL are heated to 130 ℃ of following backflow 10hr then, are cooled to 50 ℃, add the ethyl acetate of 80mL then, stir, the sherwood oil that adds 40mL again, stir about 20 minutes becomes solid, add the solution of 80g NaOH in 800mL water then, place 85 ℃ oil bath stirring to spend the night, shift out oil bath, cool to room temperature, filter, the concentrated hydrochloric acid that adds 160mL, it is about 4～5 to regulate pH, separates out light yellow solid, the solid re-crystallizing in ethyl acetate, obtain colourless needle 43.0g, yield 50.2%, m.p.134～136 ℃.(137 ℃ of document fusing points).
IR(KBr)(v/cm
-1)：3095.17，3070.50，3030.96，3016.14，2930.92，2732.30，1699.96(υ
c＝o)，1409.51，1297.81，1240.15，1145.54，1090.27，965.89，779.03
The preparation of embodiment 4:3-methoxyl group-4-trans-cinnamoyloxy group phenyl aldehyde
After styracin 3.7g (0.025mol) and thionyl chloride 3.0g (0.025mol) mix, reflux 3hr in the middle of 70～80 ℃ oil bath, adding vanillin food grade,1000.000000ine mesh 3.8g (0.025mol) adds the pyridine of 5mL again, reflux 3.0hr in the middle of 70～80 ℃ oil bath pours in the cold water of 200mL, and viscous material solidifies gradually, use ethyl alcohol recrystallization, obtain the 6.5g white solid, yield 85.0%, m.p.89～89.9 ℃.
IR(KBr)(v/cm
-1)：3440.44，3061.59，3014.16，2970.66，2836.89，2738.08，1732.27(υ
c＝o)，1702.66(υ
c＝o)，1635.17，1597.02，1502.75，1424.95，1268.43，1205.74，1140.18，1119.59，1031.37，763.94
The preparation of embodiment 5:3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde
Vanillin food grade,1000.000000ine mesh 1.52g (0.01mol) is dissolved in the middle of the methyl alcohol of 6mL, and cooling in the middle of cryosel is bathed drips the solution of 1.76g (0.011mol) bromine water in the methyl alcohol of 6mL, after dropwising with 10 minutes times, restir 0.5hr shifts out cryosel then and bathes, and at room temperature stirs 3hr again, the water of Dropwise 5 mL then, separate out white solid, filter, the heavy 2.0g in dry back, yield 86.5%, m.p.163～164 ℃.(163～164 ℃ of document fusing points).
IR(KBr)(v/cm
-1)：3308.30，3102.58，1675.03(υ
c＝o)，1590.56，1501.31，1463.81，1430.65，1353.87，1291.51，1158.78，1046.68，680.26
The preparation of embodiment 6:3-bromo-4-hydroxy benzaldehyde
With the reaction of 4-hydroxy benzaldehyde 1.22g (0.01mol) and 1.76g (0.011mol) bromine water, the same mmx of method obtains white solid 1.3g, yield 65.0%, m.p.123～124 ℃.(124 ℃ of document fusing points).
IR(KBr)(v/cm
-1)：3091.42，2850.97，1679.39(υ
c＝o)，1592.46，1498.71，1422.00，1275.12，1173.28，1037.05，820.06，622.03
Embodiment 7:3, the preparation of 4-dimethoxy-5-bromo-phenyl aldehyde
3-bromo-4-hydroxy-5-methyl oxygen benzaldehyde 0.93g (0.004mol) adds the methyl alcohol of 10mL water and 5mL, 100 ℃ of heating down, drip several NaOH solution earlier, drip methyl-sulfate 1.5g (0.0088mol) and NaOH solution (0.015mol) then simultaneously, 0.5hr time dropwise, heat 1.5hr down at 100 ℃ again, room temperature cooling, the strong aqua of adding 2.0mL, then, white solid is separated out in 0 ℃ of refrigeration, filters, solid ether recrystallization, obtain the brilliant 0.8g of white fine needle, yield 82.0%, m.p.59.5～61.0 ℃.
IR(KBr)(v/cm
-1)：3345.87，3071.82，2945.58，2860.22，2834.88，1691.80(υ
c＝o)，1565.79，1486.32，1312.15，1281.15，1133.26，1047.55，991.35，856.08，836.64，666.37
The preparation of embodiment 8:3-bromo-4-methoxybenzaldehyde
The water that 3-bromo-4-hydroxy benzaldehyde 0.8g (0.004mol) is added 10mL, 100 ℃ of heating down, drip several NaOH solution earlier, drip methyl-sulfate 1.5g (0.0088mol) and NaOH solution (0.015mol) then simultaneously, 0.5hr time dropwise, heat 1.5hr down at 100 ℃ again, room temperature cooling, the strong aqua of adding 2.0mL, then, white solid is separated out in 0 ℃ of refrigeration, filters, solid ether recrystallization, obtain the brilliant 0.75g of white fine needle, yield 94.0%, m.p.43～44 ℃.
IR(KBr)(v/cm
-1)：3339.61，3084.22，2948.79，2835.68，2822.38，2739.28，1687.79(υ
c＝o)，1593.33，1493.53，1284.02，1196.79，1048.39，1012.63，820.91，811.76，665.60，636.77
" preparation of target compound "
Compound code name that relates among the following embodiment and title correspondence table (seeing Table-1)
Table-1
| Sequence number | Code name | The target compound title |
| 1 | hsmy | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid |
| 2 | hsmj | (E)-2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) vinylformic acid |
| 3 | hsmr | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-trans-cinnamoyloxy group phenyl) vinylformic acid |
| 4 | hsny | (E)-2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) vinylformic acid |
| 5 | hsnj | (E)-2-(4-first sulfone phenyl)-3-(4-p-methoxy-phenyl) vinylformic acid |
| 6 | hsnr | (E)-2-(4-first sulfone phenyl)-3-(4-trans-cinnamoyloxy group phenyl) vinylformic acid |
| 7 | hsmyx | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group-5-bromophenyl) vinylformic acid |
| 8 | hsmjx | (E)-2-(4-first sulfone phenyl)-3-(3,4-dimethoxy-5-bromophenyl) vinylformic acid |
| 9 | hsnyx | (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-acetoxyl group phenyl) vinylformic acid |
| 10 | hsnjx | (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-p-methoxy-phenyl) vinylformic acid |
| 11 | hsmt | (E)-2-(4-first sulfone phenyl)-3-(3, the 5-Dimethoxyphenyl) vinylformic acid |
| 12 | hsmm | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxy phenyl) vinylformic acid |
| 13 | hsnn | (E)-2-(4-first sulfone phenyl)-3-(4-hydroxy phenyl) vinylformic acid |
| 14 | hsmmx | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxyl-5-bromophenyl) vinylformic acid |
| 15 | hsnnx | (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-hydroxy phenyl) vinylformic acid |
| 16 | hzmm | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxy phenyl) ethyl propenoate |
| 17 | hzmj | (E)-2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) ethyl propenoate |
| 18 | hznn | (E)-2-(4-first sulfone phenyl)-3-(4-hydroxy phenyl) ethyl propenoate |
| 19 | hznj | (E)-2-(4-first sulfone phenyl)-3-(4-p-methoxy-phenyl) ethyl propenoate |
| 20 | hzmt | (E)-2-(4-first sulfone phenyl)-3-(3, the 5-Dimethoxyphenyl) ethyl propenoate |
| 21 | hzmmx | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxyl-5-bromophenyl) ethyl propenoate |
| 22 | hzmjx | (E)-2-(4-first sulfone phenyl)-3-(3,4-dimethoxy-5-bromophenyl) ethyl propenoate |
| 23 | hznnx | (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-hydroxy phenyl) ethyl propenoate |
| 24 | hznjx | (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-p-methoxy-phenyl) ethyl propenoate |
| 25 | hzmy | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) ethyl propenoate |
| 26 | hzny | (E)-2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) ethyl propenoate |
| 27 | hzmyx | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group-5-bromophenyl) ethyl propenoate |
| 28 | hznyx | (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-acetoxyl group phenyl) ethyl propenoate |
| 29 | hzmr | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-trans-cinnamoyloxy group phenyl) ethyl propenoate |
| 30 | hznr | (E)-2-(4-first sulfone phenyl)-3-(4-trans-cinnamoyloxy group phenyl) ethyl propenoate |
| 31 | hsmyn | (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) sodium acrylate |
| 32 | hsmjn | (E)-2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) sodium acrylate |
Embodiment 1:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid (hsmy)
With 4-first sulfone toluylic acid 1.07g (0.005mol), vanillin food grade,1000.000000ine mesh 0.76g (0.005mol), diacetyl oxide 5.0mL, after triethylamine 0.5mL mixes, move in the middle of 130～140 ℃ the oil bath stirring heating 3.0hr, shift out oil bath then, cool to 100 ℃, add the water of 5.0mL, in the middle of 100 ℃ oil bath, stirred 5 minutes, shift out oil bath then, the water that adds 20mL again stirred 30 minutes at room temperature, and 0 ℃ refrigerates 3h down, separate out the about 1.3g of lurid solid, heated scrub in acetate, room temperature leaves standstill, and filters, dry, obtain off-white color solid 1.1g, yield 56.4%, m.p.225.7-226.2 ℃.
1H-NMR(DMSO)δ(ppm)：2.0264(3H，s，-COCH
3)，3.2490(3H，s，-SO
2CH
3)，3.3721(3H，s，-OCH
3)，6.6248(1H，s，9-H)，6.7833(1H，dd，13-H)，6.9936(1H，d，12-H)，7.5152(2H，d，J＝8.21Hz，4-H)，7.9769(2H，d，J＝8.26Hz，3H)，7.8503(1H，s，7-H)，12.9048(1H，s，-COOH)；
13C-NMR(DMSO)δ(ppm)：20.465(-COCH
3)，43.558(-SO
2CH
3)，55.263(-OCH
3)，114.030(9-C)，123.141(12-C)，123.823(13-C)，127.431(3-C)，130.897(4-C)，132.055(6-C)，132.705(8-C)，139.570(7-C)，140.195(2-C)，140.268(11-C)，142.169(5-C)，150.474(10-C)，167.679(-COOH)，168.387(-COCH
3)；
MS(m/z)：391.3[M+H]+，408.5[M+NH
4]+；
IR(KBr)(v/cm-1)：3434.61，2623.64(υ-OH，-COOH)；3025.15，2975.14，2941.93；1771.40(υC＝O，-COCH
3)；1675.53(υ
C＝O，-CH＝CCOOH)；1611.50，1595.86(υ
C-C-，-CH＝CCOOH)；1508.27；1465.43，1451.94；1416.83，1389.63；1296.78，1256.79；1195.40，1155.88，1090.74；1024.49(υ
C-O-C，Ar-O-CH
3)；957.92(δ
-OH，-CH＝CCOOH)；832.55(δ
＝CH-，-CH＝CCOOH)。
Embodiment 2:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) vinylformic acid (hsmj)
With 4-first sulfone toluylic acid 1.07g (0.005mol) and 3,4-dimethoxy benzaldehyde 0.83g (0.005mol) uses triethylamine catalysis in the diacetyl oxide solvent, reacted 30 minutes, the same hsmy of method separates out red decorating film, the acetate recrystallization, filter, be lurid solid 0.5g, yield 27.3%, m.p.232.2-233.4 ℃.
1H-NMR(DMSO)δ(ppm)：2.7749(3H，s，-OCH
3)，3.2417(3H，s，-SO
2CH
3)，3.7147(3H，s，-OCH
3)，6.3776(1H，s)，6.8082(1H，dd)，6.8594(1H，d)，7.4872(2H，d)，7.9690(2H，d)，7.7848(1H，s)，12.3386(1H，s，-COOH)。
Embodiment 3:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-trans-cinnamoyloxy group phenyl) vinylformic acid (hsmr)
4-first sulfone toluylic acid 1.07g (0.005mol) and 3-methoxyl group-4-trans-cinnamoyloxy group phenyl aldehyde 1.4g (0.005mol) are used triethylamine catalysis in the diacetyl oxide solvent, reaction 3.0hr, the same hsmy of method, separate out lurid solid, solid washs with the acetate reflux, obtain light yellow solid 1.2g, yield 50.2%m.p.250.1-250.9 ℃.
1H-NMR(DMSO)δ(ppm)：3.2505(3H，s，-SO
2CH
3)，3.3816(3H，s，-OCH
3)，6.6633(1H，s)，6.8177(1H，d)，6.8333(1H，d)，7.0811(1H，d)，7.4481(3H，6)，7.5314(2H，d)，7.7913(3H，t)，7.8751(1H，s)，7.9848(2H，s)，12.8(1H，s，-COOH)。
Embodiment 4:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) vinylformic acid (hsny)
4-first sulfone toluylic acid 1.07g (0.005mol) and 4-hydroxy benzaldehyde 0.61g (0.005mol) are used triethylamine catalysis in the diacetyl oxide solvent, reaction 3.0hr, the same hsmy of method, obtain yellow solid, add the acetate recrystallization, obtain white solid 0.76g, yield 42.2%, m.p.213.5～214.2 ℃.
1H-NMR(DMSO)δ(ppm)：2.2218(3H，s，-COCH
3)，3.2436(3H，s，-SO
2CH
3)，7.0122(2H，d)，7.0887(2H，d)，7.4770(2H，d)，7.4767(2H，d)，7.8646(1H，s)，12.9048(1H，s，-COOH)。
Embodiment 5:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-p-methoxy-phenyl) vinylformic acid (hsnj)
4-first sulfone toluylic acid 1.07g (0.005mol) and 4-methoxybenzaldehyde 0.68g (0.005mol) are used triethylamine catalysis in the diacetyl oxide solvent, reacted 30 minutes, the same hsmy of method, separate out red decorating film, the acetate recrystallization, be white solid 0.62g, yield 37.3%, m.p.239.5～242.5 ℃.
1H-NMR(DMSO)δ(ppm)：3.2577(3H，s，-SO
2CH
3)，3.7174(3H，s，-OCH
3)，6.8030(2H，d)，7.0028(2H，d)，7.4656(2H，d)，7.8087(1H，s)，7.9428(2H，d)，12.6366(1H，s，-COOH)。
Embodiment 6:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-trans-cinnamoyloxy group phenyl) vinylformic acid (hsnr)
4-first sulfone toluylic acid 1.07g (0.005mol) and 4-trans-cinnamoyloxy group phenyl aldehyde 1.26g (0.005mol) are used triethylamine catalysis in the diacetyl oxide solvent, reaction 3.0hr, the same hsmy of method, separate out lurid solid, solid washs with the acetate reflux, obtain light yellow solid 1.1g, yield 47.0%, m.p.257.1～256.5 ℃.
1H-NMR(DMSO)δ(ppm)：3.2638(3H，s，-SO
2CH
3)，6.8320(1H，d)，7.1210(4H，dd)，7.4497(3H，t)，7.4977(2H，d)，7.7792(2H，4)，7.8332(1H，d)，7.8932(1H，s)，7.9522(2H，d)，12.9159(1H，s，-COOH)。
Embodiment 7:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group-5-bromophenyl) vinylformic acid (hsmyx)
4-first sulfone toluylic acid 1.07g (0.005mol) and 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde 1.16g (0.005mol) are used triethylamine catalysis in the diacetyl oxide solvent, reaction 3.0hr, the same hsmy of method, obtain yellow solid, add acetate backflow washing, obtain white solid 1.2g, yield 48.0%, m.p.223.8～225.8 ℃.
1H-NMR(DMSO)δ(ppm)：2.2711(3H，s，-COCH
3)，3.2309(3H，s，-SO
2CH
3)，3.4071(3H，s，-OCH
3)，6.6509(1H，s，9-H)，7.0297(1H，d，13-H)，7.5247(2H，d，J＝8.18Hz，4-H)，7.9836(2H，d，J＝8.19Hz，3-H)，7.8204(1H，s，7-H)，12.8584(1H，s，-COOH)。
Embodiment 8:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3,4-dimethoxy-5-bromophenyl) vinylformic acid (hsmjx)
With 4-first sulfone toluylic acid 1.07g (0.005mol) and 3,4-dimethoxy-5-bromobenzaldehyde 1.23g (0.005mol) uses triethylamine catalysis in the diacetyl oxide solvent, reaction 0.5hr, the same hsmy of method, separate out red decorating film, the acetate recrystallization is lurid solid 0.72g, yield 32.5%, m.p.214.9～215.6 ℃.
1H-NMR(DMSO)δ(ppm)：3.2675(3H，s，-SO
2CH
3)，3.4308(3H，s，-OCH
3)，3.7155(3H，s，-OCH3)，6.5677(1H，s)，6.9993(1H，s)，7.5252(2H，d)，7.8046(1H，s)，8.0108(2H，d)，12.8238(1H，s，-COOH)；
Embodiment 9:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-bromo-4-acetoxyl group phenyl) vinylformic acid (hsnyx)
4-first sulfone toluylic acid 1.07g (0.005mol) and 3-bromo-4-hydroxy benzaldehyde 1.0g (0.005mol) are used triethylamine catalysis in the diacetyl oxide solvent, reaction 3.0hr, the same hsmy of method, obtain yellow solid, add the acetate recrystallization, obtain white solid 1.0g, yield 45.2%, m.p.209.6～212.0 ℃.
1H-NMR(DMSO)δ(ppm)：1.9331(3H，s，-COCH
3)，2.3039(3H，s，-SO2CH3)，7.0820(1H，dd)，7.1797(1H，d)，7.3785(1H，d)，7.5151(2H，d)，7.8659(1H，s)，7.9815(2H，d)，12.5662(1H，s，-COOH)。
Embodiment 10:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-bromo-4-p-methoxy-phenyl) vinylformic acid (hsnjx)
4-first sulfone toluylic acid 1.07g (0.005mol) and 3-bromo-4-methoxybenzaldehyde 1.1g (0.005mol) are used triethylamine catalysis in the diacetyl oxide solvent, reacted 30 minutes, the same hsmy of method, separate out red decorating film, the acetate recrystallization, be lurid solid 0.62g, yield 30.3%, m.p.213.0～214.0 ℃.
1H-NMR(DMSO)δ(ppm)：3.2422(3H，s，-SO
2CH
3)，3.80968(3H，s，-OCH
3)，6.5677(1H，s)，6.9857(1H，d)，7.0541(2H，dd)，7.1932(1H，d)，7.4739(2H，d)，7.7784(1H，s)，7.9615(2H，d)，12.3271(1H，s，-COOH)。
Embodiment 11:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3, the 5-Dimethoxyphenyl) vinylformic acid (hsmt)
With 4-first sulfone toluylic acid 1.07g (0.005mol) and 3,5-dimethoxy benzaldehyde 0.83g (0.005mol) uses triethylamine catalysis in the diacetyl oxide solvent, reaction 2.0hr, the same hsmy of method, separate out yellow decorating film, use the acetate recrystallization, obtain the solid 1.0g of off-white color, yield 54.2%, m.p.220.4～221.5 ℃.
1H-NMR(DMSO)δ(ppm)：3.2381(3H，s，-SO
2CH
3)，3.4911(6H，s，-OCH
3)，6.2050(2H，d)，6.3937(1H，t)，7.4813(2H，d)，7.7875(2H，d)，7.9543(1H，s)，12.8652(1H，s，-COOH)。
Embodiment 12:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxy phenyl) vinylformic acid (hsmm)
The water that (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid (hsmy) 1.0g (2.56mmol) is added 10mL, under agitation drip 10% NaOH solution, reaction solution yellowing clear solution, regulate pH value about 10, heated and stirred is 1.0 hours in the middle of 80 ℃ oil bath, shift out oil bath then, dripping concentrated hydrochloric acid regulates about pH value to 3.0, separate out the solid of oyster, filter drying, recrystallization in acetate, can obtain white solid 0.85g, yield 86.4%, m.p.222.7～223.3 ℃.
1H-NMR(DMSO)δ(ppm)：3.2482(3H，s，-SO
2CH
3)，3.3043(3H，s，-OCH
3)，6.3292(1H，d)，6.6640(1H，d)，6.7110(1H，dd)，7.4883(2H，d)，7.7453(1H，s)，7.9731(2H，d)，9.5555(1H，s，-OH)，12.9048(1H，s，-COOH)。
Embodiment 13:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-hydroxy phenyl) vinylformic acid (hsnn)
With (E)-2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) vinylformic acid (hsny) 1.0g (2.77mmol) and NaOH solution reaction, the same hsmm of method, obtain the oyster solid, recrystallization in acetate, can obtain white solid 0.75g, yield 85.0%, m.p.218.9～219.5 ℃.
1H-NMR(DMSO)δ(ppm)：3.2557(3H，s，-SO
2CH
3)，6.6043(3H，s，-OCH
3)，6.8034(2H，d)，7.4682(2H，dd)，7.7604(1H，s)，7.9346(2H，d)，9.8552(1H，s)，12.5672(1H，s，-COOH)。
Embodiment 14:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxyl-5-bromophenyl) vinylformic acid (hsmmx)
With (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group-5-bromophenyl) vinylformic acid (hsmyx) 1.0g (2.01mmol) and NaOH solution reaction, the same hsmm of method, obtain the oyster solid, recrystallization in acetate, can obtain white solid 0.76g, yield 89.0%, m.p.225.2～227.5 ℃.
1H-NMR(DMSO)δ(ppm)：3.2275(3H，s，-SO
2CH
3)，3.3886(3H，s，-OCH
3)，6.3980(1H，d)，6.9405(1H，d)，7.4880(2H，d)，7.7271(1H，s)，7.9763(2H，d)，9.9035(1H，s)，12.7214(1H，s，-COOH)。
Embodiment 15:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-bromo-4-hydroxy phenyl) vinylformic acid (hsnnx)
With (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-acetoxyl group phenyl) vinylformic acid (hsnyx) 1.0g (2.27mmol) and NaOH solution reaction, the same hsmm of method, obtain the oyster solid, recrystallization in acetate, obtain white solid 0.77g, yield 85.6%, m.p.215.5～217.6 ℃.
1H-NMR(DMSO)δ(ppm)：3.2498(3H，s，-SO
2CH
3)，6.8009(1H，d)，6.9103(1H，dd)，7.1188(2H，d)，7.4846(2H，d)，7.7535(1H，s)，7.9785(2H，d)，10.6981(1H，s)，12.7240(1H，s，-COOH)。
Embodiment 16:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxy phenyl) ethyl propenoate (hzmm)
The dehydrated alcohol that (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid (hsmy) 1.0g (2.56mmo1) is added 10mL, 98% the vitriol oil that adds 0.5mL again, reflux 5hr in 90 ℃ oil bath, cool to room temperature, the water that adds about 5mL 0 ℃ of refrigeration down, is separated out the about 0.7g of colourless needle, yield 73.0%, m.p.178.1～178.6 ℃.
1H-NMR(DMSO)δ(ppm)：1.3236(3H，t，-CH
2CH
3)，3.1068(3H，s，-SO
2CH
3)，3.4752(3H，s，-OCH
3)，4.2921(2H，q，-CH
2CH
3)，5.7906(1H，s，Ar-OH)，6.2933(1H，s，9-H)，6.7397(1H，d，13-H)，6.7862(1H，d，12-H)，7.5043(2H，d，J＝8.21Hz，4-H)，7.8586(1H，s，7-H)，7.9888(2H，d，J＝8.24Hz，3-H)。
Embodiment 17:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) ethyl propenoate (hzmj)
With (E)-2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) become ester with 98% vitriol oil in vinylformic acid (hsmj) 1.0g (2.76mmol) the adding dehydrated alcohol, the same hzmm of method obtains colourless needle 0.67g, yield 62.5%, m.p.163.1～163.4 ℃.
1H-NMR(DMSO)δ(ppm)：1.3255(3H，t，-CH
2CH
3)，3.1024(3H，s，-SO
2CH
3)，3.4641(3H，s，-OCH
3)，3.8604(3H，s，-OCH
3)，4.2896(2H，q，-CH2CH3)，6.3901(1H，s)，6.7258(1H，d)，6.7483(1H，d)，7.5060(2H，d)，7.9900(2H，d)，7.8766(1H，s)。
Embodiment 18:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-hydroxy phenyl) ethyl propenoate (hznn)
To become ester with 98% vitriol oil in (E)-2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) vinylformic acid (hsny) 1.0g (2.77mmol) adding dehydrated alcohol, the same hzmm of method, obtain white solid 0.54g, yield 56.0%, m.p.149.1～150.1 ℃.
1H-NMR(DMSO)δ(ppm)：1.3182(3H，t，-CH
2CH
3)，3.1036(3H，s，-SO
2CH
3)，4.2871(2H，q，-CH
2CH
3)，6.6500(2H，d)，7.4600(2H，d)，7.8769(1H，s)，7.9473(2H，d)。
Embodiment 19:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-p-methoxy-phenyl) ethyl propenoate (hznj)
To become ester with 98% vitriol oil in (E)-2-(4-first sulfone phenyl)-3-(4-hydroxy phenyl) vinylformic acid (hsnj) 1.0g (3.0mmol) adding dehydrated alcohol, the same hzmm of method, separate out the velvet-like crystal 0.77g of off-white color, yield 71.2%, m.p.118.5～119.1 ℃.
1H-NMR(DMSO)δ(ppm)：1.3205(3H，t，-CH
2CH
3)，3.1116(3H，s，-SO
2CH
3)，3.7826(3H，s，-OCH
3)，4.2883(2H，q，-CH
2CH
3)，6.7222(1H，s)，6.7967(1H，d)，7.4687(2H，d)，7.9611(2H，d)，7.8933(1H，s)。
Embodiment 20:(E)-2-(4-first sulfone phenyl)-3-(3, the 5-Dimethoxyphenyl) ethyl propenoate (hzmt) preparation
With (E)-2-(4-first sulfone phenyl)-3-(3, the 5-Dimethoxyphenyl) become ester with 98% vitriol oil in vinylformic acid (hsmt) 1.0g (2.76mmol) the adding dehydrated alcohol, the same hzmm of method obtains colourless needle 0.8g, yield 74.1%, m.p.134.0～135.1 ℃.
1H-NMR(DMSO)δ(ppm)：1.2282(3H，t，-CH
2CH
3)，3.2490(3H，s，-SO
2CH
3)，3.4919(6H，s，-OCH
3)，4.2146(2H，q，-CH
2CH
3)，6.2072(2H，d)，6.4028(1H，t)，7.5008(2H，d)，7.9900(2H，d，J＝8.28Hz，3-H)，7.8166(1H，s，7-H)，7.9664(2H，d)。
Embodiment 21:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxyl-5-bromophenyl) ethyl propenoate (hzmmx)
To become ester with 98% vitriol oil in (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-hydroxyl-5-bromophenyl) vinylformic acid (hsmmx) 1.0g (2.01mmol) adding dehydrated alcohol, the same hzmm of method, obtain the off-white color solid, get solid 0.75g with 75% ethyl alcohol recrystallization, yield 82.0%, m.p.171.4～172.3 ℃.
1H-NMR(DMSO)δ(ppm)：1.3271(3H，t，-CH2CH3)，3.1022(3H，s，-SO
2CH
3)，3.4846(3H，s，-OCH
3)，4.3022(2H，q，-CH
2CH
3)，6.0500(1H，s，Ar-OH)，6.2348(1H，s，9-H)，6.9458(1H，d，13-H)，7.4881(2H，d，J＝8.29Hz，4-H)，7.7785(1H，s，7-H)，8.0023(2H，d，J＝8.28Hz，3-H)。
Embodiment 22:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3,4-dimethoxy-5-bromophenyl) ethyl propenoate (hzmjx)
With (E)-2-(4-first sulfone phenyl)-3-(3,4-dimethoxy-5-bromophenyl) becomes ester with 98% vitriol oil in vinylformic acid (hsmjx) 1.0g (2.26mmol) the adding dehydrated alcohol, the same hzmm of method, obtain yellow solid, get solid 0.81g with ethyl alcohol recrystallization, yield 76.0%, m.p.120.3～121.6 ℃.
1H-NMR(DMSO)δ(ppm)：1.3500(3H，t，-CH
2CH
3)，3.1209(3H，s，-SO
2CH
3)，3.4722(3H，s，-OCH
3)，3.8548(3H，s，-OCH
3)，4.3282(2H，q，-CH
2CH
3)，6.3505(1H，d)，6.9405(1H，d)，7.5051(2H，d)，7.8084(1H，s)，8.0158(2H，d)。
Embodiment 23:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-bromo-4-hydroxy phenyl) ethyl propenoate (hznnx)
To become ester with 98% vitriol oil in (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-hydroxy phenyl) vinylformic acid (hsnnx) 1.0g (2.43mmol) adding dehydrated alcohol, the same hzmm of method, obtain the off-white color solid, use 75% ethyl alcohol recrystallization, obtain product 0.80g, yield 76.2%, m.p.109.8～110.8 ℃.
1H-NMR(DMSO)δ(ppm)：1.3155(3H，t，-CH
2CH
3)，3.1101(3H，s，-SO
2CH
3)，4.2889(2H，q，-CH
2CH
3)，5.7635(1H，s，Ar-OH)，6.8150(1H，d)，6.8517(1H，dd)，7.1266(1H，d)，7.4512(2H，d)，7.8049(1H，s)，7.9789(2H，d)。
Embodiment 24:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-bromo-4-p-methoxy-phenyl) ethyl propenoate (hznjx)
To become ester with 98% vitriol oil in (E)-2-(4-first sulfone phenyl)-3-(3-bromo-4-hydroxy phenyl) vinylformic acid (hsnjx) 1.0g (2.43mmol) adding dehydrated alcohol, the same hzmm of method, obtain light yellow solid, wash with alcohol reflux, obtain product 1.0g, yield 92.5%, m.p.195.7～197.0 ℃.
1H-NMR(DMSO)δ(ppm)：1.3202(3H，t，-CH
2CH
3)，3.1079(3H，s，-SO2CH3)，3.8778(3H，s，-OCH3)，4.2950(2H，q，-CH
2CH
3)，6.6984(1H，d)，6.8965(1H，dd)，7.1970(1H，d)，7.4539(2H，d)，7.8132(1H，s)，7.9821(2H，d)。
Embodiment 25:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) ethyl propenoate (hzmy)
With (E)-2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) ethyl propenoate (hzmm) 0.5g (1.33mmol) adds the diacetyl oxide of 3.0mL, 3h refluxes in the middle of 120 ℃ oil bath, diacetyl oxide is removed in decompression, the ethanol heating for dissolving that adds 3mL then, white needle 0.36g is separated out in 0 ℃ of refrigeration, yield 65.2%, m.p.128.8～129.6 ℃.
1H-NMR(DMSO)δ(ppm)：1.3308(3H，t，-CH
2CH
3)，2.2844(3H，s，-COCH
3)，3.1090(3H，s，-SO
2CH
3)，3.4641(3H，s，-OCH3)，4.3066(2H，q，-CH
2CH
3)，6.4804(1H，s)，6.7273(1H，dd)，6.9060(1H，d)，7.4957(2H，d)，7.9843(2H，d)，7.8852(1H，s)。
Embodiment 26:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-acetoxyl group phenyl) ethyl propenoate (hzny)
(E)-2-(4-first sulfone phenyl)-3-(4-p-methoxy-phenyl) ethyl propenoate (hznn) 0.5g (1.43mmol) is placed on acetylize in the diacetyl oxide, and the same hzmy of method separates out white solid 0.3g; filter; with ether washing, yield 52.3%, m.p.142.4～143.4 ℃.
1H-NMR(DMSO)δ(ppm)：1.3403(3H，t，-CH
2CH
3)，2.2878(3H，s，-COCH
3)，3.1182(3H，s，-SO
2CH
3)，4.3163(2H，q，-CH
2CH
3)，6.9645(2H，d)，7.0546(2H，d)，7.4717(2H，d，)，7.9278(2H，s)，7.9628(1H，d)。
Embodiment 27:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group-5-bromophenyl) ethyl propenoate (hzmyx)
(E)-2-(4-first sulfone phenyl)-3-(3,4-dimethoxy-5-bromophenyl) ethyl propenoate (hzmmx) 0.5g (1.1mmol) is placed on acetylize in the diacetyl oxide, the same hzmy of method; separate out white solid; wash 0.36g with ether, yield 66.2%, m.p.148.3～149.5 ℃.
1H-NMR(DMSO)δ(ppm)：1.3269(3H，t，-CH
2CH
3)，2.3217(3H，s，-COCH
3)，3.0901(3H，s，-SO
2CH
3)，3.4182(3H，s，-OCH
3)，4.3070(2H，q，-CH
2CH
3)，6.3722(1H，s，9-H)，6.9380(1H，dd，13-H)，7.4815(2H，d，4-H)，7.7985(1H，s，7-H)，7.9975(2H，d，3-H)。
Embodiment 28:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-bromo-4-acetoxyl group phenyl) ethyl propenoate (hznyx)
(E)-2-(4-first sulfone phenyl)-3-(4-methoxyl group-5-bromophenyl) ethyl propenoate (hznnx) 0.5g (1.16mmol) is placed on acetylize in the diacetyl oxide, and the same hzmy of method separates out white solid 0.33g; filter; with ether washing, yield 61.3%, m.p.103.3～105.2 ℃.
1H-NMR(DMSO)δ(ppm)：1.3058(3H，t，-CH
2CH
3)，2.3078(3H，s，-COCH
3)，3.0866(3H，s，-SO
2CH
3)，4.2878(2H，q，-CH
2CH
3)，6.9344(2H，d)，7.2559(2H，d)，7.4284(2H，d)，7.8146(1H，s)，7.8110(1H，d)。
Embodiment 29:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-trans-cinnamoyloxy group phenyl) ethyl propenoate (hzmr)
Drip thionyl chloride 6.5g (0.055mol) in styracin 7.5g (0.05mol), moves into heating 3hr in the middle of 70 ℃ the oil bath, have irritant gas to emit, room temperature is cooled off and is obtained slightly xanchromatic solid then, is cinnamyl chloride, m.p.33～35 ℃; Get (E)-2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) ethyl propenoate (hzmm) 0.45g (1.2mmol) and cinnamyl chloride 0.2g (1.2mmol) add methylene dichloride 3.0mL and triethylamine 1.0mL, reflux 3hr in the middle of 45 ℃ oil bath, evaporated under reduced pressure then, the water that adds 5mL, drip dense HCl, regulate about pH to 3.0, stirring at room 0.5hr filters then and obtains white solid, solid adds ethanol 10mL, reflux washing 0.5hr, room temperature leaves standstill then, filters to obtain white solid 0.5g, yield 83.0%, m.p.171.6～173.3 ℃.
1H-NMR(DMSO)δ(ppm)：1.3375(3H，t，-CH
2CH
3)，3.0892(3H，s，-SO
2CH
3)，3.4665(3H，s，-OCH
3)，4.3157(2H，q，-CH
2CH
3)，6.5221(1H，d)，6.6165(1H，d)，6.7710(1H，dd)，7.0000(1H，d)，7.4200(3H，6)，7.5120(2H，d)，7.5819(2H，dd)，7.8500(1H，d)，7.9102(1H，s)，7.9900(2H，d)。
Embodiment 30:(E)-preparation of 2-(4-first sulfone phenyl)-3-(4-trans-cinnamoyloxy group phenyl) ethyl propenoate (hznr)
Get (E)-2-(4-first sulfone phenyl)-3-(4-p-methoxy-phenyl) ethyl propenoate (hznn) 0.5g (1.43mmol) and cinnamyl chloride 0.2g and add methylene dichloride 3.0mL and triethylamine 1.0mL, the same hzmr of reaction method, obtain the about 0.55g of white solid, yield 80.0%, m.p.159.1～162.3 ℃.
1H-NMR(DMSO)δ(ppm)：1.3353(3H，t，-CH
2CH
3)，3.0828(3H，s，-SO
2CH
3)，4.3114(2H，q，-CH
2CH
3)，6.5921(1H，d)，7.0620(4H，d)，7.4362(3H，t)，7.4776(2H，d)，7.5871(2H，t)，7.8576(1H，d)，7.9394(1H，s)，7.9690(2H，d)：
Embodiment 31:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) sodium acrylate (hsmyn)
The water that (E)-2-(4-first sulfone phenyl)-3-(3-methoxyl group-4-acetoxyl group phenyl) vinylformic acid (hsmy) 0.5g (1.28mmol) is added 3.0mL, at room temperature, the NaOH solution of dropping 10%, about 0.4mL, regulating pH is 8～9,60 ℃ of following heated and stirred 0.5hr, become graminaceous solution, vacuum is drained then, obtains graminaceous solid, add the small amount of ethanol dissolving, add ether again and separate out solid, add ether after the filtration immediately, and drain the solid 0.43g that obtains off-white color in a vacuum, yield 83.0%, m.p.197.4～199.0 ℃.
1H-NMR(DMSO)δ(ppm)：2.2772(3H，s，-COCH
3)，3.2694(3H，s，-SO
2CH
3)，3.3796(3H，s，-OCH
3)，6.5089(1H，s，9-H)，6.8142(1H，dd，13-H)，6.9509(1H，d，12-H)，7.4739(2H，d，4-H)，7.5186(2H，d，3-H)，7.5677(1H，s，7-H)。
Embodiment 32:(E)-preparation of 2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) sodium acrylate (hsmjn)
With (E)-2-(4-first sulfone phenyl)-3-(3, the 4-Dimethoxyphenyl) vinylformic acid (hsmj) 0.5g (1.38mmol) and NaOH solution reaction, the same hsmyn of method obtains the white solid 0.46g of mao shape, yield 86.2%, m.p.251.2～253.0 ℃.
1H-NMR(DMSO)δ(ppm)：3.2794(3H，s)，3.2997(3H，s)，3.7653(3H，s，-OCH
3)，6.2303(1H，s)，6.8314(2H，dd)，7.4279(2H，d)，7.5212(2H，d)，7.9326(2H，d)。
" compound application example "
Embodiment 1: prepare dispersible tablet by The compounds of this invention
A) by table-2 described weight proportion weighting raw materials and auxiliary materials
Table-2
1000 of former, auxiliary material titles
Compound hsmy 50g
Microcrystalline Cellulose 20g
Lactose 20g
Hydroxypropylcellulose 20g
Polyvinylpolypyrrolidone 10g
Magnesium Stearate 1.0g
B) prepare tablet with ordinary method.
Embodiment 2: the application examples of The compounds of this invention in treatment inflammation in mammals or pain.
Test method
The Kunming mouse random packet, 10 every group, the weight of animals (18～22) g.Irritate stomach respectively and give the corresponding test-compound that 5 ‰ CMC-Na are made into suspension.Blank group is made into suspension for 5 ‰ CMC-Na of equivalent, and positive controls is an indomethacin.Behind the mouse stomach last administration 1h, evenly be coated with 50 μ l dimethylbenzene in mouse right ear two sides, left ear is not handled and is compared.Cutting two ears along auricle after causing scorching 1h, get auricle in the same position of two ears with the 8mm punch tool and weigh, calculate the swelling degree with two auricle weight differences, is the pharmacologically active of index evaluation test-compound with the inhibitory rate of intumesce.
Test-results
Swelling degree=auris dextra sheet weight-left auricle is heavy
First treated animal test (seeing Table-3)
Table-3
Second treated animal test (seeing Table-4)
Table-4
The 3rd treated animal test (seeing Table-5)
Table-5
* compare with the blank group: *: P＜0.05, * *: P＜0.01
Experimentation on animals is the result show, the part test-compound has apparent antiphlogistic effects, and its anti-inflammatory activity is equivalent to the positive control drug indomethacin.
Claims (8)
1. the compound of following general formula (I):
Wherein,
R
1Expression-H ,-CH
3,-COCH
3,-COCH=CHC
6H
5One of;
R
2, R
3Expression-H ,-OCH
3One of ,-Br ,-Cl;
R
4Expression-H ,-K ,-Na ,-CH
3,-CH
2CH
3One of.
2. compound as claimed in claim 1 is characterized in that, R in the described compound
1Expression-H ,-CH
3,-COCH
3,-COCH=CHC
6H
5One of, R
2, R
3Expression-H ,-OCH
3One of, R
4Expression-H ,-K ,-Na ,-CH
3,-CH
2CH
3One of.
3. compound as claimed in claim 2 is characterized in that, R in the described compound
1Expression-COCH
3,-COCH=CHC
6H
5One of, R
2, R
3Expression-H ,-OCH
3One of, R
4Expression-H ,-K ,-Na ,-CH
2CH
3One of.
4. compound as claimed in claim 3 is characterized in that, R in the described compound
1Expression-COCH
3, R
2, R
3Expression-H ,-OCH
3One of, R
4Expression-H ,-Na ,-CH
2CH
3One of.
5. compound as claimed in claim 4 is characterized in that, R in the described compound
1Expression-COCH
3, R
2Expression-H, R
3Expression-H ,-OCH
3One of, R
4Expression-H ,-CH
2CH
3One of.
6. the application of the described compound of one of claim 1～5 in the medicine of preparation inhibition cyclooxygenase 2.
7. the application of the described compound of one of claim 1～5 in the medicine of preparation treatment inflammation in mammals or pain.
8. the pharmaceutical composition that is used for the treatment of inflammation in mammals or pain wherein contains one of the claim 1～5 for the treatment of effective dose described compound and pharmaceutically acceptable carrier.
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| CN103951594B (en) * | 2009-12-18 | 2015-04-22 | 山东中医药大学 | Traditional Chinese medicine active ingredient p-hydroxy cinnamic acid derivative and application thereof |
| CN107641089A (en) * | 2016-07-21 | 2018-01-30 | 天津药物研究院有限公司 | A kind of preparation method of the mesyl phenylacetic acid of Etoricoxib intermediate 4 |
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