CN105753702B - 3,4- dihydroxyphenyl ethanol fenofibrate acid esters and its preparation method and application - Google Patents
3,4- dihydroxyphenyl ethanol fenofibrate acid esters and its preparation method and application Download PDFInfo
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- CN105753702B CN105753702B CN201610108885.6A CN201610108885A CN105753702B CN 105753702 B CN105753702 B CN 105753702B CN 201610108885 A CN201610108885 A CN 201610108885A CN 105753702 B CN105753702 B CN 105753702B
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- acid esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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Abstract
The invention discloses 3,4 dihydroxyphenyl ethanol fenofibrate acid esters and its preparation method and application, belong to field of medicine preparing technology.Disclosed by the invention 3,4 dihydroxyphenyl ethanol fenofibrate acid esters, it is a kind of novel more efficacy activity compounds, it can be used to treat diabetes and hyperlipidemia, blood glucose and blood fat (triglycerides and cholesterol) can be reduced, and the oxidative stress effect under diabetes and hyperlipidemia state can be improved to Anti-lipid peroxidation.The invention also discloses above-mentioned 3; the preparation method of 4 dihydroxyphenyl ethanol fenofibrate acid esters; by 3; the 3 of 4 dihydroxyphenyl ethanols; after 4 dihydroxy benzyl protections, then with fenofibrate it is condensed into ester, then sloughs benzyl under the effect of hydrogen palladium carbon; 3,4 dihydroxyphenyl ethanol fenofibrate acid esters are made.The preparation method is easy to operate, low for equipment requirements, environmental-friendly.
Description
Technical field
The invention belongs to field of medicine preparing technology, and in particular to a kind of Hydroxytyrosol fenofibrate acid esters and
Preparation method and application.
Background technology
Diabetes have become the major public health problem for threatening human health, and the whole world has diabetic 4.15 hundred million,
China diabetic is up to more than 100,000,000, and incidence is in increase trend year by year, wherein 90%~95% is (non-for diabetes B
Insulin-dependent diabetes mellitus, T2DM).The main harm of diabetes is the multisystem, more that hyperglycemia and insulin resistance induce
The generation of organ complication and fast development, wherein cardiovascular and cerebrovascular diseases account for 80% or more.T2DM is with hyperglycemia, hyperlipidemia and pancreas
The metabolism disturbance syndrome that insulin resistance is characterized is the common risk factor of the cardiovascular and cerebrovascular diseases such as atherosclerosis, sugar
It urinates the incidence such as hypertension, hyperlipidemia, coronary heart disease in patient and is far above non-diabetic people.
Diabetes are extremely closely related with glucose-lipid metabolism with cardiovascular and cerebrovascular diseases.Dyslipidemia is caused such as coronary heart disease, sugar
Urinate disease, an important pathogenic factor of myocardial infarction, cardiac sudden death and the medium disease of ischemic cerebral apoplexy.Clinical research confirmation,
Reduction total cholesterol (TC), triglycerides (TG) can prevent and reversal of atherosclerosis lesion, makes Incidence of CHD and disease
Dead rate is substantially reduced.It is hyperlipidemia and diabetes reciprocal causation, interrelated.The triglycerides, low of merging in diabetic more
The raised Combination disorders of lipid metabolism of density lipoprotein-cholesterol, hyperlipidemia incidence is up to 60%.Studies have shown that T2DM patient
Triglycerides and low-density lipoprotein cholesterol level are the risk factors of Future Cardiovascular Events, and triglyceride levels increase
Not only closely related with diabetes but also its variation can predict the onset risk of diabetes well.Studies have shown that baseline is high
Serum triglyceride level is the independent influencing factor of onset diabetes, and hyperlipidemia complication with diabetes coronary artery disease likelihood ratio is without height
The diabetic of pionemia is higher by 3 times.
Free fatty (FFA) level increases in most T2DM patient's blood.When FFA horizontal abnormalities increase more than fat in blood
The storage capacity and body of fat tissue are deposited in the form of triglycerides (TG) in non-fat tissue its oxidability.
FFA causes adipocyte glucose transport ability significantly to lower in the dystopy of muscle and liver organization deposition, and causes insulin
Sensibility reduces, and excessively deposition can trigger and accelerate islet beta-cell apoptosis in pancreas islet;Fatty group of FFA stimulation oversaturations accumulation
Knit the inflammatory factors such as generation and the excessive tumor necrosis factor α (TNF-α) of release, interleukin-6 (IL-6), these inflammation
The factor is combined with adipose tissue and other histiocytic receptors, the normal glycolipid metabolism of interference body;FFA makees in insulin
Target tissue such as liver, skeletal muscle excess accumulation leads to insulin resistance;Dystopy is deposited on beta Cell of islet and causes pancreas islet β thin
Born of the same parents are undermined insulin secretion obstacle, eventually lead to the generation and exacerbation of diabetes.
On the other hand, insulin comes regulating cell proliferation, differentiation except through metabolic signals access and growth signals access
Outside, also the metabolism of sugar, fat, protein is regulated and controled, under diabetic disease states, biological insulin Regulate signal access hinders
Hinder, the disorder of lipid-metabolism occur, abnormalities of sugar/lipid metabolism then occur, forms dyslipidemia;When poor blood glucose control, low-density
The activity of lipoprotein lipase will significantly reduce, and reduce the accretion rate of triglycerides, and serum triglyceride level increases, and finally leads
Cause diabetic keratopathy triglyceride.It can be seen that the level of insulin is in close relations with hyperlipidemia in vivo.
A large amount of clinical research prompts, improve the blood lipid level of diabetic, especially reduce triglycerides, can obviously change
The glycolipid exception of kind diabetic, generation and the progress for preventing and mitigating angiocardiopathy and other complication.It is clinical at present
Upper widely applied reducing blood lipid first-line drug is lipid-lowering statins, such as Simvastatin, Ah 's statin, and lipid-lowering statins
If owner reduces the conjunction of endogenous cholesterol by the rate-limiting enzyme HMG-CoA reductase of inhibition cholesterol biosynthesis
At being had no significant effect to triglycerides, and the risk of statins induced Diabetic increasingly draws attention.Due to high sweet
Outstanding role of oily three esters in the occurrence and development of diabetes and its complication, the fibrates drop characterized by reducing triglycerides
Fat medicine, such as Clofibrate, fenofibrate top grade, the advantage in diabetes and hyperlipidemia with diabetes treatment is increasingly subject to weight
Depending on.
Studies have shown that high sugar and it is high in fat can excite oxidative stress, generate excessive active chalcogen (ROS) and active nitrogen race
(RNS), lead to lipid peroxidation and blood vessel endothelium injury.Oxidative stress has been found to be diabetes and its complication occurrence and development
Common pathologic basis, anti-oxidant intervention is to treat the Critical policies of diabetes and its complication.
In the evolution of the metabolic diseases such as diabetes, hyperlipidemia, the metabolism such as hyperglycemia, hyperlipidemia and oxidative stress
Disorder is interweaved, and causes the cause of disease of metabolic disease and pathogenesis extremely complex, need by more targets, multipath it is dry
In advance, more single hypoglycemic or lipid-loweringing are more effective.
Invention content
The purpose of the present invention is to provide a kind of 3,4- dihydroxyphenyl ethanols fenofibrate acid esters and preparation method thereof and answer
There is apparent hypoglycemic activity with, the Hydroxytyrosol fenofibrate acid esters, at the same also have reduce cholesterol with
And oxidation resistant multiple activities.
The present invention is to be achieved through the following technical solutions:
The invention discloses a kind of Hydroxytyrosol fenofibrate acid esters, structural formula is as follows:
The invention also discloses the preparation methods of above-mentioned Hydroxytyrosol fenofibrate acid esters, by 3,4- dihydroxy
After 3, the 4- dihydroxy benzyl protections of benzyl carbinol, then with fenofibrate it is condensed into ester, is then taken off under the effect of hydrogen palladium carbon
Benzyl is removed, Hydroxytyrosol fenofibrate acid esters is made.
The preparation method of the Hydroxytyrosol fenofibrate acid esters, includes the following steps:
1) by Hydroxytyrosol, potassium carbonate and bromobenzyl at 50~60 DEG C, heating reflux reaction, after completion of the reaction
It filters, concentration, concentrate is subjected to column chromatography for separation;
2) take step 1) detach product, fenofibrate and 4-dimethylaminopyridine, be with n,N-Dimethylformamide
After stirring and dissolving, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides, room temperature are added into reaction system for solvent
Under be stirred to react, by reactant washing, dry, concentration;
3) product made from step 2) is dissolved in absolute ethyl alcohol, making catalyst with palladium carbon carries out hydrogenolysis, has reacted
It is filtered after finishing, concentration, concentrate is subjected to column chromatography for separation, Hydroxytyrosol fenofibrate acid esters is made.
In step 1), the reaction molar ratio of Hydroxytyrosol, potassium carbonate and bromobenzyl is 1:(4~6):(2~3);
In step 2), the reaction molar ratio of product, fenofibrate and 4-dimethylaminopyridine that step 1) detaches is 1:(1~2):
(0.2~0.4);In step 3), product made from step 2) is 1 with the molar ratio of reacting of palladium carbon:0.2~0.4.
Solvent used by step 1) column chromatography for separation is that petroleum ether and ethyl acetate press 4:1 volume ratio is formulated;
Solvent used by step 3) column chromatography for separation is that petroleum ether and ethyl acetate press 3:1 volume ratio is formulated.
Step 1) the heating reflux reaction time is for 24 hours;Step 2) is stirred to react the time as 12h at room temperature;Step 3) hydrogenolysis
Reaction time is for 24 hours.
The invention also discloses above-mentioned 3,4- dihydroxyphenyl ethanols fenofibrate acid esters in preparing antidiabetic medicine
Using.
The invention also discloses above-mentioned 3,4- dihydroxyphenyl ethanols fenofibrate acid esters prepare anti-diabetic merge it is high in fat
Application in the drug of mass formed by blood stasis.
The invention also discloses above-mentioned 3,4- dihydroxyphenyl ethanols fenofibrate acid esters to prepare treatment diabetic complication
Drug in application.
Compared with prior art, the present invention has technique effect beneficial below:
Hydroxytyrosol fenofibrate acid esters disclosed by the invention is a kind of novel more efficacy activity compounds,
It can be used to treat diabetes and hyperlipidemia, blood glucose and blood fat (triglycerides and cholesterol) can be reduced, and can
To Anti-lipid peroxidation, improve the oxidative stress effect under diabetes and hyperlipidemia state.
3,4- dihydroxyphenyl ethanols fenofibrate acid esters disclosed by the invention is to the hyperlipemia caused by Triton WR-1339
Disease mouse has significant effect for reducing blood fat, can obviously reduce the triglyceride levels and total cholesterol water of hyperlipemia in mice
It is flat;There is significant hypoglycemic activity to the diabetic mice caused by streptozotocin (STZ);And it shows apparent anti-oxidant
Effect.It is expected to become a kind of novel multifunctional treating diabetes and hyperlipidemia.
The invention also discloses the preparation methods of above-mentioned Hydroxytyrosol fenofibrate acid esters, by 3,4- dihydroxy
After 3, the 4- dihydroxy benzyl protections of benzyl carbinol, then with fenofibrate it is condensed into ester, is then taken off under the effect of hydrogen palladium carbon
Benzyl is removed, Hydroxytyrosol fenofibrate acid esters is made.The preparation method is easy to operate, low for equipment requirements, environment
It is friendly.
Description of the drawings
Fig. 1 is each group mouse blood sugar concentration (mmol/L) result figure, n=8;
Fig. 2 is each group mice plasma mda content (nmmol/L) result figure, n=8;
Fig. 3 is each group mice plasma total cholesterol level (nmmol/L) result figure, n=8;
Fig. 4 each group mice plasma content of triglyceride (nmmol/L) result figure, n=8.
Specific implementation mode
With reference to specific embodiment, the present invention is described in further detail, it is described be explanation of the invention and
It is not to limit.
The present invention provides a kind of new compound 3,4- dihydroxyphenyl ethanol fenofibrate acid esters (HT-Fen) and its prepares
Method, the present invention also provides the compounds to prepare the purposes for treating diabetes and hyperlipidemia.
The present invention discloses a kind of new compound Hydroxytyrosol fenofibrate acid esters (I), the entitled 2- first of chemistry
Base -2- [4- (4- chlorobenzene formacyls) phenoxy group] propionic acid -2- (3,4- dihydroxy phenyl) ethyl ester, referred to as 3,4- dihydroxy benzenes second
Alcohol fenofibrate acid esters (hydroxytyrosol fenofibric ester, HT-Fen).
The hypoglycemic effect of HT-Fen of the present invention is by HT-Fen to diabetic mouse model caused by streptozotocin (STZ)
Hypoglycemic effect realize;The antioxidation of HT-Fen is by reducing diabetic mice mould caused by streptozotocin (STZ)
The lipid peroxidation product MDA of type is realized;The effect for reducing fat of HT-Fen is by HT-Fen to high caused by Triton WR-1339
The effect for reducing blood fat of piarhemia disease mouse model is realized.
The preparation method of novel compound of present invention HT-Fen is:(1) by hydroxytyrosol, bromobenzyl, potassium carbonate, acetone is molten
Agent is reacted under 55 DEG C of heating conditions, and reaction finishes, and is filtered, concentration.Pass through column chromatography (solvent:Petroleum ether and ethyl acetate)
Detach benzyl protection hydroxytyrosol;(2) by the hydroxytyrosol of benzyl protection, fenofibrate and 4-dimethylaminopyridine
(DMAP) flask is added together, n,N-Dimethylformamide (DMF) is added, 1- (3- dimethylaminos third are added after stirring 5min
Base) -3- ethyl-carbodiimide hydrochlorides (EDCHCl) stir at room temperature, reaction finishes, reactant with 5% NaHCO3Solution
Washing 2 times, saturated common salt water washing 2 times, anhydrous Na2SO4It is dry, concentration;(3) step (2) concentrate is dissolved in absolute ethyl alcohol
In, palladium carbon makees catalyst, hydrogenolysis, and reaction finishes, and filters, concentration.Pass through column chromatography (solvent:Petroleum ether and acetic acid second
Ester) detach to obtain product.
It is as follows:
Experiment material and instrument
Material:Streptozotocin (Streptozocin, STZ, Sigma Co., USA), fenofibrate (the farsighted health of Wuhan letter
Reagent Co., Ltd), Xi Gelieting (Wuhan Hong Ruikang reagents Co., Ltd), HT-Fen, monohydrate potassium, two citrate hydrates
Sour trisodium is that analysis is pure.
Instrument:Stable blood glucose meter and mating blood sugar test paper (Sinocare Biosensing Co., Ltd) are purple
Outside-visible spectrophotometer etc..
Animal:Kunming mice (20.0 ± 2.0g).
Embodiment 1:The preparation of HT-Fen
Hydroxytyrosol (1.00g, 6.50mmol), potassium carbonate (3.60g, 26.09mmol) are dissolved in acetone
In (25mL), bromobenzyl (1.40ml, 14.95mmol) is added, for 24 hours, reaction finishes heating reflux reaction, filters, concentration.Column chromatography
Detach (solvent:Petroleum ether and ethyl acetate) 3,4- benzyloxy benzyl carbinol faint yellow solid 1.46g are obtained, yield is
67.12%.
3,4- benzyloxy benzyl carbinols (1.00g, 3.26mmol), fenofibrate (1.56g, 4.89mmol) and DMAP
(0.08g, 0.65mmol) is added in DMF (20mL), EDCHCl (0.94g, 4.89mmol) is added after stirring 5min, at room temperature
Stirring, lamellae detection, reaction finishes, reactant with 5% NaHCO3Solution and saturated salt solution wash 2 times successively, anhydrous
Na2SO4Dry, concentration obtains yellow oil 2.13g, direct plunges into and reacts in next step.
Above-mentioned gained yellow oil is dissolved with absolute ethyl alcohol (25ml), logical hydrogen hydrogenolysis under palladium carbon (0.22g) catalysis,
For 24 hours, reaction finishes for room temperature reaction, filters, concentration.Column chromatography for separation (solvent:Petroleum ether and ethyl acetate), obtain faint yellow oil
Shape HT-Fen 1.08g, yield 72.97%.
Nuclear magnetic resoance spectrum diagram data:1H NMR(400MHz,CDCl3)δ7.27(m,1H),7.16(m,3H),7.00(m,
2H), 6.73~6.63 (m, 4H), 6.54 (m, 1H), 6.06 (s, 1H), 5.99 (s, 1H), 4.30 (t, J=7.0Hz, 2H),
2.76 (t, J=7.0Hz, 2H), 1.52 (s, 6H).
Embodiment 2:The hypoglycemic effect and antioxidation of HT-Fen
The preparation of 0.1mmol/L pH4.5 citrate buffer solutions:
The preparation (0.1mol/L aqueous citric acid solutions) of A liquid:Distilled water is added to 100ml in citric acid 2.10g.B liquid is matched
It makes (0.1mol/L trisodium citrate aqueous solutions):Trisodium citrate 2.94g adds distilled water to 100ml.0.1mol/L citric acid waters
By volume the 1 of solution and 0.1mol/L trisodium citrate aqueous solutions:1.44 are mixed, you can preparation forms 0.1mmol/L
PH4.5 citrate buffer solutions.
STZ solution is prepared:It is dissolved with 4.5 citrate buffer solutions of 0.1mmol/LpH, is configured to the solution of 20mg/ml, ice
Bath, is protected from light, and has been injected in half an hour.
The foundation of diabetic mouse model:Mouse adaptable fed 3d, fasting 12h, intraperitoneal injection STZ (use 0.1mol/
L, pH4.5 citrate buffer solution, 200mg/kg) fasting after 72h, free water.Blood glucose is surveyed after fasting 6h, and blood glucose is selected to be more than
16.0mmol/L, and it is diabetic mice more drinks, more foods, weight loss occur.
The hypoglycemic drug effect of diabetic mice is studied
Diabetic mice is taken, weigh respectively and measures fasting blood sugar, according to principle similar in weight, blood glucose value point
It is 3 groups:Model group, Xi Gelieting groups, HT-Fen groups, then take one group of normal mouse for blank group, every group 8:1. blank group fills
Stomach gives distilled water;2. model group, gavage gives distilled water;3. Xi Gelieting groups, gavage gives Xi Gelieting 13mg/kg;④
HT-Fen groups, gavage give HT-Fen16.4mg/kg.Remaining point in addition to normal group and model group gavage are given and wait dosage distilled water
Other gastric infusion, 1 time a day, continuous 8d, 7d administration after be deprived of food but not water 6h after each group mouse docking surveyed with Instrument for Measuring Blood Sugar
Determine blood glucose value, each group mouse plucks eyeball and takes whole blood after the 8th day administration 6h, and whole blood, which is placed on ice bath, stands 1h, 5000r/min centrifugations
15min obtains blood plasma, and plasma malonaldehyde content is measured according to kit method.
Dosage determines dosage according to conversion formula:
Experimental result:Each group mouse blood sugar concentration is shown in Table 1 and Fig. 1;Each group mice plasma MDA contents are shown in Table 2 and Fig. 2.
1 each group mouse blood sugar concentration (mmol/L) (n=8) of table
Note:* indicate that the P < 0.05 compared with model group, ## indicate that the P < 0.01 compared with blank group, △ are indicated and west
Ge Lieting groups compare P > 0.05.
It can show that compound F-HT can significantly reduce the blood glucose of diabetic mice from the analysis of table 1 and Fig. 1, there is drop
Blood glucose activity.
2 each group mice plasma mda content (nmmol/L) (n=8) of table
Note:# indicates that the P > 0.05 compared with blank group, ## indicate the P < 0.01 compared with blank group, and * * are indicated and mould
Type group compares P < 0.01.
It can be obtained from the analysis of table 2 and Fig. 2, compound F-HT can reduce containing for malonaldehyde in diabetic mice body
Amount, while playing the effect of anti-oxidation stress in diabetic model group.
Embodiment 3:The effect for reducing fat of HT-Fen
Mouse adaptable fed 3d is randomly divided into every group of 4 groups (blank group, model group, HT-Fen groups, fenofibrate group)
8:1. Normal group, gavage gives distilled water;2. model group, gavage gives distilled water;3. F-HT groups, gavage give F-HT
16.4mg/kg;4. fenofibrate group, gavage gives fenofibrate 11.5mg/kg.Except Normal group and model group gavage
Give equal dosage distilled water remaining outer difference gastric infusion, one time a day, continuous 7d, the 18h before last dose remove normal control
Group is outer, remaining each group tail vein injection Triton WR-1339 400mg/kg.
Dosage determines dosage according to conversion formula:
In 6h after the last administration, each group mouse plucks eyeball and takes blood, and the whole blood being collected into stands 1h on ice bath, then
5000r/min centrifugations 15min obtains blood plasma, then measures total plasma cholesterol respectively according to kit method, triglycerides contains
Amount and plasma malonaldehyde content.
Experimental result:Each group mice plasma total cholesterol and content of triglyceride are shown in Table 3 and Fig. 3, Fig. 4;Each group mouse blood
Slurry mda content is shown in Table 2 and Fig. 2.
3 each group mice plasma total cholesterol of table and content of triglyceride (mmol/L) (n=8)
Note:* indicate that the P < 0.05 compared with model group, ## indicate the P < 0.01 compared with blank group
It can be obtained from the analysis of table 3, Fig. 3 and Fig. 4, total courage that compound HT-Fen can reduce hyperlipemia in mice is solid
Alcohol and content of triglyceride have the activity for reducing total cholesterol and triglycerides.
To sum up, compound Hydroxytyrosol fenofibrate acid esters (HT-Fen) provided by the invention, has
The multiple activities of hypoglycemic, reducing blood lipid and anti-oxidation stress.
Claims (7)
1.3,4- dihydroxyphenyl ethanol fenofibrate acid esters, which is characterized in that its structural formula is as follows:
2. the preparation method of Hydroxytyrosol fenofibrate acid esters described in claim 1, which is characterized in that including with
Lower step:
1) by Hydroxytyrosol, potassium carbonate and bromobenzyl at 50~60 DEG C, heating reflux reaction for 24 hours, after completion of the reaction
It filters, concentration, concentrate is subjected to column chromatography for separation;
2) product, fenofibrate and the 4-dimethylaminopyridine for taking step 1) to detach, using n,N-Dimethylformamide as solvent,
After stirring and dissolving, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides are added into reaction system, stir at room temperature
12h is reacted, by reactant washing, dry, concentration;
3) product made from step 2) is dissolved in absolute ethyl alcohol, catalyst hydrogenolysis is made for 24 hours with palladium carbon, is taken out after completion of the reaction
Filter, concentration, column chromatography for separation is carried out by concentrate, and Hydroxytyrosol fenofibrate acid esters is made.
3. the preparation method of Hydroxytyrosol fenofibrate acid esters according to claim 2, which is characterized in that step
It is rapid 1) in, the reaction molar ratio of Hydroxytyrosol, potassium carbonate and bromobenzyl is 1:(4~6):(2~3);In step 2), step
The product, fenofibrate of rapid 1) separation and the reaction molar ratio of 4-dimethylaminopyridine are 1:(1~2):(0.2~0.4);Step
It is rapid 3) in, the molar ratio of reacting of product made from step 2) and palladium carbon is 1:0.2~0.4.
4. the preparation method of Hydroxytyrosol fenofibrate acid esters according to claim 2, which is characterized in that step
Solvent used by rapid 1) column chromatography for separation is that petroleum ether and ethyl acetate press 4:1 volume ratio is formulated;Step 3) column layer
Solvent used by analysis separation is that petroleum ether and ethyl acetate press 3:1 volume ratio is formulated.
5. application of the 3,4- dihydroxyphenyl ethanols fenofibrate acid esters described in claim 1 in preparing antidiabetic medicine.
6. 3,4- dihydroxyphenyl ethanols fenofibrate acid esters described in claim 1 is preparing anti-diabetic merging hyperlipidemia
Application in drug.
7. 3,4- dihydroxyphenyl ethanols fenofibrate acid esters described in claim 1 is in the drug for preparing treatment diabetic complication
In application.
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