阅读说明：本技术 一种α-葡萄糖苷酶抑制剂及其合成方法与应用 (A kind of alpha-glucosidase restrainer and its synthetic method and application ) 是由 盛钊君 陈小乐 简荣超 唐小文 李钰铃 吴盼盼 张焜 于 2019-09-20 设计创作，主要内容包括：本发明公开了一种α-葡萄糖苷酶抑制剂及其合成方法与应用；旨在提供一种具有较好降血糖作用的α-葡萄糖苷酶抑制剂；其结构式为：<Image he="305" wi="373" file="DDA0002208649080000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>R1选自H或者CH3；R2选自<Image he="222" wi="700" file="DDA0002208649080000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>属于医药技术领域。(The invention discloses a kind of alpha-glucosidase restrainer and its synthetic method and applications；It is intended to provide a kind of alpha-glucosidase restrainer with preferable hypoglycemic effect；Its structural formula are as follows: R1 is selected from H or CH3；R2 is selected from Belong to pharmaceutical technology field.)

1. a kind of alpha-glucosidase restrainer, which is characterized in that its structural formula is as shown in Equation 1:

Wherein:

R₁Selected from one of following substituent groups:

H、CH₃；

R₂Selected from one of following substituent groups:

Above-mentioned n are as follows: 1~15.

2. the synthetic method of alpha-glucosidase restrainer described in claim 1, which is characterized in that successively include following steps It is rapid:

1) by 2,5 dihydroxy-Isosorbide-5-Nitrae benzoquinones is dissolved in polar organic solvent, and inorganic acid is slowly added dropwise, and is stirred at room temperature 8~15 small When, then filter the intermediate product 1 for being concentrated to get yellow solid；

Wherein the molar ratio of -1,4 benzoquinones of 2,5 dihydroxy of compound and inorganic acid is 1:1~5；

2) gained intermediate product 1 is soluble in water, sodium dithionite is added, at 80~120 DEG C, 8~15 points of reaction reflux Clock, the crystallisation by cooling at -4~4 DEG C, suction filtration obtain the crystalline intermediate product 2 of white powder；

Wherein the molar ratio of the intermediate product 1 and sodium dithionite is 1:1~5；

3) intermediate product 2 is dissolved in organic solvent, inorganic base is added by the pH of reaction solution and is adjusted to 8~9, is stirred at room temperature 15~30 Minute, iodomethane is added dropwise, is stirred at room temperature 8~15 hours；Reaction solution adjusts pH to 5~6 with inorganic acid solution, and use is organic After solvent extraction, merge organic phase, then successively uses distilled water, saturated common salt water washing, it is dry, it is concentrated under reduced pressure, gained crude product Column purification is crossed, White crystal intermediate A is obtained；

Wherein the intermediate product 2, inorganic base, iodomethane molar ratio be 1:1~5:1~5；

4) compound A is put into round-bottomed flask, is placed in a vacuum drying oven and dries 15~30 minutes, addition HMPA, ventilation 2~ It 5 times, adds tetrahydrofuran and makees solvent, anhydrous and oxygen-free reacts 5~15 minutes at -50 DEG C~-30 DEG C, is slowly added to normal-butyl Lithium adjusts the temperature to -15 DEG C~-5 DEG C and reacts 40~80 minutes, bromo-hydrocarbons is added dropwise, the reaction was continued 5~15 minutes；It is placed in Room temperature reaction 10~15 hours；Be concentrated under reduced pressure to give crude product, after organic solvent dissolution, with inorganic acid solution adjust pH to 5~ 6, organic phase successively uses distilled water, saturated common salt water washing, dry, is concentrated under reduced pressure, and gained crude product crosses column purification, obtains oily Intermediate B；

Wherein the intermediate A, HMPA, n-BuLi, bromo-hydrocarbons molar ratio be 1:0.3~0.5:1~1.5:1~1.5；

5) intermediate B is dissolved in organic solvent, ammonium ceric nitrate is dissolved with a certain proportion of aqueous organopolysiloxane, in -10 DEG C~2 DEG C ice Ammonium ceric nitrate is added dropwise in salt bath in intermediate B, stirs 10 minutes；It reacts 1~2 hour at room temperature；It is concentrated under reduced pressure To crude product, after being dissolved with organic solvent, distilled water, saturated common salt water washing are successively used, it is dry, it is concentrated under reduced pressure, gained slightly produces Product cross column purification, obtain solid articles C and D；

Wherein the intermediate B, the molar ratio of ammonium ceric nitrate are 1:2~4, and the ratio of organic solvent and water is 8/1~7/3；

6) finished product C or D are dissolved in Organic Alcohol, sodium hydroxide is added, evaporation reflux 1.5~2.5 hours, subtract at 70 DEG C~90 DEG C Pressure concentration, organic solvent dissolution, with inorganic acid for adjusting pH value to 5~6, organic phase successively uses distilled water, saturated common salt water washing, It is dry, it is concentrated under reduced pressure, gained crude product is rinsed with low polar organic solvent and filtered, and final product E is obtained；

Wherein the molar ratio of the finished product C or D and inorganic base is 1:40~50.

3. the synthetic method of alpha-glucosidase restrainer according to claim 2, which is characterized in that described in step 1) Inorganic acid is concentrated hydrochloric acid or the concentrated sulfuric acid.

4. the synthetic method of alpha-glucosidase restrainer according to claim 2, which is characterized in that step 3), step 4), inorganic acid described in step 6) is dilute hydrochloric acid or saturated ammonium chloride.

5. the synthetic method of alpha-glucosidase restrainer according to claim 2, which is characterized in that described in step 3) Inorganic base is sodium hydroxide or potassium hydroxide.

6. the synthetic method of alpha-glucosidase restrainer according to claim 2, which is characterized in that step 1), step 2), step 3), step 4), step 5), organic solvent described in step 6) are ethyl acetate or methylene chloride.

7. the synthetic method of alpha-glucosidase restrainer according to claim 2, which is characterized in that the bromo-hydrocarbons For the bromo- 3- methybutane of 1- or the bromo- 3,7- dimethyl octane of 1- or the bromo- 7- phenylheptan of 1- or 2- bromoethyl hexamethylene or 2- (bromomethyl) naphthalene.

8. alpha-glucosidase restrainer described in claim 1 is as the application for preparing hypoglycemic drug or health care product.

Technical field

The invention belongs to pharmaceutical technology fields, and in particular to a kind of alpha-glucosidase restrainer and its synthetic method with answer With.

Background technique

According to international diabetic tissue, global diabetic is up to 5.52 hundred million people in the year two thousand thirty, it has also become after After tumour and cardiovascular and cerebrovascular diseases, the third-largest chronic disease for seriously threatening human life and health.Which results in medical expense and The increase of related social concern.Diabetes it is most fearful be its cause complication, fall ill it is in extensive range, almost spread whole body Each histoorgan, and the course of disease is long, it is refractory more, and it is lethal, disability rate is very high.

According to pathogenesis difference, diabetes are divided into type-1 diabetes mellitus (insulin-dependent), type-2 diabetes mellitus (non-pancreas islet Plain dependent form) and gestational diabetes mellitus, wherein type 2 diabetes patient's number accounts for the 90% of diabetic's sum.In current doctor In the case that treatment level also fundamentally can not cure diabetes, the increasing of diabetic will gradually expand diabetes use The market scale of medicine.Diabetic mainly includes oral hypoglycemic agents, insulin and the like.For Most patients Speech, oral hypoglycemic agents is economic, practical, convenient therapeutic scheme.Oral hypoglycemic agents mainly has four major class: (1) insulin sensitivity enhancing Agent class；(2) agent class is secreted in insulin increasing；(3) the similar species of amino acid；(4) alpha-glucosidase inhibitor.

Alpha-glucosidase restrainer is a kind of effective oral hypoglycemic agents, can be with the alpha-glucosidase in small intestine Central active position combines, and suppresses the performance of enzymatic activity, and retardance disaccharide is hydrolyzed to monosaccharide, prolongs to eat to reduction after soak time Hyperglycemia plays beneficial effect afterwards.Alpha-glucosidase restrainer is in addition to the prevention to diabetes and diabetic complication and controls Treatment has outside good effect, moreover it is possible to albumen and lipid be inhibited to glycosylate.But inhibit currently used for clinical alpha-glucosidase , all there is different degrees of adverse reaction, such as abdominal distension, borborygmus, abdomen in agent (acarbose, voglibose and Miglitol) Bitterly, diarrhea.Therefore, new less toxic, efficient alpha-glucosidase restrainer is developed increasingly to be valued by people.

Summary of the invention

In view of the above-mentioned problems, the first purpose of the invention is to provide a kind of phloroses with preferable hypoglycemic effect Glycosides enzyme inhibitor.

A second object of the present invention is to provide the synthetic methods of above-mentioned inhibitor.

Third object of the present invention is to provide the applications of above-mentioned inhibitor.

In view of the above-mentioned problems, first technical solution provided by the invention is such that

A kind of alpha-glucosidase restrainer, structural formula are as shown in Equation 1:

Wherein: R₁Selected from one of following substituent groups:

H、CH₃；

R₂Selected from one of following substituent groups:

Above-mentioned n are as follows: 1~15.

Second technical solution of the invention is to provide the synthetic method of the alpha-glucosidase restrainer, and this method is successively Include the following steps:

1) by 2,5 dihydroxy-Isosorbide-5-Nitrae benzoquinones is dissolved in polar organic solvent, and inorganic acid is slowly added dropwise, is stirred at room temperature 8~15 Then a hour filters the intermediate product 1 for being concentrated to get yellow solid；

The molar ratio of -1,4 benzoquinones of 2,5 dihydroxy of compound, inorganic acid described in wherein is 1:1~5；

2) gained intermediate product 1 is soluble in water, sodium dithionite is added, at 80~120 DEG C, reaction reflux 8~ 15 minutes, the crystallisation by cooling at -4~4 DEG C, suction filtration obtained the crystalline intermediate product 2 of white powder；

Wherein the molar ratio of the intermediate product 1 and sodium dithionite is 1:1~5；

3) intermediate product 2 is dissolved in organic solvent, inorganic base is added by the pH of reaction solution and is adjusted to 8~9, is stirred at room temperature 15 ~30 minutes, iodomethane is added dropwise, is stirred at room temperature 8~15 hours.Reaction solution adjusts pH to 5~6 with inorganic acid solution, uses After organic solvent extraction, merge organic phase, then successively uses distilled water, saturated common salt water washing, it is dry, it is concentrated under reduced pressure, gained is thick Product crosses column purification, obtains White crystal intermediate A；

Wherein the intermediate product 2, inorganic base, iodomethane molar ratio be 1:1~5:1~5；

4) intermediate A is put into round-bottomed flask, is placed in a vacuum drying oven drying 15~30 minutes, HMPA is added, changes It gas 2~5 times, adds tetrahydrofuran and makees solvent, anhydrous and oxygen-free reacts 5~15 minutes at -50 DEG C~-30 DEG C, is slowly added to N-BuLi, adjust the temperature to -15 DEG C~-5 DEG C react 40~80 minutes, bromo-hydrocarbons is added dropwise, the reaction was continued 5~15 points Clock.It is placed in room temperature reaction 10~15 hours.Crude product is concentrated under reduced pressure to give to be adjusted after organic solvent dissolution with inorganic acid solution PH to 5~6, organic phase successively use distilled water, saturated common salt water washing, dry, are concentrated under reduced pressure, and gained crude product crosses column purification, Obtain oily intermediate B；

Wherein the intermediate A, HMPA, n-BuLi, bromo-hydrocarbons molar ratio be 1:0.3~0.5:1~1.5:1~ 1.5；

5) intermediate B is dissolved in organic solvent, ammonium ceric nitrate is dissolved with a certain proportion of aqueous organopolysiloxane, -10 DEG C~2 Ammonium ceric nitrate is added dropwise in compound B in DEG C ice salt bath, stirs 10 minutes.It reacts 1~2 hour at room temperature.It depressurizes dense Contracting obtains crude product, after being dissolved with organic solvent, successively uses distilled water, saturated common salt water washing, dry, is concentrated under reduced pressure, gained Crude product crosses column purification, obtains solid articles C and D；

Wherein the intermediate B, the molar ratio of ammonium ceric nitrate are 1:2~4, and the ratio of organic solvent and water is 8/1~7/ 3；

6) finished product C or D are dissolved in Organic Alcohol, sodium hydroxide is added, evaporation reflux 1.5~2.5 is small at 70 DEG C~90 DEG C When, it is concentrated under reduced pressure, organic solvent dissolution, with inorganic acid for adjusting pH value to 5~6, organic phase successively uses distilled water, saturated salt solution Washing, it is dry, it is concentrated under reduced pressure, gained crude product is rinsed with low polar organic solvent and filtered, and final product E is obtained；

Wherein the molar ratio of the finished product C or D and inorganic base is 1:40~50.

Preferably, the synthetic method of above-mentioned alpha-glucosidase restrainer, inorganic acid described in step 1) be concentrated hydrochloric acid, The concentrated sulfuric acid.

Preferably, the synthetic method of above-mentioned alpha-glucosidase restrainer, step 3), step 4), described in step 6) Inorganic acid is dilute hydrochloric acid or saturated ammonium chloride.

Preferably, the synthetic method of above-mentioned alpha-glucosidase restrainer, inorganic base described in step 3) are hydroxide Sodium or potassium hydroxide.

Preferably, the synthetic method of above-mentioned alpha-glucosidase restrainer, step 1), step 2), step 3), step 4), step 5), organic solvent described in step 6) are ethyl acetate or methylene chloride.

Preferably, the synthetic method of above-mentioned alpha-glucosidase restrainer, the bromo-hydrocarbons are the bromo- 3- methyl fourth of 1- Alkane or the bromo- 3,7- dimethyl octane of 1- or the bromo- 7- phenylheptan of 1- or 2- bromoethyl hexamethylene or 2- (bromomethyl) naphthalene.

Final object of the present invention is to provide above-mentioned alpha-glucosidase restrainer as hypoglycemic drug or guarantor The application of strong product.

Compared with prior art, technical solution provided by the invention have following technological merit: the product by by naturally Lai The compound in source is prepared by structure of modification modification reaction, safer.The product has preferable suppression to alpha-glucosidase System activity, has a good application prospect in medicine, health care, field of food.

Detailed description of the invention

Fig. 1 is intermediate A¹HNMR detects spectrogram；

Fig. 2 is intermediate B 1¹HNMR detects spectrogram；

Fig. 3 is finished product E1¹HNMR detects spectrogram；

Fig. 4 is intermediate B 2¹HNMR detects spectrogram；

Fig. 5 is finished product E2¹HNMR detects spectrogram；

Fig. 6 is intermediate B 3¹HNMR detects spectrogram；

Fig. 7 is finished product E3¹HNMR detects spectrogram；

Fig. 8 is depression effect analysis chart of the finished product E1 and E3 to alpha-glucosidase；

Fig. 9 is suppression mechanism analysis chart of the finished product E1 and E3 to alpha-glucosidase；

Figure 10 is inhibition dynamics analysis chart of the finished product E1 to alpha-glucosidase；

Figure 11 is inhibition dynamics analysis chart of the finished product E3 to alpha-glucosidase.

Specific embodiment

In order to be more clear the purpose of the present invention, technical solution and advantageous effects, with reference to embodiments, to this Invention is further elaborated.It should be understood that embodiment described in this specification is just for the sake of this hair of explanation It is bright, be not intended to limit the present invention, the parameter of embodiment, ratio can adaptation to local conditions make a choice and substantive shadow had no to result It rings.