CN107746385A

CN107746385A - A kind of preparation method of Miglitol

Info

Publication number: CN107746385A
Application number: CN201711042774.0A
Authority: CN
Inventors: 帅棋; 宋平原; 生英涛; 储消和; 苏为科; 吴杰群
Original assignee: Zhejiang University of Technology ZJUT
Current assignee: Zhejiang University of Technology ZJUT
Priority date: 2017-10-31
Filing date: 2017-10-31
Publication date: 2018-03-02

Abstract

The invention discloses a kind of preparation method of Miglitol, it is raw material from the hydroxyethylamino α L sorboses of 6 deoxidation 6, alcoholic solvent is added, in presence of hydrogen, catalytic hydrogenation is carried out under the conditions of certain pressure, then through press filtration, concentration, crystallize, filter, washing, is dried in vacuo to obtain miglitol crystal.7 ~ 8 hours its reaction time, 20 ~ 30 DEG C of temperature, yield are more than 90%, and purity is more than 99% (HPLC detections).Agents useful for same green pollution-free, economical and practical, reaction yield is high, simple to operate, suitable for industrialized production.

Description

A kind of preparation method of Miglitol

Technical field

The present invention relates to a kind of preparation method of compound, and in particular to the system of type II diabetes medicine Miglitol Preparation Method.

Background technology

Miglitol (Miglitol) is antidiabetic thing of the Beyer Co., Ltd in the listing of 1997 years.It is from bar A kind of new enteron aisle α-heteroside enzyme inhibitor found in bacterium broth bouillon, it is the parent modification production of 1-DNJ Thing, belongs to N- substituted-1-deoxynojirimycin types, and structure is similar to glucose.Entitled 1- (the 2- ethoxys) -2- (hydroxyls of chemistry Methyl) -3,4,5- piperidines triols；Fusing point：146 DEG C, and optical activity [α] D20=- 8 (C, 1, CH₃OH), structural formula is as follows：

Diabetes are diseases caused by a kind of most commonly seen endocrine metabolism is lacked of proper care, and are broadly divided into type i diabetes and II type sugar Urine is sick (adult-onset diabetes, NIDD).Wherein, and based on type II diabetes.The treatment means of diabetes at present Mainly include:Dietary therapy, exercise therapy, oral hypoglycemic drug and subcutaneous insulin injections etc..The conventional type glycosuria for the treatment of II Medicine mainly has sulfonylurea, biguanides, alpha-glucosidase inhibitor etc..Sulfonylurea mainly stimulates B cell to release Insulin is put, but such drug side-effect is larger, and hypoglycemia, gastrointestinal reaction, stomachache, liver damage and serious body weight can be caused to increase Add.Biguanides is chiefly to facilitate uptake and utilization of the muscle to glucose, suppresses gluconeogenesis, it is easy to liver and kidney disease patient Cause lactic acidosis.Alpha-glucosidase inhibitor has a variety of pharmacological activity, and hypoglycemic effect is notable, Small side effects, is Treat efficient, the safe drugs of type II diabetes.

As a kind of new Alpha-glucosidase inhibitor, Miglitol (Miglitol) can Reverse transcriptase α-glucoside Enzyme, the metabolism of saccharide compound is reduced, reduce absorption of the carbohydrate in small intestine, so as to stable plasma glucose concentration after meal.The medicine Thing is safe and effective, and general tolerance is good, and oneself turns into the choice drug for the treatment of type II diabetes.

The Miglitol synthesis technique reported at present mainly has：Chemical complete synthesizing process (Tetrahedron Lett., 2000,41,7313), the method complex steps, accessory substance is more, and purifying is more difficult；Utilize gucosamine or N- substitutions Portugal Grapes glucosamine is that raw material prepares Miglitol (EP49858, DE3024901, EP55431), and the method is not directed to gucosamine or N- Substitute the preparation of gucosamine；By tetrahydrofuran sugar derivatives Miglitol is synthesized through borohydride reduction (US4611058), the method yield is relatively low, and synthesis cost is too high, is not suitable for industrialized production.

The content of the invention

For the above-mentioned problems in the prior art, present invention aims at provide a kind of preparation of new Miglitol Method.This method is raw material from 6- deoxidation -6- hydroxyethylamino-α-L- sorboses, adds alcoholic solvent, in presence of hydrogen, Catalytic hydrogenation is carried out under the conditions of certain pressure, then through press filtration, concentrates, crystallizes, filter, washing, be dried in vacuo get meter Ge Row alcohol crystals.7 ~ 8 hours its reaction time, 20 ~ 30 DEG C of temperature, yield are more than 90%, and purity is more than 99% (HPLC detections).It is used Reagent green pollution-free, economical and practical, reaction yield is high, simple to operate, suitable for industrialized production.

The preparation method of described a kind of Miglitol, it is characterised in that with 6- deoxidation -6- hydroxyl second in autoclave Base amino-α-L- sorbose cell tranquillization liquid is raw material, under solid catalyst effect, adds alcohols solvent, is passed through hydrogen and enters Row catalytic hydrogenation, react after terminating through press filtration, concentrate, crystallize, filter, washing, be dried in vacuo to obtain miglitol crystal, 6- Deoxidation -6- hydroxyethylamino-α-L- sorboses cell tranquillization liquid by 6- deoxidation -6- hydroxyethylamino-α-L- sorboses ferment, from The heart, collection obtain.

The preparation method of described a kind of Miglitol, it is characterised in that alcohols solvent is in methanol, ethanol, isopropanol One or more mixtures.

The preparation method of described a kind of Miglitol, it is characterised in that solid catalyst is in Raney's nickel, palladium carbon, platinum carbon One kind.

A kind of preparation method of described Miglitol, it is characterised in that 6- deoxidation -6- hydroxyethylamino-α-L- sorboses Cell tranquillization liquid is 10 with alcohols solvent volume rate of charge：1.

A kind of preparation method of described Miglitol, it is characterised in that 6- deoxidation -6- hydroxyethylamino-α-L- sorboses The volume of cell tranquillization liquid and the mass ratio of catalyst are 1:0.003-0.005, it is preferably 1：0.004, volume unit ml, Mass unit is g.

The preparation method of described a kind of Miglitol, it is characterised in that temperature is 20~30 DEG C, and the reaction time 7~8 is small When.

The preparation method of described a kind of Miglitol, it is characterised in that reaction pressure is 1-2 MPa.

A kind of preparation method of described Miglitol, it is characterised in that reaction end by TLC detect or HPLC detect to 6- deoxidation -6- hydroxyethylamino-α-L- sorboses disappear, and the adsorbent volume ratio of TLC detections is 4:1:2 n-butanol：Second Acid：Water, developed the color by ninhydrin.

Its reaction equation is as follows：

。

The preparation method of the Miglitol of the present invention, it is quiet from 6- deoxidation -6- hydroxyethylamino-α-L- sorbose cells Breath liquid is raw material, adds alcoholic solvent, in presence of hydrogen, catalytic hydrogenation is carried out under the conditions of certain pressure, then through press filtration, Concentration, crystallize, filter, washing, be dried in vacuo to obtain miglitol crystal.7 ~ 8 hours its reaction time, 20 ~ 30 DEG C of temperature, yield More than 90%, purity is more than 99% (HPLC detections).Agents useful for same green pollution-free, economical and practical, reaction yield is high, operation It is simple and convenient, suitable for industrialized production.

Embodiment

Illustrate technical scheme, but protection scope of the present invention not limited to this below by way of specific embodiment：

Embodiment 1

In 1L autoclaves, add 400 ml 6- deoxidation -6- hydroxyethylamino-α-L- sorbose cell tranquillization liquid and (contain 6- 40 grams of deoxidation -6- hydroxyethylamino-α-L- sorboses), 40 ml ethanol, (aqueous 50%), is replaced 1.6 gram of 10% Pd/C with hydrogen Air, the MPa of pressure 1 ~ 1.5 is maintained, 25 DEG C of temperature, is reacted 7 hours, N₂Press filtration removes palladium carbon (being used for next batch reaction), dense Contracting, alcohol crystal, filter, washing, vacuum drying obtains 34 grams of miglitol crystal, and yield 92%, (HPLC is examined purity 99.1% Survey).

The collection of illustrative plates of miglitol crystal characterizes：¹H NMR (600 MHz, D₂O-d ₆) δ: 3.81 (ddd, J ₁= 2.4 Hz, J ₂= 14.4Hz, J ₃= 15.6 Hz, 2H), 3.71~3.64 (m, 2H), 3.49~3.45 (m, 1H), 3.30 (t, J= 9 Hz, 1H), 3.20 (t, J= 9 Hz, 1H), 3.03~3.00 (m, 1H), 2.90~2.86 (m, 1H), 2.68~2.64 (m, 1H), 2.31~2.24 (m, 2H); ¹³C NMR (100MHz, D₂O-d ₆) δ: 78.23, 69.92, 68.70, 65.55, 57.86, 57.56, 56.04, 52.76; MS (ESI): m/z= 208.1[M+H]⁺。

Embodiment 2

In 1L autoclaves, add 400 ml 6- deoxidation -6- hydroxyethylamino-α-L- sorbose cell tranquillization liquid and (contain 6- 40 grams of deoxidation -6- hydroxyethylamino-α-L- sorboses), 200 ml methanol, 4 grams of Raney's nickels, with hydrogen displaced air, maintain pressure The MPa of power 1 ~ 2,27 DEG C of temperature, react 8 hours, N₂Press filtration removes Raney's nickel (being used for next batch reaction), concentrates, alcohol crystal, Filter, vacuum drying obtains 35 grams of miglitol crystal, yield 94%, purity 99.0% (HPLC detections).

Embodiment 3

In 1L autoclaves, add 400 ml 6- deoxidation -6- hydroxyethylamino-α-L- sorbose cell tranquillization liquid and (contain 6- 40 grams of deoxidation -6- hydroxyethylamino-α-L- sorboses), 200 ml isopropanols, (aqueous 50%), is put 4 gram of 10% platinum carbon with hydrogen Ventilate, maintain the MPa of pressure 1.5 ~ 2,27 DEG C of temperature, react 8 hours, N₂Press filtration removes platinum carbon (being used for next batch reaction), dense Contracting, alcohol crystal, filter, vacuum drying obtains 35 grams of miglitol crystal, yield 94%, purity 99.0% (HPLC detections).

Claims

A kind of 1. preparation method of Miglitol, it is characterised in that in autoclave with 6- deoxidation -6- hydroxyethylaminos-α - L- sorbose cell tranquillization liquid is raw material, under solid catalyst effect, adds alcohols solvent, is passed through hydrogen and carries out catalytic hydrogenation Reaction, react after terminating through press filtration, concentrate, crystallize, filter, washing, be dried in vacuo to obtain miglitol crystal.
2. the preparation method of a kind of Miglitol according to claim 1, it is characterised in that alcohols solvent is methanol, second One or more mixtures in alcohol, isopropanol.
A kind of 3. preparation method of Miglitol according to claim 1, it is characterised in that solid catalyst be Raney's nickel, One kind in palladium carbon, platinum carbon.
A kind of 4. preparation method of Miglitol according to claim 1, it is characterised in that 6- deoxidation -6- ethoxy ammonia Base-α-L- sorboses cell tranquillization liquid is 10 with alcohols solvent volume rate of charge：1.
A kind of 5. preparation method of Miglitol according to claim 1, it is characterised in that 6- deoxidation -6- ethoxy ammonia The volume of base-α-L- sorbose cell tranquillization liquid and the mass ratio of catalyst are 1:0.003-0.005, it is preferably 1：0.004, Volume unit is ml, mass unit g.
6. the preparation method of a kind of Miglitol according to claim 1, it is characterised in that temperature is 20~30 DEG C, reaction 7~8 hours time.
7. the preparation method of a kind of Miglitol according to claim 1, it is characterised in that reaction pressure is 1-2 MPa.
A kind of 8. preparation method of Miglitol according to claim 1, it is characterised in that reaction end by TLC detect or HPLC, which is detected to 6- deoxidation -6- hydroxyethylamino-α-L- sorboses, to disappear, and the adsorbent volume ratio of TLC detections is 4:1:2 N-butanol：Acetic acid：Water, developed the color by ninhydrin.