CN106588746A - Preparation method of gliclazide side chain and preparation method of gliclazide - Google Patents
Preparation method of gliclazide side chain and preparation method of gliclazide Download PDFInfo
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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Abstract
The invention relates to a preparation method of N-amino-3-azabicyalo [3.3.0] octane serving as a gliclazide side chain. The gliclazide side chain is obtained by carrying out one-step hydrogenation reduction on N-cyclopentyl amine imide through a transition metal atom-modified ruthenium-carbon catalyst. The activity of the modified ruthenium-carbon catalyst used in the method is obviously higher than that of an existing commercial ruthenium-carbon catalyst, so that the imide hydrogenation reaction which is hard to realize in the N-cyclopentyl amine imide can be carried out successfully. The preparation method of the gliclazide side chain is safe, efficient, high in yield and simple for posttreatment; the catalyst can be cyclically used indiscriminately, so that the production cost is substantially reduced, and green synthesis is basically realized; no waste water and no waste slag are produced; and the preparation method is particularly suitable for large-scale industrial production. The invention further relates to a production method of gliclazide, which has the advantages of short synthesis path, high yield, low preparation cost and the like.
Description
Technical field
The present invention relates to a kind of new preparation process of diabetes medicament Gliclazide side chain, and in particular in the middle of Gliclazide
The new preparation process of body N- amino-3-azabicyclos [3.3.0] octane, the invention further relates to a kind of preparation side of Gliclazide
Method, belongs to technical field of organic synthesis.
Background technology
Gliclazide (Gliclazide) is second filial generation sulfonylurea oral hypoglycemic drug, can be effectively reduced blood glucose and change
Kind coagulation function, is particularly well-suited to the non-insulin-dependent diabetes mellitus patient of various hypotypes, and side effect is less.With me
The increasingly raising of state's living standards of the people, diabetes receive much attention as a kind of affluenza, and research antidiabetic drugs have very
Important practical significance.
The synthesis of Gliclazide, it is crucial that the synthesis of its side chain N- amino-3-azabicyclos [3.3.0] octane.Mesh
Before, the production technology of Gliclazide side chain is outmoded, and pollution is big, and the three wastes are more, relatively costly, causes Gliclazide finished medicines price to occupy
It is high not under.At present synthesis Gliclazide side chain N- amino-3-azabicyclos [3.3.0] octane mainly has following several routes：
1. Japan Patent (publication number JP05065270 and JP06041073), disclose one kind adopt Tetrahydrocyclopenta(c)pyrrole-1,3(2H,3aH)-dione for
Raw material obtains target product through steps such as reduction, nitrosation and zinc powder reductions：
The method is the traditional and classical production method of comparison, domestic at present all to be produced using the method.But the producer
In method, the reduction difficulty of Tetrahydrocyclopenta(c)pyrrole-1,3(2H,3aH)-dione is larger, the price such as the reducing agent lithium aluminium hydride reduction for being used and alkali metal borohydride
Costly, and easily set off an explosion, all there is larger danger in transport and use.
2. Chinese patent (publication number CN101235011), mainly adopts Pentamethylene. dicarboxylic acid anhydride for raw material, with hydrazine reaction
Synthesis N- Aminocyclopentane acid imides.The patent has been briefly mentioned following route：
But the imido reduction of N- Aminocyclopentanes, it is still necessary to use the prices such as potassium borohydride and lewis acid and more hold high
Go back original reagent that is expensive and having certain danger.
3. Chinese patent (publication number CN102584677), synthetic route is as follows：
The route adopts N- Aminocyclopentanes acid imide for raw material, with zinc-copper catalyst in high temperature (200-250 DEG C), high pressure
(15MPa) hydrogenation reaction obtains Gliclazide side chain under the conditions of.But the main defect of the method is severe reaction conditions, pair set
It is standby to have high demands, high energy consumption, production is dangerous to be unfavorable for safety in production than larger, and industrialization difficulty is larger.In addition, in the method
Catalyst can not effectively recycling, single use cost is too high.
Therefore, a kind of new method for producing Gliclazide side chain of research and development, reduction production cost, and then a kind of green of offer,
The Gliclazide production method of safety, becomes one of Gliclazide preparation field technical problem in the urgent need to address.
The content of the invention
It is an object of the invention to provide the new method of a kind of new method of synthesis Gliclazide side chain and synthesis Gliclazide.
The method process is simple, safely, be easy to operation, high income, with low cost and lossless environment.
The invention provides a kind of preparation side of Gliclazide side chain N- amino-3-azabicyclos [3.3.0] octane (I)
Method, including：The ruthenium C catalyst being modified with transition metal atoms, hydrogenating reduction N- Aminocyclopentane acid imides (II) prepares N- ammonia
Base -3- azabicyclos [3.3.0] octane (I)
One of the invention concrete but non-limiting embodiment, wherein, the modified ruthenium carbon of transition metal atoms
Catalyst includes：Absorbent charcoal carrier, loads ruthenium nano particle and transition metal nanoparticles on absorbent charcoal carrier.
One of the invention concrete but non-limiting embodiment, wherein, transition metal be molybdenum, tungsten, vanadium, rhenium or
At least one in cobalt.
One of the invention concrete but non-limiting embodiment, wherein, ruthenium atom accounts for the quality hundred of catalyst
Divide than being 3%～10%, the mole of transition metal atoms is the 1/16～1/4 of ruthenium atom mole.
One of the invention concrete but non-limiting embodiment, methods described includes：By N- Aminocyclopentanes
Acid imide is dissolved in acidic aqueous solution, the ruthenium C catalyst for adding transition metal atoms modified, Hydrogen Vapor Pressure be 6～
9MPa, temperature generates N- amino-3-azabicyclos [3.3.0] octane under conditions of 90～140 DEG C, to reduce 16～20 hours.
One of the invention concrete but non-limiting embodiment, methods described is further included：Reaction is completed
Afterwards, room temperature is cooled to, pressure release is filtered, and filter cake ruthenium C catalyst is covered for reaction next time, filtrate reduced in volume, recovery acid water jacket
For lower secondary response, N- amino-3-azabicyclos [3.3.0] octane crude product, crude product HCl treatment, by first are concentrated to give
Benzene-alcohol mixed solvent recrystallization, filters, and drying obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride.
One of the invention concrete but non-limiting embodiment, wherein, catalysis acid is acetic acid, phosphoric acid, sulphuric acid
Or at least one in methanesulfonic acid.
One of the invention concrete but non-limiting embodiment, wherein, the mole of acid is N- amino cyclopentyls
1～3 times of alkane acid imide mole.
One of the invention concrete but non-limiting embodiment, wherein, Hydrogen Vapor Pressure is 8～9Mpa, is reduced
Temperature is 120～130 DEG C.
One of the invention concrete but non-limiting embodiment, wherein, the quality of catalyst is N- amino rings
The 10～30% of pentane acid imide quality.
One of the invention concrete but non-limiting embodiment, wherein, the modified ruthenium carbon of transition metal atoms
The preparation of catalyst is comprised the following steps：
By absorbent charcoal carrier and ruthenium solution mixing and absorption；
A certain amount of transition metal salt solution is added, continues stirring and adsorbing 1～3 hour；
Reductant solution is added to reduce 1～3 hour；
After reaction terminates, sucking filtration, washing is dried, and obtains the modified ruthenium C catalyst of transition metal atoms.
Present invention also offers a kind of preparation method of Gliclazide, including：Gliclazide side chain is prepared in aforementioned manners
N- amino-3-azabicyclos [3.3.0] octane (I), by obtained N- amino-3-azabicyclos [3.3.0] octane (I) with to first
Benzene sulfonylurea reacts, and prepares Gliclazide.
The beneficial effects are mainly as follows：
1. with N- Aminocyclopentane acid imides as raw material, the high activity ruthenium carbon being modified with transition metal atoms is catalyzed the present invention
The step of agent one hydrogenation obtains Gliclazide side chain N- amino-3-azabicyclos [3.3.0] octane.Modified ruthenium carbon used in the present invention
Catalyst activity is significantly higher than existing business ruthenium C catalyst, can make the acyl being difficult in N- Aminocyclopentane acid imides
Imines hydrogenation reaction is smoothed out.
2. the production method of the Gliclazide side chain of the present invention, hydrogenation reaction temperature is low, and Hydrogen Vapor Pressure is low, safe efficient；
Process route is short, and high income is up to 90% or so；Post processing is simple, and catalyst can apply mechanically (recycling) more than 20 times, and sour water steams
It is capable of circulation after evaporating to apply mechanically, green syt has been accomplished substantially, no waste water,
Waste residue is produced, it is to avoid the reduction such as boron hydride, lithium aluminium hydride reduction, zinc powder used in existing production method produces a large amount of
Solid waste and waste water, are adapted to large-scale industrial production.
3. the production method of the Gliclazide of the present invention, synthetic route is short, high income, significantly reduce preparation cost, makes
The Gliclazide medicine for obtaining has more price advantage.
Specific embodiment
Provided hereinafter specific embodiment and further illustrate the present invention, but the present invention is not limited only to following enforcement
Mode.
For achieving the above object, inventor is manufactured through constantly research discovery using the independent research of Green Kai Mo companies
The modified special ruthenium C catalyst of transition metal atoms, is hydrogenated with can the acid imide that be difficult in N- Aminocyclopentane acid imides
Reaction is smoothed out, it is achieved thereby that by the step of N- Aminocyclopentanes acid imide one hydrogenation production Gliclazide side chain, and obtain
90% or so high yield.The method not only avoid boron hydride, lithium aluminium hydride reduction, zinc powder etc. used in existing production method and urge
Agent reduction produces the problem of a large amount of solid wastes and waste water, and catalyst can significantly reduce production cost with recycling.
Gliclazide is produced with the method, not only synthetic route is short, high income, post processing are simple, and low production cost, more price
Advantage, efficiently solves the problems of the prior art.
The present invention provides a kind of preparation method of Gliclazide side chain N- amino-3-azabicyclos [3.3.0] octane (I),
With N- Aminocyclopentane acid imides (II) as raw material, the step of high activity ruthenium C catalyst one being modified with transition metal atoms is hydrogenated with
To Gliclazide side chain (I), concrete preparation method is as follows：
During N- Aminocyclopentane acid imides (II) is dissolved in into acidic aqueous solution, the height for adding transition metal atoms modified is living
Property ruthenium C catalyst, Hydrogen Vapor Pressure be 6～9MPa, temperature be 90～140 DEG C under conditions of, reduce 16～20 hours, generate
N- amino-3-azabicyclos [3.3.0] octane (I).Room temperature is cooled to afterwards, and pressure release is filtered, and filter cake ruthenium C catalyst can be applied mechanically
(recycling) can cover for reaction next time, be concentrated to give in lower secondary response, filtrate reduced in volume, the usual recovery Jing after distillation of sour water
To Gliclazide side chain crude product, crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, filter, drying is obtained
N- amino-3-azabicyclos [3.3.0] octane hydrochloride.
Wherein, it can be acetic acid, phosphoric acid, sulphuric acid or methanesulfonic acid etc. to be catalyzed acid, preferred acetic acid.It is catalyzed in acid condition,
Acid can allow ruthenium to keep activity, be not passivated by nitrogen-containing compound.The mole of acid can be N- Aminocyclopentane acid imides mole
1～3 times of amount.
Using water as solvent, the quality of water can be that N- Aminocyclopentanes are imido 2～4 times.
Preferably, Hydrogen Vapor Pressure is 8～9Mpa, reduction temperature is 120～130 DEG C.
The quality of catalyst can be the 10～30% of N- Aminocyclopentane acid imide quality.
Ruthenium C catalyst used in the present invention is by the high activity ruthenium carbon catalysis of Green Kai Mo companies independent research manufacture
Agent, including：Absorbent charcoal carrier, loads ruthenium nano particle and transition metal nanoparticles on absorbent charcoal carrier.Wherein, transition gold
Belong at least one in preferred molybdenum, tungsten, vanadium, rhenium or cobalt.It is 3wt%～10wt% that ruthenium atom accounts for the mass percent of catalyst.
The mole of transition metal atoms can be the 1/16～1/4 of ruthenium atom mole.The modified high activity ruthenium C catalyst is
The defending party to the application applies for a patent, application number：201611030379.6, denomination of invention：A kind of modified high activity of transition metal atoms
Ruthenium C catalyst and preparation method thereof, here is quoted in full.
The modified high activity ruthenium C catalyst can be prepared by following methods：
(1) by absorbent charcoal carrier and ruthenium solution mixing and absorption；
(2) a certain amount of transition metal salt solution is added, continues stirring and adsorbing 1～3 hour；
(3) reductant solution is added to reduce 1～3 hour；
(4) after reaction terminates, sucking filtration is washed with deionized to weakly acidic pH, is dried, and obtains what transition metal atoms were modified
Ruthenium C catalyst.
Wherein, in step (1), ruthenium solution is the ruthenium solution of solubility, such as ruthenic chloride, ruthenium sulfate, three nitric acid Ruthenium nitrosyls
Or ruthenium acetate solution etc..The mass percent for accounting for catalyst according to ruthenium atom is 3wt%～10wt%, and the ruthenium for preparing respective amount is molten
Liquid.
In step (2), transition metal salt solution is preferably the soluble-salt of at least one of molybdenum, tungsten, vanadium, rhenium or cobalt metal
Solution, such as ammonium molybdate solution ((NH4)6Mo7O24), tungsten chloride solution (WCl6), Ammonium Vanadate Solution (NH4VO3), ammonium perrhenate solution
(NH4ReO4) or cobalt nitrate solution (Co (NO3)2) etc..The mole of transition metal atoms can be the 1/16 of ruthenium atom mole
～1/4.Reducing agent can be sodium borohydride or sodium formate.Reducing agent should be suitably excessive, and ruthenium solution and transition metal salt is molten
Liquid reduces be advisable completely.
The modified high activity ruthenium C catalyst, by adding transition metal atoms so as to which catalysis activity is significantly carried
Rise, the activity for having broken traditional ruthenium C catalyst limits bottleneck, shows the catalysis activity more much higher than business ruthenium C catalyst.
Transition metal atoms are modified the reason for effectively improve ruthenium C catalyst activity is probably：After transition metal atoms are mixed, on the one hand
Absorption of the reaction substrate on its surface is increased, is on the other hand that transition metal atoms produce synergism with ruthenium atom, changed
The electronic structure of ruthenium atom, is conducive to activating hydrogen.Through substantial amounts of experimental study, inventor found out molybdenum, tungsten, vanadium,
Rhenium or cobalt are several very effective modified metal atoms and above-mentioned method of modifying.
With the modified step hydrogenation synthesis Gliclazide side chain N- of ruthenium C catalyst catalysis N- Aminocyclopentanes acid imide one
Amino-3-azabicyclo [3.3.0] octane, is not only achieved the acid imide hydrogenation reaction being difficult to, and obtains 90%
The high yield and more than 99% high-purity of left and right, and catalyst can apply mechanically more than 20 times, also set capable of circulation after sour water distillation
With, be truly realized green, safety synthesis.
N- amino-3-azabicyclos [3.3.0] octane (I) is further anti-with tolylsulfonylurea obtained in said method
Should, synthesizing Gliclazide, concrete reaction is as follows：
N- amino-3-azabicyclos [3.3.0] octane hydrochloride obtained in said method and tolylsulfonylurea are massaged
You compare 1：1～1.5 adds in toluene, is heated to reflux complete to reaction；Decompression rotary evaporation removes toluene, adds water, room temperature analysis
Crystalline substance, sucking filtration, solid washed with water, re-crystallizing in ethyl acetate, 70～90 DEG C of vacuum drying obtain Gliclazide product.
The present invention with N- Aminocyclopentane acid imides as raw material, with transition metal atoms be modified high activity ruthenium C catalyst
One step hydrogenation obtains Gliclazide side chain N- amino-3-azabicyclos [3.3.0] octane, then gives birth to tolylsulfonylurea reaction
Into the route of Gliclazide, with synthetic route is short, high income, post processing it is simple, the low advantage of preparation cost is especially suitable for big
Technical scale metaplasia is produced.
With reference to specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.
Experimental technique above and used in following embodiments if no special instructions, is conventional method.
Material used, reagent etc. above and in following embodiments, if no special instructions, commercially obtain or
Prepared with known conventional method.
Embodiment 1
(1) preparation of the modified ruthenium C catalyst of molybdenum atom
Weigh 47.26kg active carbon powders to be scattered in 200L deionized waters；The chloride hydrate rutheniums of 6.723kg tri- are weighed, it is molten
Solution is in 100L deionized waters；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 1.911kg ammonium molybdate solids
((NH4)6Mo7O24·4H2O), in being dissolved in 50L deionized waters, during above-mentioned Actidose is gradually added under stirring condition；Stir
After mixing absorption 1 hour, sodium borohydride aqueous solution (1.2kg sodium borohydrides are dissolved in 100L deionized waters) is gradually added into, under room temperature
After reaction 1 hour, sucking filtration, deionized water cleans 5 times to weakly acidic pH, 80 DEG C of oven dryings 12 hours, obtains molybdenum atom and is modified
Ruthenium C catalyst, the wherein weight/mass percentage composition of ruthenium is 5wt%, and the weight/mass percentage composition of molybdenum (presses the total matter of catalyst for 2wt%
Gauge).Can see from TEM electron microscopes, the granule that about 5 nanometers of size is uniformly distributed on absorbent charcoal carrier.
(2) preparation of Gliclazide side chain
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 10L, stirring and dissolving, in addition are added
State the modified ruthenium C catalyst (ruthenium content of molybdenum atom of preparation：5wt%, molybdenum content：2wt%) 600g.Under stirring, vacuum suction
In 20L autoclaves.Hydrogen Vapor Pressure be 8MPa, temperature be 130 DEG C under conditions of, react 20 hours.It is cooled to room temperature, pressure release,
Filter.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.Concentration
Obtain Gliclazide side chain crude product about 4.2kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, filters,
Drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 3.8kg, purity 99.6% (GC), yield：89%.Institute
Obtain product (GC analyses) consistent with reference substance.
(3) catalyst is applied mechanically
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 10L, stirring and dissolving is added to add back
Modified ruthenium C catalyst (the having recycled 6 times under the same reaction conditions) 600g of the molybdenum atom of receipts.Under stirring, vacuum is inhaled
Enter in 20L autoclaves.Hydrogen Vapor Pressure be 8MPa, temperature be 140 DEG C under conditions of, react 16 hours.Room temperature is cooled to, is let out
Pressure, filters.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.It is dense
Contracting obtains Gliclazide side chain crude product about 4.1kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, mistake
Filter, drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 3.9kg, purity 99.7% (GC), yield：91%.
Products obtained therefrom (GC analyses) consistent with reference substance.
It can be seen that, catalyst still keeps very high activity after applying mechanically repeatedly.
Embodiment 2
In 500L autoclaves, addition N- Aminocyclopentane acid imide 100kg, acetic acid 70L, water 250L, stirring and dissolving, plus
Enter the modified ruthenium C catalyst (ruthenium content of molybdenum atom of the preparation of embodiment 1 (1)：5wt%, molybdenum content：2wt%) 15kg.Control hydrogen
Atmospheric pressure is 8MPa, and temperature is under conditions of 135 DEG C, to react 20 hours.Room temperature is cooled to, pressure release is filtered.Filter cake ruthenium carbon is catalyzed
Agent is covered for reaction next time.Filtrate is transferred to concentration kettle concentrating under reduced pressure, and recovery of acetic acid water jacket is used for lower secondary response.It is concentrated to give lattice
Lie Qite side chains crude product about 114kg.HCl treatment is added, toluene-ethano mixed solvent recrystallization is subsequently adding, centrifuge gets rid of
Material, drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 97.7kg, purity 99.7% (GC), yield：
92%.Products obtained therefrom (GC analyses) consistent with reference substance.
Embodiment 3
(1) preparation of the modified ruthenium C catalyst of tungsten atom
Weigh 47.26kg active carbon powders to be scattered in 200L deionized waters；The chloride hydrate rutheniums of 6.723kg tri- are weighed, it is molten
Solution is in 100L deionized waters；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 1kg tungsten chloride solid (WCl6),
In being dissolved in 50L deionized waters, during above-mentioned Actidose is gradually added under stirring condition；After stirring and adsorbing 1 hour, gradually add
Enter aqueous sodium formate solution (2kg sodium formates are dissolved in 100L deionized waters), after reacting 1 hour at 80 DEG C, sucking filtration, deionized water
, to weakly acidic pH, 80 DEG C of oven dryings 12 hours obtain the modified ruthenium C catalyst of tungsten atom, the wherein quality hundred of ruthenium for cleaning 5 times
Divide content to be 5wt%, the weight/mass percentage composition of tungsten is 0.9wt% (based on catalyst gross mass).Can from TEM electron microscopes
Arrive, the granule that about 8 nanometers of size is uniformly distributed on absorbent charcoal carrier.
(2) preparation of Gliclazide side chain
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 4L, water 15L, stirring and dissolving, in addition are added
State the modified ruthenium C catalyst (ruthenium content of tungsten atom of preparation：5wt%, W content：0.9wt%) 700g.Under stirring, vacuum suction
In 20L autoclaves.Hydrogen Vapor Pressure be 9MPa, temperature be 130 DEG C under conditions of, react 17 hours.It is cooled to room temperature, pressure release,
Filter.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.Concentration
Obtain Gliclazide side chain crude product about 4.7kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, filters,
Drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 4kg, purity 99.5% (GC), yield：94%.Gained
Product (GC analyses) consistent with reference substance.
(3) catalyst is applied mechanically
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 4L, water 15L, stirring and dissolving is added to add back
Modified ruthenium C catalyst (the having recycled 6 times under the same reaction conditions) 700g of the tungsten atom of receipts.Under stirring, vacuum is inhaled
Enter in 20L autoclaves.Hydrogen Vapor Pressure be 9MPa, temperature be 140 DEG C under conditions of, react 16 hours.Room temperature is cooled to, is let out
Pressure, filters.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.It is dense
Contracting obtains Gliclazide side chain crude product about 4.8kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, mistake
Filter, drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 4.1kg, purity 99.4% (GC), yield：96%.
Products obtained therefrom (GC analyses) consistent with reference substance.
It can be seen that, catalyst still keeps very high activity after applying mechanically repeatedly.
Embodiment 4
(1) preparation of the modified ruthenium C catalyst of vanadium atom
Weigh 47.5kg active carbon powders to be scattered in 200L deionized waters；The chloride hydrate rutheniums of 6.47kg tri- are weighed, is dissolved
In 100L deionized waters；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 0.3kg ammonium vanadate solids
(NH4VO3), in being dissolved in 50L deionized waters, during above-mentioned Actidose is gradually added under stirring condition；Stirring and adsorbing 1 hour
Afterwards, sodium borohydride aqueous solution (1.2kg sodium borohydrides are dissolved in 100L deionized waters) is gradually added into, after reacting 1 hour under room temperature,
Sucking filtration, deionized water cleans 5 times to weakly acidic pH, 80 DEG C of oven dryings 12 hours, obtains the modified ruthenium C catalyst of vanadium atom,
Wherein the weight/mass percentage composition of ruthenium is 5wt%, and the weight/mass percentage composition of vanadium is 0.26wt% (based on catalyst gross mass).From
Can see in TEM electron microscopes, the granule that about 10 nanometers of size is uniformly distributed on absorbent charcoal carrier.
(2) preparation of Gliclazide side chain
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, methanesulfonic acid 5L, water 8L, stirring and dissolving, in addition are added
State the modified ruthenium C catalyst (ruthenium content of vanadium atom of preparation：5wt%, content of vanadium：0.26wt%) 650g.Under stirring, vacuum is inhaled
Enter in 20L autoclaves.Hydrogen Vapor Pressure be 6MPa, temperature be 130 DEG C under conditions of, react 20 hours.Room temperature is cooled to, is let out
Pressure, filters.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, reclaiming methanesulfonic acid water jacket is used for lower secondary response.
It is concentrated to give Gliclazide side chain crude product about 4.1kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, mistake
Filter, drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 3.9kg, purity 99.4% (GC), yield：92%.
Products obtained therefrom (GC analyses) consistent with reference substance.
(3) catalyst is applied mechanically
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, methanesulfonic acid 5L, water 8L, stirring and dissolving is added to add back
Modified ruthenium C catalyst (the having recycled 6 times under the same reaction conditions) 650g of the vanadium atom of receipts.Under stirring, vacuum is inhaled
Enter in 20L autoclaves.Hydrogen Vapor Pressure be 7MPa, temperature be 130 DEG C under conditions of, react 19 hours.Room temperature is cooled to, is let out
Pressure, filters.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, reclaiming methanesulfonic acid water jacket is used for lower secondary response.
It is concentrated to give Gliclazide side chain crude product about 4.3kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, mistake
Filter, drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 4kg, purity 99.2% (GC), yield：94%.Institute
Obtain product (GC analyses) consistent with reference substance.
It can be seen that, catalyst still keeps very high activity after applying mechanically repeatedly.
Embodiment 5
(1) preparation of the modified ruthenium C catalyst of rhenium atom
Weigh 47.5kg active carbon powders to be scattered in 200L deionized waters；The chloride hydrate rutheniums of 6.47kg tri- are weighed, is dissolved
In 100L deionized waters；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 0.66kg ammonium perrhenate solids
(NH4ReO4), in being dissolved in 50L deionized waters, during above-mentioned Actidose is gradually added under stirring condition；Stirring and adsorbing 1 hour
Afterwards, sodium borohydride aqueous solution (1.2kg sodium borohydrides are dissolved in 100L deionized waters) is gradually added into, after reacting 1 hour under room temperature,
Sucking filtration, deionized water cleans 5 times to weakly acidic pH, 80 DEG C of oven dryings 12 hours, obtains the modified ruthenium C catalyst of rhenium atom,
Wherein the weight/mass percentage composition of ruthenium is 5wt%, and the weight/mass percentage composition of rhenium is 0.9wt% (based on catalyst gross mass).
(2) preparation of Gliclazide side chain
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 2L, water 10L, stirring and dissolving, in addition are added
State the modified ruthenium C catalyst (ruthenium content of rhenium atom of preparation：5wt%, rhenium content：0.9wt%) 550g.Under stirring, vacuum suction
In 20L autoclaves.Hydrogen Vapor Pressure be 6MPa, temperature be 130 DEG C under conditions of, react 20 hours.It is cooled to room temperature, pressure release,
Filter.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.Concentration
Obtain Gliclazide side chain crude product about 4.3kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, filters,
Drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 4kg, purity 99.7% (GC), yield：94%.Gained
Product (GC analyses) consistent with reference substance.
(3) catalyst is applied mechanically
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 2L, water 10L, stirring and dissolving is added to add back
Modified ruthenium C catalyst (the having recycled 6 times under the same reaction conditions) 550g of the rhenium atom of receipts.Under stirring, vacuum is inhaled
Enter in 20L autoclaves.Hydrogen Vapor Pressure be 8MPa, temperature be 120 DEG C under conditions of, react 18 hours.Room temperature is cooled to, is let out
Pressure, filters.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.It is dense
Contracting obtains Gliclazide side chain crude product about 4.2kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, mistake
Filter, drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 3.9kg, purity 99.7% (GC), yield：92%.
Products obtained therefrom (GC analyses) consistent with reference substance.
It can be seen that, catalyst still keeps very high activity after applying mechanically repeatedly.
Embodiment 6
(1) preparation of the modified ruthenium C catalyst of cobalt atom
Weigh 47.5kg active carbon powders to be scattered in 200L deionized waters；The chloride hydrate rutheniums of 6.47kg tri- are weighed, is dissolved
In 100L deionized waters；Under agitation, the two is mixed, is adsorbed 1 hour；Weigh 0.69kg cabaltous nitrate hexahydrate solids
(Co(NO3)2·6H2O), in being dissolved in 50L deionized waters, during above-mentioned Actidose is gradually added under stirring condition；Stirring is inhaled
After attached 1 hour, sodium borohydride aqueous solution (1.2kg sodium borohydrides are dissolved in 100L deionized waters) is gradually added into, under room temperature 1 is reacted
After hour, sucking filtration, deionized water cleans 5 times to weakly acidic pH, 80 DEG C of oven dryings 12 hours, obtains the modified ruthenium carbon of cobalt atom
The weight/mass percentage composition of catalyst, wherein ruthenium is 5wt%, and the weight/mass percentage composition of cobalt (presses catalyst gross mass for 0.3wt%
Meter).Can see from TEM electron microscopes, the granule that about 5 nanometers of size is uniformly distributed on absorbent charcoal carrier.
(2) preparation of Gliclazide side chain
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 15L, stirring and dissolving, in addition are added
State the modified ruthenium C catalyst (ruthenium content of cobalt atom of preparation：5wt%, cobalt content：0.3wt%) 800g.Under stirring, vacuum suction
In 20L autoclaves.Hydrogen Vapor Pressure be 9MPa, temperature be 100 DEG C under conditions of, react 17 hours.It is cooled to room temperature, pressure release,
Filter.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.Concentration
Obtain Gliclazide side chain crude product about 4.4kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, filters,
Drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 4.1kg, purity 99.2% (GC), yield：96%.Institute
Obtain product (GC analyses) consistent with reference substance.
(3) catalyst is applied mechanically
In 20L there-necked flasks, N- Aminocyclopentane acid imide 4kg, acetic acid 3L, water 15L, stirring and dissolving is added to add back
Modified ruthenium C catalyst (the having recycled 6 times under the same reaction conditions) 800g of the cobalt atom of receipts.Under stirring, vacuum is inhaled
Enter in 20L autoclaves.Hydrogen Vapor Pressure be 8MPa, temperature be 120 DEG C under conditions of, react 16 hours.Room temperature is cooled to, is let out
Pressure, filters.Filter cake ruthenium C catalyst is covered for reaction next time.Filtrate reduced in volume, recovery of acetic acid water jacket is used for lower secondary response.It is dense
Contracting obtains Gliclazide side chain crude product about 4.3kg.Crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, mistake
Filter, drying, obtains N- amino-3-azabicyclos [3.3.0] octane hydrochloride 4kg, purity 99.3% (GC), yield：94%.Institute
Obtain product (GC analyses) consistent with reference substance.
It can be seen that, catalyst still keeps very high activity after applying mechanically repeatedly.
Embodiment 7
The preparation of Gliclazide
N- amino-3-azabicyclos [3.3.0] octane hydrochloride for adding embodiment 6 (2) to prepare in 250mL there-necked flasks
20g, tolylsulfonylurea 30g, toluene 100ml, are heated to reflux, and react 3 hours, after reaction terminates, remove toluene under reduced pressure, add
100ml water, is stirred at room temperature crystallize 12 hours, sucking filtration, washing solid, re-crystallizing in ethyl acetate, 80 DEG C of vacuum drying 15h hours,
Obtain product 37g, yield 86%.
The above is only the concrete application example of the present invention, protection scope of the present invention is not limited in any way.All employings
Equivalents or equivalence replacement and the technical scheme that formed, all fall within rights protection scope of the present invention.
Claims (12)
1. a kind of preparation method of Gliclazide side chain N- amino-3-azabicyclos [3.3.0] octane (I), including：With transition gold
The atom modified ruthenium C catalyst of category, hydrogenating reduction N- Aminocyclopentane acid imides (II) prepares N- amino-3-azabicyclos
[3.3.0] octane (I)
2. method according to claim 1, wherein, the modified ruthenium C catalyst of transition metal atoms includes：Absorbent charcoal carrier,
Ruthenium nano particle and transition metal nanoparticles are loaded on absorbent charcoal carrier.
3. method according to claim 2, wherein, transition metal is at least one in molybdenum, tungsten, vanadium, rhenium or cobalt.
4. method according to claim 2, wherein, it is 3%～10% that ruthenium atom accounts for the mass percent of catalyst, transition metal
The mole of atom is the 1/16～1/4 of ruthenium atom mole.
5. according to method arbitrary in claim 1-4, including：N- Aminocyclopentane acid imides are dissolved in into acidic aqueous solution
In, the ruthenium C catalyst for adding transition metal atoms modified is 6～9MPa in Hydrogen Vapor Pressure, and temperature is 90～140 DEG C of condition
Under, reduce 16～20 hours, generate N- amino-3-azabicyclos [3.3.0] octane.
6. method according to claim 5, further includes：After the completion of reaction, room temperature is cooled to, pressure release is filtered, filter cake ruthenium carbon
Catalyst is covered for reaction next time, and filtrate reduced in volume, recovery acid water jacket is used for lower secondary response, is concentrated to give N- amino -3- nitrogen
Miscellaneous bicyclic [3.3.0] octane crude product, crude product HCl treatment, by toluene-ethano mixed solvent recrystallization, is filtered, and drying is obtained
To N- amino-3-azabicyclos [3.3.0] octane hydrochloride.
7. method according to claim 5, wherein, it is at least one in acetic acid, phosphoric acid, sulphuric acid or methanesulfonic acid to be catalyzed acid.
8. method according to claim 5, wherein, the mole of acid is 1～3 times of N- Aminocyclopentane acid imide moles.
9. method according to claim 5, wherein, Hydrogen Vapor Pressure is 8～9Mpa, and reduction temperature is 120～130 DEG C.
10. method according to claim 5, wherein, the quality of catalyst be N- Aminocyclopentane acid imide quality 10～
30%.
11. according to method arbitrary in claim 1-4,6-10, wherein, the system of the modified ruthenium C catalyst of transition metal atoms
It is standby to comprise the following steps：
By absorbent charcoal carrier and ruthenium solution mixing and absorption；
A certain amount of transition metal salt solution is added, continues stirring and adsorbing 1～3 hour；
Reductant solution is added to reduce 1～3 hour；
After reaction terminates, sucking filtration, washing is dried, and obtains the modified ruthenium C catalyst of transition metal atoms.
A kind of 12. preparation methoies of Gliclazide, including：Gliclazide side chain N- ammonia is prepared with claim 1-11 either method
Base -3- azabicyclos [3.3.0] octane (I), by obtained N- amino-3-azabicyclos [3.3.0] octane (I) with to toluene sulphur
Uride reacts, and prepares Gliclazide.
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| RU2754708C1 (en) * | 2021-03-02 | 2021-09-06 | Акционерное общество "Щелково Агрохим" | Method for obtaining gliclazide |
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Denomination of invention: Preparation method of gliclazide side chain and preparation method of gliclazide Effective date of registration: 20220525 Granted publication date: 20190813 Pledgee: Panjin financing guarantee Group Co.,Ltd. Pledgor: GREENCHEM PANJIN SCIENCE AND TECHNOLOGY CO.,LTD. Registration number: Y2022210000051 |