Background technology
Bisoprolol fumarate's (Bisoprolol fumarate) chemistry is called 1-[4-[[2-(1-methyl ethoxy) oxyethyl group] methyl] phenoxy group]-the 3-[(1-methylethyl) amido]-2-propyl alcohol fumarate, English by name (1-[4-[[2-(1-Methylethoxy) ethoxy] methyl] phenoxy]-3-[(1-methylethyl) amino]-2-propanol fumarate), its structural formula is:
(C
18H
31NO
4)
2·C
4H
4O
4 766.96
The bisoprolol fumarate is that West Germany EMerck company researchs and develops in 1978 (No. 859,425, belgian patent).In April, 1986 official listing (IMS World Pharmaceutical Introduction1986 (1): 3), respectively at 1978 in Belgium, patented in the U.S. in 1979 and 1981.At present in more than 20 countries and regions listing such as English, method, day.
This product is the β of a tool heart selectivity
1-receptor-blocking agent, it brings about a wholesome effect to cardiovascular, and pulmonary function is not had undesirable action.Be used for stenocardia clinically, arrhythmia and hypertensive treatment.Long action time was administered once in one day.
Existing bisoprolol fumarate's synthetic route is:
By the 4-hydroxy benzaldehyde is starting raw material, makes through reduction, alcoholic extract hydroxyl group etherificate, phenolic hydroxyl group etherificate, amination, salify.
Its process flow sheet is:
According to above technology, through 2 molecular distillations, just can obtain the bisoprolol fumarate, yield is lower, and total recovery rate is 15~27%.
In addition, because this technology is to bring into use in 1994, the HPLC detection method sensitivity of test products quality at that time is low, and product only detects an impurity peaks, all be qualified, in recent years along with the development of measuring technology, the related impurities detection sensitivity improves constantly, and adds the renewal of bisoprolol fumarate's detection method and standard, method detects original qualified product now, can detect tens impurity peaks, its related impurities severe overweight, product is substantially all defective.For this reason, we are by increasing a molecular distillation (both through three molecular distillations), be adjusted to salt solvent and ratio thereof, change recrystallization number of times, removing related impurities in bisoprolol free alkali or its fumarate with multiple measures such as column chromatography separated free alkali impurity at phenolic hydroxyl group etherification reaction product.Though above measure produces effect, all can't tackle the problem at its root.Gained bisoprolol free alkali foreign matter content still usually exceeds standard, and is still defective behind the salify.Perhaps, even qualified, recovery rate is extremely low.
Therefore, the object of the present invention is to provide improving one's methods of a kind of bisoprolol fumarate of preparation, method of the present invention is compared with prior art has following advantage: technology is easy, and easy handling is suitable for suitability for industrialized production; Cost reduces, and product is pure, and total recovery is high.
Summary of the invention
According to the present invention, a kind of improving one's methods of bisoprolol that prepare is provided, it may further comprise the steps:
A, p-Hydroxybenzylalcohol is dissolved in the isopropoxide ethanol, adds a kind of catalyzer that is selected from protonic acid or lewis acid, 10 ℃~100 ℃ temperature range internal reactions 2~20 hours;
Add sodium hydroxide, chloro propylene oxide in b, the reaction soln that in step a, obtains, 10 ℃~80 ℃ temperature range internal reactions 3~70 hours;
Add Isopropylamine in c, the reaction soln that obtains in step b, 20 ℃~100 ℃ temperature range internal reactions 2~20 hours, underpressure distillation was to doing, through the pure bisoprolol product that makes.
In the method for the invention, also in the bisoprolol that can randomly in step c, obtain, add dehydrated alcohol and ethyl acetate mixed solvent and desirable acid, obtain crystallization, after filtration, drying makes the acid salt of bisoprolol.
In the method for the invention, be reflected in the homogeneous system and carry out.Selected new catalyzer to carry out the alcoholic extract hydroxyl group etherification reaction.This catalyzer belongs to lewis acid series, and under its effect, reaction is easy to carry out and to generate product very pure.For avoiding the substep operation to produce impurity, the present invention takes not separate the alcoholic extract hydroxyl group etherate, directly carries out phenolic hydroxyl group etherificate, amination reaction.One step was finished the entire reaction program, obtained the bisoprolol free alkali that quality is pure, yield is high at last, formed the bisoprolol fumarate with the fumaric acid reaction then.
Specific embodiments
We carry out arduous exploration with regard to problems in the former technology, find that therefrom whether fully the alcoholic extract hydroxyl group etherification reaction is the key of whole production; Simultaneously, even this reaction reaction is very complete, after aftertreatment, there is new impurity to produce again.Given this, we do a lot of work round the alcoholic extract hydroxyl group etherification reaction, as changing catalyzer and consumption thereof, prolong the reaction times, improve temperature of reaction, change post-treating method etc.The catalyzer that discovery alcoholic extract hydroxyl group etherification reaction is used and the aftertreatment of reactant are key factors, and we carry out more deep research from these two aspects, go through setback, have found suitable catalysts, reaction conditions and post-treating method finally.
It may further comprise the steps the method according to this invention:
A, p-Hydroxybenzylalcohol is dissolved in the isopropoxide ethanol, adds a kind of catalyzer that is selected from protonic acid or lewis acid, 10 ℃~100 ℃ temperature range internal reactions 2~20 hours;
Add sodium hydroxide, chloro propylene oxide in b, the reaction soln that in step a, obtains, 10 ℃~80 ℃ temperature range internal reactions 3~70 hours;
Add Isopropylamine in c, the reaction soln that obtains in step b, 20 ℃~100 ℃ temperature range internal reactions 2~20 hours, underpressure distillation was to doing, through the pure bisoprolol product that makes.
Though method of the present invention comprises 3 steps, only be for convenience of description, in fact preceding 3 steps can be carried out without any step discontinuously, and promptly the intermediate product of gained need not further pure system.Therefore, method of the present invention can be shown in following schema:
In the method for the invention, used catalyzer is selected from the following material a kind of among the step a: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, boron trifluoride, boron tribromide, trifluoroacetic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, o-toluene sulfonic acid etc. wherein are preferably methylsulfonic acid.
In step a, described isopropoxide ethanol is a reaction solvent, is again reaction raw materials, with the mol ratio of described p-Hydroxybenzylalcohol be 5: 1~17: 1, be preferably 8: 1~12: 1.
Temperature of reaction in step a is 10 ℃~100 ℃, is preferably 40 ℃~60 ℃, and the reaction times is 2~20 hours, is preferably 3~6 hours.
Temperature of reaction in step b is 10 ℃~80 ℃, is preferably 25 ℃~40 ℃, and the reaction times is 3~70 hours, is preferably 10~20 hours.
Temperature of reaction in step c is 20 ℃~100 ℃, is preferably 60 ℃~80 ℃, and the reaction times is 2~20 hours, is preferably 3~6 hours.
In addition, in the bisoprolol that can randomly obtain, add dehydrated alcohol and ethyl acetate mixed solvent and desirable acid in step c, obtain crystallization, then after filtration, drying makes the acid salt of bisoprolol, wherein said acid is fumaric acid preferably.In this step, the volume ratio of dehydrated alcohol and ethyl acetate is 1: 10~1: 1, is preferably 1: 6~1: 2.
According to above-mentioned we be not difficult to find out that the novel method reaction scheme shortens greatly, temperature of reaction be easy to control, easy and simple to handle.Former process alcohols hydroxyl etherificate is reflected at 150 ℃ high temperature reaction down, and the phenolic hydroxyl group etherification reaction is to use epoxy chloropropane and 5% aqueous sodium hydroxide solution, and reaction process is to carry out in two-phase, is difficult for fully; Amination reaction uses dehydrated alcohol to make solvent, excessive Isopropylamine is difficult for reclaiming, and the reaction of per step is changed container, is all needed aftertreatment and just can obtain bisoprolol (V) through 2 molecular distillations, key is that salify gained bisoprolol fumarate (VI) can't satisfy present correlated quality check, and is usually defective.On the contrary, in preparation method of the present invention, the alcoholic extract hydroxyl group etherification reaction is carrying out under the low temperature relatively, the phenolic hydroxyl group etherificate is to react in single-phase easily fully, use isopropoxide ethanol to run through whole process in the reaction process as solvent and participation reaction, alcoholic extract hydroxyl group etherificate, phenolic hydroxyl group etherificate, amination three-step reaction all carry out in same reaction vessel, product is handled through last, only need 1 step high vacuum to obtain bisoprolol (V), total recovery rate is improved, and salify gained bisoprolol fumarate (VI) is all qualified in view of the above.
The method according to this invention has shortened the production cycle, simplified production unit and has improved quality product and recovery rate.This method reaction conditions requirement is low, post-treating method is easy, recovery rate is high, and very is fit to suitability for industrialized production.
Illustrate in greater detail the present invention below with reference to embodiment.
Embodiment 1
Bisoprolol fumarate's (VI) is synthetic
In three mouthfuls of round-bottomed flasks, disubstituted-4-hydroxy phenylcarbinol (II) 400g (3.2mol) and isopropoxide ethanol 4000ml, 60 ℃ of stirring reactions in the presence of phosphoric acid.After reaction finishes, be cooled to room temperature, add epoxy chloropropane 550ml (7.0mol), sodium hydroxide 200g (5.0mol), in stirring at room reaction 20 hours.Add 1100ml Isopropylamine (10.0mol) then, stir down in 70 ℃ of reactions.Remove solvent under reduced pressure to doing, residue is dissolved in ethyl acetate, washes 4 times with appropriate amount of deionized water.Add the 200ml deionized water, under the ice bath cooling and stirring, with hcl acidifying to pH 2-3.Tell organic layer, wash 3 times.After water liquid and water layer merge, with ethyl acetate extraction.The aqueous solution is neutralized to pH 12-13 with 50% sodium hydroxide solution in the frozen water cooling down.Tell organic layer, water layer merges organic layer with ethyl acetate extraction 3 times, 200ml deionization washing 3 times, behind the anhydrous magnesium sulfate drying, be evaporated to dried, crude product 544g, bisoprolol content is more than 85%.Distillation, the cut of 170~175 ℃/0.005~0.01kPa of collection boiling range gets product (V) 354g, and recovery rate is 33.83%, and bisoprolol content is 98.4%.
Get product (V) 245g (0.75mol) that as above makes and be dissolved in dehydrated alcohol-ethyl acetate solution, add fumaric acid 43.5g (0.375mol).Be heated to moltenly entirely, place cooling, filter is assembled brilliant, with re-crystallizing in ethyl acetate, obtains the 230g colourless crystallization, 100~104 ℃ of fusing points, recovery rate 80%.
Embodiment 2
Synthesizing of bisoprolol (V)
In three mouthfuls of round-bottomed flasks, disubstituted-4-hydroxy phenylcarbinol (II) 500g (4.03mol) and isopropoxide ethanol 5000ml, 50 ℃ of stirring reactions in the presence of methylsulfonic acid.After reaction finishes, be cooled to room temperature, add epoxy chloropropane 690ml (8.8mol), sodium hydroxide 275g (6.875mol), in stirring at room reaction 20 hours.Add Isopropylamine 1500ml (17.26mol) then, stir down in 72 ℃ of reactions.Reaction finishes, and handles with embodiment 1, gets product (V) 470g, and recovery rate is 35.85%, and bisoprolol content is 97.8%.