CN102241603A - Asymmetrical synthetic method of R-/S-acebutolol - Google Patents
Asymmetrical synthetic method of R-/S-acebutolol Download PDFInfo
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Abstract
The invention relates to an asymmetrical synthetic method of R-/S-acebutolol. The method comprises the following steps of: making a p-aminoanisole solution react with ethyl acetic acid to obtain N-(4-methoxyphenyl)-butyrylamide; mixing a solution of the N-(4-methoxyphenyl)-butyrylamide with Lewis acid, dropwise adding an acylation reagent to obtain a 5-butyramide-2-hydroxyacetophenone solid product, and dissolving the solid product in an inorganic alkali solution; and dropwise adding R-/S-epoxy chloropropane in the presence of a phase transfer catalyst to obtain R-/S-5-butyramide-2-(2,3-glycidoxy)-acetophenone, and making the R-/S-5-butyramide-2-(2,3-glycidoxy)-acetophenone react with isopropylamine in the presence of water to obtain R-/S-acebutolol with high optical purity. According to the method, a small number of steps are performed, the yield of each step is over 74 percent, the total yield is over 48 percent, and proved by OD-H chiral column HPLC (High Performance Liquid Chromatography) analysis, the e.e. value of a product is up to 94 percent in maximum.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, particularly the method for asymmetric synthesis of optical purity cardiovascular medicament R-or S-acebutolol.
Background technology
Acebutolol (Ac) is a kind of beta receptor retarding agent, is used for treating hypertension, arrhythmia or stenocardia.This medicine was gone on the market by drugs approved by FDA in 1999, and is the same with many other beta-blockers medicines, and at present, this medicine is still with the mode administration of DL.But a lot of bibliographical informations, the beta receptor blocking activity of acebutolol mainly come from the enantiomorph of its S-configuration and the M B 16942 (Dc) of its metabolite S-type.As everyone knows, be the trend of present world drug development with the administration of single enantiomer medicine mode, and, all there is very big difference aspect pharmacodynamics and the pharmacokinetics between the different enantiomorphs of same medicine.Therefore, utilize the pure acebutolol of method synthesizing optical of asymmetric synthesis, and study the pharmaceutical activity of its different enantiomorphs respectively, have great importance.At present, the asymmetric synthesis of other Luo Er class medicines of a lot of bibliographical informations is arranged, as atenolol USP 23, propranolol etc.But, utilize the high acebutolol report of chirality synthetic method synthesizing optical purity seldom.
Synthesizing of optical purity acebutolol at first relates to the synthetic of key intermediate 5-amide-based small-2-hydroxy acetophenone.
The method of synthetic this intermediate of tradition is to be raw material with the p-aminophenol, obtains by butyryl amination, acetic acid esterification, Fries rearrangement reaction.Reaction formula is as shown below:
In the Fries rearrangement reaction, generally be under solvent-free situation, directly be catalyzer with the aluminum chloride, carry out the solid phase rearrangement reaction with raw material, but the reaction mixture thickness that obtains can't stir, productive rate is on the low side.And the product that obtains is solid mass, and hardness is big, brings very big trouble to aftertreatment.U.S. Pat 3726919 reported method are, are solvent with the tetrachloroethane, and aluminum chloride is a catalyzer, reacting by heating under 140 ℃ of conditions.But this method aftertreatment needs repeatedly extraction, the process complexity, and solvent-oil ratio is big, and cost is higher.Recently, it is raw material with the p-aminophenol that report is arranged again, and acetylize in the time of through amino and hydroxyl, Fries rearrangement, hydrolysis, butyryl amination obtain product.Though this method has reduced the consumption of your raw material butyryl oxide, the generation of by product when having avoided the Fries rearrangement reaction, synthetic route is long partially, and still do not avoid Fries and reset, the aftertreatment trouble, cost is still higher.In the research before us; we are raw material with the p-aminophenol; also obtained 5-amide-based small-2-hydroxy acetophenone by butyryl amination, etherificate, friedel-crafts acylation three-step reaction; successfully evaded the Fries rearrangement reaction; but in the Friedel-Crafts reaction step, solvent for use is a dithiocarbonic anhydride, dithiocarbonic anhydride exist toxicity greatly, shortcoming such as burning very easily; bring difficulty to suitability for industrialized production, and the productive rate in this step is also on the low side.Therefore, these synthetic routes still need to improve, and just can produce on a large scale.
At present, the acebutolol that obtains enantiomer-pure mainly contains direct HPLC Split Method, asymmetric synthesis method etc.The former needs expensive chiral column and preparation HPLC, the cost height, the preparation of only suitable minute quantity product with separate.U.S. Pat 4579970 has been reported a kind of method of asymmetric synthesis chirality acebutolol, and synthetic route is as follows:
This method is a raw material with intermediate 5-amide-based small-2-hydroxy acetophenone, obtains target product through the reaction of seven steps, and reactions steps is long, and overall yield has only 30%, does not meet Atom economy.The used chiral raw material tolysulfonyl acetone glyceryl ester that contracts is to be transformed through polystep reaction by D-seminose or vitamins C, and raw material is difficult for obtaining, and cost is higher.And, do not report the optical purity of gained R-or S-type acebutolol in this patent yet.Therefore, reactions steps is short, productive rate is high to develop one, and the reaction scheme that selectivity is good has important practical significance and social, economic worth.
Summary of the invention
The objective of the invention is the raw material costliness that exists in the prior art in order to overcome, complicated operation, reactions steps is long, problems such as production cost height provide a kind of raw material to be easy to get, and are easy and simple to handle, reactions steps is few, the method for asymmetric synthesis of R-that production cost is low or S-acebutolol.
The method of asymmetric synthesis of R-of the present invention or S-acebutolol may further comprise the steps:
(1) N-(4-p-methoxy-phenyl)-butyramide is synthetic
Para-Anisidine is dissolved in the organic solvent, gained solution and butanic acid were reacted 6-9 hour under temperature is 130-150 ℃, isolate N-(4-p-methoxy-phenyl)-butyramide wherein;
(2) 5-amide-based small-2-hydroxy acetophenone is synthetic
N-(4-p-methoxy-phenyl)-butyramide that step (1) is obtained is dissolved in the organic solvent, gained solution is mixed with Lewis acid, in the gained mixture, drip acylating reagent then, 10-30 ℃ was reacted 20-35 hour down, isolates 5-amide-based small-2-hydroxy acetophenone solid product wherein;
(3) R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone is synthetic
5-amide-based small-2-hydroxy acetophenone that step (2) is obtained is dissolved in the inorganic alkali solution, in the presence of phase-transfer catalyst, drip S-or R-epoxy chloropropane then, 10-30 ℃ was reacted 20-40 hour, suction filtration also adds water washing, dry and obtain R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone;
(4) R-or S-acebutolol is synthetic
R-or S-5-amide-based small-2-(2 that step (3) is obtained, the 3-glycidoxy)-methyl phenyl ketone and Isopropylamine be in the presence of water, 10-30 ℃ was reacted 7-20 hour, excessive Isopropylamine is removed in distillation, add hydrochloric acid soln, regulate the pH value, filter to 1-2, regulate filtrate to pH 10-12 with sodium hydroxide solution, obtain high R-of optical purity or S-acebutolol.
Reaction scheme is as follows:
The present invention has synthesized the acebutolol of R-or S-type through four-step reaction.
(1) N-(4-p-methoxy-phenyl)-butyramide is synthetic
In reaction vessel, Para-Anisidine is dissolved in the organic solvent (as toluene), add butanic acid, keeping temperature of reaction is 130-150 ℃ in temperature, back flow reaction 6-9 hour, stopped reaction; While hot excessive organic solvent and butanic acid are steamed, be cooled to room temperature, get solid with the sherwood oil lotion, recrystallization in ethyl acetate and sherwood oil mixed solvent (volume ratio of ethyl acetate and sherwood oil 1: 1) obtains N-(4-p-methoxy-phenyl)-butyramide white crystal.
The consumption of described toluene is that every gram Para-Anisidine adds toluene 5-10ml.The consumption of described butanic acid is 1.5-5 a times of Para-Anisidine mole number, and preferred 3-5 doubly.
In this step reaction, we have overcome the higher relatively butyryl oxide of use price, butanic acid and Para-Anisidine with cheapness react in organic solvent, utilize organic solvent and water to form azeotropic mixture, take the water that reaction produces out of reaction system, force reaction to be carried out to the right, obtain N-(4-p-methoxy-phenyl)-butyramide with high yield.In time do not remove if will not react the water that produces, can cause the reactant thickness, productive rate is low, even the reaction failure.
(2) 5-amide-based small-2-hydroxy acetophenone is synthetic
Above-mentioned N-(4-p-methoxy-phenyl)-butyramide is dissolved in the organic solvent, adds Lewis acid, drip acylating reagent again in reaction system, 10-30 ℃ is reacted after 20-35 hour stopped reaction.
Described organic solvent can use haloalkane, and described haloalkane preferably uses methylene dichloride or sym.-tetrachloroethane, and the consumption of described haloalkane is that every gram N-(4-p-methoxy-phenyl)-butyramide adds haloalkane 10-100ml.Described Lewis acid can use aluminum trichloride (anhydrous) or Zinc Chloride Anhydrous etc., and its consumption is 1-4 a times of acylating reagent mole number.Described acylating reagent is an Acetyl Chloride 98Min., and its consumption is 1.5-5 a times of N-(4-p-methoxy-phenyl)-butyramide mole number, preferred 2-3.In this step reaction, preferred temperature is 20-25 ℃.
Add trash ice and concentrated hydrochloric acid in reaction system, treat that the gained solid all after the dissolving, use the organic solvent extraction product, the washing of water and saturated sodium carbonate solution is to neutral again, and anhydrous magnesium sulfate drying filters, and rotary evaporation is except that desolvating.Thick product recrystallization in the mixed solvent (volume ratio of toluene and ethyl acetate is 1: 1) of toluene and ethyl acetate obtains white 5-amide-based small-2-hydroxy acetophenone solid.
Described organic solvent is preferably methylene dichloride, trichloromethane or ethyl acetate etc.
In this step reaction, we have avoided aftertreatment complexity, Fries rearrangement reaction that productive rate is low, utilize one step of Friedel-Crafts reaction to carry out acidylate and with the phenolic hydroxyl group deprotection on phenyl ring; obtain 5-amide-based small-2-hydroxy acetophenone; the reaction conditions gentleness, the productive rate height, aftertreatment is easy.
(3) R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone is synthetic
In reactor, add inorganic alkali solution and 5-amide-based small-2-hydroxy acetophenone, after waiting to dissolve, add phase-transfer catalyst, then, drip S-or R-epoxy chloropropane, temperature is controlled between 10-30 ℃, reacts 20-40 hour, obtains white suspension solution, suction filtration, use the distilled water wash product, vacuum-drying obtains R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone white solid.
Described inorganic alkali solution can use potassium hydroxide or sodium hydroxide, and the concentration of inorganic alkali solution is preferably 2-5wt%, and consumption is 3-5 a times of 5-amide-based small-2-hydroxy acetophenone mole number.The consumption of described S-or R-epoxy chloropropane is 2-7 a times of 5-amide-based small-2-hydroxy acetophenone mole number, is preferably 4-7 doubly.Described phase-transfer catalyst can use benzyl trimethyl ammonium chloride or tetrabutylammonium chloride etc., and consumption is 0.001-0.02 a times of 5-amide-based small-2-hydroxy acetophenone mole number.
R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-the synthetic of methyl phenyl ketone is the committed step that obtains the optical purity acebutolol.We directly react this step reaction with commercial chiral epichlorohydrin and 5-amide-based small-2-hydroxy acetophenone, introduce chiral centre, avoided in the U.S. Pat 4579970 high the and tolysulfonyl acetone that need polystep reaction just can obtain of the price the used glyceryl ester that contracts, shorten the step of reaction, reduced cost.And, this reaction is a stereospecificity, in the presence of mineral alkali, and the carbon atom on the direct attack epoxy chloropropane of the phenol negative oxygen ion triatomic ring that forms on 5-amide-based small-2-hydroxy acetophenone phenyl ring, the chlorine atom is left away simultaneously, and counter-rotating has taken place the configuration of chiral carbon atom on the triatomic ring like this.That is to say that we use the R-epoxy chloropropane, the product that obtains is S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone, and vice versa.
In this step reaction, temperature must be controlled between 10-30 ℃.Temperature is too low, reacts too slow, even also reacts in a week not exclusively, does not have practical significance.Ring-opening polymerization takes place in temperature height, epoxy chloropropane easily, and by product increases, and also influences selectivity simultaneously.Preferred temperature is 20-25 ℃.Epoxy chloropropane of using in the reaction and alkali add more effective than disposable adding in batches, add the generation can avoid the side reaction that epoxy chloropropane causes owing to partial concn is too high in batches.The R-that obtains or S-5-amide-based small-2-(2, the 3-glycidoxy)-the methyl phenyl ketone white solid, can directly carry out next step reaction, also can be in the mixed solvent (volume ratio of ethyl acetate and sherwood oil is 1: 1) of ethyl acetate and sherwood oil recrystallization or separate by column chromatography carry out next step reaction again after purifying, can use silica gel column chromatography to separate purification.Experiment shows the productive rate of next step reaction of back of purifying than the height of not purifying, and is little to the selectivity influence.
(4) R-or S-acebutolol is synthetic
In reactor, with above-mentioned R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone and Isopropylamine according to mol ratio 1: 10-1: 25, in the presence of water, 10-30 ℃ of reaction 7-20 hour.Excessive Isopropylamine is removed in distillation, adds distilled water, and dropping concentration is that the salt acid for adjusting pH value of 37wt% is 1-2, filters, and filtrate is regulated the pH value to 10-12 with concentration for the 2-10wt% sodium hydroxide solution, obtains R-or S-acebutolol white solid.
This goes on foot reaction, and preferred temperature is 20-25 ℃.We utilize less water as solubility promoter, the consumption of water is that every milliliter of Isopropylamine adds entry 0.05-0.2ml, successfully avoided Isopropylamine among the US4579970 simultaneously also with phenyl ring on the side reaction of carbonyl generation condensation, improved productive rate.The method that tradition is carried out this reaction is a reacting by heating in organic solvent, need carry out extraction repeatedly during aftertreatment, not only influences productive rate but also cost is increased greatly, and is also unfriendly to environment.We do not add any organic solvent when reaction, react mild condition under the room temperature, aftertreatment is simple, and used solvent has only water, need not to add a large amount of organic solvent extractions, the target product purity height, the selectivity that obtain are good, environmentally friendly, conform with the theory of Green Chemistry.The optical purity of R-that obtains or S-acebutolol is analyzed through HPLC, and e.e. (Enantiomericexcess) value is 92%-94%, and used chiral column is the OD-H type.
Raw materials used being easy to get in the method for the present invention, the reaction conditions gentleness, easy and simple to handle, reactions steps is few, and product handles easily and productive rate higher (per step productive rate all can reach more than 74%), selectivity are better, production cost is low, solved the raw material costliness that exists in the prior art, complicated operation, reactions steps is long, problems such as production cost height are for optical purity acebutolol synthetic provides a kind of advantageous novel method.The overall yield department of R-or S-acebutolol is to reach 48%, and product e.e. value is analyzed through OD-H chiral column HPLC, reaches as high as 94%.
Embodiment
The present invention is further illustrated below by embodiment.
Embodiment 1
Synthesizing of R-acebutolol
(1) N-(4-p-methoxy-phenyl)-butyramide is synthetic
In the 250ml reaction vessel, the 5.0g Para-Anisidine is dissolved in the 30ml toluene, add the 15ml butanic acid, be heated to 140 ℃, back flow reaction is after 6 hours, stopped reaction.While hot excessive solvent and butanic acid are steamed, be cooled to room temperature, with petroleum ether gained solid, in the volume ratio of ethyl acetate and sherwood oil is recrystallization in 1: 1 ethyl acetate and the sherwood oil mixed solvent, obtain the 6.28g white crystal, be determined as N-(4-p-methoxy-phenyl)-butyramide, productive rate: 80% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.86-87℃。
1H?NMR(400MHz，CDCl
3)：δ＝1.02(t，J＝7.36Hz，3H，CH
2CH
3)，1.77(m，2H，CH
2CH
2)，2.33(t，J＝7.36Hz，2H，CH
2CH
2)，3.79(s，3H，OCH
3)，6.86(d，J＝8.92Hz，2H，C
6H
4)，7.05(s，1H，NH)，7.42(d，J＝8.92Hz，2H，C
6H
4).
(2) 5-amide-based small-2-hydroxy acetophenone is synthetic
In the 250ml reaction vessel, 5.0g N-(4-p-methoxy-phenyl)-butyramide is dissolved in the 50ml methylene dichloride, add the 10g aluminum chloride, in reaction system, slowly drip the 3.7ml Acetyl Chloride 98Min. again.Room temperature reaction 24 hours, stopped reaction.
In reaction system, add trash ice and concentrated hydrochloric acid, after the gained solid all dissolves, separatory, with dichloromethane extraction water (15ml * 3), merge organic phase, water and saturated sodium carbonate solution washing are to neutral, anhydrous magnesium sulfate drying filters, and rotary evaporation removes and desolvates.Thick product is a recrystallization in 1: 1 toluene and the ethyl acetate mixed solvent in the volume ratio of toluene and ethyl acetate, obtain the 4.30g white solid, be determined as 5-amide-based small-2-hydroxy acetophenone, productive rate 75% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.121-123℃
1H?NMR(CDCl
3，400MHz)：δ1.02(t，J＝7.32Hz，3H)，1.76(m，2H)，2.34(t，J＝7.36Hz，2H)，2.64(s，3H)，6.92(m，1H)，7.09(s，1H)，7.30(m，1H)，8.26(m，1H)，12，1(s，1H)。
(3) R-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone is synthetic
At the 100ml reactor, 0.3g sodium hydroxide is dissolved in the 10ml water, adds 1.0g 5-amide-based small-2-hydroxy acetophenone and 0.007g benzyl trimethyl ammonium chloride, treat that solid all dissolves, drip S-epoxy chloropropane (U.S. Sigma-Aldrich company, analytical pure) 1.0ml.Temperature is controlled at 20-30 ℃, after 9 hours, adds sodium hydroxide 0.15g, S-epoxy chloropropane 0.5ml.After 18 hours, continue to add sodium hydroxide 0.15g, S-epoxy chloropropane 0.5ml.Coreaction 30 hours obtains white suspension solution.Suction filtration is used the distilled water wash product, and vacuum-drying obtains the 0.93g white solid, is determined as R-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), and yield is 74%.
Mp.141-142℃。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.76(m，2H)，2.34(t，J＝7.32Hz，2H)，2.67(s，3H)，2.77(m，1H)，2.94(t，J＝4.60Hz，1H)，3.40(m，1H)，3.98(m，1H)，4.38(m，1H)，6.94-8.05(m，3H)，7.40(s，1H)。
(4) the R-acebutolol is synthetic
In the 50ml reactor, with the 0.93g R-5-amide-based small-2-(2 that obtains in the step (3), the 3-glycidoxy)-methyl phenyl ketone is dissolved in the 5ml Isopropylamine, add 1ml water, 10-30 ℃ was reacted 8 hours, excessive Isopropylamine is removed in distillation, add 10ml distilled water, the salt acid for adjusting pH value that drips 37wt% is 1-2, filter, filtrate is regulated the pH value to 10-12 with the 2wt% sodium hydroxide solution, obtains the 0.81g white solid, is determined as the R-acebutolol through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), productive rate is 72%, optical purity is analyzed through HPLC (HIT), and the e.e. value is 92.2%, and used chiral column is OD-H (Japanese Daicel company).
Mp.125-126℃。
[α]
D 20＝-2.7(c?0.05，methanol)。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.13(d，J＝6.08Hz，6H)，1.76(m，2H)，2.33(t，J＝7.32Hz，3H)，2.62(s，3H)，2.78(m，1H)，2.94(m，2H)，4.08(s，3H)，6.94-7.88(m，3H)，7.33(s，1H)。
Embodiment 2
Synthesizing of R-acebutolol
(1) N-(4-p-methoxy-phenyl)-butyramide is synthetic
In the 250ml reaction vessel, the 10.0g Para-Anisidine is dissolved in the 60ml toluene, add the 30ml butanic acid, be heated to 150 ℃ of back flow reaction, after 8 hours, stopped reaction.While hot excessive solvent and butanic acid are steamed, be cooled to room temperature, with petroleum ether gained solid, in the volume ratio of ethyl acetate and sherwood oil is recrystallization in 1: 1 ethyl acetate and the sherwood oil mixed solvent, obtain the 13.5g white crystal, be determined as N-(4-p-methoxy-phenyl)-butyramide, productive rate: 86% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.87-88℃。
1H NMR (400MHz, CDCl
3): δ=1.02 (t, J=7.36Hz, 3H, CH
2CH
3), 1.77 (m, 2H, CH
2CH
2), 2.33 (t, J=7.36Hz, 2H, CH
2CH
2), 3.79 (s, 3H, OCH
3), 6.86 (d, J=8.92Hz, 2H, C
6H
4), 7.05 (s, 1H, NH), 7.42 (d, J=8.92Hz, 2H, C
6H
4). synthesizing of (2) 5-amide-based small-2-hydroxy acetophenone
In the 250ml reaction vessel, 10.0g N-(4-p-methoxy-phenyl)-butyramide is dissolved in the 100ml methylene dichloride, adds the 14g aluminum chloride, again Dropwise 5 .6ml Acetyl Chloride 98Min. slowly in reaction system.Behind the room temperature reaction 10 hours, add the 4g aluminum chloride, the 1ml Acetyl Chloride 98Min..Coreaction 35 hours, stopped reaction.
In reaction system, add trash ice and concentrated hydrochloric acid, treat the gained solid all after the dissolving, separatory, with dichloromethane extraction water (25ml * 3), merge organic phase, water and saturated sodium carbonate solution washing are to neutral, anhydrous magnesium sulfate drying filters, and rotary evaporation removes and desolvates.Thick product is a recrystallization in 1: 1 toluene and the ethyl acetate mixed solvent in the volume ratio of toluene and ethyl acetate, obtain the 9.90g white solid, be determined as 5-amide-based small-2-hydroxy acetophenone, productive rate 87% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.121-122℃。
1H?NMR(CDCl
3，400MHz)：δ1.02(t，J＝7.32Hz，3H)，1.76(m，2H)，2.34(t，J＝7.36Hz，2H)，2.64(s，3H)，6.92(m，1H)，7.09(s，1H)，7.30(m，1H)，8.26(m，1H)，12，1(s，1H)。
(3) R-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone is synthetic
At the 100ml reactor, 0.4g potassium hydroxide is dissolved in the 10ml water, adds 1.0g 5-amide-based small-2-hydroxy acetophenone and 0.01g benzyl trimethyl ammonium chloride, treat that solid all dissolves, drip S-epoxy chloropropane (U.S. Sigma-Aldrich company, analytical pure) 1.0ml.Temperature is controlled at 20-30 ℃.After 9 hours, add potassium hydroxide 0.20g, S-epoxy chloropropane 0.5ml.Coreaction 20 hours obtains white suspension solution.Suction filtration is with distilled water water washing product, vacuum-drying.In the volume ratio of ethyl acetate and sherwood oil is recrystallization in 1: 1 ethyl acetate and the sherwood oil mixed solvent, obtain the 1.01g white solid, be determined as R-5-amide-based small-2-(2 through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), the 3-glycidoxy)-and methyl phenyl ketone, yield is 81%.
Mp.141-143℃。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.76(m，2H)，2.34(t，J＝7.32Hz，2H)，2.67(s，3H)，2.77(m，1H)，2.94(t，J＝4.60Hz，1H)，3.40(m，1H)，3.98(m，1H)，4.38(m，1H)，6.94-8.05(m，3H)，7.40(s，1H)。
(4) R-or S-acebutolol is synthetic
In the 50ml reactor, with the 1.01g R-5-amide-based small-2-(2 that obtains in the step (3), the 3-glycidoxy)-methyl phenyl ketone is dissolved in the 6ml Isopropylamine, add 1ml water, 10-30 ℃ was reacted 7 hours, excessive Isopropylamine is removed in distillation, add 10ml distilled water, the salt acid for adjusting pH value that drips 37wt% is 1-2, filter, filtrate is regulated the pH value to 10-12 with the 2wt% sodium hydroxide solution, obtains the 0.98g white solid, be determined as the R-acebutolol through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), productive rate is 80%.Optical purity is analyzed through HPLC (HIT), and the e.e. value is 93.8%, and used chiral column is OD-H (Japanese Daicel company).
Mp.125-126℃
[α]
D 20＝-2.7(c?0.05，methanol)。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.13(d，J＝6.08Hz，6H)，1.76(m，2H)，2.33(t，J＝7.32Hz，3H)，2.62(s，3H)，2.78(m，1H)，2.94(m，2H)，4.08(s，3H)，6.94-7.88(m，3H)，7.33(s，1H)。
Embodiment 3
Synthesizing of R-acebutolol
(1) N-(4-p-methoxy-phenyl)-butyramide is synthetic
In 250 milliliters of reaction vessels, 5.0 gram Para-Anisidines are dissolved in 50 milliliters of toluene, add 18 milliliters of butanic acids, be heated to 130 ℃, back flow reaction is after 9 hours, stopped reaction.While hot excessive solvent and butanic acid are steamed, be cooled to room temperature, with petroleum ether gained solid, in the volume ratio of ethyl acetate and sherwood oil is recrystallization in 1: 1 ethyl acetate and the sherwood oil mixed solvent, obtain 6.24 gram white crystals, be determined as N-(4-p-methoxy-phenyl)-butyramide, productive rate: 80% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.86-87℃。
1H?NMR(400MHz，CDCl
3)：δ＝1.02(t，J＝7.36Hz，3H，CH
2CH
3)，1.77(m，2H，CH
2CH
2)，2.33(t，J＝7.36Hz，2H，CH
2CH
2)，3.79(s，3H，OCH
3)，6.86(d，J＝8.92Hz，2H，C
6H
4)，7.05(s，1H，NH)，7.42(d，J＝8.92Hz，2H，C
6H
4).
(2) 5-amide-based small-2-hydroxy acetophenone is synthetic
In 250 milliliters of reaction vessels, 5.0 gram N-(4-p-methoxy-phenyl)-butyramides are dissolved in 50 milliliters of methylene dichloride, add 18 gram Zinc Chloride Anhydrouss, again Dropwise 5 .5 milliliter Acetyl Chloride 98Min. slowly in reaction system.Room temperature reaction 35 hours, stopped reaction.
In reaction system, add trash ice and concentrated hydrochloric acid, after the gained solid all dissolves, separatory, with dichloromethane extraction water (15 milliliters * 3), merge organic phase, water and saturated sodium carbonate solution washing are to neutral, anhydrous magnesium sulfate drying filters, and rotary evaporation removes and desolvates.Thick product is a recrystallization in the mixed solvent of 1: 1 toluene and ethyl acetate in the volume ratio of toluene and ethyl acetate, obtain 4.50 gram white solids, be determined as 5-amide-based small-2-hydroxy acetophenone, productive rate 75% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.121-123℃
1H?NMR(CDCl
3，400MHz)：δ1.02(t，J＝7.32Hz，3H)，1.76(m，2H)，2.34(t，J＝7.36Hz，2H)，2.64(s，3H)，6.92(m，1H)，7.09(s，1H)，7.30(m，1H)，8.26(m，1H)，12，1(s，1H)。
(3) R-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone is synthetic
At 100 milliliters of reactors, 0.3 gram sodium hydroxide is dissolved in 10 ml waters, adds 1.0 gram 5-amide-based small-2-hydroxy acetophenones and 0.016 gram benzyl trimethyl ammonium chloride, treat that solid all dissolves, drip S-epoxy chloropropane (U.S. Sigma-Aldrich company, analytical pure) 1.2 milliliters.Temperature is controlled at room temperature ℃, after 15 hours, adds sodium hydroxide 0.3 gram, 0.6 milliliter of S-epoxy chloropropane.After 20 hours, continue to add sodium hydroxide 0.2 gram, 0.6 milliliter of S-epoxy chloropropane.Coreaction 40 hours obtains white suspension solution.Suction filtration is used the distilled water wash product, and vacuum-drying obtains 0.93 gram white solid, after 80 purpose silica gel column chromatographies separation purification, be determined as R-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), yield is 74%.
Mp.141-142℃。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.76(m，2H)，2.34(t，J＝7.32Hz，2H)，2.67(s，3H)，2.77(m，1H)，2.94(t，J＝4.60Hz，1H)，3.40(m，1H)，3.98(m，1H)，4.38(m，1H)，6.94-8.05(m，3H)，7.40(s，1H)。
(4) the R-acebutolol is synthetic
In 50 milliliters of reactors, with the 1 gram R-5-amide-based small-2-(2 that obtains in (3), the 3-glycidoxy)-methyl phenyl ketone is dissolved in 3.1 milliliters of Isopropylamines, add 0.18 ml water, 10-30 ℃ was reacted 20 hours, excessive Isopropylamine is removed in distillation, add 10 ml distilled waters, the salt acid for adjusting pH value of dropping 37% is 1-2, filter, filtrate is regulated the pH value to 10-12 with the 2wt% sodium hydroxide solution, obtains 0.81 gram white solid, is determined as the R-acebutolol through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), productive rate is 72%, optical purity is analyzed through HPLC (HIT), and the e.e. value is 93.0%, and used chiral column is OD-H (Japanese Daicel company).
Mp.125-126℃。
[α]
D 20＝-2.7(c?0.05，methanol)。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.13(d，J＝6.08Hz，6H)，1.76(m，2H)，2.33(t，J＝7.32Hz，3H)，2.62(s，3H)，2.78(m，1H)，2.94(m，2H)，4.08(s，3H)，6.94-7.88(m，3H)，7.33(s，1H)。
Embodiment 4
Synthesizing of R-acebutolol
(1) N-(4-p-methoxy-phenyl)-butyramide is synthetic
In 250 milliliters of reaction vessels, 10.0 gram Para-Anisidines are dissolved in 80 milliliters of toluene, add 12 milliliters of butanic acids, be heated to 140 ℃ of back flow reaction, after 7 hours, stopped reaction.While hot excessive solvent and butanic acid are steamed, be cooled to room temperature, with petroleum ether gained solid, in the volume ratio of ethyl acetate and sherwood oil is recrystallization in 1: 1 ethyl acetate and the sherwood oil mixed solvent, obtain 12.9 gram white crystals, be determined as N-(4-p-methoxy-phenyl)-butyramide, productive rate: 86% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.87-88℃。
1H?NMR(400MHz，CDCl
3)：δ＝1.02(t，J＝7.36Hz，3H，CH
2CH
3)，1.77(m，2H，CH
2CH
2)，2.33(t，J＝7.36Hz，2H，CH
2CH
2)，3.79(s，3H，OCH
3)，6.86(d，J＝8.92Hz，2H，C
6H
4)，7.05(s，1H，NH)，7.42(d，J＝8.92Hz，2H，C
6H
4).
(2) 5-amide-based small-2-hydroxy acetophenone is synthetic
In 250 milliliters of reaction vessels, 10.0 gram N-(4-p-methoxy-phenyl)-butyramides are dissolved in 100 milliliters of the sym.-tetrachloroethane, add 40 gram anhydrous stannic chlorides, slowly drip 4.5 milliliters of Acetyl Chloride 98Min.s again in reaction system.Behind the room temperature reaction 16 hours, add 10 gram anhydrous stannic chlorides, 1 milliliter of Acetyl Chloride 98Min..Coreaction 20 hours, stopped reaction.
In reaction system, add trash ice and concentrated hydrochloric acid, treat the gained solid all after the dissolving, separatory, with dichloromethane extraction water (25 milliliters * 3), merge organic phase, water and saturated sodium carbonate solution washing are to neutral, anhydrous magnesium sulfate drying filters, and rotary evaporation removes and desolvates.Thick product is a recrystallization in the mixed solvent of 1: 1 toluene and ethyl acetate in the volume ratio of toluene and ethyl acetate, obtain 8.90 gram white solids, be determined as 5-amide-based small-2-hydroxy acetophenone, productive rate 87% through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer).
Mp.121-122℃。
1H?NMR(CDCl
3，400MHz)：δ1.02(t，J＝7.32Hz，3H)，1.76(m，2H)，2.34(t，J＝7.36Hz，2H)，2.64(s，3H)，6.92(m，1H)，7.09(s，1H)，7.30(m，1H)，8.26(m，1H)，12，1(s，1H)。
(3) R-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone is synthetic
At 100 milliliters of reactors, 0.8 gram potassium hydroxide is dissolved in 10 ml waters, adds 1.0 gram 5-amide-based small-2-hydroxy acetophenones and 0.0013 gram tetrabutylammonium chloride, treat that solid all dissolves, drip S-epoxy chloropropane (U.S. Sigma-Aldrich company, analytical pure) 1.0 milliliters.Temperature is controlled at 25-30 ℃.After 9 hours, add potassium hydroxide 0.4 gram, 0.4 milliliter of S-epoxy chloropropane.Coreaction 20 hours obtains white suspension solution.Suction filtration is with distilled water water washing product, vacuum-drying.In the volume ratio of ethyl acetate and sherwood oil is recrystallization in 1: 1 ethyl acetate and the sherwood oil mixed solvent, obtain 0.98 gram white solid, be determined as R-5-amide-based small-2-(2 through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), the 3-glycidoxy)-and methyl phenyl ketone, yield is 81%.
Mp.141-143℃。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.76(m，2H)，2.34(t，J＝7.32Hz，2H)，2.67(s，3H)，2.77(m，1H)，2.94(t，J＝4.60Hz，1H)，3.40(m，1H)，3.98(m，1H)，4.38(m，1H)，6.94-8.05(m，3H)，7.40(s，1H)。
(4) the R-acebutolol is synthetic
In 50 milliliters of reactors, with the 1 gram R-5-amide-based small-2-(2 that obtains in (3), the 3-glycidoxy)-methyl phenyl ketone is dissolved in 7.7 milliliters of Isopropylamines, add 1.5 ml waters, 10-30 ℃ was reacted 15 hours, excessive Isopropylamine is removed in distillation, add 10 ml distilled waters, the salt acid for adjusting pH value of dropping 37% is 1-2, filter, filtrate is regulated the pH value to 10-12 with the 2wt% sodium hydroxide solution, obtains 0.89 gram white solid, be determined as the R-acebutolol through nuclear magnetic resonance analyser (the Switzerland 400MHz of Bruker company nuclear magnetic resonance spectrometer), productive rate is 80%.Optical purity is analyzed through HPLC (HIT), and the e.e. value is 93.8%, and used chiral column is OD-H (Japanese Daicel company).
Mp.125-126℃
[α]
D 20＝-2.7(c?0.05，methanol)。
1H?NMR(CDCl
3，400MHz)：δ1.00(t，J＝7.36Hz，3H)，1.13(d，J＝6.08Hz，6H)，1.76(m，2H)，2.33(t，J＝7.32Hz，3H)，2.62(s，3H)，2.78(m，1H)，2.94(m，2H)，4.08(s，3H)，6.94-7.88(m，3H)，7.33(s，1H)。
Embodiment 5
Synthesizing of S-acebutolol
Except the S-epoxy chloropropane with the step (3) of embodiment 1 changes R-epoxy chloropropane (U.S. Sigma-Aldrich company, analytical pure) in addition,, can obtain the S-acebutolol according to the synthetic S-acebutolol of the method for embodiment 1 synthetic R-acebutolol.Except the specific rotation of the S-acebutolol of present embodiment is different with the R-acebutolol of embodiment 1, other result and embodiment 1 the result all identical.
Claims (10)
1.R-or the method for asymmetric synthesis of S-acebutolol, it is characterized in that: said method comprising the steps of:
(1) N-(4-p-methoxy-phenyl)-butyramide is synthetic
Para-Anisidine is dissolved in the organic solvent, gained solution and butanic acid were reacted 6-9 hour under temperature is 130-150 ℃, isolate N-(4-p-methoxy-phenyl)-butyramide wherein;
(2) 5-amide-based small-2-hydroxy acetophenone is synthetic
N-(4-p-methoxy-phenyl)-butyramide that step (1) is obtained is dissolved in the organic solvent, gained solution is mixed with Lewis acid, in the gained mixture, drip acylating reagent then, 10-30 ℃ was reacted 20-35 hour down, isolates 5-amide-based small-2-hydroxy acetophenone solid product wherein;
(3) R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone is synthetic
5-amide-based small-2-hydroxy acetophenone that step (2) is obtained is dissolved in the inorganic alkali solution, in the presence of phase-transfer catalyst, drip S-or R-epoxy chloropropane then, 10-30 ℃ was reacted 20-40 hour, suction filtration also adds water washing, dry and obtain R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone;
(4) R-or S-acebutolol is synthetic
R-or S-5-amide-based small-2-(2 that step (3) is obtained, the 3-glycidoxy)-methyl phenyl ketone and Isopropylamine be in the presence of water, 10-30 ℃ was reacted 7-20 hour, excessive Isopropylamine is removed in distillation, add hydrochloric acid soln, regulate the pH value, filter to 1-2, regulate filtrate to pH 10-12 with sodium hydroxide solution, obtain high R-of optical purity or S-acebutolol.
2. method according to claim 1 is characterized in that: in described step (1), the consumption of described butanic acid is 1.5-5 a times of Para-Anisidine mole number.
3. method according to claim 2 is characterized in that: in described step (1), the consumption of described butanic acid is 3-5 a times of Para-Anisidine mole number.
4. according to claim 1,2 or 3 described methods, it is characterized in that: in described step (1), described organic solvent is a toluene, and its consumption is that every gram Para-Anisidine adds toluene 5-10ml.
5. method according to claim 1 is characterized in that: in described step (2), described organic solvent is a haloalkane, and its consumption is that every gram N-(4-p-methoxy-phenyl)-butyramide adds haloalkane 10-100ml;
In described step (2), described acylating reagent is an Acetyl Chloride 98Min., and its consumption is 1.5-5 a times of N-(4-p-methoxy-phenyl)-butyramide mole number;
In described step (2), described Lewis acid is selected from aluminum trichloride (anhydrous), Zinc Chloride Anhydrous or anhydrous stannic chloride, and its consumption is 1-4 a times of acylating reagent mole number.
6. method according to claim 5 is characterized in that: in described step (2), described haloalkane is methylene dichloride or sym.-tetrachloroethane.
7. method according to claim 1, it is characterized in that: in described step (3), the concentration of described inorganic alkali solution is 2-5wt%, the consumption of described mineral alkali is 3-5 a times of 5-amide-based small-2-hydroxy acetophenone mole number, and described inorganic alkali solution is potassium hydroxide solution or sodium hydroxide solution;
In described step (3), described phase-transfer catalyst is selected from benzyl trimethyl ammonium chloride or tetrabutylammonium chloride, and the consumption of described phase-transfer catalyst is 0.001-0.02 a times of 5-amide-based small-2-hydroxy acetophenone mole number;
In described step (3), the consumption of S-or R-epoxy chloropropane is 2-7 a times of 5-amide-based small-2-hydroxy acetophenone mole number;
8. method according to claim 1, it is characterized in that: in described step (3), after separation obtains R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone, by carrying out next step reaction after the column chromatography separation purification, perhaps carry out next step reaction behind the recrystallization.
9. method according to claim 1 is characterized in that: in described step (4), the mol ratio of R-or S-5-amide-based small-2-(2, the 3-glycidoxy)-methyl phenyl ketone and Isopropylamine is 1: 10-1: 25;
In described step (4), the consumption of described water is that every milliliter of Isopropylamine adds entry 0.05-0.2ml;
In described step (4), the concentration of described hydrochloric acid is 37wt%, and described concentration sodium hydroxide is 2-10wt%.
10. method according to claim 1 is characterized in that: the e.e. value of described R-or S-acebutolol is 92%-94%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113527123A (en) * | 2021-06-21 | 2021-10-22 | 山东盛安贝新能源有限公司 | Photochemical Fries rearrangement synthesis of beta receptor blocker Acebutonol intermediate |
| CN113979881A (en) * | 2021-11-16 | 2022-01-28 | 山东盛安贝新能源有限公司南京分公司 | Synthesis of side-chain fully-deuterated D17Method for preparing (S) -acebutolol |
| CN114230479A (en) * | 2021-12-16 | 2022-03-25 | 山东盛安贝新能源有限公司南京分公司 | Synthesis of side-chain fully-deuterated D13Method of treatment of (S) -diacetone |
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| CN113979881A (en) * | 2021-11-16 | 2022-01-28 | 山东盛安贝新能源有限公司南京分公司 | Synthesis of side-chain fully-deuterated D17Method for preparing (S) -acebutolol |
| CN114230479A (en) * | 2021-12-16 | 2022-03-25 | 山东盛安贝新能源有限公司南京分公司 | Synthesis of side-chain fully-deuterated D13Method of treatment of (S) -diacetone |
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