CN101768153B - Method for preparing israbipine medicament for treating hypertension - Google Patents
Method for preparing israbipine medicament for treating hypertension Download PDFInfo
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- CN101768153B CN101768153B CN2008102050141A CN200810205014A CN101768153B CN 101768153 B CN101768153 B CN 101768153B CN 2008102050141 A CN2008102050141 A CN 2008102050141A CN 200810205014 A CN200810205014 A CN 200810205014A CN 101768153 B CN101768153 B CN 101768153B
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- benzo furazan
- isrodipine
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Abstract
The invention relates to a method for preparing an israbipine medicament for treating hypertension. Particularly the method of the invention comprises the following steps: (a) carrying out oxidative cyclization on 2-amino-3-methyl nitrobenzene to form 4-methyl benzofuroxan oxide; (b) reducing the 4-methyl benzofuroxan oxide to form 4-methyl benzofuroxan; (c) carrying out substitution bromination on the 4-methyl benzofuroxan to form 4-bromomethyl benzofuroxan; (d) carrying out hydrolyzation on the 4-bromomethyl benzofuroxan to form 4-hydroxymethyl benzofuroxan; (e) carrying out oxidation on the 4-hydroxymethyl benzofuroxan to form 4-formaldehyde benzofuroxan; and (f) performing a reaction of the 4-formaldehyde benzofuroxan amd alpha-aminocrotonic acid isopropyl ester to form israbipine. The method of the invention has high yield and simple and convenient operation and can prepare high-purity israbipine.
Description
Technical field
The present invention relates to the preparation method of compound, relate more specifically to the preparation method of medicine Isrodipine (Isradipine).
Background technology
Isrodipine (Isradipine) is a kind of novel dihydropyridine calcium channel blocker.Isrodipine is by the exploitation of Switzerland mountain pass scholar (Sandoz) company, and first push to market by Britain vapour Ba-Jia Ji (Ciba-Geigy) company in February, 1989.
Isrodipine reduces peripheral vascular resistance by vasodilation, and coronary blood flow increasing improves the myocardial oxygen delivery function and reaches the purpose that brings high blood pressure down.
Isrodipine has stronger vasorelaxation action, and the acardia restraining effect causes reflex tachycardia hardly.Clinical and experimentation on animals proves; this medical instrument has tangible hypotensive effect and study of anti-atherogenic effect; by keeping or recovering the SE blood flow of left ventricle; prevent the ischemic infringement; improve the amount of exercise of stenocardia and congestive heart failure patients; in the hypertensive while of treatment, heart there is provide protection.Isrodipine can increase the drainage of sodium ion and water, and diuretic properties is arranged, and energy nephrectasia efferent artery and efferent artery reduce capillary of kidney and press, and kidney is had provide protection.
According to reports, the researchist finds to treat the hypertension agents Isrodipine and can also delay even end the Parkinsonism state of an illness.
Isrodipine is a class benzo furazan dihydropyridine compounds, and the purifying of its synthetic more complicated, particularly raw material is difficulty particularly.
U.S. Pat 4466972 and PCT application WO2005/00437 disclose the synthetic method of two kinds of Isrodipines respectively.Yet the product of existing method preparation all contains a certain amount of following formula homologue impurity, and the impurity structure is as follows:
In the formula, R
1, R
2Be methyl, ethyl and sec.-propyl at the same time or separately.Described homologue impurity and Isrodipine are separated very difficulty, cause effectively purifying Isrodipine.
In addition, relate to crucial intermediate 4-methyl benzo furazan among the existing preparation technology.Yet the preparation method of this key intermediate still is difficult to satisfactory.For example, disclose a kind of preparation method of intermediate 4-methyl benzo furazan in the Chinese patent application 200510125267 (publication number CN1847233A), its preparation flow is as follows:
Obviously, above method steps length, operational hazards, poor controllability, and cause a large amount of pollutions.
Therefore, this area presses for the exploitation method for preparing Isrodipine and important intermediate 4-methyl benzo furazan thereof new, high-efficient simple.
Summary of the invention
One of purpose of the present invention is to provide a kind of yield height, the high and method for preparing the medicine Isrodipine easy and simple to handle of purity.
Be to provide a kind of yield height in two of purpose of the present invention, the method for preparing medicine Isrodipine intermediate easy and simple to handle.
Three of purpose of the present invention is to provide a kind of yield height, the method for preparing beta-amino Ba Dousuan isopropyl ester that purity is high.
In a first aspect of the present invention, a kind of preparation method of Isrodipine is provided, comprise step:
(a) in inert solvent, 2-amino-3-methyl oil of mirbane is carried out oxidation close ring, form 4-methyl benzo furazan oxide compound, i.e. formula 2 compounds;
(b) in inert solvent, make the reduction of 4-methyl benzo furazan oxide compound to form 4-methyl benzo furazan, i.e. formula 3 compounds;
(c) in inert solvent, 4-methyl benzo furazan is replaced bromination, form 4-brooethyl benzo furazan;
(d) in inert solvent, 4-brooethyl benzo furazan is hydrolyzed, form 4-methylol benzo furazan;
(e) in inert solvent, 4-methylol benzo furazan is carried out oxidation, form 4-carboxaldehyde radicals benzo furazan; With
(f), form Isrodipine by step (f1) or (f2):
(f1) in inert solvent,, form Isrodipine with 4-carboxaldehyde radicals benzo furazan, beta-amino Ba Dousuan isopropyl ester (compound 8) and methyl acetoacetate reaction; Perhaps
(f2) in inert solvent, 4-carboxaldehyde radicals benzo furazan is carried out dehydrating condensation, form formula 7 compounds, and react with beta-amino Ba Dousuan isopropyl ester (compound 8),
Thereby formation Isrodipine.
In another preference, described method also comprises step:
(g) Isrodipine that forms in the purification procedures (f).
In another preference, crystallization process is adopted in described separation and purification.
In another preference, the Isrodipine that forms in the step (f) is carried out crystallization in ethanol, thereby make purity＞99% () Isrodipine more preferably＞99.5%.
In another preference, in the presence of the mineral alkali that is selected from potassium hydroxide or sodium hydroxide, carry out in the step (a).
In another preference, inert solvent comprises the arbitrary combination of methyl alcohol, ethanol, Virahol, water or above-mentioned solvent in the step (a), more preferably is ethanol.
In another preference, in the presence of hypochlorite, carry out in the step (a) as oxygenant.
In another preference, the temperature of reaction of step (a) is-20-40 ℃.
In another preference, described method also comprises following one or more feature:
Step (b) is being selected from oxammonium hydrochloride or Pd/C-H
2Reduction system under carry out; And/or
Step (d) is carried out under the hydrolysing agent that is selected from sulfuric acid, hydrochloric acid, lime carbonate, salt of wormwood, lithium hydroxide, sodium hydroxide or potassium hydroxide; And/or
In step (e), the oxygenant of use comprises: DMP
Or Manganse Dioxide.
In another preference, the inert solvent in the step (f1) comprises: ethanol, Virahol, the trimethyl carbinol or its combination.
In another preference, the inert solvent in the step (f1) is the trimethyl carbinol and ethanol mixed solvent, and wherein the trimethyl carbinol/alcoholic acid blending ratio is 5: 1-1: 5.
In another preference, the inert solvent in this rapid (f12) comprises: ethanol, Virahol, the trimethyl carbinol or its both combination arbitrarily.
In another preference, described inert solvent is the trimethyl carbinol and ethanol mixed solvent, and wherein the trimethyl carbinol/alcoholic acid blending ratio is 5: 1-1: 5.
In another preference, step (f2) is carried out in the presence of catalyzer, and described catalyzer comprises concentrated hydrochloric acid, the vitriol oil and aceticanhydride/vitriol oil.
In another preference, described method also comprises step (h): isolating Isrodipine is mixed with pharmaceutically acceptable carrier, thereby make the pharmaceutical composition that contains Isrodipine.
Embodiment
Extensive studies has been improved preparation technology, the especially preparation technology of its intermediate 4-carboxaldehyde radicals benzo furazan of Isrodipine to the inventor through going deep into, thereby can prepare highly purified Isrodipine efficiently, easily.Finished the present invention on this basis.
As used herein, term " Isrodipine " refers to the compound that structure is represented as shown in the formula I:
The Chinese of Isrodipine another name comprises that Isradipine, Prescal, leader are suitable.Its outer literary fame comprises Isradipine, PN-200-110, COMIR, PRESCAL, DYNACIRC, Vascal.Should be understood that described term not only comprises formula I compound, also can comprise the pharmacy acceptable salt of formula I compound.
Preparation method of the present invention is more specifically described below.However, it should be understood that the present invention is not limited to following given concrete reaction conditions (as the amount of solvent, compound used therefor, temperature of reaction, reaction required time etc.).
In flow process of the present invention, each reaction in inert solvent, is carried out to reflux temperature (as 0 ℃～100 ℃, preferred 0 ℃～80 ℃) in room temperature usually.Reaction times was generally 0.1 hour-60 hours, preferably was 0.5-48 hour.
Preparation method of the present invention can represent with following flow process:
Flow process 1 is described below more specifically:
(a) .2-amino-3-methyl oil of mirbane closes ring through oxidation, forms 4-methyl benzo furazan oxide compound (compound 2)
In this step, spendable inert solvent comprises the arbitrary combination of methyl alcohol, ethanol, Virahol, water or above-mentioned solvent.A kind of preferred solvent is an ethanol.
Employed oxygenant is a hypochlorite.
Alkali is not particularly limited, and can adopt mineral alkalis such as potassium hydroxide, sodium hydroxide, preferred potassium hydroxide.
Temperature of reaction is not particularly limited, and is generally-20-40 ℃, preferably is 10-25 ℃.
Reaction times is not particularly limited, and is generally 3-20 hour, preferably is 5-10 hour.
(b). compound 2 forms 4-methyl benzo furazan (compound 3) through reduction reaction
In this step, spendable inert solvent (reaction system) comprises the proton type solvent of methyl alcohol, ethanol, Virahol or its arbitrary combination.A kind of particularly preferred solvent is an ethanol.
Reduction system can use oxammonium hydrochloride/alkali or Pd/C-H
2As reduction system, preferred oxammonium hydrochloride/alkali systems.
In addition, this step also can adopt inert solvent to make reaction solvent, preferred toluene, and adopt trihydrocarbyl phosphine as going back original reagent, triphenylphosphine.
Temperature of reaction is not particularly limited, and is generally 0-100 ℃, preferably is 75-90 ℃.
Reaction times is not particularly limited, and is generally 1-12 hour, preferably is 3-8 hour.
(c) but. by compound 3 preparation compounds 6 ordinary methods, for example press document Eur.J.Med.Chem (1996) 31,3-10 enforcement.
Compound 3 is substituted bromination reaction, forms 4-brooethyl benzo furazan (compound 4).
In this step, spendable inert solvent comprises inert solvents such as chlorobenzene, tetracol phenixin.
Bromide reagent is not particularly limited, and can adopt bromine, bromo-succinimide (NBS) and other bromide reagents of this area routine.A kind of preferred bromide reagent is NBS.
The available initiator comprises (but being not limited to): Benzoyl Peroxide or azo dibutyronitrile, preferred Benzoyl Peroxide.
Temperature of reaction is not particularly limited, and is generally 25-100 ℃, preferably is 70-90 ℃.
Reaction times is not particularly limited, and is generally 1-24 hour, preferably is 2-5 hour.
(d). compound 4 forms 4-methylol benzo furazan (compound 5) through hydrolysis reaction.
In this step, spendable inert solvent comprises (but being not limited to): 1, and the arbitrary combination of 4-dioxane, tetrahydrofuran (THF), ethanol, methyl alcohol, Virahol, water or above-mentioned solvent.The mixture that a kind of preferred solvent is tetrahydrofuran (THF) and water (both blending ratios are 1: 1 to 5: 1).
Spendable hydrolysing agent comprises (but being not limited to): mineral acid (as sulfuric acid, hydrochloric acid etc.), perhaps mineral alkali (as lime carbonate, salt of wormwood, lithium hydroxide, sodium hydroxide, potassium hydroxide etc.).A kind of preferred hydrolysing agent is a lime carbonate.
Temperature of reaction is not particularly limited, and is generally 50-100 ℃, preferably carries out under reflux temperature.
Reaction times is not particularly limited, and is generally 1-48 hour, preferably is 3-24 hour.
(e). compound 5 forms 4-carboxaldehyde radicals benzo furazan (compound 6) through oxidizing reaction
In this step, adoptable inert solvent comprises (but being not limited to): methylene dichloride, chlorobenzene, tetracol phenixin, chloroform or its combination.A kind of preferred inert solvent is a chlorobenzene.
Spendable oxygenant comprises (but being not limited to): DMP
Or Manganse Dioxide.Preferred oxygenant is a Manganse Dioxide.
Temperature of reaction is not particularly limited, and is generally 10-100 ℃, preferably is 50-70 ℃.
Reaction times is not particularly limited, and is generally 1-24 hour, preferably is 3-10 hour.
(f). by step (f1) or (f2), form Isrodipine:
(f1) compound 6 is obtained compound 7 through dehydrating condensation.It is catalyzer that this dehydration condensation should adopt aceticanhydride-sulfuric acid.
ISOPROPYL ACETOACETATE and ammonium formiate be prepared in reaction compound 8 in solvent.
Then, compound 7 and compound 8 are obtained the compound Isrodipine through condensation reaction.
In this step, spendable inert solvent comprises (but being not limited to): ethanol, Virahol, the trimethyl carbinol or its both combination arbitrarily.A kind of preferred inert solvent is the trimethyl carbinol and ethanol mixed solvent, and wherein the trimethyl carbinol/alcoholic acid blending ratio is 5: 1-1: 5, and preferably be 2: 1-1: 2 (as 1: 1).
In this step, reaction system should adopt protection of inert gas such as nitrogen, argon gas.
Temperature of reaction is not particularly limited, and is generally 5-70 ℃, preferably is 15-25 ℃.
Reaction times is not particularly limited, and is generally 1-72 hour, for the reaction times is 2-36 hour, more preferably is 8-24 hour preferably.
(f2) compound 6, beta-amino Ba Dousuan isopropyl ester (compound 8) and methyl acetoacetate one pot reaction form Isrodipine.
In this step, spendable inert solvent comprises (but being not limited to): ethanol, Virahol, the trimethyl carbinol or its both combination arbitrarily.A kind of preferred inert solvent is the trimethyl carbinol and ethanol mixed solvent, and wherein the trimethyl carbinol/alcoholic acid blending ratio is 5: 1-1: 5, and preferably be 2: 1-1: 2 (as 1: 1).
In this step, reaction system should adopt protection of inert gas such as nitrogen, argon gas.
Temperature of reaction is not particularly limited, and is generally 5-70 ℃, preferably is 15-25 ℃.
Reaction times is not particularly limited, and is generally 1-72 hour, for the reaction times is 2-36 hour, more preferably is 8-24 hour preferably.
Reaction process needs the catalyst reaction, and adoptable catalyzer has concentrated hydrochloric acid, the vitriol oil, aceticanhydride/vitriol oil, is preferably aceticanhydride/vitriol oil system.
The major advantage of the inventive method is:
(a) compound 2 is synthetic, adopts oxidation to close the ring method, abandons the shortcoming of the employing azide reaction of former method.
(b) compound 6 is synthetic, process stabilizing, constant product quality.
(c) adopt the trimethyl carbinol/ethanol mixed system as solvent in the building-up process of compound 8 and Isrodipine (Isradipine), gone out the homologous compound impurity in the end product effectively, can obtain qualified product easily.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Among all embodiment, fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct; 1H-NMR Varian Mercury 400 nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm); Separate with the unaccounted 200-300 order that is of silica gel.Ultimate analysis is measured with Elementa Vario EL III type elemental analyser; Mass spectrum is measured with Agilent1100 LC-MS mass spectrograph; HPLC is Tianjin, island system.
Embodiment 14-methyl benzo furazan oxide compound (compound 2)
(22.8g 0.15mol), adds the ethanolic soln (200ml) of KOH (10g) then, and the ice bath cooling drips NaClO solution (100ml) down, dropwises to continue ice-water bath reaction down to add compound 1 in three mouthfuls of round-bottomed flasks of 1L.Reaction finishes, and adds CH in the system
2Cl
2(150ml) stir, the elimination insolubles, filtrate is told organic phase, anhydrous Na
2SO
4Drying concentrates.Get the 20.77g crude product.Add re-crystallizing in ethyl acetate and get the yellow needle-like crystal of 15.5g, productive rate 68.9%.
Embodiment 24-methyl benzo furazan oxide compound (compound 2)
(a) add in three mouthfuls of round-bottomed flasks of 500mL compound 1 (30.4g, 0.2mol), water (80mL) and concentrated hydrochloric acid (45mL), after the ice bath cooling, drip Sodium Nitrite (14.5g, aqueous solution 0.21mol) (50mL), drip end after, insulated and stirred 1 hour.
(b) suction filtration, filtrate are poured in the 1L beaker, add under the condition of ice bath in batches sodium azide (13g, 0.2mol), after adding, insulated and stirred 1 hour, suction filtration, filter cake washing (100mL, 2 times).
(c) gained filter cake input in (b) process is equipped with in three mouthfuls of round-bottomed flasks of toluene (60mL), slowly be warming up to backflow, back flow reaction 5 hours, system is cooled to room temperature, and suction filtration is gone out insolubles, and filtrate concentrates, the residue cooling crystallization, the dry compound crude product (15g) that gets of suction filtration, re-crystallizing in ethyl acetate gets the yellow needle-like crystal of 11.5g, productive rate 38.3%.
Embodiment 3 4-methyl benzo furazans (compound 3)
(17.4g 116.0mmol) is dissolved in ethanol (200ml), adds NH with compound 2
2OHHCl (9.7g, aqueous solution 139.6mmol), mixture are chilled to 0 ℃, add while stirring then KOH (23.4g, aqueous solution 417.9mmol) (150ml), after adding, reflux.The monitoring of TLC plate.Reaction finishes, and reactant is chilled to room temperature, n-hexane extraction (400ml * 2,200ml * 2), and normal hexane is washed (500ml), anhydrous Na mutually
2SO
4Drying concentrates.Get 4-methyl benzo furazan, be orange powder (11.55g) that productive rate is 74.3%.
1H-NMR(CDCl
3)：7.64-7.61(1H，d)，7.32-7.27(1H，m)，7.11-7.09(1H，d)，2.65(3H，s)
Embodiment 4 4-brooethyl benzo furazans (compound 4)
With compound 3 (16.1g 120mmol) is dissolved in the tetracol phenixin (150ml), add then NBS (23.5g, 132mmol) and Bz
2O
2(0.29g, 1.2mmol), mixture is warming up to 80-85 ℃ of reaction, and reaction finishes, and system is reduced to 40 ℃, filters filtrate washing (200ml * 2), organic phase anhydrous Na
2SO
4Drying, concentrating under reduced pressure gets crude product (25.6g), and sherwood oil (80ml) recrystallization forms the Powdered crystal of milk yellow, i.e. 4-brooethyl benzo furazan (18.47g).Productive rate is 72%.(HPLC measures, and purity is 88%)
1H-NMR(CDCl
3)：7.83-7.80(1H，m)，7.47-7.39(2H，m)，4.83(2H，s)
Embodiment 5 4-methylol benzo furazans (compound 5)
In the there-necked flask, (18.0g 84.5mmol) is dissolved in tetrahydrofuran (THF) (200ml) to compound 4, adds CaCO then
3(42.1g, 421mmol) and water (200ml), mixture heating up refluxes, TLC plate monitoring reaction.Reaction finishes, and filters, and concentrates.Residue adds CH
2Cl
2(90ml) and H
2O (100ml) stirring and dissolving, separatory, water CH
2Cl
2(50ml * 2) extraction, drying, concentrate the 12.37g crude product, ethyl acetate (25ml) recrystallization gets yellow needle-like crystal, i.e. 4-methylol benzo furazan (6.68g), the purity that HPLC measures is 98.7%, productive rate is 52.7%.
1H-NMR(CDCl
3)：7.76-7.73(1H，m)，7.43-7.39(2H，m)，5.11-5.09(2H，d)
Embodiment 6 4-carboxaldehyde radicals benzo furazans (compound 6)
(6.5g 43.3mmol) is dissolved in the chlorobenzene (270ml), adds MnO with compound 5
2(34.7g, 398.9mmol), 60 ℃ of stirrings of mixture, reaction finishes, and filters filter cake chlorobenzene (60ml) washing.Filtrate concentrates, and gets 4-carboxaldehyde radicals benzo furazan 6 (5.9g) of light yellow solid shape, productive rate 92.0%.
1H-NMR(CDCl
3)：10.40(1H，s)，8.19-8.17(1H，m)，8.09-8.07(1H，m)，7.68-7.65(1H，m)
Embodiment 7 beta-amino Ba Dousuan isopropyl esters (compound 8)
With ISOPROPYL ACETOACETATE (72.0g, 0.5mol), ammonium acetate (57.8g, 0.75mol) and the trimethyl carbinol/ethanol (1: 1,600ml) be mixed in the 1000ml flask, add 300 order molecular sieves (50g), reflux, TLC plate monitoring.After the basic end of reaction, reduce to room temperature, filter, filtrate is concentrated into absence of liquid and steams, and the residual liquid underpressure distillation is collected 110-120 ℃ of cut (vacuum tightness 0.1MPa) and got compound 8 (66.0g).Y＝92.4％。
1H-NMR(CDCl
3)：5.02-4.95(1H，m)，4.48(1H，s)，1.88(3H，d)，1.23-1.21(6H，d)
Embodiment 8 Isrodipines (Isradipine)
At N
2Protection down, in the there-necked flask with compound 6 (3.0g, 20mmol), beta-amino Ba Dousuan isopropyl ester (compound 8) (2.7g, 16.6mmol), methyl acetoacetate (3.50g, 30mol), Ac
2O (2.05g, 20mmol), dense H
2SO
4(0.4g, 4mmol) and the trimethyl carbinol/ethanol (1: 1,65ml) mix to stir, the liquid phase monitoring, when compound 6 residues are less than 3.7%, stopped reaction.Reactant is concentrated residue CH
2Cl
2Dissolving (55ml), washing (45ml * 2), drying concentrates, and oil pump is drained, and gets the yellow bubble of 6.7g powder solid.Add ethanol (20ml) heating for dissolving, stirring and crystallizing (spending the night) gets pale yellow powder Isrodipine (4.3g) (HPLC purity＞99.8%, the homologue foreign matter content is all less than 0.1%), productive rate 66.8%.
1H-NMR(CDCl
3)：7.62-7.60(1H，m)，7.31-7.26(2H，m)，5.46(1H，s)，4.92-4.86(1H，m)，3.57(3H，s)，2.32-2.30(6H，m)，1.21-1.19(3H，d)，0.95-0.94(3H，d)
The comparative example 1
Isrodipine (Isradipine) prepares by U.S. Pat 4466972 methods:
At N
2Protection down, in the there-necked flask with compound 6 (3.0g, 20mmol), beta-amino Ba Dousuan isopropyl ester (compound 8) (2.7g, 16.6mmol), methyl acetoacetate (3.50g, 30mol), Ac
2O (2.05g, 20mmol), dense H
2SO
4(0.4g, 4mmol) and ethanol (65ml) mix to stir, the liquid phase monitoring, when compound 6 residues are less than 3.7%, stopped reaction.Reactant is concentrated residue CH
2Cl
2Dissolving (55ml), washing (45ml * 2), drying concentrates, and oil pump is drained, and gets the yellow bubble of 6.3g powder solid.Add ethanol (20ml) heating for dissolving, stirring and crystallizing (spending the night), pale yellow powder Isrodipine (4.1g) (HPLC purity: 99.0%, the homologue foreign matter content is all greater than 0.3%), productive rate 63.7%.
Compare with comparative example 1 (the homologue foreign matter content is all greater than 0.3%), by homologue foreign matter content in the prepared Isrodipine of embodiment of the invention 1-8 less than 0.1%.
Embodiment 10 Isrodipines
Repeat embodiment 8, difference is, with the trimethyl carbinol/ethanol (1: 2,70ml) or the trimethyl carbinol/ethanol (2: 1,70ml) replace the trimethyl carbinol/ethanol (1: 1,65ml).
The result shows, the productive rate of Isrodipine is about 62%, and the homologue foreign matter content is less than 0.1% after measured.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (9)
1. the preparation method of an Isrodipine is characterized in that, comprises step:
(a) in inert solvent, 2-amino-3-methyl oil of mirbane is carried out oxidation close ring, form 4-methyl benzo furazan oxide compound, i.e. formula 2 compounds;
(b) in inert solvent, make the reduction of 4-methyl benzo furazan oxide compound to form 4-methyl benzo furazan, i.e. formula 3 compounds;
(c) in inert solvent, 4-methyl benzo furazan is replaced bromination, form 4-brooethyl benzo furazan;
(d) in inert solvent, 4-brooethyl benzo furazan is hydrolyzed, form 4-methylol benzo furazan;
(e) in inert solvent, 4-methylol benzo furazan is carried out oxidation, form 4-carboxaldehyde radicals benzo furazan; With
(f), form Isrodipine by step (f1) or (f2):
(f1) in inert solvent,, form Isrodipine with 4-carboxaldehyde radicals benzo furazan, beta-amino Ba Dousuan isopropyl ester and methyl acetoacetate reaction; Perhaps
(f2) in inert solvent, 4-carboxaldehyde radicals benzo furazan is carried out dehydrating condensation, form formula 7 compounds, and react with beta-amino Ba Dousuan isopropyl ester,
Thereby formation Isrodipine.
2. the method for claim 1 is characterized in that, described method also comprises step:
(g) Isrodipine that forms in the purification procedures (f).
3. method as claimed in claim 2 is characterized in that, crystallization process is adopted in described separation and purification.
4. the method for claim 1 is characterized in that, carries out in the presence of the mineral alkali that is selected from potassium hydroxide or sodium hydroxide in the step (a).
5. the method for claim 1 is characterized in that, inert solvent is selected from the arbitrary combination of methyl alcohol, ethanol, Virahol, water or above-mentioned solvent in the step (a).
6. the method for claim 1 is characterized in that, carries out in the presence of the hypochlorite as oxygenant in the step (a).
7. the method for claim 1 is characterized in that, described method also comprises following one or more feature:
Step (b) is being selected from oxammonium hydrochloride or Pd/C-H
2Reduction system under carry out; And/or
Step (d) is carried out under the hydrolysing agent that is selected from sulfuric acid, hydrochloric acid, lime carbonate, salt of wormwood, lithium hydroxide, sodium hydroxide or potassium hydroxide; And/or
In step (e), the oxygenant of use is selected from: DMP
Or Manganse Dioxide.
8. the method for claim 1 is characterized in that, the inert solvent in the step (f1) is selected from: ethanol, Virahol, the trimethyl carbinol or its combination; And/or
Inert solvent in the step (f2) is selected from: ethanol, Virahol, the trimethyl carbinol or its both combination arbitrarily.
9. the method for claim 1 is characterized in that, step (f2) is carried out in the presence of catalyzer, and described catalyzer is selected from concentrated hydrochloric acid, the vitriol oil and aceticanhydride/vitriol oil.
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| CN103613584B (en) * | 2013-11-27 | 2016-04-27 | 沈阳药科大学 | The method of a kind of Isrodipine synthetic product aftertreatment |
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| CN102276547B (en) * | 2011-05-04 | 2013-07-17 | 山东省医药工业研究所 | Preparation method of isradipine key intermediate 4-formoxylbenzofuran |
| CN102846609B (en) * | 2011-06-27 | 2015-01-21 | 合肥华方医药科技有限公司 | Synthesis method for antihypertensive agent isradipine and preparation of isradipine |
| CN102766137B (en) * | 2012-08-07 | 2015-07-08 | 四川百利药业有限责任公司 | Method for preparing high-purity isradipine |
| CN102942534A (en) * | 2012-12-13 | 2013-02-27 | 牟英迪 | Preparation of drug intermediate 4-formoxyl benzofuroxan |
| CN115010622B (en) * | 2022-06-20 | 2024-01-09 | 山东百启生物医药有限公司 | Preparation method of 2-bromo-5-cyanobenzaldehyde |
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| CN103613584B (en) * | 2013-11-27 | 2016-04-27 | 沈阳药科大学 | The method of a kind of Isrodipine synthetic product aftertreatment |
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