CN108530359A - A kind of preparation method of Ivabradine impurity - Google Patents
A kind of preparation method of Ivabradine impurity Download PDFInfo
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- CN108530359A CN108530359A CN201710116177.1A CN201710116177A CN108530359A CN 108530359 A CN108530359 A CN 108530359A CN 201710116177 A CN201710116177 A CN 201710116177A CN 108530359 A CN108530359 A CN 108530359A
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- 0 C*CC(Cc1c2)c1cc(OI=C)c2O* Chemical compound C*CC(Cc1c2)c1cc(OI=C)c2O* 0.000 description 8
- BGQGHNWCZFMWLS-UHFFFAOYSA-N CNC1=CC(C(CNCCCN(CCC(C(C2)=CC3OC)=CC3OC)C2=[U])C2)C2CC1O Chemical compound CNC1=CC(C(CNCCCN(CCC(C(C2)=CC3OC)=CC3OC)C2=[U])C2)C2CC1O BGQGHNWCZFMWLS-UHFFFAOYSA-N 0.000 description 1
- RSTADEZTEPXMFI-UHFFFAOYSA-N COc(cc(CC1C[N]2(CCCN(CCc(cc3OC)c(C4)cc3[U]C)C4=O)CC2)c1c1)c1OC Chemical compound COc(cc(CC1C[N]2(CCCN(CCc(cc3OC)c(C4)cc3[U]C)C4=O)CC2)c1c1)c1OC RSTADEZTEPXMFI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of Ivabradine impurity preparation methods, it is raw material to specifically include SM01 and SM02, impurity I and II are obtained through multistep reaction, the preparation method of the present invention is simple, obtained impurity purity is high, it can be used for qualitative and quantitative analysis, to improve the drug safety of Ivabradine.
Description
Technical field
The present invention relates to a kind of preparation methods of Ivabradine impurity.
Background technology
Ivabradine (Ivabradine, trade name:Procoralan) it is the anti-of Servier companies of France development
Angina pectoris new drug, in November, 2005 examine office's approval in the country's listing of 27, Europe through European medicine, block beta-receptor for treating
Medicine is avoided or intolerable chronic stable angina pectoris.The medicine is first selection Specific cardiac pacemaker current inhibitor, tool
There is special reduction heart rate function.
Chemistry entitled 3- { 3- [{ [bicyclic [4.2.0] octyl- 1,3 of (7S) -3,4- dimethoxys, the 5- tri- of Ivabradine
Alkene -7- bases]-methyl } (methyl) amino] propyl } -7,8- dimethoxys -1,3,4,5- tetrahydrochysene -2H-3- benzazepines -2-
Ketone, molecular formula:C27H36N2O5, relative molecular mass:468, structural formula is as follows:
According to the preparation method for the Ivabradine reported in existing literature, in preparing Ivabradine reaction, benzo
Methyl on four-membered ring is easy to leave away, and generates phenolic hydroxyl group;Benzo heptatomic ring and benzo four-membered ring can also give birth in docking is reacted
At by-product, structural formula is as follows:
Work as R5For hydrogen when, Formula V chemical combination be impurity I, corresponding impurity structure be Ia, Ib, Ic and Id, work as R5For methyl when, formula
V chemical combination is impurity II, and corresponding impurity structure is IIa, IIb and IIc.Concrete structure is as follows:
The relative substance of Ivabradine it has been reported that《General bureau's import drugs registration mark is supervised in state food drug control
It is accurate》Standard No. JX20120088 reports two kinds of impurity in standard, at present by Literature Consult, does not also find there is text at present
Offer the open specific preparation method for reporting this impurity.
Invention content
Technical problem solved by the invention is to provide a kind of preparation method of Ivabradine impurity, the preparation method
Simply, purification process is simple, and impurity high income obtained solves Ivabradine impurity and prepares difficult problem.
The present invention solves above-mentioned technical problem by the following technical programs.
The present invention provides a kind of preparation methods of Ivabradine impurity comprising following step:
1. formula III compound is reacted to obtain formula IV compound;2. the hydroxyl protection base of formula IV compound is deprotected, simultaneously
Double bond restores to get Formula V compound;
Wherein R1、R2And R5It is respectively selected from hydrogen or methyl, R1、R2And R5It is asynchronously methyl;R3、R4It is respectively selected from benzyl, Bian
Oxygen carbonyl, acetyl group, trimethyl silicon substrate, tert-butyl diphenyl silicon substrate, THP trtrahydropyranyl, methoxy or methyl;R6It is selected from
Halogen or aldehyde radical.
By common sense in the field, the R in formula III compound5For hydrogen when, obtained Formula V compound is impurity I;R5For methyl
When, obtained Formula V compound is impurity II;
Formula III compound and conventional method and item that the method and condition of SM02 reacted can be the such reaction in this field
Part.In the specific implementation mode of the present invention, R6For halogen when, formula III compound is substituted in the presence of a base with SM02 reacts
Obtain formula IV compound;As the R in SM026For aldehyde radical when, formula III compound and SM02 are in the presence of alkali and reducing agent through restoring amine
Formula IV compound is reacted to obtain in change.It is following preferred routes one or route two from the reacted formula IV compound that obtains of formula III compound:
Route one:R6For halogen when, formula III compound is substituted in the presence of a base with SM02 reacts to obtain formula IV compound;
Route two:R6For aldehyde radical when, formula III compound obtains in the presence of alkali and reducing agent through reductive amination process with SM02
Formula IV compound;
Step is 1.) in reaction carry out in the presence of a base, the alkali be triethylamine, diisopropylethylamine, pyridine, DBU, DMAP
Sodium bicarbonate, saleratus, caesium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, lithium hydroxide, sodium hydroxide and hydrogen
It is one or more in potassium oxide;The solvent of reaction is selected from toluene, acetone, dichloromethane, dioxane, DMF, DMSO and acetonitrile
In it is one or more;The reducing agent of reduction reaction be selected from acetic acid sodium borohydride, sodium cyanoborohydride, sodium borohydride, potassium borohydride,
Tetra isopropyl oxygen titanium/sodium cyanoborohydride, zinc/acetic acid, zinc borohydride/zinc chloride are one or more in borine/pyridine;Also
The solvent of original reaction is selected from toluene, methanol, ethyl alcohol, acetic acid, and tetrahydrofuran and 1 is one or more in 2- dichloroethanes.
Step is 2.) in deprotection and double bond reduction reaction solvent be selected from acetic acid, methanol, ethyl alcohol, ethyl acetate, tetrahydrochysene furan
Mutter with it is one or more in methyltetrahydrofuran;Catalyst is selected from palladium charcoal, palladium dydroxide or Raney's nickel;Hydrogen donor is selected from hydrogen
Gas, hydrogen, ammonium chloride, cyclohexene are one or more in cyclohexadiene and tetrahydronaphthalene.
In the preferred embodiment of the present invention, R5For hydrogen, the formula III compound (i.e. compound 7) is by following sides
Method one is made:
1) using compound SM01 as starting material, compound 2 is obtained by the reaction through hydroxyl protection;
2) compound 2 obtains compound 3 with cyanoacetic acid through condensation reaction;
3) compound 3 obtains compound 4 through reduction reaction;
4) compound 4 reacts to obtain compound 5 through depickling;
5) compound 5 obtains compound 6 through ring closure reaction;
6) compound 6 through reduction reaction to get;
In another preferred embodiment of the present invention, R5For methyl, the formula III compound (compound 9) is by following
Method two is made:
7) compound 7 reacts to obtain compound 8 through the protection of amino active ester;
8) 8 active ester of compound reduction to get;
R7Selected from methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl or Bian oxygen carbonyl.
The method and condition of above-mentioned reaction can be the conventional method and condition of the such reaction in this field.
In step 1) hydroxyl protection react alkali be selected from sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide and
Lithium hydroxide it is one or more;The solvent of reaction be selected from DMF, dichloromethane, toluene, tetrahydrofuran, methyltetrahydrofuran, two
It is one or more in six ring of oxygen and DMSO;Reaction temperature is selected from -10 DEG C~50 DEG C.
The condensing agent of condensation reaction described in step 2) is selected from dicyclohexylcarbodiimide, 1- hydroxy benzo triazoles, O-
Benzotriazole-tetramethylurea hexafluorophosphate, O- benzotriazole-N, N, N, N- tetramethylurea tetrafluoro boric acid and hexafluorophosphoric acid
Benzotriazole -1- bases-oxygroup tripyrrole alkyl phosphorus it is one or more;The solvent of reaction is selected from toluene, isopropyl acetate and second
It is one or more in acid butyl ester;The solvent of reaction be selected from DMF, tetrahydrofuran, dimethyl sulfoxide (DMSO), trifluoroethanol, trifluoroacetone,
Dichloromethane, it is one or more in 1,2- dichloroethanes.
Solvent in step 3) in reduction reaction is selected from methanol, ethyl alcohol, water, dioxane, tetrahydrofuran and methyl tetrahydrochysene
It is one or more in furans;The alkali of reaction is selected from sodium bicarbonate, saleratus, sodium carbonate, potassium carbonate, cesium carbonate, hydroxide
Lithium, sodium hydroxide, potassium hydroxide are one or more in potassium acetate and sodium acetate;The reducing agent of reduction reaction is selected from hydroboration
Sodium, potassium borohydride, sodium cyanoborohydride are one or more in cyano potassium borohydride or borine;The acid of reaction is selected from hydrochloric acid, sulphur
It is one or more in acid, phosphoric acid, acetic acid, citric acid, oxalic acid or methanesulfonic acid;The extractant of post-reaction treatment is selected from acetic acid second
It is one or more in ester, isopropyl acetate, dichloromethane or toluene.
The solvent that depickling is reacted in step 4) is selected from DMF, DMSO, N-methyl pyrrolidones, toluene, dimethylbenzene and hexichol first
It is one or more in ether.
The solvent of ring closure reaction is selected from tetrahydrofuran, methyltetrahydrofuran, toluene, ether or methyl tertbutyl in step 5)
It is one or more in ether;The alkali of ring closure reaction is selected from lithium diisopropylamine, hexamethl disilamine base lithium, butyl lithium, methanol
It is one or more in sodium and potassium tert-butoxide;The acid of ring closure reaction be selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid and
It is one or more in methanesulfonic acid.
The solvent of reduction reaction is selected from tetrahydrofuran, methyltetrahydrofuran, toluene, ether and methyl tertbutyl in step 6)
It is one or more in ether.
The protection reaction of amino active ester described in step 7) carries out in the presence of a base, and the alkali is triethylamine, diisopropyl
Ethamine, pyridine, DBU, DMAP, sodium bicarbonate, saleratus, caesium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, hydrogen
Lithia, it is one or more in sodium hydroxide and potassium hydroxide.
The solvent of reduction reaction is selected from tetrahydrofuran, methyltetrahydrofuran, toluene, ether and methyl tertbutyl in step 8)
It is one or more in ether.
It is as follows to prepare impurity I preferred routes:
It is as follows to prepare impurity II preferred routes:
On the basis of common knowledge of the art, above-mentioned each optimum condition can be combined arbitrarily to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that:
A kind of preparation method of Ivabradine impurity is provided, the preparation method is simple, and high income, purification process is simple,
It solves Ivabradine impurity and prepares difficult problem.It is formed simultaneously quality standard, the impurity of Ivabradine is carried out qualitative
With quantitative detection.Application of the impurity in the quality control of Ivabradine raw material and its preparation is provided simultaneously, to improve
The drug safety of Ivabradine.
Description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of impurity I.
Fig. 2 is the HPLC collection of illustrative plates of impurity II.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
Product specification selects.
It is prepared by 1 impurity Ia of embodiment
In single-necked flask, SM01a, potassium carbonate (1.5eq) is added, DMF is stirred at room temperature, and benzyl bromine (1.2eq), room is added
Temperature stirring adds water to having reacted, and solid, filtering is precipitated, and water washing obtains compound 2a, directly casts single step reaction;In three necks
Flask, loads onto reflux condensing tube, and compound 2a, toluene, cyanoacetic acid (1.2eq), ammonium acetate (0.1eq), pyrrole is added in water knockout drum
Pyridine, stirring, is heated to reflux, until there is no moisture to go out, stops heating, is stayed overnight with water-bath cooling, so that yellow solid is precipitated as possible, mistake
Filter, obtains yellow powdery solid, is poured into 10% hydrochloric acid and is acidified to PH less than 1.0, filtering obtains yellow solid
Object 3a is closed, single step reaction is directly cast;In single neck bottle, ice-water bath cooling is added methanol, compound 3a is added, stirs, dropwise
Saturation NaHCO3 solution is added dropwise, until system is in alkalinity, system is that yellow foam is sticky at this time, is slowly added into NaBH4
(3.0eq), system gradually becomes achromaticity and clarification, continues stirring 2 hours after adding at room temperature, and contact plate tracking has been reacted.It is spin-dried for
Methanol obtains white solid, after 10% hydrochloric acid acidification, is extracted with ethyl acetate 2 times, oil reservoir merges, and uses saturated salt solution
Washing, anhydrous sodium sulfate drying, filtering are spin-dried for solvent, obtain white solid, are compound 4a;Compound 4a is added in single neck bottle,
DMF, stirring, is heated to reflux 3 hours, and system is in faint yellow clarified solution, and system is poured into appropriate ice, places, and it is outstanding to obtain white
Turbid, filtering, obtains white solid, is washed with water, and vacuum drying obtains white powdery solid, is compound 5a;Dry three
In neck bottle, anhydrous tetrahydro furan is added under nitrogen protection, is cooled to -10 DEG C, lithium diisopropylamine (2.2eq) is added, instills
The anhydrous tetrahydrofuran solution of compound 5a (1.0eq) after having reacted, is warming up to 0 DEG C, instills 1N hydrochloric acid, and control temperature is not high
It in 20 DEG C, adding, stirs 10min, liquid separation, water phase is extracted with ethyl acetate, merging organic phase, after 1N salt acid elutions, saturation food
Salt water washing, organic phase are concentrated to give compound 6a, this step molar yield:75%;In 100 milliliters of dry three-necked bottles, nitrogen is protected
Under shield, the THF of 50 milliliters of Non-aqueous processings, NaBH4 (5.0eq) is added, trifluoroacetic acid (5.2eq) is slowly added dropwise in ice salt bath cooling,
It is dissolved in anhydrous THF solution, is dripped off within 10 minutes, room temperature is warmed naturally to, compound 6a is slowly added dropwise after 0.5 hour in stirring
(1.0eq) is dissolved in the solution of the THF of Non-aqueous processing, drips off within 10 minutes, stirs 4 hours, is spin-dried for solvent, in saturation NaHCO3
It is extracted three times with, dichloromethane, merges organic phase, saturated common salt is washed 2 times, and anhydrous sodium sulfate drying obtains faint yellow oily
Compounds 7a.In three-necked flask, compound 7a (1.0eq) is added, anhydrous tetrahydro furan is cooled to 0~5 DEG C and is added portionwise
Sodium hydrogen (3.5eq) is added SM02a (1.0eq), stirs to having reacted, add water quenching to go out reaction, ethyl acetate after stirring 0.5 hour
Extraction, water washing, organic phase concentration is dry, and column chromatography purifies to obtain compound 10a;In single-necked flask, compound 10a, second is added
Acid, palladium/charcoal, atmospheric hydrogenation, room temperature are stirred to having reacted, filter, be spin-dried for acetic acid, sodium bicarbonate is added to neutralize, and dichloromethane extraction has
Machine mutually concentrates dry, and column chromatography obtains impurity Ia, molar yield 48.3%.Purity 95%.
It is prepared by 2 impurity Ib of embodiment
In single-necked flask, SM01b, triethylamine (1.5eq) is added, dichloromethane is stirred at room temperature, and benzyl bromine is added
(1.2eq) is stirred at room temperature to having reacted, after reaction solution concentration, adds water, solid, filtering is precipitated, and water washing obtains compound 2b,
Directly cast single step reaction;In three-neck flask, reflux condensing tube is loaded onto, compound 2b, isopropyl acetate, cyanogen is added in water knockout drum
Guanidine-acetic acid (1.2eq), ammonium acetate (0.1eq), pyridine, stirring are heated to reflux, until there is no moisture to go out, are stopped heating, are used water-bath
It is cooling, so that yellow solid is precipitated as possible, filters, obtain yellow powdery solid, be poured into 10% hydrochloric acid and be acidified to PH
Less than 1.0, filtering obtains yellow solid, and single step reaction is directly cast without further purification for compound 3b;In single neck bottle, ice water
Bath cooling, is added compound 3b, methanol, and saturation NaHCO is gradually added dropwise in stirring3Solution, until system is in alkalinity, system is at this time
Yellow foam is sticky, is slowly added into NaBH4(3.0eq), system gradually becomes achromaticity and clarification.Continue to stir at room temperature after adding
It mixes 2 hours, contact plate, which tracks to, has reacted.It is spin-dried for methanol, obtains white solid, after 10% hydrochloric acid acidification, uses ethyl acetate
Extraction 3 times, oil reservoir merge, and with saturated common salt water washing, anhydrous sodium sulfate drying, filtering is spin-dried for solvent, obtains white solid chemical combination
Object 4b;In single neck bottle, compound 4b, DMF is added, stirring is heated to reflux 3 hours to having reacted, and system is in faint yellow clarified solution,
System is poured into appropriate ice, places, obtains white suspension, is filtered, is obtained white solid, be washed with water, vacuum drying obtains
White powdery solid compound 5b;In dry three-necked bottle, anhydrous tetrahydro furan is added under nitrogen protection, is cooled to -10 DEG C,
Lithium diisopropylamine (3.0eq) is added, instills the anhydrous tetrahydrofuran solution of compound 5b (1.0eq), after having reacted, heating
To 0 DEG C, 10% citric acid is instilled, control temperature is not higher than 20 DEG C, adds, stirs 10 minutes, liquid separation, water phase is extracted with ethyl acetate
It takes, merging organic phase, after 10% lemon acid elution, saturated common salt water washing, organic phase is concentrated to give compound 6b;Three dry necks
In bottle, under nitrogen protection, the THF of Non-aqueous processing, KBH is added4(4.5eq), ice salt bath cooling, is slowly added dropwise (5.2eq) trifluoro
Acetic acid is dissolved in anhydrous THF solution, after dripping off, warms naturally to room temperature, compound 6b is slowly added dropwise after 0.5 hour in stirring
(1.0eq) is dissolved in the THF solution of Non-aqueous processing, drips off within 10 minutes, stirs 4 hours, is spin-dried for solvent, is neutralized with saturation NaHCO3,
DCM is extracted three times, merges organic phase, and saturated common salt is washed 2 times, and anhydrous sodium sulfate drying obtains pale yellow oil, is chemical combination
Object 7-b;In three-necked flask, compound 7b (1.0eq) is added, SM02 (1.0eq) is added in toluene, reflux water-dividing to having reacted,
It is spin-dried for toluene, ethyl alcohol is added, is cooled to 0 DEG C, sodium cyanoborohydride (2.0eq) is added, stirs to having reacted, adds water, acetic acid second
Ester extracts, water washing, and organic phase concentration is dry, and column chromatography purifies to obtain compound 10b;Compound 10b, second are added in single-necked flask
Acid, catalytic amount palladium/charcoal, atmospheric hydrogenation are stirred at room temperature reaction to having reacted, filter, be spin-dried for acetic acid, sodium bicarbonate is added to neutralize, and two
Chloromethanes extracts, and organic phase concentration is dry, and column chromatography obtains impurity Ib, molar yield 50.2%, purity 95%.
It is prepared by 3 impurity Ic of embodiment
In single-necked flask, SM01c, potassium carbonate (3.0eq) is added, dichloromethane is stirred at room temperature, and benzyl bromine is added
(2.5eq) is stirred at room temperature to having reacted, after reaction solution concentration, adds water, solid, filtering is precipitated, and water washing obtains compound 2c.
Without further purification, single step reaction is directly cast;In three-neck flask, reflux condensing tube is loaded onto, water knockout drum is added compound 2c, toluene,
Cyanoacetic acid (1.3eq), ammonium acetate (0.15eq), pyridine, stirring are heated to reflux, until there is no moisture to go out, are stopped heating, are used
Water-bath cooling crosses liquid, and yellow solid is made to be precipitated as possible, and filtering obtains yellow powdery solid, is poured into 10% hydrochloric acid
It is acidified to PH and is less than 1.0, filtering obtains yellow solid, and single step reaction is directly cast without further purification for compound 3c;In single neck
Compound 3c, methanol is added in bottle, ice-water bath cooling, and saturation NaHCO is gradually added dropwise in stirring3Solution, until system is in alkalinity, slowly
Acetic acid sodium borohydride (3.0eq) is added, system gradually becomes achromaticity and clarification.Continue stirring 2 hours, contact plate after adding at room temperature
It tracks to and has reacted.It is spin-dried for methanol, obtains white solid, after 10% hydrochloric acid acidification, is extracted with ethyl acetate 3 times, oil reservoir
Merge, with saturated common salt water washing, anhydrous sodium sulfate drying, filtering is spin-dried for solvent, obtains compound as white solid 4c;In single neck
Compound 4c, DMSO is added in bottle, and stirring is heated to reflux 3.5 hours, and system is in faint yellow clarified solution, and system is poured into appropriate ice
In, it places, obtains white suspension, filter, obtain white solid, be washed with water, vacuum drying obtains white powdery solid chemical combination
Object 5c.In dry three-necked bottle, anhydrous tetrahydro furan is added under nitrogen protection, is cooled to -8 DEG C, diisopropylaminoethyl is added
Lithium (3.0eq) instills the anhydrous tetrahydrofuran solution of compound 5c (1.0eq), after having reacted, is warming up to 0 DEG C, instills 1N salt
Acid, control temperature are not higher than 20 DEG C, add, and stir 10min, liquid separation, and water phase is extracted with ethyl acetate, and merges organic phase, 1N salt
After acid elution, saturated common salt water washing, organic phase is concentrated to give compound 6c;In 100 milliliters of dry three-necked bottles, nitrogen protection
Under, the THF, KBH of 50 milliliters of Non-aqueous processings is added4(4.0eq), ice salt bath cooling are slowly added dropwise (5.2eq) trifluoroacetic acid and are dissolved in
Anhydrous THF solution drips off for 10 minutes, warms naturally to room temperature, it is molten that compound 6c (1.0eq) is slowly added dropwise after 0.5 hour in stirring
It in the THF solution of Non-aqueous processing, drips off within 10 minutes, stirs 5 hours, be spin-dried for solvent, neutralized with saturation NaHCO3, DCM extractions three
Time, merge organic phase, saturated common salt is washed 2 times, and anhydrous sodium sulfate drying obtains pale yellow oil, is compound 7c;In three
7c is added in mouth flask, anhydrous tetrahydro furan is cooled to -10 DEG C~-5 DEG C and instills lithium diisopropylamines (2.5eq), stirring
After 0.5 hour, SM02 (1.0eq) is added, stirs to having reacted, water quenching is added to go out reaction, ethyl acetate extracts, and water washing is organic
It mutually concentrates and does, column chromatography purifies to obtain compound 10c;Compound 10c, methanol, catalytic amount palladium charcoal, normal pressure are added in single-necked flask
Add hydrogen, reaction is stirred at room temperature to having reacted, filters, concentration, column chromatography obtains impurity Ic, molar yield 46.5%, purity 96%.
It is prepared by 4 impurity Id of embodiment
In three-neck flask, reflux condensing tube is loaded onto, compound 2d, toluene, cyanoacetic acid (1.2eq), second is added in water knockout drum
Acid amide (0.1eq), pyridine, stirring are heated to reflux, until there is no moisture to go out, are stopped heating, are stayed overnight with water-bath cooling, make yellow
Solid is precipitated as possible, filtering, obtain yellow powdery solid, be poured into 10% hydrochloric acid be acidified to PH be less than 1.0, mistake
Filter, obtains yellow solid, obtains compound 3d, without further purification, directly cast single step reaction;It cools down, is added in single neck bottle ice-water bath
Compound 3d is added methanol, stirring, and saturation NaHCO is gradually added dropwise3Solution, until system is slowly added into NaBH in alkalinity4
(3.0eq), system gradually becomes achromaticity and clarification, continues stirring 2 hours after adding at room temperature, and contact plate tracking has been reacted.It is spin-dried for
Methanol obtains white solid, after 10% hydrochloric acid acidification, is extracted with ethyl acetate 3 times, oil reservoir merges, and uses saturated salt solution
Washing, anhydrous sodium sulfate drying, filtering are spin-dried for solvent, obtain white solid, are compound 4d;In single neck bottle, compound is added
4d, DMF, stirring, are heated to reflux 3 hours, and system is in faint yellow clarified solution, and system is poured into appropriate ice, place, obtain white
Suspension, filtering, obtains white solid, is washed with water, and vacuum drying obtains white powdery solid, is compound 5d;Dry
In three-necked bottle, anhydrous tetrahydro furan is added under nitrogen protection, is cooled to -10 DEG C, lithium diisopropylamine (2.2eq), drop is added
The anhydrous tetrahydrofuran solution for entering compound 5d (1.0eq) after having reacted, is warming up to 0 DEG C, instills 1N hydrochloric acid, control temperature is not
It higher than 20 DEG C, adding, stirs 10 minutes, liquid separation, water phase is extracted with ethyl acetate, merging organic phase, after 1N salt acid elutions, saturation
Brine It, organic phase are concentrated to give compound 6d;In three-necked bottle, under nitrogen protection, 50 milliliters of Non-aqueous processings of addition
THF, NaBH4(4.5eq), ice salt bath cooling, is slowly added dropwise trifluoroacetic acid (5.0eq), is dissolved in anhydrous THF solution, drips within 10 minutes
It is complete, room temperature is warmed naturally to, stirring is slowly added dropwise compound 6d (1.0eq) after 0.5 hour, is dissolved in the molten of the THF of Non-aqueous processing
Liquid drips off for 10 minutes, stirs 4 hours, is spin-dried for solvent, with saturation NaHCO3It neutralizes, DCM is extracted three times, saturated common salt washing 2
Time, anhydrous sodium sulfate drying obtains pale yellow oil compound 7d;In three-necked flask, compound 7d (1.0eq) is added,
Anhydrous tetrahydro furan is cooled to 0~5 DEG C and sodium hydrogen (4.0eq) is added portionwise, and after stirring 0.5 hour, SM02 (1.0eq) is added, stirs
It mixes to having reacted, water quenching is added to go out reaction, ethyl acetate extraction, water washing, organic phase concentration is dry, and column chromatography purifies to obtain compound
10d;In single-necked flask, it being added compound 10d, acetic acid, catalytic amount palladium/charcoal, atmospheric hydrogenation, room temperature stirs to react, suction filtration,
It is spin-dried for acetic acid, sodium bicarbonate is added to neutralize, dichloromethane extraction, organic phase concentration is dry, and column chromatography obtains impurity Id, molar yield
45.7%, purity 93.8%.
The preparation of 5 impurity of embodiment, II a
In single-necked flask, SM01-a, potassium carbonate (1.5eq) is added, DMF is stirred at room temperature, and benzyl bromine (1.2eq), room is added
Temperature stirring adds water to having reacted, and solid, filtering is precipitated, and water washing obtains compound 2-a.Without further purification, it directly throws in next step
Reaction;In three-neck flask, reflux condensing tube is loaded onto, compound 2-a, toluene, cyanoacetic acid (1.2eq), acetic acid is added in water knockout drum
Amine (0.1eq), pyridine, stirring are heated to reflux, until there is no moisture to go out, are stopped heating, with water-bath cooling, yellow solid are made to use up
Amount is precipitated, and filtering obtains yellow powdery solid, is poured into 10% hydrochloric acid and is acidified to PH less than 1.0, filtering obtains
Yellow solid obtains compound 3-a, without further purification, directly casts single step reaction;In single neck bottle, compound is added in ice-water bath cooling
Saturation NaHCO is added dropwise in 3-a, methanol, stirring3Solution, until system is slowly added into NaBH in alkalinity4(2.5eq), in room after adding
Continue stirring 2 hours, contact plate tracking under temperature.It is spin-dried for methanol, obtains white solid, after 10% hydrochloric acid acidification, with acetic acid second
Ester extracts 3 times, and oil reservoir merges, and with saturated common salt water washing, anhydrous sodium sulfate drying, filtering is spin-dried for solvent, obtains white solid,
For compound 4-a;Compound 4-a, DMF is added to single neck bottle, stirring is heated to reflux to having reacted, and system is in faint yellow clarification
Liquid pours into system in appropriate ice, places, obtains white suspension, filters, obtains white solid, be washed with water, vacuumize dry
It is dry, white powdery solid is obtained, is compound 5-a.In dry three-necked bottle, anhydrous tetrahydro furan is added under nitrogen protection, drops
Lithium diisopropylamine (2.2eq) is added to -10 DEG C in temperature, instills the anhydrous tetrahydrofuran solution of compound 5-a (1.0eq), instead
After having answered, it is warming up to 0 DEG C, instills 10% citric acid, control temperature is not higher than 20 DEG C, adds, and stirs 10min, liquid separation, and water phase is used
Ethyl acetate extracts, merging organic phase, and after 10% lemon acid elution, saturated common salt water washing, organic phase is concentrated to give compound 6-
a.This step molar yield:85%;In dry three-necked bottle, under nitrogen protection, anhydrous THF, NaBH is added4(5.0eq), ice salt bath
It is cooling, the solution that trifluoroacetic acid (5.2eq) is dissolved in anhydrous THF is slowly added dropwise, drips off, warms naturally to room temperature, stir 0.5 hour
The solution that compound 6-a (1.0eq) is dissolved in the THF of Non-aqueous processing is slowly added dropwise afterwards, drips off, stirs 4 hours, be spin-dried for solvent, use
It is saturated NaHCO3It neutralizing, DCM is extracted three times, merges organic phase, and saturated common salt is washed 2 times, anhydrous sodium sulfate drying, obtain light
Yellow oil is compound 7-a;In single neck bottle, addition compound 7-a (1.0eq), triethylamine (1.5eq), anhydrous THF,
Stirring, ice-water bath are cooled to 0-5 DEG C, and nitrogen protection is added dropwise ethyl chloroformate (1.5eq), warms naturally to room temperature, continue to stir
1 hour, it is spin-dried for solvent, adds water, ethyl acetate to extract three times, oil reservoir merges, and is washed with dilute hydrochloric acid, is saturated NaHCO3It washes, saturation food
Salt is washed, and anhydrous sodium sulfate drying, concentration obtains white solid, is compound 8-a;In single neck bottle, by compound 8-a (1.0eq)
It is dissolved in the THF of Non-aqueous processing, is added drop-wise to LiAlH at room temperature4In the THF suspensions of the Non-aqueous processing of (3.8eq), after dripping
It is heated to reflux, until raw material point disappears.Temperature is down to room temperature, and water is added, and the NaOH aqueous solutions of 20% (w/w) are then added, and filters,
It is spin-dried for, obtains pale yellow oil, be compound 9-a.M/z=284.2 [M+H]+;In three-necked flask, compound 9-a is added
Potassium carbonate (3.0eq) is added in (1.0eq), acetone, water, stirs 1 hour, SM02 (1.1eq) is added, stirring is to having reacted, mistake
Filter, concentration add water, and dichloromethane extraction, water washing, organic contracting that mixes is dry, and column chromatography purifies to obtain compound 11-a;It is burnt in single port
In bottle, it is added compound 11-a, acetic acid, catalytic amount palladium charcoal, atmospheric hydrogenation is stirred at room temperature reaction to having reacted, filters, be spin-dried for second
Acid adds sodium bicarbonate to neutralize, dichloromethane extraction, and organic phase concentration is dry, and column chromatography obtains II a of impurity.Molar yield 59.2% is pure
Degree 95.2%.
The preparation of 6 impurity of embodiment, II b
In single-necked flask, SM01-b, potassium carbonate (1.5eq) is added, DMF is stirred at room temperature, and benzyl bromine (1.2eq), room is added
Temperature stirring adds water to having reacted, and solid, filtering is precipitated, and water washing obtains compound 2-b.Without further purification, it directly throws in next step
Reaction.In three-neck flask, reflux condensing tube is loaded onto, compound 2-b, toluene, cyanoacetic acid (1.2eq), acetic acid is added in water knockout drum
Amine (0.1eq), pyridine, stirring are heated to reflux, until there is no moisture to go out, are stopped heating, with water-bath cooling, yellow solid are made to use up
Amount is precipitated, and filtering obtains yellow powdery solid, is poured into 10% hydrochloric acid and is acidified to PH less than 1.0, filtering obtains
Yellow solid directly casts single step reaction without further purification for compound 3-b;In single neck bottle, compound is added in ice-water bath cooling
Saturation NaHCO is added dropwise in 3-b, methanol, stirring3Solution, until system is slowly added into NaBH in alkalinity4(2.5eq), system gradually becomes
Obtain achromaticity and clarification.Continue stirring 2 hours after adding at room temperature, contact plate, which tracks to, has reacted.It is spin-dried for methanol, it is solid to obtain white
Body is extracted with ethyl acetate 3 times, oil reservoir merges, with saturated common salt water washing, anhydrous sodium sulfate after 10% hydrochloric acid acidification
Dry, filtering is spin-dried for solvent, obtains white solid, is compound 4-b.In single neck bottle, compound 4-b, DMF is added, stirring adds
Heat, which is back to, has reacted, and system is in faint yellow clarified solution, and system is poured into appropriate ice, places, and filtering obtains white solid,
It is washed with water, vacuum drying obtains white powdery solid, is compound 5-b.In dry three-necked bottle, it is added under nitrogen protection
Anhydrous tetrahydro furan is cooled to -10 DEG C, and lithium diisopropylamine (3.0eq) is added, and instills the anhydrous of compound 5-b (1.0eq)
Tetrahydrofuran solution after having reacted, is warming up to 0 DEG C, instills 1N hydrochloric acid, and control temperature is not higher than 20 DEG C, adds, and stirs 10 points
Clock, liquid separation, water phase are extracted with ethyl acetate, merging organic phase, after 1N salt acid elutions, saturated common salt water washing, and organic phase concentration
Obtain compound 6-b, molar yield:80%;In dry three-necked bottle, under nitrogen protection, water process THF, NaBH is added4
(5.0eq), ice salt bath cooling are slowly added dropwise the solution that trifluoroacetic acid (5.0eq) is dissolved in anhydrous THF, after dripping off, warm naturally to
Room temperature, the THF solution that compound 6-b (1.0eq) is dissolved in Non-aqueous processing is slowly added dropwise after 0.5 hour in stirring, and after dripping off, stirring is extremely
It has been reacted that, be spin-dried for solvent, with saturation NaHCO3It neutralizing, DCM is extracted three times, and saturated common salt is washed 2 times, anhydrous sodium sulfate drying,
Pale yellow oil is obtained, is compound 7-b.In single neck bottle, compound 7-b (1.0eq), triethylamine (1.5eq), nothing is added
Water process THF, stirring, ice-water bath cooling, nitrogen protection are added dropwise benzyl chloroformate (1.2eq), warm naturally to room temperature, continue
Stirring 1 hour, is spin-dried for solvent, and water, ethyl acetate is added to extract three times, and oil reservoir merges, and is washed with dilute hydrochloric acid, and saturation NaHCO3 is washed, and is satisfied
It is washed with salt, anhydrous sodium sulfate drying, concentration obtains compound as white solid 8-b.In single neck bottle, compound 8-b (1.0eq)
It is dissolved in the THF of Non-aqueous processing, is added drop-wise to LiAlH at room temperature4In the THF suspensions of the Non-aqueous processing of (3.0eq), after dripping
It is heated to reflux 3.0 hours, until raw material point disappears.Temperature is down to room temperature, and water is added, and the NaOH that 20% (w/w) is then added is water-soluble
Liquid, filtering, is spin-dried for, obtains pale yellow oil compound 9-b.In three-necked flask, compound 9-b (1.0eq), first is added
SM02 (1.0eq) is added in benzene, and reflux water-dividing is spin-dried for toluene to having reacted, and ethyl alcohol is added, and is cooled to 0 DEG C, and cyano boron hydrogen is added
Change sodium (2.0eq), stir to having reacted, adds water, ethyl acetate extraction, water washing, organic contracting that mixes is dry, and column chromatography purifies to change
Close object 11-b.In single-necked flask, be added compound 11-b, acetic acid, catalytic amount palladium charcoal, atmospheric hydrogenation, be stirred at room temperature reaction extremely
It has been reacted that, filter, be spin-dried for acetic acid, sodium bicarbonate is added to neutralize, dichloromethane extraction, organic phase concentration is dry, and column chromatography obtains impurity II
B, molar yield 55.6%.
The preparation of 7 impurity of embodiment, II c
In single-necked flask, SM01-c, potassium carbonate (3.0eq) is added, dichloromethane is stirred at room temperature, and benzyl bromine is added
(2.5eq) is stirred at room temperature to having reacted, after reaction solution concentration, adds water, solid, filtering is precipitated, and water washing obtains compound 2-
c.Without further purification, single step reaction is directly cast;In three-neck flask, reflux condensing tube is loaded onto, compound 2-c, first is added in water knockout drum
Benzene, cyanoacetic acid (1.2eq), ammonium acetate (0.1eq), pyridine, stirring are heated to reflux, until there is no moisture to go out, stop heating,
Liquid is crossed with water-bath cooling, yellow solid is made to be precipitated as possible, is filtered, is obtained yellow powdery solid, be poured into 10% hydrochloric acid
In be acidified to PH and be less than 1.0, filtering obtains yellow solid, directly casts single step reaction without further purification for compound 3-c;In
Compound 3-c, methanol is added in single neck bottle, ice-water bath cooling, and saturation NaHCO is added dropwise in stirring3Solution, until system is in alkalinity, this
When system be yellow foam it is sticky, be slowly added into acetic acid sodium borohydride (3.0eq), system gradually becomes achromaticity and clarification.It adds
Continue stirring 2 hours at room temperature afterwards, contact plate, which tracks to, has reacted.It is spin-dried for methanol, obtains white solid, with 10% hydrochloric acid acid
It after change, is extracted with ethyl acetate 3 times, oil reservoir merges, and with saturated common salt water washing, anhydrous sodium sulfate drying, filtering is spin-dried for molten
Agent obtains compound as white solid 4-c;Compound 4-c, DMF is added in single neck bottle, stirring is heated to reflux 4 hours, and system is in light
Yellow clarified solution pours into system in appropriate ice, places, obtains white suspension, filters, obtains white solid, be washed with water, and takes out
Vacuum drying, obtains white powdery solid compound 5-c.In dry three-necked bottle, anhydrous tetrahydro furan is added under nitrogen protection,
- 10 DEG C are cooled to, butyl lithium (3.0eq) is added, the anhydrous tetrahydrofuran solution of compound 5-c (1.0eq) is instilled, has reacted
Afterwards, it is warming up to 0 DEG C, instills 1N hydrochloric acid, control temperature is not higher than 20 DEG C, adds, stirs 10 minutes, liquid separation, water phase acetic acid second
Ester extracts, merging organic phase, and after 1N salt acid elutions, saturated common salt water washing, organic phase is concentrated to give compound 6-c, this step mole
Yield:80%;In 100 milliliters of dry three-necked bottles, under nitrogen protection, anhydrous THF, KBH is added4(4.5eq), ice salt bath is cold
But, (5.0eq) trifluoroacetic acid is added dropwise and is dissolved in anhydrous THF solution, drip off within 10 minutes, warm naturally to room temperature, after stirring 0.5 hour
The THF solution that compound 6-c (1.0eq) is dissolved in Non-aqueous processing is slowly added dropwise, drips off within 10 minutes, stirs 5 hours, be spin-dried for solvent,
It being neutralized with saturation NaHCO3, dichloromethane extracts three times, merges organic phase, and saturated common salt is washed 2 times, anhydrous sodium sulfate drying,
Pale yellow oil is obtained, is compound 7-c;In single neck bottle, compound 7-c (1.0eq), dichloromethane, triethylamine is added
(1.5eq), stirring, ice-water bath are cooled to 0~5 DEG C, and di-tert-butyl dicarbonate (1.5eq) is slowly added dropwise in nitrogen protection, rises naturally
It warms to room temperature, continues stirring 1 hour, add water, extract liquid separation, dichloromethane takes, and oil reservoir merges, with lemon pickling, saturation
NaHCO3It washes, saturated common salt washing, anhydrous sodium sulfate drying is concentrated to give white solid, is compound 8-c;It, will in single neck bottle
Compound 8-c (1.0eq) is dissolved in the THF of Non-aqueous processing, is added drop-wise to the THF of the Non-aqueous processing of LiAlH4 (4.0eq) at room temperature
It in suspension, is heated to reflux after dripping 3.0 hours, until raw material point disappears.Temperature is down to room temperature, and saturation sodium sulphate, mistake is added
Filter, is spin-dried for, obtains pale yellow oil, is compound 9-c.M/z=360.2 [M+H]+;In three-necked flask, compound is added
9-c (1.0eq), dichloromethane add potassium carbonate (3.0eq), stir 1 hour, and SM02 (1.0eq) is added, and stir to having reacted, add
Water extracts liquid separation, and water phase, dichloromethane extraction, water washing, organic contracting that mixes is dry, and column chromatography purifies to obtain compound 11-c;Yu Dan
In mouthful flask, it is added compound 11-c, ethyl alcohol, catalytic amount palladium charcoal, atmospheric hydrogenation is stirred at room temperature reaction to having reacted, filters, rotation
Dry ethyl alcohol, column chromatography obtain II c of impurity.Molar yield 57.2%.
Effect example
HPLC detections are carried out to impurity I and impurity II.
Relevant parameter:
Chromatographic column:Discovery RP-Amide C16 4.6 × 150mm, 5 μm;
Column temperature:40℃;Flow velocity:1.0ml/min;Detection wavelength:220nm;
Sample size:20ul mobile phases;Mobile phase A:(potassium dihydrogen phosphate 4.54g adds water 1000ml molten to phosphate buffer
Solution adjusts Ph values to 3.0), Mobile phase B with phosphoric acid:Acetonitrile;
Gradient is as follows:
Time (min) | A% | B% |
0 | 88 | 12 |
5 | 88 | 12 |
30 | 82 | 18 |
35 | 82 | 18 |
50 | 30 | 70 |
55 | 30 | 70 |
Run time 10min afterwards;
Wash needle dissolved in acetonitrile:Water=50: 50, V/V.
After testing, the HPLC test results of impurity I and impurity II are shown in Fig. 1 and Fig. 2.
The impurity I and impurity that the preparation method by the Ivabradine impurity of the present invention obtains are can be seen that according to Fig. 1 and Fig. 2
The purity of II is respectively 93.8% and 95.2%, and purity is higher, and side reaction is few, can be to Ivabradine after being further purified
Impurity carry out qualitative and quantitative detection.
Claims (10)
1. a kind of preparation method of Ivabradine impurity, which is characterized in that it includes the following steps:
1. formula III compound is reacted to obtain formula IV compound;2. the hydroxyl protection base of formula IV compound is deprotected, while double bond
Reduction is to get Formula V compound;
Wherein R1、R2And R5It is respectively selected from hydrogen or methyl, R1、R2And R5It is asynchronously methyl;R3、R4It is respectively selected from benzyl, Bian oxygen carbonyl
Base, acetyl group, trimethyl silicon substrate, tert-butyl diphenyl silicon substrate, THP trtrahydropyranyl, methoxy or methyl;R6Selected from halogen
Or aldehyde radical.
2. preparation method according to claim 1, which is characterized in that the method for formula III preparation of compounds of formula IV compounds
For following routes one or route two:
Route one:R6For halogen, under alkaline environment, formula III compound and SM02 are substituted and react to obtain formula IV compound;
Route two:R6For aldehyde radical, under water-less environment, formula III compound and SM02 obtain formula IV compound through reductive amination process;
3. preparation method according to claim 1, which is characterized in that the formula III compound is made by following methods:
R5For hydrogen, compound 7 is made by following methods one:
1) using compound SM01 as starting material, compound 2 is obtained by the reaction through hydroxyl protection;
2) compound 2 obtains compound 3 with cyanoacetic acid through condensation reaction;
3) compound 3 obtains compound 4 through reduction reaction;
4) compound 4 reacts to obtain compound 5 through depickling;
5) compound 5 obtains compound 6 through ring closure reaction;
6) compound 6 through reduction reaction to get;
R5For methyl, compound 9 is made by following methods two:
7) compound 8 is reacted to obtain in 7 amino active ester of compound protection;
8) 8 active ester of compound reduction to get;
R7Selected from methoxycarbonyl group, carbethoxyl group, tertbutyloxycarbonyl or Bian oxygen carbonyl.
4. preparation method according to claim 3, which is characterized in that the hydroxyl protection reaction of base protection reaction in step 1)
Alkali be selected from sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide it is one or more;That reacts is molten
Agent is selected from DMF, dichloromethane, toluene, tetrahydrofuran, and methyltetrahydrofuran is one or more in dioxane and DMSO;Instead
Temperature is answered to be selected from -10 DEG C~50 DEG C.
5. preparation method according to claim 3, which is characterized in that the condensing agent of condensation reaction is selected from two rings in step 2)
Hexyl carbodiimide, 1- hydroxy benzo triazoles, O- benzotriazole-tetramethylurea hexafluorophosphate, O- benzotriazole-N,
N, N, N- tetramethylurea tetrafluoro boric acid and hexafluorophosphoric acid benzotriazole -1- bases-oxygroup tripyrrole alkyl phosphorus it is one or more;Contracting
The solvent for closing reaction is selected from toluene, one or more in isopropyl acetate or butyl acetate.
6. preparation method according to claim 3, which is characterized in that the solvent of reduction reaction is selected from methanol in step 3),
Ethyl alcohol, water, dioxane are one or more in tetrahydrofuran and methyltetrahydrofuran;The alkali of reaction is selected from sodium bicarbonate, carbon
Potassium hydrogen phthalate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, one kind in potassium acetate and sodium acetate
Or it is a variety of;The reducing agent of reduction reaction is selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride, cyano potassium borohydride or borine
In it is one or more;The acid of reduction reaction is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, and one in oxalic acid or methanesulfonic acid
Kind is a variety of;And/or the solvent that depickling is reacted in step 4) is selected from DMF, DMSO, N-methyl pyrrolidones, toluene, dimethylbenzene
With it is one or more in two methyl phenyl ethers anisoles.
7. preparation method according to claim 3, which is characterized in that the solvent of ring closure reaction is selected from tetrahydrochysene furan in step 5)
It mutters, methyltetrahydrofuran, toluene is one or more in ether and methyl tertiary butyl ether(MTBE);The alkali of ring closure reaction is selected from diisopropyl
Base lithium amide, hexamethl disilamine base lithium, butyl lithium are one or more in sodium methoxide and potassium tert-butoxide;The acid of ring closure reaction
Selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid is one or more in oxalic acid and methanesulfonic acid;And/or reduction in step 6)
The solvent of reaction is selected from tetrahydrofuran, methyltetrahydrofuran, and toluene is one or more in ether and methyl tertiary butyl ether(MTBE).
8. preparation method according to claim 3, which is characterized in that amino active ester protection reaction is deposited in alkali in step 7)
In lower progress, the alkali is triethylamine, diisopropylethylamine, pyridine, DBU, DMAP, sodium bicarbonate, saleratus, bicarbonate
Caesium, sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, lithium hydroxide are one or more in sodium hydroxide and potassium hydroxide;With/
Or, active ester reduction solvent used is selected from tetrahydrofuran, methyltetrahydrofuran, toluene, ether and methyl- tert fourth in step 8)
It is one or more in base ether.
9. preparation method according to claim 1, it is characterised in that step is 1.) in reaction carry out in the presence of a base, it is described
Alkali is triethylamine, diisopropylethylamine, pyridine, DBU, DMAP sodium bicarbonates, saleratus, caesium bicarbonate, sodium carbonate, carbonic acid
Potassium, cesium carbonate, potassium acetate, lithium hydroxide are one or more in sodium hydroxide and potassium hydroxide;The solvent of reaction is selected from first
It is one or more in benzene, acetone, dichloromethane, dioxane, DMF, DMSO and acetonitrile;The reducing agent of reduction reaction is selected from acetic acid
Sodium borohydride, sodium cyanoborohydride, sodium borohydride, potassium borohydride, tetra isopropyl oxygen titanium/sodium cyanoborohydride, zinc/acetic acid, boron
Zinc hydride/zinc chloride, it is one or more in borine/pyridine;The solvent of reduction reaction be selected from toluene, methanol, ethyl alcohol, acetic acid,
It is one or more in tetrahydrofuran and 1,2- dichloroethanes.
10. preparation method according to claim 1, it is characterised in that step is 2.) in deprotection and double bond reduction solvent
Selected from acetic acid, methanol, ethyl alcohol, ethyl acetate is one or more in tetrahydrofuran and methyltetrahydrofuran;Catalyst is selected from palladium
Charcoal, it is one or more in palladium dydroxide and Raney's nickel;Hydrogen donor is selected from hydrogen, ammonium chloride, cyclohexene, cyclohexadiene or tetrahydrochysene
Change one or more in naphthalene.
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CN113480481A (en) * | 2021-07-21 | 2021-10-08 | 海南鑫开源医药科技有限公司 | Preparation method of degradation impurities in ivabradine hydrochloride |
CN114369062A (en) * | 2020-10-15 | 2022-04-19 | 鲁南制药集团股份有限公司 | Preparation method of ivabradine gene toxic impurities |
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EP2460797A2 (en) * | 2006-11-30 | 2012-06-06 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
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CN114369062A (en) * | 2020-10-15 | 2022-04-19 | 鲁南制药集团股份有限公司 | Preparation method of ivabradine gene toxic impurities |
CN113480481A (en) * | 2021-07-21 | 2021-10-08 | 海南鑫开源医药科技有限公司 | Preparation method of degradation impurities in ivabradine hydrochloride |
CN113480481B (en) * | 2021-07-21 | 2022-11-29 | 海南鑫开源医药科技有限公司 | Preparation method of degradation impurities in ivabradine hydrochloride |
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