CN108424389A - A kind of preparation method of Ivabradine impurity - Google Patents
A kind of preparation method of Ivabradine impurity Download PDFInfo
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- CN108424389A CN108424389A CN201710075765.5A CN201710075765A CN108424389A CN 108424389 A CN108424389 A CN 108424389A CN 201710075765 A CN201710075765 A CN 201710075765A CN 108424389 A CN108424389 A CN 108424389A
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- BMPIAMMIUINAOW-FQEVSTJZSA-N CN(CCCN(CCc(c(C1)c2)cc(OC)c2O)C1=O)C[C@H](C1)c(cc2OC)c1cc2OC Chemical compound CN(CCCN(CCc(c(C1)c2)cc(OC)c2O)C1=O)C[C@H](C1)c(cc2OC)c1cc2OC BMPIAMMIUINAOW-FQEVSTJZSA-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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- 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
Abstract
The invention discloses a kind of preparation methods of Ivabradine impurity, it specifically includes respectively with 3 hydroxyl, 4 methoxyphenylacetic acid (formula 1a) and 4 hydroxyl, 3 methoxyphenylacetic acid (formula 1b) for starting material, two impurity of Ivabradine are obtained by multistep reaction, the preparation method of the present invention is simple, purity is high, obtained impurity 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), { [{ [(7S) -3,4- dimethoxys are bicyclic [4.2.0] by 3- by the entitled 3- of chemistry
Octyl- 1,3,5- triolefin -7- bases]-methyl } (methyl) amino] propyl } -7,8- dimethoxys -1,3,4,5- tetrahydrochysene -2H-3- benzos
Azatropylidene -2- ketone, molecular formula：C27H36N2O5, relative molecular mass:468, it is the anti-heart that French Servier companies develop
Angina new drug lists for 2006 in the first batch Irish, normally chronic to disabling or not tolerating beta-blockers, sinus rhythm
Patients with stable angina pectoris has obvious curative effects, clinically can be used for treating various myocardial ischemias, such as angina pectoris, cardiac muscle stalk
Plug and relevant rhythm disorder are a kind of to treat the boundless cardiovascular drugs of new generation of foreground.Its structural formula such as formula institute
Show：.
According to the preparation method for having Ivabradine reported in the literature, in its preparation process, on benzo heptatomic ring
Methyl be easy to leave away, generate phenolic hydroxyl group.Reaction can generate 2 kinds of by-products, and structural formula 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 impurity S33173 and impurity S33174 in standard, structure be it is above-mentioned shown in structure,
By Literature Consult, also finds no document and disclose the specific preparation method for reporting this two kinds of impurity.
Invention content
Technical problem solved by the invention is to provide a kind of preparation method of Ivabradine impurity, formation quality mark
Standard carries out qualitative and quantitative detection to the impurity of Ivabradine.The impurity is provided in Ivabradine raw material and its system simultaneously
Application in the quality control of agent, to improve the drug safety of Ivabradine.
Since Ivabradine structural formula is altogether containing the methoxyl group on 4 phenyl ring, this requires preparing the impurity
When, targetedly two substituent groups on benzo heptatomic ring are protected and are deprotected, while controlling benzo four-membered ring
On two methoxyl groups it is unaffected.
Technical solutions according to the invention are as follows, and the specific preparation method of Ivabradine impurity A or impurity B includes following
Step：5 compound of formula is obtained into 8 compound of formula through multistep reaction, then to the hydroxyl protection base of 8 compound of formula be deprotected to get
Impurity A or impurity B：
Wherein R1、R2It is differently selected from methyl and hydroxyl protection base, the hydroxyl protection base is substituted or unsubstituted benzyl
Base, it is described to be substituted by methyl, ethyl, fluorine, chlorine, bromine or iodine substitution, the integer that substituent group number is 0~3；
It is following routes one or route two from the method for 5 preparation of compounds of formula of formula, 8 compound：
Route one：5) 5 compound of formula obtains 6 compound of formula through halogenating reaction；6) 5 ' compound pair of 6 compound of formula and formula
It connects, obtains 8 compound of formula.
Route two：5) 5 ' compound of formula obtains 6 ' compound of formula through halogenating reaction；6) 6 ' compound of formula and 5 compound pair of formula
Connect 8 compound of the formula of being obtained by the reaction.
Wherein X1、X2Differently it is selected from fluorine, chlorine, bromine or iodine.
Wherein, 5 compound of the formula can be produced by this field customary preparation methods, and in the present invention, 5 compound of the formula is excellent
Choosing is made by following routes 1 or route 2：
Route 1：1) formula 1a or 1b compounds are reacted in alkaline environment through hydroxyl protection, obtain 2 compound of formula；2) formula 2 is changed
Object is closed under strong alkali environment, hydrolysis obtains 3 compound of formula；3) 3 compound of formula is condensed to yield the change of formula 4 with 2,2- dimethoxy-ethylamines
Close object；4) cyclization obtains 5 compound of formula to 4 compound of formula in acid condition；
Route 2：1) formula 1a or 1b compounds are condensed to yield formula 2a or 2b compound with 2,2- dimethoxy-ethylamines；2) formula 2a
Or cyclization obtains formula 3a or 3b compound to 2b compounds in acid condition；3) formula 3a or 3b compounds are reacted through hydroxyl protection,
Obtain 5 compound of formula.
It is specific as follows：1) 2 compound of formula is obtained by the reaction through hydroxyl protection in the presence of a base in formula 1a or formula 1b compounds；Institute
The alkali stated preferably be selected from sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide and sodium tert-butoxide one kind or
It is a variety of.The solvent preferably is selected from one kind or more of acetone, tetrahydrofuran, dimethylformamide, acetonitrile, toluene and dimethylbenzene
Kind.
2) for 2 compound of formula under strong alkali environment, hydrolysis obtains 3 compound of formula；The highly basic preferably is selected from sodium hydroxide, hydrogen
Potassium oxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide it is one or more.The solvent of reaction preferably is selected from ethyl alcohol, methanol, tetrahydrochysene
Furans, acetonitrile, acetone, dioxane and water it is one or more.
3) 3 compound of formula is condensed to yield 4 compound of formula with 2,2- dimethoxy-ethylamines；The condensing agent of condensation reaction preferably is selected from
Dicyclohexylcarbodiimide (DCC), 1- hydroxy benzo triazoles (HOBT), O- benzotriazole-tetramethylurea hexafluorophosphate
(HBTU), O- benzotriazole-N, N, N, N- tetramethylureas tetrafluoro boric acid (TBTU) and hexafluorophosphoric acid benzotriazole -1- bases-oxygen
Base tripyrrole alkyl phosphorus (PyBop) it is one or more.
4) cyclization obtains 5 compound of formula to 4 compound of formula in acid condition；The acid of the acid condition preferably be selected from hydrochloric acid,
Sulfuric acid, acetic acid, methanesulfonic acid and phosphoric acid it is one or more.
In the present invention, 5 compound of step 5) Chinese style obtains 6 compound of formula through halogenating reaction.The alkali of halogenating reaction is selected from uncle
Butanol potassium, sodium tert-butoxide, sodium methoxide, sodium ethoxide and sodium hydroxide it is one or more.Work as X1Or X2It is preferably right when not being iodine
6 compound of formula carries out iodization and 7 compound of formula is obtained by the reaction；The reagent of the iodization reaction is selected from sodium iodide and potassium iodide.
6) formula 6 or 7 compound of formula dock to obtain 8 compound of formula with 5 compound of formula；The alkali of docking reaction preferably is selected from three second
Amine, Tri-n-Propylamine, potassium carbonate, sodium carbonate and lithium carbonate；The solvent of docking reaction preferably is selected from acetone, acetonitrile, dimethylformamide
It is one or more with dimethyl sulfoxide (DMSO).
7) under hydrogen environment, palladium carbon is catalyzed to obtain impurity A or impurity B 8 compound of formula.Hydroxyl protection base deprotection reaction
Solvent preferably be selected from the one or more of methanol, ethyl alcohol, formic acid, acetic acid and tetrahydrofuran.
Prepare impurity A and impurity B preferred routes as shown in formula：
Wherein R1、R2It is differently selected from methyl and hydroxyl protection base, the hydroxyl protection base is substituted or unsubstituted benzyl
Base, it is described to be substituted by methyl, ethyl, fluorine, chlorine, bromine or iodine substitution, the integer that substituent group number is 0~3.
X1、X2Differently it is selected from fluorine, chlorine, bromine or iodine.
There is a plurality of route that can realize from the method for 5 compound of formula 1a or 1b preparation of compounds of formula, following is route 1 or route
2；
Route 1：Formula 1a or 1b compound is reacted through hydroxyl protection, obtains 2 compound of formula, 2 compound of formula is in strong alkali environment
Under, hydrolysis obtains 3 compound of formula, and 3 compound of formula is condensed to yield 4 compound of formula with 2,2- dimethoxy-ethylamines；4 compound of formula exists
Cyclization obtains 5 compound of formula under acid condition；
Route 2：Formula 1a or 1b compound are condensed to yield formula 2a or 2b compound, formula 2a or 2b with 2,2- dimethoxy-ethylamines
Cyclization obtains formula 3a or 3b compound to compound in acid condition, and formula 3a or 3b compound is reacted through hydroxyl protection, obtains formula 5
Compound.
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：
The preparation method of the Ivabradine impurity of the present invention is simple, and obtained impurity A and impurity B purity is high, can be formed
Quality standard carries out qualitative and quantitative detection to the impurity of Ivabradine.The impurity is provided in Ivabradine raw material simultaneously
And its application in the quality control of preparation, to improve the drug safety of Ivabradine.
Description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of impurity A.
Fig. 2 is the HPLC collection of illustrative plates of impurity B.
Specific implementation mode
Embodiment 1：The preparation of impurity A
By 15g formula 1a compounds, 65g potassium carbonate and 300ml acetone mixings, stirring.41.5g cylites are at the uniform velocity added dropwise to body
In system, it is warming up to back flow reaction after finishing and stays overnight.After reaction, it is down to room temperature, is filtered, filtrate is collected and is concentrated under reduced pressure,
2 compound of 37g formulas is obtained, is not required to purify, is directly thrown in next step.
2 compound of 37g formulas and 180ml ethyl alcohol mixings are stirred.At the uniform velocity be added be mixed with 6.3g sodium hydroxides 160ml it is water-soluble
Liquid after finishing, rises to 50 DEG C of reactions.After reaction, it is cooled to room temperature.Decompression steams most of ethyl alcohol, and 200ml acetic acid is added
Ethyl ester and 150ml water, are extracted, and water layer is collected.Water layer is adjusted to pH value to 2-3 with concentrated hydrochloric acid, then with 150ml*2 ethyl acetate
Ethyl acetate layer is collected in extraction, dry, and filtering is concentrated under reduced pressure to give 3 compound of 30.1g formulas, is not required to purify, directly casts one
Step.
3 compound of 30g formulas is dissolved in the dichloromethane of 450ml, puts into 9.5g 2,2- dimethoxy-ethylamines, stirring is
It is even.Put into 18.9g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI), 13.4g 1- hydroxyls successively later
Base benzotriazole (HOBT), reacts at room temperature after finishing.After reaction, reaction system is added to 300ml saturated sodium bicarbonates
In aqueous solution, extraction, water layer 200ml dichloromethane is stripped once, collects dichloromethane layer, and anhydrous sodium sulfate is dried, filtering,
It is concentrated to give 4 compound of 25.8g formulas.It is not required to purify, directly throw in next step.
In 500ml single-necked flasks, be added 4 compound of 25g formulas, 100ml glacial acetic acid and 25ml concentrated hydrochloric acid, finish rear chamber
Temperature reaction is overnight.After raw material disappears, 60 DEG C of water-baths steam most of glacial acetic acid, and 100ml water is added in residue, with unsaturated carbonate hydrogen
Sodium water solution adjusts pH value to alkalinity.Ethyl acetate extracts, dry, and the residue being concentrated to give uses ethyl acetate：Normal heptane=
1：4(V:V), column chromatographic isolation and purification is carried out, target eluent is collected, is concentrated to give 5 compound of 6g formulas.
5 compound of 2g formulas is dissolved in the dimethyl sulfoxide (DMSO) of 10ml, magnetic agitation.The tertiary fourths of 1g are added portionwise under nitrogen protection
Potassium alcoholate, is stirred at room temperature 0.5h, is then slowly added dropwise the 5ml DMSO solutions containing the bromo- 3- chloropropanes of 1.25g1-, 5 minutes
It drips off, continues to stir 0.5h at room temperature.After reaction, reaction system is poured into 50ml ice water, with the second of 50ml*3
Acetoacetic ester extracts, and collects ethyl acetate layer, anhydrous sodium sulfate drying, and filtering is concentrated under reduced pressure to give 6 compound of 1.8g formulas.
6 compound of 1.8g formulas, 870mg sodium iodides and 40ml acetone are mixed evenly, setting temperature 70 C flows back anti-
After reaction, it should be down to room temperature for 24 hours, be filtered to remove solid, the filtrate decompression concentration of collection obtains 7 compound of 1g formulas.
7 compound of 0.5g formulas and 0.73g triethylamines are dissolved in 30ml acetone, 0.72g (1S) -4 is added under nitrogen protection,
5- dimethoxys -1- [(methylamino) methyl] benzocyclobutane hydrochloride, after finishing, is warming up to back flow reaction for 24 hours.It is cooled to
Room temperature, decompression steam acetone, are extracted with the ethyl acetate of 50ml*3, and residue is concentrated under reduced pressure in anhydrous sodium sulfate drying, filtering,
Use methanol：Dichloromethane=1：30(V:V), column chromatographic isolation and purification is carried out, target product is collected, is concentrated to give the change of 0.3g formulas 8
Close object.
0.3g intermediates 8,60mg10% palladium carbons and 15ml glacial acetic acid are mixed, magnetic agitation, nitrogen charging gas shielded, then uses hydrogen
Gas is replaced three times, and under the hydrogen environment of 3 atmospheric pressure, 60 DEG C of reactions are for 24 hours.After raw material disappearance, diatomite is filtered to remove palladium
Carbon, filtrate decompression are concentrated to give 0.1g impurity As, yield 40%.
The synthesis of 2 impurity B of embodiment
By 30g formula 1b compounds, 120g sodium carbonate and 600ml toluene mixings, stirring.82g benzyl chlorides are at the uniform velocity added dropwise to body
In system, 60 DEG C of reactions are warming up to after finishing overnight.After reaction, it is down to room temperature, is filtered, filtrate is collected and is concentrated under reduced pressure,
2 compound of 50g formulas is obtained, is not required to purify, is directly thrown in next step.
2 compound of 30g formulas and 180ml ethyl alcohol mixings are stirred.At the uniform velocity be added be mixed with 6.3g potassium hydroxide 100ml it is water-soluble
Liquid after finishing, rises to 45 DEG C of reactions.After reaction, it is cooled to room temperature.Decompression steams most of ethyl alcohol, and 200ml acetic acid is added
Ethyl ester and 150ml water, are extracted, and water layer is collected.Water layer is adjusted to pH value to 2-3 with concentrated hydrochloric acid, then with 150ml*2 ethyl acetate
Ethyl acetate layer is collected in extraction, dry, and filtering is concentrated under reduced pressure to give 3 compound of 25g formulas, is directly thrown in next step.
3 compound of 60g formulas is dissolved in the dichloromethane of 900ml, 19g2 is put into, 2- dimethoxy-ethylamines stir evenly.
Put into 36g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI), 27g1- hydroxy benzos three successively later
Nitrogen azoles (HOBT), reacts at room temperature after finishing.After reaction, reaction system is added in 600ml saturated sodium bicarbonate aqueous solutions,
Extraction, water layer 400ml dichloromethane are stripped primary, collection dichloromethane layer, anhydrous sodium sulfate drying, and filtering is concentrated to give
4 compound of 50.1g formulas is directly thrown in next step.
In 500ml single-necked flasks, be added 5 compound of 12g formulas, 50ml glacial acetic acid and 12ml concentrated hydrochloric acid, finish rear chamber
Temperature reaction is overnight.After raw material disappears, 60 DEG C of water-baths steam most of glacial acetic acid, and 100ml water is added in residue, with unsaturated carbonate hydrogen
Sodium water solution adjusts pH value to alkalinity.Ethyl acetate extracts, dry, and the residue being concentrated to give uses ethyl acetate：Normal heptane=
1：4(V:V), column chromatographic isolation and purification is carried out, target eluent is collected, is concentrated to give 6 compound of 5g formulas.
5 compound of 4g formulas is dissolved in the dimethyl sulfoxide (DMSO) of 20ml, magnetic agitation.The tertiary fourths of 2g are added portionwise under nitrogen protection
Potassium alcoholate, is stirred at room temperature 0.5h, and the 5ml DMSO solutions containing the bromo- 3- chloropropanes of 2.5g 1-, 10min is then slowly added dropwise
It drips off, continues to stir 1h at room temperature.After reaction, reaction system is poured into 100ml ice water, with the acetic acid of 80ml*3
Ethyl ester extracts, and collects ethyl acetate layer, anhydrous sodium sulfate drying, and filtering is concentrated under reduced pressure to give 6 compound of 3g formulas.
6 compound of 3.6g formulas, 1.6g sodium iodides and 80ml acetone are mixed evenly, temperature 70 C back flow reaction is set
For 24 hours, after reaction, it is down to room temperature, is filtered to remove solid, the filtrate decompression concentration of collection obtains 7 compound of 1.8g formulas.
7 compound of 1.5g formulas and 2.2g triethylamines are dissolved in 100ml acetone, 2.1g (1S) -4 is added under nitrogen protection,
5- dimethoxys -1- [(methylamino) methyl] benzocyclobutane hydrochloride, after finishing, is warming up to back flow reaction for 24 hours.It is cooled to
Room temperature, decompression steam acetone, are extracted with the ethyl acetate of 80ml*3, and residue is concentrated under reduced pressure in anhydrous sodium sulfate drying, filtering,
Use methanol：Dichloromethane=1：30(V:V), column chromatographic isolation and purification is carried out, target product is collected, is concentrated to give the change of 0.7g formulas 8
Close object.
8 compound of 0.7g formulas, 70mg10% palladium carbons and 15ml glacial acetic acid are mixed, magnetic agitation, nitrogen charging gas shielded, then used
Hydrogen is replaced three times, and under the hydrogen environment of 3 atmospheric pressure, 60 DEG C of reactions are for 24 hours.After raw material disappearance, diatomite is filtered to remove
Palladium carbon, filtrate decompression are concentrated to give 0.3g impurity Bs, yield 58%.
Embodiment 3：The preparation of impurity A
By 5g formula 1a compounds, 3.75g2, the mixing of 2- dimethoxy-ethylamines is dissolved in the dichloromethane of 50ml, and stirring is equal
It is even.Put into 6.3g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI), 4.4g 1- hydroxyls successively later
Benzotriazole (HOBT), reacts at room temperature after finishing.After reaction, reaction system is added to 100ml saturated sodium bicarbonate waters
In solution, extraction, water layer 100ml dichloromethane is stripped once, collects dichloromethane layer, and anhydrous sodium sulfate is dried, and filtering is dense
Contracting obtains 5.8g formula 2a compounds.It is not required to purify, directly throw in next step.
In 100ml single-necked flasks, be added 5g formula 2a compounds, 10ml glacial acetic acid and 3ml concentrated hydrochloric acid, finish rear room temperature
Reaction is overnight.After raw material disappears, 60 DEG C of water-baths steam most of glacial acetic acid, and residue is added 100ml water, uses saturated sodium bicarbonate
Aqueous solution adjusts pH value to alkalinity.Ethyl acetate extracts, dry, and the residue being concentrated to give uses ethyl acetate：Normal heptane=1：
4(V:V), column chromatographic isolation and purification is carried out, target eluent is collected, is concentrated to give 2g formula 3a compounds.
By 10g formula 3a compounds, 40g sodium carbonate and 100ml acetone mixings, stirring.15g cylites are at the uniform velocity added dropwise to system
In, 50 DEG C of reactions are warming up to after finishing overnight.After reaction, it is down to room temperature, is filtered, filtrate is collected and is concentrated under reduced pressure, it is residual
Excess adds water to be extracted with ethyl acetate, and concentration of organic layers obtains 5 compound of 13g formulas, is not required to purify, and directly throws in next step.
5 ' compound of 20g formulas, the bromo- 3- chloropropanes of 23 grams of 1- and 30g triethylamines are dissolved in 100ml acetone, stirred evenly
Afterwards, it is warming up to back flow reaction for 24 hours.It is cooled to room temperature, decompression steams acetone, is extracted with the ethyl acetate of 80ml*3, anhydrous slufuric acid
Sodium is dried, and filtering is concentrated under reduced pressure to obtain 25 grams of 6 ' compounds of formula, is not required to purify, and is directly thrown in next step.
6 ' compound of 20g formulas, 15g sodium iodides and 150ml acetone are mixed evenly, temperature 70 C back flow reaction is set
For 24 hours, after reaction, it is down to room temperature, is filtered to remove solid, the filtrate decompression concentration of collection, residue adds water ethyl acetate
Extraction, concentration of organic layers obtain 7 ' compound of 16g formulas.
5 compound of 4g formulas is dissolved in the dimethyl sulfoxide (DMSO) of 40ml, magnetic agitation.The tertiary fourths of 2g are added portionwise under nitrogen protection
Potassium alcoholate, is stirred at room temperature 0.5h, and the 15ml DMSO solutions containing 6 gram of 7 ' compound are then slowly added dropwise, and 10min is dripped off,
Continue to stir 1h at room temperature.After reaction, reaction system is poured into 100ml ice water, is extracted with the ethyl acetate of 80ml*3
It takes, collects ethyl acetate layer, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure to give 8 compound of 2g formulas.
0.5g intermediates 8,100mg10% palladium carbons and 15ml glacial acetic acid are mixed, magnetic agitation, nitrogen charging gas shielded, then used
Hydrogen is replaced three times, and under the hydrogen environment of 3 atmospheric pressure, 60 DEG C of reactions are for 24 hours.After raw material disappearance, diatomite is filtered to remove
Palladium carbon, filtrate decompression are concentrated to give 0.2g impurity As, yield 47%.
Embodiment 4：The preparation of impurity B
By 15g formula 1b compounds, 65g potassium carbonate and 300ml acetone mixings, stirring.41.5g cylites are at the uniform velocity added dropwise to body
In system, it is warming up to back flow reaction after finishing and stays overnight.After reaction, it is down to room temperature, is filtered, filtrate is collected and is concentrated under reduced pressure,
2 compound of 37g formulas is obtained, is not required to purify, is directly thrown in next step.
2 compound of 37g formulas and 180ml ethyl alcohol mixings are stirred.At the uniform velocity be added be mixed with 6.3g sodium hydroxides 160ml it is water-soluble
Liquid after finishing, rises to 50 DEG C of reactions.After reaction, it is cooled to room temperature.Decompression steams most of ethyl alcohol, and 200ml acetic acid is added
Ethyl ester and 150ml water, are extracted, and water layer is collected.Water layer is adjusted to pH value to 2-3 with concentrated hydrochloric acid, then with 150ml*2 ethyl acetate
Ethyl acetate layer is collected in extraction, dry, and filtering is concentrated under reduced pressure to give 3 compound of 30.1g formulas, is not required to purify, directly casts one
Step.
3 compound of 30g formulas is dissolved in the dichloromethane of 450ml, puts into 9.5g 2,2- dimethoxy-ethylamines, stirring is
It is even.Put into 18.9g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI), 13.4g 1- hydroxyls successively later
Base benzotriazole (HOBT), reacts at room temperature after finishing.After reaction, reaction system is added to 300ml saturated sodium bicarbonates
In aqueous solution, extraction, water layer 200ml dichloromethane is stripped once, collects dichloromethane layer, and anhydrous sodium sulfate is dried, filtering,
It is concentrated to give 4 compound of 25.8g formulas.It is not required to purify, directly throw in next step.
In 500ml single-necked flasks, be added 4 compound of 25g formulas, 100ml glacial acetic acid and 25ml concentrated hydrochloric acid, finish rear chamber
Temperature reaction is overnight.After raw material disappears, 60 DEG C of water-baths steam most of glacial acetic acid, and 100ml water is added in residue, with unsaturated carbonate hydrogen
Sodium water solution adjusts pH value to alkalinity.Ethyl acetate extracts, dry, and the residue being concentrated to give uses ethyl acetate：Normal heptane=
1：4(V:V), column chromatographic isolation and purification is carried out, target eluent is collected, is concentrated to give 5 compound of 6g formulas.
5 ' compound of 20g formulas, the bromo- 3- chloropropanes of 23 grams of 1- and 30g triethylamines are dissolved in 100ml acetone, stirred evenly
Afterwards, it is warming up to back flow reaction for 24 hours.It is cooled to room temperature, decompression steams acetone, is extracted with the ethyl acetate of 80ml*3, anhydrous slufuric acid
Sodium is dried, and filtering is concentrated under reduced pressure to obtain 25 grams of 6 ' compounds of formula, is not required to purify, and is directly thrown in next step.
6 ' compound of 20g formulas, 15g sodium iodides and 150ml acetone are mixed evenly, temperature 70 C back flow reaction is set
For 24 hours, after reaction, it is down to room temperature, is filtered to remove solid, the filtrate decompression concentration of collection, residue adds water ethyl acetate
Extraction, concentration of organic layers obtain 7 ' compound of 16g formulas.
5 compound of 4g formulas is dissolved in the dimethyl sulfoxide (DMSO) of 40ml, magnetic agitation.The tertiary fourths of 2g are added portionwise under nitrogen protection
Potassium alcoholate, is stirred at room temperature 0.5h, and the 15ml DMSO solutions containing 6 gram of 7 ' compound are then slowly added dropwise, and 10min is dripped off,
Continue to stir 1h at room temperature.After reaction, reaction system is poured into 100ml ice water, is extracted with the ethyl acetate of 80ml*3
It takes, collects ethyl acetate layer, anhydrous sodium sulfate drying, filtering is concentrated under reduced pressure to give 8 compound of 2g formulas.
0.5g intermediates 8,100mg10% palladium carbons and 15ml glacial acetic acid are mixed, magnetic agitation, nitrogen charging gas shielded, then used
Hydrogen is replaced three times, and under the hydrogen environment of 3 atmospheric pressure, 60 DEG C of reactions are for 24 hours.After raw material disappearance, diatomite is filtered to remove
Palladium carbon, filtrate decompression are concentrated to give 0.2g impurity Bs, yield 47.1%.
Effect example
HPLC detections are carried out to impurity A and impurity B.
1. relevant parameter：
2. solution is prepared
Phosphate buffer solution：Potassium dihydrogen phosphate 4.54g adds water 1000ml to dissolve, and Ph values are adjusted to 3.0 with phosphoric acid
Diluent (blank)：Phosphate buffer solution：Acetonitrile=88:12, it is labeled as blank.
Test solution
Take test sample appropriate, it is accurately weighed, it sets in suitable capacity bottle, scale is dissolved and be diluted to diluent, is shaken up, i.e.,
, mixing is parallel to prepare 3 parts.It is protected from light operation.
The HPLC test results of impurity A and impurity B are shown in Fig. 1 and Fig. 2.
The impurity A 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 B is respectively 92.74% and 92.85%, 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 (9)
1. a kind of preparation method of Ivabradine impurity, which is characterized in that it includes the following steps：By 5 compound of formula through more
8 compound of formula is obtained by the reaction in step, then is deprotected the hydroxyl protection base of 8 compound of formula to get impurity A or impurity B；
Wherein R1、R2It is differently selected from methyl and hydroxyl protection base, the hydroxyl protection base is substituted or unsubstituted benzyl, institute
It states and is substituted by methyl, ethyl, fluorine, chlorine, bromine or iodine substitution, the integer that substituent group number is 0~3；
It is following routes one or route two from the method for 5 preparation of compounds of formula of formula, 8 compound：
Route one：5) 5 compound of formula obtains 6 compound of formula through halogenating reaction；6) 6 compound of formula and the docking of 5 ' compound of formula, obtain
To 8 compound of formula
Route two：5) 5 ' compound of formula obtains 6 ' compound of formula through halogenating reaction；6) 6 ' compound of formula is docked with 5 compound of formula
8 compound of formula is obtained by the reaction
Wherein X1、X2Difference is selected from fluorine, chlorine, bromine or iodine.
2. preparation method according to claim 1, which is characterized in that 5 compound of formula is made by following routes 1 or route 2
：
Route 1：1) formula 1a or 1b compounds are reacted through hydroxyl protection, obtain 2 compound of formula；2) 2 compound of formula is in strong alkali environment
Under, hydrolysis obtains 3 compound of formula；3) 3 compound of formula is condensed to yield 4 compound of formula with 2,2- dimethoxy-ethylamines；4) 4 chemical combination of formula
Cyclization obtains 5 compound of formula to object in acid condition；
Route 2：1) formula 1a or 1b compounds are condensed to yield formula 2a or 2b compound with 2,2- dimethoxy-ethylamines；2) formula 2a or 2b
Cyclization obtains formula 3a or 3b compound to compound in acid condition；3) formula 3a or 3b compounds are reacted through hydroxyl protection, are obtained
5 compound of formula；
3. preparation method as claimed in claim 2, which is characterized in that the alkali of step 1) the hydroxyl protection reaction preferably is selected from carbon
Sour sodium, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide it is one or more；Reaction solvent used is preferred
From the one or more of acetone, tetrahydrofuran, dimethylformamide, acetonitrile, toluene and dimethylbenzene.
4. preparation method as claimed in claim 2, which is characterized in that the highly basic described in step 2) preferably be selected from sodium hydroxide,
Potassium hydroxide, lithium hydroxide, potassium tert-butoxide and sodium tert-butoxide it is one or more；Reaction solvent used preferably is selected from ethyl alcohol, first
Alcohol, tetrahydrofuran, acetonitrile, acetone, dioxane and water it is one or more.
5. preparation method as claimed in claim 2, which is characterized in that the condensing agent of step 3) condensation reaction is selected from dicyclohexyl
Carbodiimide, 1- hydroxy benzo triazoles, O- benzotriazole-tetramethylurea hexafluorophosphate, O- benzotriazole-N, N, N,
N- tetramethylureas tetrafluoro boric acid and hexafluorophosphoric acid benzotriazole -1- bases-oxygroup tripyrrole alkyl phosphorus it is one or more.
6. preparation method as claimed in claim 2, which is characterized in that the acid in the ring closure reaction of step 4) preferably be selected from hydrochloric acid,
Sulfuric acid, acetic acid, methanesulfonic acid, phosphoric acid.
7. the halogenating reaction of preparation method as described in claim 1, step 5) carries out in the presence of a base, the alkali of reaction preferably is selected from
Potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide and sodium hydroxide it is one or more；If X1And X2It is preferably right when not being iodine
Formula 6 or formula 6 ' carry out iodization and obtain 7 ' compound of formula 7 or formula, and the reagent of the iodization reaction is selected from sodium iodide and iodate
Potassium.
8. preparation method as described in claim 1, which is characterized in that step 6) forms the docking reaction of 8 compound of formula, in alkali
In the presence of carry out, the alkali be selected from triethylamine, Tri-n-Propylamine, potassium carbonate, sodium carbonate and lithium carbonate it is one or more；It is described
The solvent of reaction is selected from the one or more of acetone, acetonitrile, dimethylformamide and dimethyl sulfoxide (DMSO).
9. preparation method as described in claim 1, which is characterized in that in the hydroxyl protection base deprotection reaction of 8 compound of formula
Solvent be selected from methanol, ethyl alcohol, formic acid, acetic acid, tetrahydrofuran it is one or more.
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| CN114324715A (en) * | 2021-01-05 | 2022-04-12 | 海南鑫开源医药科技有限公司 | Method for detecting related substances in 7, 8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-ketone |
| 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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