CN108003102A - A kind of synthetic method of Ivabradine - Google Patents
A kind of synthetic method of Ivabradine Download PDFInfo
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- CN108003102A CN108003102A CN201710760174.1A CN201710760174A CN108003102A CN 108003102 A CN108003102 A CN 108003102A CN 201710760174 A CN201710760174 A CN 201710760174A CN 108003102 A CN108003102 A CN 108003102A
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- ivabradine
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- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims abstract description 42
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 42
- 238000010189 synthetic method Methods 0.000 title claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000006482 condensation reaction Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 7
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- HYOAGWAIGJXNQH-UHFFFAOYSA-N 1-bromo-1-chloropropane Chemical compound CCC(Cl)Br HYOAGWAIGJXNQH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000006192 iodination reaction Methods 0.000 claims abstract description 5
- 125000002346 iodo group Chemical group I* 0.000 claims abstract description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims 1
- WTCBONOLBHEDIL-UHFFFAOYSA-M Sodium iodate Chemical group [Na+].[O-]I(=O)=O WTCBONOLBHEDIL-UHFFFAOYSA-M 0.000 claims 1
- ZEGDXSGIGIQDPG-UHFFFAOYSA-N carbon dioxide;magnesium Chemical compound [Mg].O=C=O ZEGDXSGIGIQDPG-UHFFFAOYSA-N 0.000 claims 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 235000009518 sodium iodide Nutrition 0.000 description 6
- 0 *C1NCC(CC(N(CCCCl)CC2)=*)=C2C=C1* Chemical compound *C1NCC(CC(N(CCCCl)CC2)=*)=C2C=C1* 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 210000001013 sinoatrial node Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- -1 tert-butyl alcohols Chemical class 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical compound C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of synthetic method of Ivabradine, and specific reactions steps are as follows:Step 1:Compound (II) is alkylated reaction with bromo-chloropropane under the catalysis of the first alkali and obtains compound (III);Step 2:Compound (III) carries out hydrogenation under palladium carbon and ammonium formate system and obtains compound (IV);Step 3:Compound (IV) carries out iodination reaction with iodo reagent, obtains compound (V);Step 4:Compound (V) carries out condensation reaction with compound (VI) under the catalysis of the second alkali, obtains compound (I).This method is easy to operate, mild condition, raw materials used to have been commercialized, and synthetic method is simple, of low cost, greatly reduces the synthesis difficulty of Ivabradine.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of synthetic method of Ivabradine.
Background technology
Ivabradine, the compound as shown in formula (I), chemical name:7,8- dimethoxys -3- (3- [[(1S) (4,5- bis-
Methoxyl group benzocyclobutane -1- bases) methyl]-methylamino] propyl group) -2 hydrogen of -1,3,4,5- tetrahydros-benzazepine -2- ketone:
Ivabradine (Ivabradine), the approval of the medical evaluation office (EMEA) in Europe is obtained on November 3rd, 2005
In the country's listing of 27, Europe, name of product Procoralan, for treating with normal sinus rhythm, to beta-blocker
Taboo or the symptomatic treatment of intolerable chronic stable angina pectoris.
Procoralan is researched and developed by Shi Weiya company, and the cardiovascular treatment field in 20 years that becomes history obtain it is most important
One of progress.Procoralan is that the 1st pure heart rate lowers medicine, is responsible for controlling sinoatrial node automatic by selective depression
The If passages of depolarising and adjusting heart rate play a role.Procoralan selectively actings are in sinoatrial node, to intracardiac conduction, cardiac muscle
Convergent force or ventricular repolarisation do not influence.Different from anginal common medicine beta-blocker, Procoralan does not cause sexual function
Obstacle, respiratory system adverse reaction and bradycardia or rebound phenomenon caused by airway contraction and spasm.
Report has EP05348059 in relation to the patent for preparing the compound earliest, its related patents is US5296482, this is special
Sharp synthetic method is as follows:
This method yield is relatively low, and particularly chiral starting material is expensive, and catalytic hydrogenation this step, yield only 40%,
Total recovery is 18%, and product need to be purified through column chromatography, greatly improve manufacturing cost, be not suitable for industrialized production.
In addition Chinese patent CN20051005779 reports the new method of synthesis of ivabradine, its route is as follows:
Each step of this method uses palladium-carbon catalyst, and is high-pressure hydrogenation, although total recovery is higher, from cost and work
There are larger drawback for this route from the aspect of industry.
The content of the invention
In order to solve the above technical problems, the present invention provides a kind of synthetic method of Ivabradine, this method is easy to operate,
Mild condition, raw materials used to have been commercialized, synthetic method is simple, of low cost, greatly reduces the synthesis of Ivabradine
Difficulty.
To reach above-mentioned purpose, the present invention provides a kind of synthetic method of Ivabradine, and specific reactions steps are as follows:
Step 1:Compound (II) is alkylated reaction under the catalysis of the first alkali with bromo-chloropropane and obtains compound
(III);
Step 2:Compound (III) carries out hydrogenation under palladium carbon and ammonium formate system and obtains compound (IV);
Step 3:Compound (IV) carries out iodination reaction with iodo reagent, obtains compound (V);
Step 4:Compound (V) carries out condensation reaction with compound (VI) under the catalysis of the second alkali, obtains compound
(I)。
Further, the present invention provides a kind of synthetic method of Ivabradine, and first alkali is sodium hydroxide, hydrogen-oxygen
Change potassium, potassium tert-butoxide etc., more preferably potassium tert-butoxide.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the alkylated reaction is in the first solvent
Middle progress, first solvent for tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO) etc.,
It is preferred that N,N-dimethylformamide.
Further, the present invention provides a kind of synthetic method of Ivabradine, the compound (III) and ammonium formate
Molar ratio is 1:(1~20), preferably 1:(8~15).
Further, the present invention provides a kind of synthetic method of Ivabradine, and the hydrogenation carries out under normal pressure.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the temperature of the hydrogenation is 10-
100 DEG C, preferably 40-70 DEG C.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the hydrogenation is in the second solvent
Carry out, second solvent is methanol, ethanol, isopropanol, propane diols etc., more preferably methanol.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the iodo reagent is sodium iodide, iodate
Potassium, magnesium iodide etc., more preferably sodium iodide.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the iodination reaction is in the 3rd solvent
Carry out, the 3rd solvent is acetone, butanone, methyl ethyl ketone, hexone etc., more preferably acetone.
Further, the present invention provides a kind of synthetic method of Ivabradine, the temperature of the iodide reaction for 30~
80 DEG C, preferably 50~60 DEG C.
Further, the present invention provides a kind of synthetic method of Ivabradine, and second alkali is anhydrous magnesium carbonate, nothing
Aqueous sodium carbonate, Anhydrous potassium carbonate etc., more preferably Anhydrous potassium carbonate.
Further, the present invention provides a kind of synthetic method of Ivabradine, the compound (V) and compound (VI)
Molar ratio be (1.0~1.3):1, it is preferably 1.2:1.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the condensation reaction is in the 4th solvent
Carry out, the 4th solvent is tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO) etc., more
Preferably N,N-dimethylformamide.
Further, the present invention provides a kind of synthetic method of Ivabradine, and the reaction temperature of the condensation reaction is
Room temperature, is preferably 20~30 DEG C.
Further, the present invention provides a kind of synthetic method of Ivabradine, needed after the completion of the condensation reaction into
Row post processing, the process of the post processing are as follows:Add water quenching to go out reaction, add concentrated hydrochloric acid and adjust pH < 2, water phase is collected in liquid separation;
Water is added ammonium hydroxide and adjusts pH > 8, and after being extracted with ethyl acetate, with purifying water washing organic phase, organic phase, which is concentrated to dryness, to be changed
Compound (I).
Beneficial effect
A kind of synthetic method of Ivabradine of the present invention, the synthetic method is easy to operate, and reaction condition is gentle, yield
Height, total recovery reach 60%, and wherein catalytic hydrogenation high income thoroughly solves hydrogenation operation with high pressure danger, yield is low up to 90%
Drawback, has good Industry Foundation and actual application value.
The experimentation of the preparation method is succinct, and route is clear and definite, irredundant operation, and end-product is post-processed without column layer
Analysis, simplification of flowsheet, reaction condition is gentle, reduces the three wastes and produces, is easy to industrial applications, to drug quality control and clinic
Curative effect is of great significance.
Embodiment
In order to make those skilled in the art more fully understand technical scheme, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Embodiment 1
At room temperature, 10g compounds (II) are taken, 100ml n,N-Dimethylformamide stirs evenly, and adds the 6.2g tert-butyl alcohols
Gone to after potassium activation 30min in the container for filling 8.6g bromo-chloropropane dilutions, 25 ± 5 DEG C of temperature control, reacts 30min, instead
It should finish to go in 1L frozen water and crystallization 5h is quenched, filter, crude product is in acetone/water (volume ratio 1:6) recrystallization, obtains white in
Solid 9.8g.
In reaction bulb, 8g compounds (III), 80ml methanol, 14g ammonium formates, 1.6g palladium carbons are added, normal pressure is warming up to 60
DEG C reaction 6h, filtering, filtrate is concentrated to dryness to obtain compound (IV).
Take 7g compounds (IV), 40ml acetone, 18g sodium iodides, temperature rising reflux 24h, cold filtration, be concentrated under reduced pressure into it is dry,
50ml dichloromethane stirring and dissolvings are added at room temperature, and filtering removes excessive sodium iodide, and filtrate decompression is concentrated to dryness to obtain chemical combination
Thing (V) 8.1g.
In reaction bulb, 3.0g compounds (VI), 50ml n,N-Dimethylformamide, 12g Anhydrous potassium carbonate room temperatures are added
1h is stirred, adds 5.7g compounds (V), reaction 6h is stirred at room temperature, reaction finishes, and adds 100ml frozen water that reaction is quenched, and adds hydrochloric acid
PH < 2 are adjusted, add ethyl acetate to extract (100ml × 3), discard organic phase, collect water phase, water is added concentrated ammonia liquor and adjusts pH > 8,
Ethyl acetate extracts (100ml × 3), merges organic phase, adds purifying water washing (200ml × 3) organic phase, and organic phase is concentrated under reduced pressure
It is extremely dry to obtain 5.4g Ivabradines, yield 94.1%, HPLC:99.5%.
Embodiment 2:
At room temperature, 20g compounds (II) are taken, 200mlN, dinethylformamide stirs evenly, and adds the 12.4g tert-butyl alcohols
Gone to after potassium activation 30min in the container for filling 17.2g bromo-chloropropane dilutions, 25 ± 5 DEG C of temperature control, reacts 30min, instead
It should finish to go in 1L frozen water and crystallization 5h is quenched, filter, crude product is in acetone/water (volume ratio 1:6) recrystallization, obtains white in
Solid 20.1g.
In reaction bulb, 15g compounds (III), 200ml methanol, 32g ammonium formates, 3.0g palladium carbons are added, normal pressure is warming up to
60 DEG C of reaction 6h, filtering, filtrate are concentrated to dryness to obtain compound (IV).
12g compounds (IV), 80ml acetone, 30, g sodium iodides are taken, temperature rising reflux 24h, cold filtration, is concentrated under reduced pressure into
It is dry, 150ml dichloromethane stirring and dissolvings are added at room temperature, and filtering removes excessive sodium iodide, and filtrate decompression is concentrated to dryness to obtain
Compound (V) 14.3g.
In reaction bulb, 5.0g compounds (VI), 50ml n,N-Dimethylformamide, 20g Anhydrous potassium carbonate room temperatures are added
1h is stirred, adds 9.6g compounds (V), reaction 6h is stirred at room temperature, reaction finishes, and adds 100ml frozen water that reaction is quenched, and adds hydrochloric acid
PH < 2 are adjusted, add ethyl acetate to extract (100ml × 3), discard organic phase, collect water phase, water is added concentrated ammonia liquor and adjusts pH > 8,
Ethyl acetate extracts (100ml × 3), merges organic phase, adds purifying water washing (200ml × 3) organic phase, and organic phase is concentrated under reduced pressure
It is extremely dry to obtain 9.2g Ivabradines.Yield 95.8%, HPLC:99.1%.
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the invention, for the skill of this area
For art personnel, the invention may be variously modified and varied.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of Ivabradine, it is characterised in that specific reactions steps are as follows:
Step 1:Compound (II) is alkylated reaction with bromo-chloropropane under the catalysis of the first alkali and obtains compound (III);
Step 2:Compound (III) carries out hydrogenation under palladium carbon and ammonium formate system and obtains compound (IV);
Step 3:Compound (IV) carries out iodination reaction with iodo reagent, obtains compound (V);
Step 4:Compound (V) carries out condensation reaction with compound (VI) under the catalysis of the second alkali, obtains compound (I).
2. the synthetic method of Ivabradine according to claim 1, it is characterised in that first alkali is hydroxide
Sodium, potassium hydroxide, potassium tert-butoxide.
3. the synthetic method of Ivabradine according to claim 1, it is characterised in that the alkylated reaction is first
Carried out in solvent, first solvent is tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl are sub-
Sulfone.
4. the synthetic method of Ivabradine according to claim 1, it is characterised in that the compound (III) and first
The molar ratio of sour ammonium is 1:(1~20).
5. the synthetic method of Ivabradine according to claim 1, it is characterised in that the hydrogenation is under normal pressure
Carry out;The temperature of the hydrogenation is 10-100 DEG C.
6. the synthetic method of Ivabradine according to claim 1, it is characterised in that the hydrogenation is molten second
Carried out in agent, second solvent is methanol, ethanol, isopropanol, propane diols.
7. the synthetic method of Ivabradine according to claim 1, it is characterised in that the iodo reagent is iodate
Sodium, potassium iodide, magnesium iodide;The iodination reaction carries out in the 3rd solvent, and the 3rd solvent is acetone, butanone, methyl second
Base ketone, hexone;The temperature of the iodide reaction is 30~80 DEG C.
8. the synthetic method of Ivabradine according to claim 1, it is characterised in that second alkali is Carbon Dioxide
Magnesium, natrium carbonicum calcinatum, Anhydrous potassium carbonate;The compound (V) and the molar ratio of compound (VI) are (1.0~1.3):1.
9. the synthetic method of Ivabradine according to claim 1, it is characterised in that the condensation reaction is molten the 4th
Carried out in agent, the 4th solvent is tetrahydrofuran, n,N-Dimethylformamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO);
The reaction temperature of the condensation reaction is room temperature.
10. the synthetic method of Ivabradine according to claim 1, it is characterised in that after the completion of the condensation reaction
Need to be post-processed, the process of the post processing is as follows:Add water quenching to go out reaction, add concentrated hydrochloric acid and adjust pH < 2, liquid separation is collected
Water phase;Water is added ammonium hydroxide and adjusts pH > 8, and after being extracted with ethyl acetate, with purifying water washing organic phase, organic phase is concentrated to dryness
Obtain compound (I).
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CN111187211A (en) * | 2020-01-19 | 2020-05-22 | 北京鑫开元医药科技有限公司海南分公司 | Preparation method of dimer impurity in ivabradine hydrochloride intermediate |
CN115286577A (en) * | 2022-08-25 | 2022-11-04 | 江苏永安制药有限公司 | Preparation method of ivabradine hydrochloride and intermediate thereof |
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CN115286577A (en) * | 2022-08-25 | 2022-11-04 | 江苏永安制药有限公司 | Preparation method of ivabradine hydrochloride and intermediate thereof |
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