CN114369062A - Preparation method of ivabradine gene toxic impurities - Google Patents
Preparation method of ivabradine gene toxic impurities Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 37
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 7
- 231100000331 toxic Toxicity 0.000 title claims abstract description 7
- 230000002588 toxic effect Effects 0.000 title claims abstract description 7
- 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 description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 238000006243 chemical reaction Methods 0.000 claims description 112
- 238000003756 stirring Methods 0.000 claims description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- 238000001514 detection method Methods 0.000 claims description 43
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 28
- 238000001704 evaporation Methods 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 13
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 229960001701 chloroform Drugs 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 3
- XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- WUAXWQRULBZETB-UHFFFAOYSA-N homoveratric acid Chemical compound COC1=CC=C(CC(O)=O)C=C1OC WUAXWQRULBZETB-UHFFFAOYSA-N 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 13
- 231100000024 genotoxic Toxicity 0.000 abstract description 7
- 230000001738 genotoxic effect Effects 0.000 abstract description 7
- 238000007142 ring opening reaction Methods 0.000 abstract description 6
- 239000013558 reference substance Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- -1 3-bromopropyl Chemical group 0.000 abstract description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 2
- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 abstract 4
- BNNSFQWIRZKSBR-UHFFFAOYSA-N 1-bromo-n-methylmethanamine Chemical compound CNCBr BNNSFQWIRZKSBR-UHFFFAOYSA-N 0.000 abstract 1
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract 1
- 229960000504 ivabradine hydrochloride Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 92
- 230000001276 controlling effect Effects 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000001035 drying Methods 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 29
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000012074 organic phase Substances 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 11
- 239000008213 purified water Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000004321 preservation Methods 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 239000005457 ice water Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910015900 BF3 Inorganic materials 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical compound C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 229940097320 beta blocking agent Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 210000001013 sinoatrial node Anatomy 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000013577 regulation of ventricular cardiomyocyte membrane repolarization Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000010189 synthetic method Methods 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 invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of ivabradine gene toxic impurities. The preparation method of the ivabradine genotoxic impurity compound provided by the invention comprises the following steps: 3, 4-dimethoxyphenylacetic acid and 1-bromo-N-methyl methylamine protected by Boc are subjected to alkylation reaction, and the obtained product is subjected to carboxyl reduction and nucleophilic substitution with 3- (3-bromopropyl) -7, 8-dimethoxy-1, 3,4, 5-tetrahydro-2H-benzo [ d ] o-2-ketone to obtain the ivabradine ring-opening chloro impurity compound. The impurity compound provided by the invention can be used as an impurity reference substance and is used for an ivabradine hydrochloride intermediate, a bulk drug and/or a preparation in the production process.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of ivabradine gene toxic impurities.
Background
Ivabradine (ivabradine) with chemical name 3- (3- { [ ((7S) -3, 4-dimethoxybicyclo [4.2.0 ]]Octane-1, 3, 5-trien-7-yl) methyl]Methylamino } propyl) -1,3,4, 5-tetrahydro-7, 8-dimethoxy-2H-3-benzazepine
2-keto, the first selective specific IF (controlling spontaneous diastolic depolarization in the sinoatrial node and regulating heart rate) inhibitor, has a selective effect on the sinoatrial node and no effect on intracardiac conduction, myocardial contraction or ventricular repolarization; the pharmaceutical composition is approved by European medical evaluation agency (EMA) to be marketed at 25.10.2005, is named Procoralan, and is used for symptomatic treatment of chronic stable angina pectoris accompanied by normal sinus rhythm, contraindication to beta-blockers or intolerance to beta-blockers, and has the following structure:
genotoxic impurities (Genotoxic impurities) are compounds that themselves directly or indirectly damage cellular DNA, produce genetic mutations or right-hand side effects in vivo, and have carcinogenic potential or propensity. Genotoxic impurities are characterized by causing damage to human genetic material at very low concentrations, leading to genetic mutations and possibly contributing to tumorigenesis. It is highly toxic. The safety of the drug is strongly threatened, so that the comprehensive presumption of the structure of the possible genotoxic impurities and the determination of the content of the genotoxic impurities are very important for the quality control of the final product.
According to the preparation method of ivabradine reported in the prior literature, in the process of acidification by hydrochloric acid of the ivabradine, benzocyclobutane is easy to open a ring and generate impurities, and the structural formula of the benzocyclobutane is shown as the formula I:
in the process of research and development of new drugs, the quality of drugs is an important standard for measuring the quality of drugs, the quality standard of drugs has strict regulations on the purity of active ingredients of the drugs and the limit of impurities, generally, more than 0.1% of drug impurities should be identified and quantified by a selective method, and for drug research and development personnel, the impurities generated in the efficient impurity synthesis route oriented synthesis process are developed so as to obtain an impurity reference substance, so that the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material drugs is also very important work.
With the advancement of the national research work on the consistency of medicines, the preparation method of the ivabradine open-loop impurities is determined, qualified reference substances are provided, and the positive effect on the quality control of the ivabradine is achieved. At present, no specific preparation method for the impurity is disclosed and reported in the literature.
Therefore, the problem to be solved at present is to explore a process route with low production cost, simple and convenient operation and higher yield for the ivabradine ring-opening impurity.
Disclosure of Invention
The invention aims to provide a preparation method of an ivabradine gene toxic impurity compound, wherein the impurity compound can be used as an impurity reference substance in an ivabradine detection standard and is used in a quality control link of qualitative and quantitative analysis of impurities in the production process of the ivabradine. The preparation method is novel, the raw materials are easy to obtain, the operation is simple, and the sample purity is high.
The specific technical scheme of the invention is as follows:
the invention provides a preparation method of an ivabradine ring-opening impurity compound I, which comprises the following steps: step 1, reacting a compound II with a compound III under the action of a catalyst to obtain a compound IV; step 2, reducing the compound IV to obtain a compound V; and 3, reacting the compound V with thionyl chloride to obtain a compound VI, and performing nucleophilic substitution on the compound VI and the compound VII to obtain an ivabradine ring-opening impurity compound I.
Preferably, the above steps are described in further detail in the following sections:
step 1 preparation of Compound IV
Adding the compound II and the dried organic solvent A into a reaction bottle, adding a catalyst at low temperature, controlling the temperature after the addition, stirring for reaction, adding the compound III after the detection reaction is completed, and reacting at room temperature to obtain an intermediate compound IV.
Preferably, the catalyst is selected from one or a combination of n-butyl lithium, isobutyl lithium, lithium diisopropylamide, propyl lithium and phenyl lithium, wherein n-butyl lithium is particularly preferred.
Preferably, the feeding molar ratio of the compound II, the compound III and the catalyst is 1: 1.0-2.0: 2.0-3.0, and particularly preferably 1:1.2: 2.5.
Preferably, the organic solvent A is selected from one or a combination of anhydrous tetrahydrofuran, dichloromethane, acetonitrile and toluene, wherein the anhydrous tetrahydrofuran is particularly preferred.
Preferably, the temperature of the added catalyst is-80 ℃ to-40 ℃, wherein-50 ℃ is particularly preferred.
Preferably, the reaction temperature after the catalyst is added is-30 ℃ to 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: slowly adding the reaction solution into ice bath water to adjust the pH value to 2, extracting by an extracting agent, washing an organic phase by water and saturated saline solution, drying by anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing residues to obtain a compound IV; the extractant used for extraction is selected from one or the combination of ethyl acetate, dichloromethane and trichloromethane; the recrystallization is selected from one or the combination of equal volume of ethyl acetate/normal hexane, chloroform/normal hexane and ethyl acetate/cyclohexane system.
Step 2 preparation of Compound V
And adding the compound IV into an organic solvent B, controlling the temperature, adding a reducing agent system, and reacting at room temperature to obtain a compound V.
Preferably, the reducing agent system is selected from NaBH4/H2SO4、LiAlH4、KBH4/BF3、KBH4/I2、KBH4/CF3One of COOH, of which NaBH is particularly preferred4/H2SO4。
Preferably, the feeding molar ratio of the compound IV to the reducing agent system is 1: 2.0-5.0, and particularly preferably 1: 3.5; wherein the reducing agent is NaBH4、KBH4、LiAlH4Metering NaBH in reduction system4、KBH4And H2SO4、BF3、I2、CF3The molar ratio of COOH was 1:2.
Preferably, the organic solvent B is selected from one of dichloromethane, tetrahydrofuran, acetonitrile and chloroform, wherein dichloromethane is particularly preferred.
Preferably, the reducing agent is added at a temperature of-5 ℃ to 5 ℃, with 0 ℃ being particularly preferred.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: adding an extracting agent and purified water after the reaction is finished, stirring, layering, drying an organic layer by using anhydrous sodium sulfate, filtering, and evaporating filtrate under reduced pressure to obtain a compound V; the extractant is selected from one or the combination of ethyl acetate, dichloromethane and trichloromethane.
Step 3 preparation of Compound I
And adding the compound V into thionyl chloride, stirring at a controlled temperature for reaction, evaporating the thionyl chloride after detection reaction is finished, adding an organic solvent C and a compound VII, adding alkali, stirring at a controlled temperature until the reaction is finished to obtain an impurity compound I of the ivabradine.
Preferably, the base is one of potassium carbonate, cesium carbonate, sodium bicarbonate, triethylamine and pyridine, wherein potassium carbonate is particularly preferred.
Preferably, the feeding molar ratio of the compound V, the compound VII and the base is 1: 1.0-1.8: 2.0-4.0, and particularly preferably 1:1.2: 3.0.
Preferably, the organic solvent C is selected from one or a combination of N, N-dimethylformamide, tetrahydrofuran, acetonitrile and toluene, wherein N, N-dimethylformamide is particularly preferred.
Preferably, the reaction temperature after adding the thionyl chloride is 35-55 ℃; after the alkali is added, the reaction temperature is 45-55 ℃.
In a preferred scheme, after the reaction is finished, post-treatment operation is required, specifically, the reaction solution is cooled to room temperature, purified water and an extraction solvent are added, stirring is carried out, an organic layer is dried by anhydrous sodium sulfate, filtering is carried out, and the filtrate is dried after the organic solvent is removed by evaporation to obtain the ivabradine ring-opening impurity compound I.
The compounds of formula I may be converted into pharmaceutically acceptable salts, solvates.
The compound of the formula I, and the salt or solvate thereof can be applied to detection of ivabradine intermediate, bulk drug and/or preparation.
In conclusion, the technical effects obtained by the invention are as follows:
1. provides a high-purity ivabradine genotoxic impurity compound which can be used as an impurity reference substance and used for controlling the quality of the ivabradine in the production process.
2. The method for efficiently preparing the ivabradine ring-opening impurity compound I is provided, the whole synthetic method is short in route, the operation steps are simple, the reaction yield is high, and the product purity is high.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Characterization of the novel compounds and the final products:
1H-NMR(400MHz,CDCl3)δ:8.25(s,1H),6.81(s,1H),6.67-6.41(d,J＝8.4Hz,1H),6.27-6.05(d,J＝8.6Hz,1H),4.60(m,1H),3.78(s,6H),3.02(d,J＝6.4Hz,2H),2.79(s,3H),2.46(m,1H),1.43(s,9H)；；13C-NMR(100MHz,CDCl3)δ:172.5,171.1,150.2,148.8,128.7,126.0,112.3,111.4,56.1,53.2,39.7,25.2,15.8.ESI-HRMS(m/z):340.1686[M+H]+.
1H-NMR(400MHZ,CDCl3):δ6.75(s,1H),6.62-6.35(d,J＝8.4Hz,1H),6.27-6.08(d,J＝8.6Hz,1H),4.45(m,1H),3.77(m,6H),3.04(d,J＝6.4Hz,2H),2.71(s,3H),2.55(m,2H),2.42(m,1H),1.40(s,9H)；13C-NMR(100MHZ,CDCl3)δ:171.5,149.6,146.9,127.5,125.0,112.8,111.256.1,54.7,46.9,33.2,20.8,17.5.ESI-HRMS(m/z):326.2140[M+H]+.
1H-NMR(400MHZ,CDCl3):δ6.75(s,1H),6.62-6.35(d,J＝8.4Hz,1H),6.27-6.08(d,J＝8.6Hz,1H),4.25(br,1H),3.75(m,6H),2.97(d,J＝6.4Hz,2H),2.88(d,J＝8.8Hz,2H),2.65(m,2H),2.22(m,1H)；13C-NMR(100MHZ,CDCl3):δ150.6,147.6,128.8,126.7,112.8,110.5,56.7,54.3,44.2,32.8,21.6.ESI-HRMS(m/z):245.1050[M-HCl+H]+.
1H-NMR(400MHZ,CDCl3):δ6.84(s,1H),6.79(s,1H),6.71(s,1H),6.70-6.57(d,J＝8.8Hz1H),6.49(m,1H),3.78(s,6H),3.76(s,6H),3.73(t,2H),3.70(s,2H),3.59(m,1H),3.50(d,J＝6.0Hz,2H),3.37(t,2H),3.27-3.10(dd,2H),3.06(t,2H),2.99(t,2H),2.80(s,3H),1.92(m,2H).13C-NMR(100MHZ,CDCl3):δ171.4,149.7,148.6,147.9,147.1,136.2,135.0,128.0,122.9,115.0,114.2 109.2,108.6,57.0,55.8,54.3,52.9,46.0,43.3,42.0,40.1,37.4,36.0,31.8,22.9.ESI-HRMS(m/z):506.2511[M+H]+.
preparation of Compound IV
Example 1
Dissolving a compound II, namely 3, 4-dimethoxyphenylacetic acid (3.92g,20mmol) in 10mL of anhydrous tetrahydrofuran, controlling the temperature to be 50 ℃ below zero, adding n-butyllithium (3.20g,50mmol) under the protection of nitrogen, controlling the temperature to be 20 ℃ below zero after the addition is finished, stirring, dissolving a compound III (5.38g,24mmol) in 20mL of tetrahydrofuran for injection after the detection reaction is finished, stirring at room temperature, slowly adding a reaction system into 100mL of ice water after the detection reaction is finished, adjusting the pH to be 2 by using dilute hydrochloric acid, extracting by using ethyl acetate (20mL multiplied by 2), combining organic phases, washing the organic phase once by using water and a saturated saline solution respectively, and mixing the organic phases by using water and a saturated saline solutionDried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue taken up in 50mL of ethyl acetate and n-hexane (V)Ethyl acetate：VN-hexane1:1) to obtain the compound IV with the yield of 98.7% and the HPLC purity of 99.95%.
Example 2
Dissolving 3, 4-dimethoxyphenylacetic acid (3.92g,20mmol) in 10mL of anhydrous dichloromethane, controlling the temperature to-50 ℃, adding isobutyl lithium (3.20g,50mmol) under the protection of nitrogen, controlling the temperature to-20 ℃ after the addition is finished, stirring, dissolving compound III (4.48g,20mmol) in 20mL of tetrahydrofuran for injection after the detection reaction is finished, stirring at room temperature, slowly adding the reaction system into 100mL of ice water after the detection reaction is finished, adjusting the pH value to 2 with dilute hydrochloric acid, extracting with ethyl acetate (20mL multiplied by 2), combining organic phases, washing with water and saturated saline solution once respectively, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and using 50mL of ethyl acetate and n-hexane (V) to obtain a residueEthyl acetate：VN-hexane1:1) to obtain compound IV with a yield of 94.7% and an HPLC purity of 99.77%.
Example 3
Dissolving 3, 4-dimethoxyphenylacetic acid (3.92g,20mmol) in 10mL of anhydrous tetrahydrofuran, controlling the temperature to-50 ℃, adding lithium diisopropylamide (5.36g,50mmol) under the protection of nitrogen, controlling the temperature to 0 ℃ after the addition, stirring, dissolving compound III (8.96g,40mmol) in 20mL of tetrahydrofuran for injection after the detection reaction is finished, stirring at room temperature, slowly adding the reaction system into 100mL of ice water after the detection reaction is finished, adjusting the pH value to 2 with dilute hydrochloric acid, extracting with dichloromethane (20mL multiplied by 2), combining organic phases, washing with water and saturated saline solution once respectively, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and using 50mL of trichloromethane and n-hexane (V) for residuesTrichloromethane：VN-hexane1:1) to obtain compound IV with the yield of 93.2% and the HPLC purity of 99.70%.
Example 4
Dissolving 3, 4-dimethoxyphenylacetic acid (3.92g,20mmol) in 10mL anhydrous tetrahydrofuran, controlling the temperature at-50 ℃, adding propyllithium (2.52g,50mmol) under the protection of nitrogen, controlling the temperature at-20 ℃ after the addition is finished, stirring, and dissolving a compound III (9.86g,44mmol) in 20mL tetrahydrofuran after the detection reaction is finishedAdding pyran by injection, stirring at room temperature, slowly adding the reaction system into 100mL of ice water after detecting the reaction, adjusting the pH value to 2 by using dilute hydrochloric acid, extracting by using ethyl acetate (20mL multiplied by 2), combining organic phases, washing by using water and saturated salt aqueous solution once respectively, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and using 50mL of ethyl acetate and n-hexane (V) to obtain a residueEthyl acetate：VN-hexane1:1) to obtain compound IV with yield of 86.2% and HPLC purity of 99.25%.
Example 5
Dissolving 3, 4-dimethoxyphenylacetic acid (3.92g,20mmol) in 10mL of anhydrous dichloromethane, controlling the temperature to 80 ℃, adding phenyllithium (3.36g,40mmol) under the protection of nitrogen, controlling the temperature to-30 ℃ after the addition is finished, stirring, dissolving compound III (5.38g,24mmol) in 20mL of tetrahydrofuran for injection after the detection reaction is finished, stirring at room temperature, slowly adding the reaction system into 100mL of ice water after the detection reaction is finished, adjusting the pH to 2 with dilute hydrochloric acid, extracting with ethyl acetate (20mL multiplied by 2), combining organic phases, washing with water and saturated saline solution once respectively, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and using 50mL of ethyl acetate and cyclohexane (V) for residuesEthyl acetate：VCyclohexane1:1) to obtain compound IV with yield of 94.4% and HPLC purity of 99.66%.
Example 6
Dissolving 3, 4-dimethoxyphenylacetic acid (3.92g,20mmol) in 10mL of anhydrous dichloromethane, controlling the temperature to-40 ℃, adding n-butyllithium (3.84g,60mmol) under the protection of nitrogen, controlling the temperature to 0 ℃ after the addition, stirring, dissolving compound III (5.38g,24mmol) in 20mL of tetrahydrofuran for injection after the detection reaction is finished, stirring at room temperature, slowly adding the reaction system into 100mL of ice water after the detection reaction is finished, adjusting the pH value to 2 with dilute hydrochloric acid, extracting with trichloromethane (20mL multiplied by 2), combining organic phases, washing with water and saturated saline solution once respectively, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and using 50mL of trichloromethane and n-hexane (V) for residuesTrichloromethane：VN-hexane1:1) to obtain compound IV with a yield of 93.5% and an HPLC purity of 99.72%.
Example 7
Mixing 3, 4-dimethoxyphenylacetic acid (3.92g, 20)mmol) is dissolved in 10mL of anhydrous acetonitrile, the temperature is controlled to be 35 ℃ below zero, n-butyllithium (2.31g,36mmol) is added under the protection of nitrogen, the temperature is controlled to be 40 ℃ below zero after the addition is finished, the compound III (5.38g,24mmol) is dissolved in 20mL of tetrahydrofuran for injection and is stirred at room temperature, the reaction system is slowly added into 100mL of ice water after the detection reaction is finished, the pH value is adjusted to be 2 by dilute hydrochloric acid, then the ethyl acetate (20mL multiplied by 2) is used for extraction, the organic phases are combined, the organic phases are washed once by water and saturated saline solution respectively, anhydrous sodium sulfate is dried and decompressed and concentrated, the residue is added with 50mL of ethyl acetate and n-hexane (V)Ethyl acetate：VN-hexane1:1) to obtain compound IV with yield of 86.5% and HPLC purity of 99.42%.
Example 8
Dissolving 3, 4-dimethoxyphenylacetic acid (3.92g,20mmol) in 10mL of anhydrous toluene, controlling the temperature to-85 ℃, adding n-butyllithium (4.10g,64mmol) under the protection of nitrogen, controlling the temperature to-20 ℃ after the addition is finished, stirring, dissolving compound III (5.38g,24mmol) in 20mL of tetrahydrofuran for injection after the detection reaction is finished, stirring at room temperature, slowly adding the reaction system into 100mL of ice water after the detection reaction is finished, adjusting the pH value to 2 with dilute hydrochloric acid, extracting with ethyl acetate (20mL multiplied by 2), combining organic phases, washing with water and saturated saline solution once respectively, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and using 50mL of ethyl acetate and n-hexane (V) for residuesEthyl acetate：VN-hexane1:1) to obtain compound IV with yield of 86.9% and HPLC purity of 98.92%.
Preparation of Compound V
Example 9
Adding compound IV (3.39g,10mmol) and 30mL of dichloromethane into a 100mL reaction bottle, stirring, controlling the temperature to be 0 ℃, adding sodium borohydride (1.32g,35mmol) in batches, slowly adding concentrated sulfuric acid (4.34g, 17mmol), stirring for 20min after the addition is finished, heating to room temperature, stirring for reaction, adding 30mL of dichloromethane and 70mL of water after the detection reaction is finished, stirring, layering, drying an organic layer with anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 98.5%, and the HPLC purity is 99.91%.
Example 10
Adding compound IV (3.4g,10mmol) and 30mL of dichloromethane into a 100mL reaction bottle, stirring, controlling the temperature to be 0 ℃, adding sodium borohydride (0.76g,20mmol) in batches, slowly adding concentrated sulfuric acid (2.56g, 10mmol), stirring for 20min after the addition is finished, heating to room temperature, stirring for reaction, adding 30mL of dichloromethane and 70mL of water after the detection reaction is finished, stirring, layering, drying an organic layer with anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 93.5%, and the HPLC purity is 99.76%.
Example 11
Adding compound IV (3.4g,10mmol) and 30mL of tetrahydrofuran into a 100mL reaction bottle, stirring, controlling the temperature to be 0 ℃, adding sodium borohydride (1.89g,50mmol) in batches, slowly adding concentrated sulfuric acid (6.38g, 25mmol), stirring for 20min after the addition is finished, heating to room temperature, stirring for reaction, adding 30mL of dichloromethane and 70mL of water after the reaction is detected, stirring, layering, drying an organic layer by anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 92.5%, and the HPLC purity is 99.62%.
Example 12
Adding compound IV (3.4g,10mmol) and 30mL of acetonitrile into a 100mL reaction bottle, stirring, controlling the temperature to be 0 ℃, adding sodium borohydride (0.57g,15mmol) in batches, slowly adding concentrated sulfuric acid (1.79g, 7mmol), stirring for 20min after the addition is finished, heating to room temperature, stirring for reaction, adding 30mL of dichloromethane and 70mL of water after the detection reaction is finished, stirring, layering, drying an organic layer by anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 84.9%, and the HPLC purity is 99.05%.
Example 13
Adding compound IV (3.4g,10mmol) and 30mL of trichloromethane into a 100mL reaction bottle, stirring, controlling the temperature to be 0 ℃, adding sodium borohydride (2.08g,55mmol) in batches, slowly adding concentrated sulfuric acid (6.89g, 27mmol), stirring for 20min after the addition is finished, heating to room temperature, stirring for reaction, removing the solvent by reduced pressure evaporation after the detection reaction is finished, adding 30mL of dichloromethane and 70mL of water, stirring, layering, drying an organic layer by anhydrous sodium sulfate, and drying by reduced pressure evaporation at the temperature of below 40 ℃ to obtain compound V, wherein the yield is 82.9%, and the HPLC purity is 98.94%.
Example 14
Adding compound IV (3.39g,10mmol) and 30mL of tetrahydrofuran into a 100mL reaction bottle, stirring, controlling the temperature to be-5 ℃, adding lithium aluminum hydride (1.33g,35mmol) in batches, stirring for 20min after the addition is finished, heating to room temperature, stirring for reaction, adding 30mL of ethyl acetate and 70mL of water after the reaction is detected, stirring, layering, drying an organic layer by anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 92.5%, and the HPLC purity is 99.63%.
Example 15
Adding compound IV (3.39g,10mmol) and 30mL of tetrahydrofuran into a 100mL reaction bottle, stirring, controlling the temperature to be 5 ℃, adding potassium borohydride (1.89g,35mmol) in batches, dropwise adding boron trifluoride (0.68g, 10mmol), stirring for 20min, heating to room temperature, stirring for reaction, adding 30mL of trichloromethane and 70mL of water after the reaction is detected, stirring, layering, drying an organic layer by anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 93.8%, and the HPLC purity is 99.58%.
Example 16
Adding compound IV (3.39g,10mmol) and 30mL of tetrahydrofuran into a 100mL reaction bottle, stirring, controlling the temperature to be 0 ℃, adding potassium borohydride (1.89g,35mmol) in batches, adding iodine (2.54g, 10mmol), stirring for 20min, heating to room temperature, stirring for reaction, adding 30mL of ethyl acetate and 70mL of water after detecting the reaction is finished, stirring, layering, drying an organic layer by using anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 92.6%, and the HPLC purity is 99.63%.
Example 17
Adding compound IV (3.39g,10mmol) and 30mL of tetrahydrofuran into a 100mL reaction bottle, stirring, controlling the temperature to be-10 ℃, adding potassium borohydride (1.89g,35mmol) in batches, adding trifluoroacetic acid (1.14g, 10mmol), stirring for 20min, heating to room temperature, stirring for reaction, adding 30mL of ethyl acetate and 70mL of water after the reaction is detected, stirring, layering, drying an organic layer by using anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 40 ℃ under reduced pressure to obtain compound V, wherein the yield is 87.6%, and the HPLC purity is 99.62%.
Preparation of Compound I
Example 18
Adding 10mL of thionyl chloride into 3.25g and 10mmol of a compound V, controlling the temperature to 45 ℃ for reaction, after the detection reaction is finished, evaporating the thionyl chloride under reduced pressure, adding 10mL of N, N-dimethylformamide, 4.11g and 12mmol of a compound VII and 4.15g and 30mmol of potassium carbonate, heating to 50 ℃, carrying out heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of ethyl acetate, stirring, drying an organic phase through anhydrous sodium sulfate, carrying out suction filtration, evaporating the solvent under reduced pressure, and carrying out vacuum drying at 40 ℃ to obtain a compound I, wherein the yield is 99.2%, and the HPLC purity is 99.90%.
Example 19
Adding 10mL of thionyl chloride into 3.25g and 10mmol of a compound V, controlling the temperature to 45 ℃ for reaction, after the detection reaction is finished, evaporating the thionyl chloride under reduced pressure, adding 10mL of N, N-dimethylformamide, 3.42g and 10mmol of a compound VII and 9.76g and 30mmol of cesium carbonate, heating to 50 ℃, carrying out heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of ethyl acetate, stirring, drying an organic phase through anhydrous sodium sulfate, carrying out suction filtration, evaporating the solvent under reduced pressure, and carrying out vacuum drying at 40 ℃ to obtain a compound I, wherein the yield is 94.2%, and the HPLC purity is 99.65%.
Example 20
Adding 10mL of thionyl chloride into 3.25g and 10mmol of a compound V, controlling the temperature to 45 ℃ for reaction, after the detection reaction is finished, evaporating the thionyl chloride under reduced pressure, adding 10mL of N, N-dimethylformamide, 6.16g and 18mmol of a compound VII and 2.52g and 30mmol of sodium bicarbonate, heating to 50 ℃ for heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of ethyl acetate for stirring, drying an organic phase through anhydrous sodium sulfate, carrying out suction filtration, evaporating the solvent under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound I, wherein the yield is 95.5%, and the HPLC purity is 99.68%.
Example 21
Adding 10mL of thionyl chloride into a compound V (3.25g,10mmol), controlling the temperature to 45 ℃ for reaction, after the detection reaction is finished, evaporating the thionyl chloride under reduced pressure, adding 10mL of N, N-dimethylformamide, 6.84g,20mmol of a compound VII and 3.04g,30mmol of triethylamine, heating to 50 ℃, carrying out heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of ethyl acetate, stirring, drying an organic phase through anhydrous sodium sulfate, carrying out suction filtration, evaporating the solvent under reduced pressure, and carrying out vacuum drying at 40 ℃ to obtain a compound I, wherein the yield is 85.5%, and the HPLC purity is 98.95%.
Example 22
Adding 10mL of thionyl chloride into a compound V (3.25g and 10mmol), controlling the temperature to 35 ℃ for reaction, after the detection reaction is finished, evaporating the thionyl chloride under reduced pressure, adding 10mL of N, N-dimethylformamide, 4.11g and 12mmol of a compound VII and 2.37g and 30mmol of pyridine, heating to 50 ℃ for heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of dichloromethane for stirring, drying an organic phase through anhydrous sodium sulfate, performing suction filtration, evaporating the solvent under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound I, wherein the yield is 96.0%, and the HPLC purity is 99.89%.
Example 23
Adding 10mL of thionyl chloride into a compound V (3.25g,10mmol), controlling the temperature to be 55 ℃ for reaction, after the detection reaction is finished, decompressing and steaming to remove the thionyl chloride, adding 10mL of tetrahydrofuran, 4.11g,12mmol of a compound VII and 2.76g,20mmol of potassium carbonate, controlling the temperature to be 45 ℃ for heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of ethyl acetate for stirring, drying an organic phase through anhydrous sodium sulfate, performing suction filtration, decompressing and steaming to remove a solvent, and performing vacuum drying at 40 ℃ to obtain a compound I, wherein the yield is 95.6%, and the HPLC purity is 99.68%.
Example 24
Adding 10mL of thionyl chloride into a compound V (3.25g,10mmol), controlling the temperature to be 30 ℃ for reaction, after the detection reaction is finished, evaporating the thionyl chloride under reduced pressure, adding 10mL of acetonitrile, 4.11g,12mmol of a compound VII and 5.53g,40mmol of potassium carbonate, controlling the temperature to be 55 ℃ for heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of ethyl acetate, stirring, drying an organic phase through anhydrous sodium sulfate, carrying out suction filtration, evaporating a solvent under reduced pressure, and drying in vacuum at 40 ℃ to obtain a compound I, wherein the yield is 94.2%, and the HPLC purity is 99.62%.
Example 25
Adding 10mL of thionyl chloride into a compound V (3.25g,10mmol), controlling the temperature to be 60 ℃ for reaction, after the detection reaction is finished, carrying out reduced pressure distillation to remove the thionyl chloride, adding 10mL of toluene, 4.11g,12mmol of a compound VII and 2.07g,15mmol of potassium carbonate, controlling the temperature to be 60 ℃ for heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of ethyl acetate for stirring, drying an organic phase through anhydrous sodium sulfate, carrying out suction filtration, carrying out reduced pressure distillation to remove a solvent, and carrying out vacuum drying at 40 ℃ to obtain a compound I, wherein the yield is 85.2%, and the HPLC purity is 98.94%.
Example 26
Adding 10mL of thionyl chloride into a compound V (3.25g,10mmol), controlling the temperature to be 60 ℃ for reaction, after the detection reaction is finished, evaporating the thionyl chloride under reduced pressure, adding 10mL of N, N-dimethylformamide, 4.11g,12mmol of a compound VII and 6.22g,45mmol of potassium carbonate, controlling the temperature to be 40 ℃ for heat preservation reaction, cooling to room temperature after the detection reaction is finished, adding 60mL of purified water and 30mL of trichloromethane for stirring, drying an organic phase through anhydrous sodium sulfate, carrying out suction filtration, evaporating the solvent under reduced pressure, and carrying out vacuum drying at 40 ℃ to obtain a compound I, wherein the yield is 82.2%, and the HPLC purity is 98.90%.
Claims (10)
1. The preparation method of ivabradine gene toxic impurities is characterized by comprising the following steps:
(1) adding the compound II and a dried organic solvent A into a reaction bottle, adding a catalyst at a low temperature, controlling the temperature after the addition is finished, stirring for reaction, adding the compound III after the detection reaction is completed, and reacting at room temperature to obtain an intermediate compound IV;
(2) adding the compound IV into an organic solvent B, controlling the temperature, adding a reduction system, and reacting at room temperature to obtain a compound V;
(3) adding the compound V into thionyl chloride, performing temperature-controlled stirring reaction to obtain a compound VI, evaporating the thionyl chloride after detection reaction is finished, adding an organic solvent C and the compound VII, adding alkali, performing temperature-controlled stirring until the reaction is finished to obtain an impurity compound I of the ivabradine, wherein the reaction route is as follows:
2. the method according to claim 1, wherein in the step (1), the catalyst is selected from one of n-butyllithium, isobutyllithium, lithium diisopropylamide, propyllithium and phenyllithium.
3. The method according to claim 1, wherein in the step (1), the compound II, the compound III and the catalyst are fed in a molar ratio of 1:1.0 to 2.0:2.0 to 3.0.
4. The preparation method according to claim 1, wherein in the step (1), the dried organic solvent A is one or a combination of tetrahydrofuran, dichloromethane, acetonitrile and toluene; the temperature of the added catalyst is-80 ℃ to-40 ℃; the reaction temperature after the catalyst is added is-30 ℃ to 0 ℃.
5. The method of claim 1, wherein in step (2), the reducing system is selected from NaBH4/H2SO4、LiAlH4、KBH4/BF3、KBH4/I2、KBH4/CF3One kind of COOH.
6. The preparation method according to claim 1, wherein the compound IV and the reducing agent system are fed in the step (2) in a molar ratio of 1:2.0 to 5.0.
7. The preparation method according to claim 1, wherein the organic solvent B in the step (2) is selected from one or a combination of dichloromethane, tetrahydrofuran, acetonitrile and trichloromethane; the temperature of the reducing agent is-5 ℃ to 5 ℃.
8. The method according to claim 1, wherein the base in the step (3) is one selected from the group consisting of potassium carbonate, cesium carbonate, sodium hydrogen carbonate, triethylamine and pyridine.
9. The method according to claim 1, wherein the compound V, VII and the base are fed in the step (3) in a molar ratio of 1:1.0 to 1.8:2.0 to 4.0.
10. The method according to claim 1, wherein the reaction temperature after the addition of thionyl chloride in the step (3) is 35 to 55 ℃; after the alkali is added, the reaction temperature is 45-55 ℃.
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