CN105461609B - A kind of preparation method of Nintedanib - Google Patents
A kind of preparation method of Nintedanib Download PDFInfo
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- CN105461609B CN105461609B CN201510985373.3A CN201510985373A CN105461609B CN 105461609 B CN105461609 B CN 105461609B CN 201510985373 A CN201510985373 A CN 201510985373A CN 105461609 B CN105461609 B CN 105461609B
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- nintedanib
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- halogen
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- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 title claims abstract description 29
- 229960004378 nintedanib Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 14
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 150000004820 halides Chemical class 0.000 claims abstract description 6
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 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 7
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 3
- 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 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- -1 methyl [2- (4- methyl-1-piperazinyl) acetyl] ammonia Chemical compound 0.000 description 2
- 229940095102 methyl benzoate Drugs 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- APXZJEKJKQANJV-UHFFFAOYSA-N 2-oxoindole-6-carboxylic acid Chemical compound N=1C(C=C2C=CC(=CC=12)C(=O)O)=O APXZJEKJKQANJV-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229940015847 ofev Drugs 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the preparation method of Nintedanib (I) a kind of, preparation step includes: that condensation reaction occurs for raw material with 2- Oxoindole -6- methyl formate (III) and benzaldehyde (II) to obtain compounds Ⅳ；Then halogen or halide reagent is added, substitution reaction occurs and obtains compound V；Compound V and compound VI are condensed to yield Nintedanib (chemical compounds I) in the presence of alkali.Reactions steps of this method is short, at low cost, high income, and the reagent environmental protection used is suitable for industrial production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation method of Nintedanib.
Background technique
Ethanesulfonic acid Nintedanib is that triple tyrosine kinase suppressions are taken orally by one kind of German Boehringer Ingelheim company research and development
Preparation is currently used primarily in oncotherapy, such as colorectal cancer, oophoroma, Huppert's disease.For respiratory disease
Research mainly around the clinical treatment of advanced Non-small cell lung (NSCLC) and idiopathic pulmonary interstitial fibrosis (IPF) carry out.
In June, 2014 Boehringer Ingelheim company announces that ethanesulfonic acid Nintedanib treats idiopathic pulmonary fibrosis (IPF)
Listing license application obtains the confirmation of European drug administration (EMA) and is included in acceleration examination & approval list by EMA.In October, 2014
15, U.S. Food and Drug Administration FDA approval ethanesulfonic acid Nintedanib (trade name: Ofev) new oral drugs were used for
Idiopathic pulmonary fibrosis (IPF) treatment.
Entitled (the 3Z)-2,3- dihydro-3- of Nintedanib chemistry [[[4- [methyl [2- (4- methyl-1-piperazinyl) acetyl] ammonia
Base] phenyl] amino] benzylidene] -2- oxo -1H- methyl indole-6-carboxylate, structural formula are as follows:
The synthetic method of Nintedanib is few in the prior art, wherein reports synthesis Formulas I in patent CN101883756A
A kind of method of compound (Nintedanib), is shown below:
This method protects amino base with chloroacetic anhydride in toluene using 2- Oxoindole -6- methyl formate as starting material
Then with former benzoic acid trimethyl condensation reaction occurs for group, then with sodium hydroxide Deprotection, is finally condensed with compound VI
To Nintedanib (I).Document report has the following disadvantages: that process route is long, and upper protecting group and Deprotection operation are numerous
Trivial, the DMF solvent used is not environmentally friendly enough.In addition, document " synthesis chemistry " the 8th the 763-766 pages of phase report of volume 23 in 2015
Nintedanib preparation route and CN101883756A it is almost the same, protective agent chloroacetic anhydride is only changed into acetic anhydride, former benzene
The problem of trimethyl orthoformate changes original acid triethyl into, technique is again without solution.
A kind of method that patent CN 104844499A reports one kettle way preparation Nintedanib, reaction equation are as follows:
This method is with 2- Oxoindole -6- methyl formate (III), methyl benzoate and N- (4- aminophenyl)-N- methyl -
2- (4- methylpiperazine-1-yl) acetamide (VI) is starting material, 2- Oxoindole -6- formic acid first under the action of inorganic base
The substitution reaction of α-hydrogen occurs for ester and methyl benzoate, then is docked with compound VI, and one kettle way prepares Nintedanib.This road
Line uses one kettle way, and one kettle way is often difficult to control product quality in the production of actual industrial metaplasia, is not suitable for industrialization amplification,
And DMF solvent has equally been used in reaction process, it is unfavorable to environment.
The present invention is using 2- Oxoindole -6- methyl formate and benzaldehyde as starting material, by designing new route, selection
The solvent and reagent of safety and environmental protection prepare Nintedanib, solve prior art trivial operations, pollute environment, are difficult to realize work
The problems such as industry.This invention simplifies technological operation step, safety and environmental protection, while total recovery are suitble to industrialization up to 80% or more
Production.
Summary of the invention
The purpose of the present invention is to provide a kind of simple process, safety and environmental protection, the Nintedanib for being suitable for industrialized production
Preparation method.
To achieve the above object, the present inventor devises the preparation method for being different from the Nintedanib of the prior art,
A kind of preparation method of Nintedanib (I),
It is characterized in that, the preparation method includes the following steps:
(1) using alcohols as reaction dissolvent, condensation occurs for benzaldehyde (II) and 2- Oxoindole -6- methyl formate (III) instead
It should obtain compounds Ⅳ；
(2) using halogenated hydrocarbon as reaction dissolvent, substitution reaction occurs for compound IV and halogen or halide reagent, obtains chemical combination
Object V；
(3) compound V and compound VI are further condensed to yield Ni Dani using alcohols as reaction dissolvent in the presence of alkali
Cloth I.
Preparation method of the invention can be indicated with following reaction equations:
Wherein, R=Cl, Br or I.
In the step (1), the mol ratio of compound III and compound ii is 1:1.1~2.0.Setting-up point
It is 20 DEG C -80 DEG C.
In the step (1) or the step (3), alcohols solvent is selected from methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol or just
Butanol, preferred alcohol.
In the step (2), compound IV is 1:0.5~1.7 with the mol ratio of halogen or halide reagent；Halogen used
It can be selected from methylene chloride, chloroform or carbon tetrachloride, preferably methylene chloride for hydrocarbon solvent；Halogen or halide reagent used is optional
Use Cl2, Br2, I2, N- bromo-succinimide or N- chlorosuccinimide, preferably Br2。
In the step (3), the mol ratio of compound V and compound VI are 1:1.0~1.5；Alkali used is nothing
Machine alkali or organic base, inorganic base can be selected from saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium carbonate or
Cesium carbonate；Triethylamine, diethylamine or n,N-diisopropylethylamine can be selected in organic base；It is preferred that inorganic base sodium bicarbonate.
Compared with prior art, the invention has the following advantages: 1, shorten operating procedure, simplify and operated
Journey improves production efficiency.2, safety and environmental protection is suitble to industrialized production.
Specific embodiment
Below with reference to test example and specific embodiment, the present invention is described in further detail.But this should not be understood
It is all that this is belonged to based on the technology that the content of present invention is realized for the scope of the above subject matter of the present invention is limited to the following embodiments
The range of invention.
Embodiment 1:
The preparation of compound IV
2- Oxoindole -6- the methyl formate of 28.7g is added in the reaction flask of 250ml, 130ml ethyl alcohol opens stirring,
Add 16.8ml(17.6g) benzaldehyde, 2.97ml piperidines is heated to 70 DEG C -80 DEG C, and reaction naturally cooled to 20 after 2 hours
DEG C -30 DEG C, filtering precipitating, filter cake is washed with dehydrated alcohol, 50 DEG C vacuum drying 5 hours 40.2g yellow solid (IV), receive
Rate: 96.0%.
The preparation of compound V
30g compound IV, methylene chloride 360ml are added in the reaction flask of 500ml, is cooled to 0-5 DEG C with ice water, drop
Add bromine 9.6ml(29.9g), it drips off and is warming up to 20-30 DEG C, react 3 hours, end of reaction, reaction solution washes one with 150ml
It is secondary, dichloromethane layer it is dense it is dry to obtain grease, be added 200ml dehydrated alcohol crystallization, filtering, 60 DEG C be dried in vacuo 35.1g class is white
Color solid (V), yield: 91.2%.
The synthesis of Nintedanib (I)
30g compound V, 22.5g compound VI, ethyl alcohol 300ml, sodium bicarbonate 15g are added in the reaction flask of 500ml,
After being heated to back flow reaction 2 hours, 600ml water is added into reaction solution, there are a large amount of solids to be precipitated, filtering, filter cake 100ml water
It washes once, obtains 41.9g yellow solid Nintedanib (I) with refining methanol.Yield 92.7%.
1H NMR (400 MHz, dmso) δ11.97 (s, 1H), 8.38 (s, 1H), 7.97 (dd, J =
11.9, 5.0 Hz, 2H), 7.67 (d, J= 8.1 Hz, 1H), 7.16 (ddd, J= 26.9, 22.1, 7.0 Hz,
5H), 6.85 (d, J = 8.6 Hz, 2H), 6.63 (d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 2.99
(s, 3H), 2.69 (s, 2H), 2.51–2.24 (m, 8H), 2.20 (s, 3H).
MS:m/z 540 (M+1)+
Embodiment 2:
The preparation of compound IV
2- Oxoindole -6- the methyl formate of 28.7g is added in the reaction flask of 250ml, 130ml ethyl alcohol opens stirring,
Add 30.3ml(31.8g) benzaldehyde, 2.97ml piperidines, be heated to 70 DEG C -80 DEG C reaction 2 hours after, naturally cool to 20
DEG C -30 DEG C, filtering precipitating, filter cake is washed with dehydrated alcohol, 50 DEG C vacuum drying 5 hours 38.7g yellow solid (IV), receive
Rate: 92.4%.
The preparation of compound V
30g compound IV, methylene chloride 360ml are added in the reaction flask of 500ml, is cooled to 0-5 DEG C with ice water, drop
Add bromine 3.1ml(9.7g), it drips off after being warming up to 20-30 DEG C, reaction 3 hours, reaction solution washes primary, dichloromethane with 150ml
Alkane layer is dense dry that grease, addition 200ml dehydrated alcohol crystallization filter, and 60 DEG C are dried in vacuo to obtain 36.1g off-white powder (V),
Yield: 93.8%.
The synthesis of Nintedanib (I)
30g compound V, 33.0g compound VI, ethyl alcohol 300ml, sodium bicarbonate 15g are added in the reaction flask of 500ml,
After being heated to back flow reaction 2 hours, 600ml water is added into reaction solution, there are a large amount of solids to be precipitated, filtering, filter cake 100ml water
It washes once, obtains 42.3g yellow solid Nintedanib (I) with refining methanol.Yield 93.6%.
1H NMR (400 MHz, dmso) δ 11.94 (s, 1H), 8.36 (s, 1H), 7.96 (dd, J =
11.9, 5.0 Hz, 2H), 7.67 (d, J= 8.1 Hz, 1H), 7.16 (ddd, J= 26.9, 22.1, 7.0 Hz,
5H), 6.85 (d, J = 8.6 Hz, 2H), 6.61(d, J = 8.7 Hz, 2H), 3.90 (s, 3H), 2.99
(s, 3H), 2.65 (s, 2H), 2.50–2.30 (m, 8H), 2.20 (s, 3H).
MS:m/z 540 (M+1)+ 。
Claims (4)
1. a kind of preparation method of Nintedanib (I),
It is characterized in that, the preparation method includes the following steps:
(1) using alcohols as reaction dissolvent, benzaldehyde (II) occurs condensation reaction with 2- Oxoindole -6- methyl formate (III) and obtains
To compounds Ⅳ；
(2) using halogenated hydrocarbon as reaction dissolvent, substitution reaction occurs for compound IV and halogen or halide reagent, obtains compound
Ⅴ；
(3) the addition 30g compound V in the reaction flask of 500ml, 33.0g compound VI, ethyl alcohol 300ml, sodium bicarbonate 15g,
It is heated to back flow reaction 2 hours, 600ml water is added into reaction solution, there are a large amount of solids to be precipitated, filtering, filter cake is washed with 100ml
Once, Nintedanib I is obtained with refining methanol；
Its reaction equation is as follows:
Wherein, R=Br.
2. the preparation method of Nintedanib (I) according to claim 1, wherein in the step (1), compound III with
The mol ratio of compound ii is 1:1.1~2.0.
3. the preparation method of Nintedanib (I) according to claim 1, wherein the setting-up point in the step (1)
It is 20 DEG C -80 DEG C.
4. the preparation method of Nintedanib (I) according to claim 1, wherein in the step (2), compounds Ⅳ with
The mol ratio of halogen or halide reagent is 1:0.5~1.7.
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| WO2017198202A1 (en) * | 2016-05-19 | 2017-11-23 | 上海诚妙医药科技有限公司 | Novel crystal form of nintedanib, manufacturing method thereof, and application of same |
| US10836751B2 (en) | 2016-10-12 | 2020-11-17 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Methods for preparing Nintedanib and intermediates thereof |
| CN107935908A (en) * | 2016-10-12 | 2018-04-20 | 上海科胜药物研发有限公司 | A kind of Nintedanib（nintedanib）Preparation Method And Their Intermediate |
| CN107935909B (en) * | 2016-10-13 | 2023-03-17 | 上海科胜药物研发有限公司 | Synthesis method of nintedanib and intermediate thereof |
| JP7306697B2 (en) * | 2017-03-14 | 2023-07-11 | オールジェネシス バイオセラピューティクス インコーポレイテッド | 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6- Crystal form of methoxycarbonyl-2-indolinone |
| WO2019048974A1 (en) * | 2017-09-06 | 2019-03-14 | Glenmark Pharmaceuticals Limited | Process for the preparation of nintedanib |
| JP7382317B2 (en) | 2017-11-17 | 2023-11-16 | フェルミオン オサケ ユキチュア | Synthesis of 2-indolinone derivatives known as intermediates for producing nintedanib |
| WO2022029805A1 (en) * | 2020-08-07 | 2022-02-10 | Bdr Lifesciences Private Limited | An improved highly efficient process for the prepration of nintedanib and pharmaceutically acceptable salt thereof |
| CN113234013B (en) * | 2021-05-21 | 2022-05-24 | 杭州医学院 | A compound for inhibiting collagen synthesis and deposition and its application |
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