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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- 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
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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| CN105461609B true CN105461609B (en) | 2019-08-23 |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109415314A (en) * | 2016-05-19 | 2019-03-01 | 上海诚妙医药科技有限公司 | Novel crystal forms of Nintedanib and preparation method thereof and application thereof |
| 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 |
| 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 |
| WO2018068733A1 (en) * | 2016-10-12 | 2018-04-19 | 浙江华海药业股份有限公司 | Method for preparing nintedanib and intermediate thereof |
| WO2018165865A1 (en) * | 2017-03-14 | 2018-09-20 | 新源生物科技股份有限公司 | Crystal forms of 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone |
| WO2019048974A1 (en) * | 2017-09-06 | 2019-03-14 | Glenmark Pharmaceuticals Limited | Process for the preparation of nintedanib |
| CA3082714A1 (en) | 2017-11-17 | 2019-05-23 | Fermion Oy | Synthesis of a 2-indolinone derivative known as intermediate for preparing nintedanib |
| AU2021321561A1 (en) * | 2020-08-07 | 2023-03-09 | 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 | Compound for inhibiting collagen synthesis and deposition and application thereof |
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Effective date of registration: 20191204 Address after: Room 1201 and 1203, building e, 1378 Wenyi Road, Cangqian street, Yuhang District, Hangzhou City, Zhejiang Province Patentee after: Hangzhou Nortel o Sano Pharmaceutical Technology Development Co., Ltd. Address before: Hangzhou City, Zhejiang province 310030 Xihu District three Town Xiyuan Road No. 8 Patentee before: Hangzhou Xin Bosi biological medicine company limited |