CN105461609A - Preparation method of nintedanib - Google Patents
Preparation method of nintedanib Download PDFInfo
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- CN105461609A CN105461609A CN201510985373.3A CN201510985373A CN105461609A CN 105461609 A CN105461609 A CN 105461609A CN 201510985373 A CN201510985373 A CN 201510985373A CN 105461609 A CN105461609 A CN 105461609A
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- danibu
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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 invention relates to a preparation method of nintedanib (I). The preparation method comprises the steps that 2-oxoindole-6-methyl formate (III) and benzaldehyde (II) are used as raw materials to generate a condensation reaction, so as to obtain a compound IV; then halogen or halogenating reagents are added to generate a substitution reaction, so as to obtain a compound V; the compound V and the compound IV are condensed under the action of alkali, so as to obtain the nintedanib (a compound I). The method has the advantages of short reaction time, low cost, high yield and environmental friendliness of used reagents and is suitable for industrial production. The structural formulas are shown in the description.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to the preparation method of a kind of Ni Danibu.
Background technology
Ethyl sulfonic acid Ni Danibu is the oral triple tyrosine kinase inhibitor of one researched and developed by German Boehringer Ingelheim company, is mainly used in oncotherapy at present, as colorectal carcinoma, ovarian cancer, multiple myeloma etc.Research for respiratory system disease is mainly carried out around the clinical treatment of advanced Non-small cell lung (NSCLC) and idiopathic pulmonary interstitial fibrosis (IPF).
In June, 2014, Boehringer Ingelheim company announced, the listing that ethyl sulfonic acid Ni Danibu treats idiopathic pulmonary fibrosis (IPF) permits the confirmation of the application European drug administration of acquisition (EMA) and included in by EMA to accelerate examination & approval list.On October 15th, 2014, U.S. food Drug Administration FDA ratifies the new oral pharmaceutical of ethyl sulfonic acid Ni Danibu (trade(brand)name: Ofev) and is used for idiopathic pulmonary fibrosis (IPF) treatment.
Ni Danibu chemistry (3Z)-2 by name, 3-dihydro-3-[[[4-[methyl [2-(4-methyl isophthalic acid-piperazinyl) acetyl] is amino] phenyl] is amino] α-tolylene]-2-oxo-1H-methyl indole-6-carboxylate, its structural formula is:
In prior art, the synthetic method of Ni Danibu is few, reports a kind of method of synthetic compound of formula i (Ni Danibu), be shown below in its Patent CN101883756A:
The method with 2-Oxoindole-6-methyl-formiate for starting raw material; amino group is protected with sym-dichloroacetic anhydride in toluene; then with former phenylformic acid trimethyl generation condensation reaction, then use sodium hydroxide Deprotection, last and compound VI condensation obtains Ni Danibu (I).There is following shortcoming in document report: operational path is long, upper protecting group and Deprotection complex operation, the inadequate environmental protection of DMF solvent of use.In addition; Ni Danibu syntheti c route and the CN101883756A of document " synthetic chemistry " the 23rd volume the 8th phase 763-766 page report in 2015 are basically identical; just protective material sym-dichloroacetic anhydride is changed into diacetyl oxide; former phenylformic acid trimethyl changes original acid triethyl into, and in technique, Problems existing does not still solve.
Patent CN104844499A reports a kind of method that one kettle way prepares Ni Danibu, and reaction formula is as follows:
The method with 2-Oxoindole-6-methyl-formiate (III), methyl benzoate and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazine-1-yl) ethanamide (VI) for starting raw material, there is the substitution reaction of α-hydrogen in 2-Oxoindole-6-methyl-formiate and methyl benzoate under the effect of mineral alkali, dock with compound VI, one kettle way prepares Ni Danibu again.This route adopts one kettle way, and one kettle way is often difficult to control quality product in actual industrialization is produced, and is not suitable for industrialization and amplifies, and used DMF solvent in reaction process equally, unfavorable to environment.
The present invention with 2-Oxoindole-6-methyl-formiate and phenyl aldehyde for starting raw material, by designing new route, select the solvent of safety and environmental protection and reagent to prepare Ni Danibu, solve that existing technological operation is numerous and diverse, contaminate environment, be difficult to realize the problems such as industrialization.This invention simplifies technological operation step, safety and environmental protection, total recovery can reach more than 80% simultaneously, is applicable to suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of simple process, safety and environmental protection, be suitable for the preparation method of the Ni Danibu of suitability for industrialized production.
For achieving the above object, the present inventor devises the preparation method that is different from the Ni Danibu of prior art, the preparation method of a kind of Ni Danibu (I),
It is characterized in that, described preparation method comprises the steps:
(1) taking alcohols as reaction solvent, there is condensation reaction and obtains compounds Ⅳ in phenyl aldehyde (II) and 2-Oxoindole-6-methyl-formiate (III);
(2) take halogenated hydrocarbon as reaction solvent, compound IV and halogen or halide reagent generation substitution reaction, obtain compound V;
(3) compound V and compound VI take alcohols as reaction solvent, and under the effect of alkali, further condensation obtains Ni Danibu I.
Preparation method of the present invention can represent with following reaction formula:
Wherein, R=Cl, Br or I.
In described step (1), the mol ratio of compound III and compound ii is 1:1.1 ~ 2.0.Setting-up point is 20 DEG C-80 DEG C.
In described step (1) or described step (3), alcoholic solvent is selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol or propyl carbinol, preferred alcohol.
In described step (2), the mol ratio of compound IV and halogen or halide reagent is 1:0.5 ~ 1.7; Halogenated hydrocarbon solvent used can be selected from methylene dichloride, chloroform or tetracol phenixin, preferred methylene dichloride; Halogen used or halide reagent can select Cl
2, Br
2, I
2, N-bromo-succinimide or N-chlorosuccinimide, preferred Br
2.
In described step (3), the mol ratio of compound V and compound VI is 1:1.0 ~ 1.5; Alkali used is mineral alkali or organic bases, mineral alkali selected from potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, Quilonum Retard or cesium carbonate; Organic bases can select triethylamine, diethylamine or DIPEA; Preferred mineral alkali sodium bicarbonate.
Compared with prior art, the present invention has following beneficial effect: 1, shorten operation steps, simplifies operating process, improves production efficiency.2, safety and environmental protection, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with test example and embodiment, the present invention is described in further detail.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on content of the present invention all belong to scope of the present invention.
Embodiment 1:
The preparation of compound IV
2-Oxoindole-6-the methyl-formiate of 28.7g is added in the reaction flask of 250ml, 130ml ethanol, open and stir, then add 16.8ml(17.6g) phenyl aldehyde, 2.97ml piperidines, be heated to 70 DEG C-80 DEG C, react after 2 hours and naturally cool to 20 DEG C-30 DEG C, filtering-depositing, filter cake absolute ethanol washing, 50 DEG C of vacuum-dryings obtain 40.2g yellow solid (IV), yield: 96.0% in 5 hours.
The preparation of compound V
In the reaction flask of 500ml, add 30g compound IV, methylene dichloride 360ml, is cooled to 0-5 DEG C with frozen water, drip bromine 9.6ml(29.9g), drip off and be warmed up to 20-30 DEG C, react 3 hours, react complete, reaction solution 150ml washes once, dichloromethane layer is dense does to obtain oily matter, adds 200ml dehydrated alcohol crystallization, filters, 60 DEG C of vacuum-dryings obtain 35.1g off-white color solid (V), yield: 91.2%.
The synthesis of Ni Danibu (I)
30g compound V is added in the reaction flask of 500ml, 22.5g compound VI, ethanol 300ml, sodium bicarbonate 15g, is heated to back flow reaction after 2 hours, adds 600ml water in reaction solution, a large amount of solid is had to separate out, filter, filter cake 100ml washes once, obtains 41.9g yellow solid Ni Danibu (I) with refining methanol.Yield 92.7%.
1HNMR(400MHz,dmso)δ11.97(s,1H),8.38(s,1H),7.97(dd,J=11.9,5.0Hz,2H),7.67(d,J=8.1Hz,1H),7.16(ddd,J=26.9,22.1,7.0Hz,5H),6.85(d,J=8.6Hz,2H),6.63(d,J=8.7Hz,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/z540(M+1)
+
Embodiment 2:
The preparation of compound IV
2-Oxoindole-6-the methyl-formiate of 28.7g is added in the reaction flask of 250ml, 130ml ethanol, open and stir, then add 30.3ml(31.8g) phenyl aldehyde, 2.97ml piperidines, be heated to 70 DEG C-80 DEG C reactions after 2 hours, naturally cool to 20 DEG C-30 DEG C, filtering-depositing, filter cake absolute ethanol washing, 50 DEG C of vacuum-dryings obtain 38.7g yellow solid (IV), yield: 92.4% in 5 hours.
The preparation of compound V
30g compound IV is added in the reaction flask of 500ml, methylene dichloride 360ml, is cooled to 0-5 DEG C with frozen water, drips bromine 3.1ml(9.7g), drip off and be warmed up to 20-30 DEG C, react after 3 hours, reaction solution 150ml washes once, and dense the doing of dichloromethane layer to obtain oily matter, add 200ml dehydrated alcohol crystallization, filter, 60 DEG C of vacuum-dryings obtain 36.1g off-white color solid (V), yield: 93.8%.
The synthesis of Ni Danibu (I)
30g compound V is added in the reaction flask of 500ml, 33.0g compound VI, ethanol 300ml, sodium bicarbonate 15g, is heated to back flow reaction after 2 hours, adds 600ml water in reaction solution, a large amount of solid is had to separate out, filter, filter cake 100ml washes once, obtains 42.3g yellow solid Ni Danibu (I) with refining methanol.Yield 93.6%.
1HNMR(400MHz,dmso)δ11.94(s,1H),8.36(s,1H),7.96(dd,J=11.9,5.0Hz,2H),7.67(d,J=8.1Hz,1H),7.16(ddd,J=26.9,22.1,7.0Hz,5H),6.85(d,J=8.6Hz,2H),6.61(d,J=8.7Hz,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/z540(M+1)
+。
Claims (8)
1. the preparation method of Yi Zhong Ni Danibu (I),
It is characterized in that, described preparation method comprises the steps:
(1) taking alcohols as reaction solvent, there is condensation reaction and obtains compounds Ⅳ in phenyl aldehyde (II) and 2-Oxoindole-6-methyl-formiate (III);
(2) take halogenated hydrocarbon as reaction solvent, compound IV and halogen or halide reagent generation substitution reaction, obtain compound V;
(3) compound V and compound VI take alcohols as reaction solvent, and under the effect of alkali, further condensation obtains Ni Danibu I;
Its reaction formula is as follows:
Wherein, R=Cl, Br or I.
2. the preparation method of Ni Danibu (I) according to claim 1, wherein, in described step (1), the mol ratio of compound III and compound ii is 1:1.1 ~ 2.0.
3. the preparation method of Ni Danibu (I) according to claim 1, wherein, in described step (1) or described step (3), alcoholic solvent is selected from methyl alcohol, ethanol, Virahol, the trimethyl carbinol or propyl carbinol, preferred alcohol.
4. the preparation method of Ni Danibu (I) according to claim 1, wherein, in described step (1), setting-up point is 20 DEG C-80 DEG C.
5. the preparation method of Ni Danibu (I) according to claim 1, wherein, in described step (2), the mol ratio of compounds Ⅳ and halogen or halide reagent is 1:0.5 ~ 1.7.
6. the preparation method of Ni Danibu (I) according to claim 1, wherein, in described step (3), compound V is 1:1.0 ~ 1.5 with the mol ratio of compound VI.
7. the preparation method of Ni Danibu (I) according to claim 1, wherein, in described step (2), halogenated hydrocarbon solvent used can be selected from methylene dichloride, chloroform or tetracol phenixin, preferred methylene dichloride; Halogen used or halide reagent can select Cl
2, Br
2, I
2, N-bromo-succinimide or N-chlorosuccinimide, preferred Br
2.
8. the preparation method of Ni Danibu (I) according to claim 1, wherein, in described step (3), alkali used is mineral alkali or organic bases, mineral alkali selected from potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, Quilonum Retard or cesium carbonate; Organic bases can select triethylamine, diethylamine or DIPEA; Preferred mineral alkali sodium bicarbonate.
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Cited By (9)
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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 |
| 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 |
| CN107935909A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | A kind of Nintedanib（nintedanib）And its synthetic method of intermediate |
| 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 |
| 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 |
| CN113234013A (en) * | 2021-05-21 | 2021-08-10 | 杭州医学院 | Compound for inhibiting collagen synthesis and deposition and application thereof |
| 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 |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
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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 |
| 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 |
| 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 |
| CN109803954B (en) * | 2016-10-12 | 2021-12-07 | 浙江华海药业股份有限公司 | Preparation method of nintedanib and intermediate thereof |
| CN109803954A (en) * | 2016-10-12 | 2019-05-24 | 浙江华海药业股份有限公司 | The preparation method of Nintedanib and its intermediate |
| US10836751B2 (en) | 2016-10-12 | 2020-11-17 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Methods for preparing Nintedanib and intermediates thereof |
| CN107935909A (en) * | 2016-10-13 | 2018-04-20 | 上海科胜药物研发有限公司 | A kind of Nintedanib（nintedanib）And its synthetic method of 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 |
| JP2020508979A (en) * | 2017-03-14 | 2020-03-26 | 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 |
| CN110072849A (en) * | 2017-03-14 | 2019-07-30 | 新源生物科技股份有限公司 | The crystal form of 3-Z- [1- (4- (N- ((4- thyl-piperazin -1- base)-first carbonyl)-N- Methyl-amino)-phenylamino) -1- phenyi-methylene] -6- methoxycarbonyl group -2- dihydroindole ketone |
| US10961203B2 (en) | 2017-03-14 | 2021-03-30 | Allgenesis Biotherapeutics Inc. | Crystalline forms of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone |
| JP2021176899A (en) * | 2017-03-14 | 2021-11-11 | 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 | Crystal form of 3-z-[1-(4 -(n-(4-methyl-piperazine-1-yl)- methylcarbonyl)-n-methyl-amino)- phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone |
| 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 |
| 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 |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
| 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 |
| CN113234013A (en) * | 2021-05-21 | 2021-08-10 | 杭州医学院 | Compound for inhibiting collagen synthesis and deposition and application 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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