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Preparation method and key intermediates of Nintedanib

A technology for nintedanib and a compound is applied in the field of preparation of the drug nintedanib, which can solve the problems of unsuitability for industrial scale-up and low yield, and achieve the effects of easy availability of raw materials and simple process

Inactive Publication Date: 2018-04-20
SHANGHAI SYNCORES TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As shown in the following formula, this method firstly performs condensation of two fragments, and then performs reduction and ring closure reactions, but most of the reactions in this process are carried out at high temperature and the yield is low, which is not suitable for industrial scale-up

Method used

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  • Preparation method and key intermediates of Nintedanib
  • Preparation method and key intermediates of Nintedanib
  • Preparation method and key intermediates of Nintedanib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Methyl 4-(1-methoxy-1,3-dioxo-3-phenylpropan-2-yl)-3-nitrobenzoate (IV)

[0024] Add 160 mL of N,N-dimethylformamide and 18.8 g of 4-chloro-3-nitro-benzoic acid methyl ester into a 500 mL reaction flask, and stir until it dissolves at 25°C. Then 17.1 g of 3-oxo-3-phenylpropionate and 24.1 g of anhydrous potassium carbonate were added in sequence, and the temperature of the reaction was raised to 80-90 to start the reaction for 4-6 hours until TLC showed that the raw materials disappeared. Add glacial acetic acid to the reaction solution to adjust the pH to neutral, add 600mL water and extract with 200mL*3 times of ethyl acetate. The combined ethyl acetate layers were washed with 300 mL*2 times of 5% NaCl solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was spin-dried to obtain 28.7 g of compound IV, with a yield of 92.1%. 1 H NMR (400MHz, CDCl 3 ):δ8.38-8.33(m,2H),7.98-7.93(m,2H),7.79(d,J=7.6,1H),7.64-7.56(m,1H)...

Embodiment 2

[0025] Example 2: Methyl 3-benzoyl-2-oxoindoline-6-carboxylate (V)

[0026] Dissolve 24.0g of compound IV in 240mL of ethyl acetate in a 500mL reaction flask, add 2.4g of 10% palladium carbon catalyst, place the reaction in a hydrogen atmosphere of 3 atmospheres and react at 20-30 degrees for 16 hours until TLC shows the raw material Complete conversion leads to intermediates. Then the temperature of the reaction was raised to 80-90°C for 4-6 hours until TLC showed that the intermediate was completely converted. After cooling down to room temperature, the palladium-carbon catalyst was removed by filtration, and the ethyl acetate solution was evaporated to dryness, replaced with methyl tert-butyl ether to recrystallize the product to obtain 14.2 g of white crystals, with a yield of 71.6%. 1 H NMR (400MHz, CDCl 3 )δ8.55(br,1H),8.13(s,1H),8.09–8.01(m,2H),7.88(dd,J=7.6,1.6Hz,1H),7.76–7.65(m,2H),7.52 –7.40(m,2H),5.33(s,1H),3.87(s,3H).Mass:296.0[M+H + ].

Embodiment 3

[0027] Embodiment 3: nintedanib (I)

[0028] Dissolve 21.2g of compound V in 210mL of toluene in a 500mL reaction flask, add 20.7g of compound IV and 2.47g of p-toluenesulfonic acid, heat the reaction to reflux at 100-110 degrees and use Dean-Stark to separate the generated water. After 28 hours of reaction, TLC showed complete conversion of starting material. After cooling down to room temperature, wash once with 5% NaHCO3 solution and twice with 5% NaCl solution, then dry with 10 g of anhydrous magnesium sulfate. After the toluene was evaporated to dryness, 120 mL of methanol / n-heptane was added for recrystallization to obtain 24.7 g of the product nintedanib, with a yield of 63.8%. 1 H NMR (400MHz, DMSO-d 6 ):12.17(s,1H),11.03(s,1H),7.64–7.59(t,J=7.6Hz,2H),7.56–7.52(t,J=7.6Hz,2H),7.50–7.45(d, J=7.6Hz, 1H), 7.43–7.40(d, J=1.6Hz, 1H), 7.21–7.17(d, J=8.3Hz, 1H), 7.15–7.07(m, 2H), 6.82–6.77(m ,2H),5.85–5.83(d,J=8.3Hz,1H),3.79(s,3H),3.11–3.04(m,3H),2.75–2.66(m,2H),2.27–2.19(...

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Abstract

The present invention relates to a completely-new preparation method of Nintedanib, and key intermediates thereof (such as 4-(1-alkoxy-1,3-dioxo-3-phenylpropane-2-yl)-3-nitro methyl benzoate and 3-benzoyl-2-oxodihydroindol-6-methyl formate), and a preparation method of the key intermediates. According to the present invention, the method has advantages of easily available raw materials, simple process, economy and environmental protection, and is suitable for industrial production; and the preparation method comprises that 1, 4-(1-alkoxy-1,3-dioxo-3-phenylpropane-2-yl)-3-nitro methyl benzoateis prepared from 4-halo-3-nitro-methyl benzoate and 3-oxo-3-phenylpropionate, 2, the compound reacts to generate a compound 3-benzoyl-2-oxodihydroindol-6-methyl formate, and 3, the compound reacts with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide to generate Nintedanib (I).

Description

Technical field: [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw material drug intermediates, and particularly relates to a preparation method of nintedanib, a drug used for treating idiopathic pulmonary fibrosis, its key intermediates, and its key Methods of preparation of intermediates. Background technique: [0002] Nintedanib is a new oral drug developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease that seriously harms humans. The median survival time of patients after diagnosis is only 2 to 3 years. Nintedanib simultaneously blocks vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor. Blockade of these receptors results in inhibition of angiogenesis. Nintedanib is the first and only tyrosine kinase inhibitor approved for the treatment of idiopathic pulmo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34C07C205/61C07C201/12
CPCC07C201/12C07C205/61C07D209/34
Inventor 栗增程小松何先亮张继承黄鲁宁陶安平顾虹
Owner SHANGHAI SYNCORES TECH INC
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