A synthetic method of Nintedanib and an intermediate of Nintedanib

A synthesis method and technology of nintedanib, applied in the field of medicine and chemical industry, can solve the problems of low reaction efficiency of chloroacetic anhydride, unstable route repeatability, unfavorable scale-up production, etc., to reduce potential safety hazards, rational route design, and save capital. Effect

Active Publication Date: 2016-08-10
SOUTHEAST UNIV
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0008] The repeatability of the route described in this article is unstable, the reaction efficiency of chloroacetic anhydride is low, resulting in a large amount of use, and the multi-step design of high-temperature reflux, the harsh reaction conditions are not conducive to scale-up production

Method used

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  • A synthetic method of Nintedanib and an intermediate of Nintedanib
  • A synthetic method of Nintedanib and an intermediate of Nintedanib
  • A synthetic method of Nintedanib and an intermediate of Nintedanib

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Effect test

Embodiment 1

[0064] Embodiment 1: the preparation of compound 4-chloro-3-nitrobenzoic acid methyl ester

[0065] After suspending 200g (1mol) of 4-chloro-3-nitrobenzoic acid in methanol, add 59g (490mmol) of thionyl chloride within 15min, heat and reflux for reaction, react at 70°C for 3 hours and then cool to 5°C, the product After centrifugal separation and drying at 45° C., 189.2 g of a solid, namely the target compound, was obtained with a yield of 88.5%.

Embodiment 2

[0066] Embodiment 2: the preparation of compound 2-oxindole-6-methyl carboxylate

[0067] Add 128.7 g (974 mmol) dimethyl malonate to a hot melt (75° C.) of 107.3 g (974 mmol) sodium tert-amylate in 350 mL N-methyl-2-pyrrolidone; add at 75° C. 100g (463mmol) methyl 4-chloro-3-nitrobenzoate in 250mL of N-methyl-2-pyrrolidone. Stir at about 75°C for 1.5 hours, and cool to 20°C, acidify the mixture to pH=1 with 1000mL dilute hydrochloric acid, filter to obtain 137.6g of solid, dissolve the solid in 880mL of acetic acid, add 10% palladium carbon catalyst at 45°C Catalytic hydrogenation under low temperature; after the hydrogenation stopped, the reactant was heated to 115°C for 2 hours, the catalyst was filtered off, and 1800mL of water was added at about 50°C, the reaction product was cooled to 5°C, centrifuged, and Dry at 50°C to obtain 69.6 g of solid, namely the target compound, with a yield of 82.6%.

Embodiment 3

[0068] Embodiment 3: Preparation of compound 1-chloroacetyl-2-oxoindoline-6-formic acid methyl ester

[0069] At room temperature, 19.1g (100mmol) of 2-oxindole-6-methyl carboxylate was suspended in 60ml of toluene, and then 25.6g (150mmol) of chloroacetic anhydride was added, and the mixture was heated under reflux at 120°C for 3 hours, then cooled to 80°C, add 30ml of methylcyclohexane within 30min, and slowly lower to room temperature; separate the mother liquor, wash the solid with frozen methanol, and dry to obtain 25.36g of white crystals, namely the target compound, with a yield of 95%.

[0070] 1 H-NMR (400MHz, DMSO-d 6 )δ: 8.66(m, 1H); 7.86(d, J=8.0Hz, 1H); 7.52(d, J=8.0Hz, 1H); 4.99(s, 2H); 4.27(s, 3H); s, 2H). MS:m / z 268(M+H) + .

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Abstract

A synthetic method of Nintedanib and an intermediate of Nintedanib are disclosed. The method includes reacting a compound shown as a formula (II) and a compound shown as a formula (I) under acidic conditions to produce a compound shown as a formula (III), removing t-butyloxycarboryl of the compound shown as the formula (III) with an acid, adding an alkali, reacting to produce a compound shown as a formula (V), reacting the compound shown as the formula (V) with an activated derivative of chloroacetic acid to produce a compound shown as a formula (VI), and reacting with N-methyl piperazine to produce the Nintedanib. The novel synthetic method with mild reaction conditions for the Nintedanib is provided. The intermediate for synthesizing the Nintedanib is also provided.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method and a synthesis intermediate of nintedanib. Background technique [0002] Idiopathic pulmonary fibrosis (IPF) is characterized by fibrosis (hardening) of the tissue between the alveoli in the lungs, resulting in a dry cough, difficulty breathing, and limited physical activity. Unpredictable exacerbations may occur in some patients and may result in death. Survival rates for patients with IPF are similar to those of many tumors, with an average survival of 3 to 5 years after diagnosis. [0003] At the same time, most lung cancer patients need radiation therapy, which may cause acute radiation pneumonitis, leading to severe pulmonary fibrosis and even death. The incidence of lung cancer in my country is high, reaching more than 400,000 people every year, and has become the number one killer of cancer. This has also increased the urgenc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/34
CPCC07D209/34
Inventor 吉民陈浩蔡进刘海东李锐
Owner SOUTHEAST UNIV
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