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Preparation method of nintedanib ethyl sulfonate

A technology of nintedanib ethanesulfonate and nintedanib, which is applied in the field of chemical drug synthesis, can solve the problems of unreported quality of nintedanib ethanesulfonic acid, the need for metal catalysts, long synthesis steps, etc., and achieve The effect of reducing the introduction of solvent types, reducing post-treatment operations, and mild reaction conditions

Inactive Publication Date: 2017-08-04
常州佳德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The process uses methyl 2-oxindole-6-carboxylate as the starting material to prepare nintedanib through steps such as substitution, condensation, deprotection, and reduction; in the synthesis process, not only acid chlorides are used multiple times, but also metal catalysts are required and synthesis The steps are long, the reaction temperature is high during the condensation process, and the reaction time is long when the temperature is low
[0008] The preparation process of the patent CN200880119069.9 is similar to the above method, and the above two methods have not reported the relevant quality of nintedanib ethanesulfonic acid

Method used

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  • Preparation method of nintedanib ethyl sulfonate
  • Preparation method of nintedanib ethyl sulfonate
  • Preparation method of nintedanib ethyl sulfonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of Compound C: Put 100g of methyl 2-oxindole-6-carboxylate and 100g of acetic anhydride into a 1L round-bottomed flask, stir and heat up to 110°C, and keep it warm for 1h; cool down to 76°C, add 340ml of triethyl orthobenzoate, Insulate and stir for 8 hours; turn off the heating, remove excess acetic anhydride by distillation under reduced pressure, and precipitate a large amount of reddish-brown solid. After the residue is cooled to room temperature, add 1.6L methyl tert-butyl ether at room temperature (30°C) for beating for 1 hour, and then filter with 1L methanol The tert-butyl ether was repeatedly beaten once, and fully pumped and air-dried at 80°C for 4 hours to obtain 139.5 g of a reddish-brown solid. The purity of compound C was 96%, and the molar yield was 70.4%.

[0029] Preparation of nintedanib free base (compound F): add 130g of compound C and 89.9g of material D (converted into molar ratio in line with the feeding ratio, compound C has been puri...

Embodiment 2

[0041] The preparation reaction of compound C is consistent with that of Example 1, and will not be repeated here.

[0042]Preparation of compound F: 10.0 g of compound C and 7.2 g of compound D were added to 2 groups of 250 ml reaction devices, 8V methanol (i.e. 138 ml of methanol) was added to one group, and 10 V methanol (i.e. 170 ml of methanol) was added to the other group; after nitrogen protection , the first group was slightly difficult to stir but the reaction could occur, the second group was stirred normally, and the temperature was raised to reflux temperature of 67°C. After 5 hours, the reaction feed liquid was detected by HPLC, and the remaining raw materials were 47.1% and 48.2% respectively. After the reaction, the molar yield of nintedanib free base (compound F) was 87.3%, the purity was 99.7%, and the largest single impurity was less than 0.1%.

[0043] Preparation of nintedanib ethanesulfonate (compound G): consistent with Example 1, no further details are g...

Embodiment 3

[0045] The preparation reaction of compound C is consistent with that of Example 1, and will not be repeated here.

[0046] Preparation of Compound F: 10.0g of Compound C, 7.2g of Compound D and 170ml of methanol were added to a 250ml reaction device, stirred under nitrogen protection, heated and refluxed for 7.5h, and then the liquid was detected by HPLC, containing 76.5% of Compound F and only 15.2% of Compound C %.

[0047] Under the same conditions, but the solvent was changed to DMF, ethanol or 1,4-dioxane as the solvent, the temperature was raised to 75-77°C for the reaction, and samples were taken at 7.5h and 9.5h respectively. The product compound F was tested at 7.5h and 9.5h respectively. For: (3.2%, 4.5%), (4.7%, 6.3%), (7.5%, 8.6%), the rest is mainly compound E.

[0048] Examples 2 and 3 are mainly to illustrate that the use of solvent methanol in the preparation of compound F can directly react compounds C and D to compound F in one step, while other solvents ne...

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Abstract

The invention discloses a preparation method of nintedanib ethyl sulfonate. The method comprises the steps of reacting by taking 2-oxoindole-6-carboxylic acid methyl ester, triethyl orthobenzoate and acetic anhydride as starting materials to obtain a compound; and carrying out condensation on (Z)-1-acetyl-3-(ethoxy (phenyl) methylene)-2-oxo indoline-6-carboxylic acid methyl ester and the starting material N-(4-aminophenyl)-N-methyl-2-(4-methyl piperazine-1-yl) acetamide to obtain nintedanib free alkali and carrying out salt-forming reaction of ethanesulfonic acid to prepare the nintedanib ethyl sulfonate. The method is short in step and easy to treat, and a high-quality nintedanib ethyl sulfonate crystal product is obtained without purification.

Description

technical field [0001] The invention belongs to the technical field of chemical drug synthesis and relates to (Z)-3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)( A preparation method of methyl phenyl)methylene)-2-oxoindoline-6-carboxylate ethanesulfonate. Background technique [0002] Nintedanib is a triple tyrosine kinase inhibitor and growth factor antagonist belonging to oxindole derivatives, which simultaneously blocks vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptor (PDGFRα and β) and fibroblast growth factor receptors (FGFR 1-3), for the treatment of idiopathic pulmonary fibrosis (IPF), is the first targeted therapy drug that can alleviate lung failure by 50% in IPF patients. [0003] Nintedanib esylate is a hemihydrate crystalline compound with the structural formula: [0004] [0005] PCT patent WO 2012068441A2 mentions the process route for preparing nintedanib as follows: [0006] [0007...

Claims

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Application Information

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IPC IPC(8): C07D209/34C07C309/04C07C303/32
CPCC07D209/34
Inventor 王自富
Owner 常州佳德医药科技有限公司
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