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Preparation of pimobendan

A technology for the preparation of pimobendan, which is applied in the field of preparation of pimobendan, can solve the problems of being unsuitable for industrial scale-up production, and achieve the effects of short steps, mild reaction conditions and simple operation

Active Publication Date: 2017-09-19
WISDOM PHARM CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Based on the above-mentioned methods for the synthesis of pimobendan that have been publicly reported, the US4361563 patent, the synthetic route reported by Piao Riyang, the synthetic route reported by Wang Sisi, etc., and the synthetic route reported by Xu Youjun, etc. respectively use Br2, which is limited in industrial use. , KCN, NaH / Br2, etc., and all involve the implementation of nitration reaction, these routes are not suitable for industrial scale-up production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] The formula III compound (R 1 =Me) The crude product (262g) was dissolved in anhydrous toluene (2000mL), the temperature of the system was cooled to 0-5°C in an ice-salt bath, and POCl was slowly added dropwise through the dropping funnel under nitrogen protection 3 (450mL), after the addition was complete, the system was slowly heated to reflux for 2 hours until the TLC spot plate tracked the disappearance of the compound of formula III. Slowly lower the temperature of the system to about 50°C, then carefully remove the solvent and unreacted POCl under reduced pressure 3 . CH was added to the residue 2 Cl 2 (1000mL) and H 2 O (500mL), after stirring for 10min, the system was carefully added saturated NaHCO 3 Adjust the pH of the system to about 6.5. Separate the organic phase and add CH to the aqueous phase 2 Cl 2 (2 x 500 mL) extraction. The organic phases were combined, washed twice with saturated brine (2×500 mL), dried over anhydrous sodium sulfate, filter...

Embodiment 5

[0052] Compound V (R1=Me) (95g, 231mmol) prepared in Example 5 was dissolved in EtOH (150mL), and then an aqueous solution of NaOH (37g NaOH dissolved in 520mL H2O, 4.0eq) was added to the system. After the addition was complete, the system was stirred overnight at room temperature. The ethanol solvent was carefully removed under reduced pressure in the system at 50°C, and the remaining aqueous solution was adjusted to pH 1.0-1.5 with 3M HCl. The system was extracted with EtOAc (3×500mL), the organic phase was washed twice with saturated brine (2×300mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain compound VI (83.8g), without purification , used directly in the next step.

[0053] 8. Preparation of 4-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)-3-methyl-4-oxobutanoic acid (formula VII)

Embodiment 7

[0054]Compound VI (83.8 g) prepared in Example 7 was dissolved in DMF (150 mL), and the system was slowly warmed up to 130-140° C., and kept for 3 hours for reaction. The system was cooled naturally, and then the organic solvent was removed under high vacuum with a rotary evaporator. The obtained residue was the compound of formula VII (72.1 g), which was directly used in the next reaction without purification.

[0055] 9. Preparation of Pimobendan

[0056] Ethanol EtOH (250 mL) and hydrazine hydrate (120 mL) were directly added to compound formula VII (72.1 g) prepared in Example 8, and the system was slowly heated to reflux for 12 hours after the addition was complete. The system was cooled naturally, and then the organic solvent and unreacted hydrazine hydrate were removed under high vacuum and reduced pressure. Add DMF (250mL) to the residue, slowly raise the temperature and stir until it dissolves, then slowly add H 2 O (250 mL), stirred for 1 hour after the dropwise a...

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Abstract

The invention relates to a novel preparation process of pimobendan. The process comprises short steps, does not refer to dangerous and highly toxic reagents such as Br2, KCN and NaH which have limitation in wide industrial use, is simple in operation and mild in reaction conditions and has obvious superiorities in industrial production.

Description

technical field [0001] The present invention relates to the preparation of pimobendan. Background technique [0002] Pimobendan (Pimobendan) (commercial name Vetmedin) is developed by Boehringer Ingelheim of Germany, a kind of cardiotonic drug with vasodilator effect listed in Japan for the first time in 1994, belonging to phosphodiesterase inhibitor, clinical It is mainly used in the treatment of heart failure. The compound is a cardiotonic dilator with calcium sensitization and type III phosphatase inhibitors. Its mechanism of action is different from that of traditional cardiotonic drugs. 2+ Sensitivity and inhibition of phosphodiesterase III (PDE III), is the first calcium sensitizer drug on the market. Studies have shown that the drug has a strong vasodilator effect and anti-platelet aggregation effect, almost no side effects, can also treat chronic heart insufficiency and angina, and can also prevent and treat arterial thrombosis. In addition, a large number of clin...

Claims

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Application Information

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IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 邹平张新刚王平邱小龙胡林时光好沈伟储玲玲苟少华彭陟辉张义森王东辉邓贤明游正伟江中兴曹雷陈俊
Owner WISDOM PHARM CO LTD
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