Preparation method of timolol hydrate

The technology of timolol hydrate and timolol maleate is applied in the field of preparation of timolol hydrate, and can solve the problems of complicated S-timolol hydrate process, harsh conditions and unfriendly environment And other issues

Active Publication Date: 2020-10-27
WUHAN CONFORM PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved by the present invention is to overcome the problems such as complex process, harsh conditions and unfriendly environment for preparing S-timolol hydrate in the prior art , thereby providing a preparation method of timolol hydrate

Method used

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  • Preparation method of timolol hydrate
  • Preparation method of timolol hydrate
  • Preparation method of timolol hydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] 119.50 grams of S-timolol maleate, 720 milliliters of water and 240 milliliters of dichloromethane were added to a three-necked reaction flask, then the temperature was lowered to 0° C. and 10% NaOH aqueous solution was added to adjust the pH of the reaction solution to 14. The dichloromethane phase and the aqueous phase were extracted twice with 240 ml of dichloromethane, and then the dichloromethane phases were combined. After washing the dichloromethane phase with 240 ml of saturated NaCl aqueous solution for 3 times, the dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 84.51 grams of S-timolol oil. The analytical detection results of the chemical purity of the substance are shown in Table 2, and the optical purity detection results are shown in Table 3.

[0049] Table 2

[0050]

[0051]

[0052] As can be seen from the table, the percentage content of S-timolol and R-t...

Embodiment 2

[0069] 213.52 grams of S-timolol maleate, 1500 milliliters of water and 230 milliliters of dichloromethane were added to a three-necked reaction flask, then the temperature was lowered to 0° C. and 10% NaOH aqueous solution was added to adjust the pH of the reaction solution to 14. The dichloromethane phase and the aqueous phase were extracted twice with 230 ml of dichloromethane, and then the dichloromethane phases were combined. After washing the dichloromethane phase with 230 ml of saturated NaCl aqueous solution for 3 times, the dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 154.12 g of S-timolol oil. The analytical detection results of the chemical purity of the S-timolol oil are shown in Table 6, and the optical purity detection results are shown in Table 7.

[0070] Table 6

[0071]

[0072]

[0073] As can be seen from the table, the percentage content of S-timolol and R...

Embodiment 3

[0088] 175.44 grams of S-timolol maleate, 1 liter of water and 350 milliliters of dichloromethane were added to the three-necked reaction flask, then the temperature was lowered to 0° C. and 10% NaOH aqueous solution was added to adjust the pH of the reaction solution to 14. The methyl chloride phase and the aqueous phase were extracted twice with 350 ml of dichloromethane, and then the dichloromethane phases were combined. After washing the dichloromethane phase with 350 ml of saturated NaCl aqueous solution for 3 times, the dichloromethane phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 127.82 g of S-timolol oil. The analytical detection results of the chemical purity of the S-timolol oil are shown in Table 10, and the optical purity detection results are shown in Table 11.

[0089] Table 10

[0090] peak number keep time area high peak width area% Number of theoretical plates ...

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Abstract

The invention discloses a preparation method of a timolol hydrate. The preparation method of the S-timolol hydrate comprises the following steps: reacting timolol with water at 5-30 DEG C under the action of an organic solvent or no organic solvent, and carrying out solid-liquid separation to obtain a solid product, namely obtaining the S-timolol hydrate, wherein the timolol is S-timolol of whichthe ee value is not less than 90%, and the organic solvent is an alcohol solvent and / or an amide solvent. According to the invention, the timolol hydrate is prepared by reacting timolol with water under specific conditions; the preparation method has the advantages of simple operation, cheap raw materials, avoiding of the use of a volatile low-polarity organic solvent and environmental protection;and the prepared timolol hydrate is high in yield, good in optical purity and chemical purity, and suitableness for industrialization.

Description

technical field [0001] The invention relates to a preparation method of timolol hydrate. Background technique [0002] S-timolol (Timolol) is a non-selective potent β-receptor blocker with no endogenous sympathomimetic activity, no local anesthetic effect, and weak membrane stabilizing effect. After medication, the heart rate can be slowed down, the myocardial contractility is weakened, and the myocardial oxygen consumption is reduced. It can block the hypotensive effect caused by isoproterenol and isoamyl nitrite. It is used to treat arrhythmia, angina pectoris and prevent further expansion of infarction after myocardial infarction; it is also used to treat mild and moderate hypertension, primary open-angle glaucoma, aphakic glaucoma, secondary glaucoma and ocular hypertension It can be used as an adjuvant treatment for poorly controlled intraocular pressure after glaucoma filtration surgery, and has a preventive effect on high intraocular pressure after laser peripheral ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/10
CPCC07D285/10C07B2200/07
Inventor 童国富周小顺牟东升赵志雄周政虎
Owner WUHAN CONFORM PHARMA CO LTD
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