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Preparation method of timolol impurity

A timolol and impurity technology, applied in the field of timolol impurity preparation, can solve the problems such as the public report of no impurity synthesis route, and achieve the effect of simple operation, high purity and quality assurance

Active Publication Date: 2021-06-08
成都摩尔生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Timolol European Pharmacopoeia impurity B is of great significance to the in-depth study of timolol, but there is no public report on the synthetic route of this impurity in the prior art

Method used

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  • Preparation method of timolol impurity
  • Preparation method of timolol impurity
  • Preparation method of timolol impurity

Examples

Experimental program
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Embodiment 1

[0031] The present embodiment 1 provides a kind of preparation method of timolol impurity, specifically comprises the following process:

[0032] step 1):

[0033]

[0034] Add 50 g of 3-chloro-4-morpholino-1,2,5-thiadiazole to 200 ml of dimethyl sulfoxide, add 500 ml of aqueous solution containing 80 g of sodium hydroxide, and react at 120°C for 5 hours. Cool the reaction solution to room temperature, adjust the pH to 1 with dilute hydrochloric acid, filter the precipitated solid, and dry the solid in an oven to obtain intermediate M1 (95% yield);

[0035] Step (2):

[0036]

[0037] Monoethyl malonate potassium salt 30g, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride 40g, tert-butylamine 15g, 4-dimethylaminopyridine 2.5g, dichloro Add 400ml of methane into the reaction flask, stir at room temperature for 12 hours, add 500ml of aqueous hydrochloric acid solution with an equivalent concentration of 1N for washing, dry the organic phase and evaporate to dryne...

Embodiment 2

[0048] This Example 2 provides a preparation method of Apremilast impurity, the difference from Example 1 is only: 3-halo-4-morpholinyl-1,2,5-thiadiazole in step (1) It is 3-bromo-4-morpholino-1,2,5-thiadiazole, the monoethyl malonate metal salt in step (2) is monoethyl malonate sodium salt, and the condensing agent is N,N -Carbonyldiimidazole.

Embodiment 3

[0050] This Example 3 provides a preparation method of Apremilast impurity, the difference from Example 1 is only: 3-halo-4-morpholinyl-1,2,5-thiadiazole in step (1) 3-iodo-4-morpholino-1,2,5-thiadiazole, monoethyl malonate metal salt is monoethyl malonate sodium salt in step (2), and the condensing agent is 2-( 7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

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Abstract

The invention discloses a timolol impurity preparation method, and belongs to the technical field of timolol impurity synthesis. 3-halo-4-morpholinyl-1,2,5-thiadiazole is used as an initial raw material to prepare an intermediate M1 through alkaline hydrolysis and acid treatment, potassium ethyl malonate and tert-butyl amine are subjected to a condensation reaction to prepare an intermediate M2, the intermediate M2 and liquid bromine are subjected to a substitution reaction to prepare an intermediate M3, the intermediate M3 and the intermediate M1 are subjected to a nucleophilic substitution reaction to prepare an intermediate M4, and the intermediate M4 is subjected to a reduction reaction and alkaline hydrolysis to prepare a target product. The method has the characteristics of reasonable synthetic route, easily available raw materials, simple and easy operation, high yield and high purity. The prepared timolol can be used as a reference substance for qualitative and quantitative research of impurities in timolol quality research, the content of related substances in bulk drugs is controlled, and the quality of the bulk drugs is guaranteed.

Description

technical field [0001] The invention relates to the technical field of synthesizing timolol impurities, in particular to a preparation method of timolol impurities. Background technique [0002] Timolol, the chemical name is S-(-)-1-tert-butylamino-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2 - Propyl maleate. Clinical pharmacological studies have confirmed that timolol is a new type of β-receptor blocker, which can change the resting heart rate and the heart rate response to body position changes, inhibit the tachycardia caused by isoproterenol, and change the effect on Valsa The response of Wahl's test can reduce the changes of heart rate and blood pressure during activity, and reduce the positive inotropic, positive chronotropic, broncho and vasodilation effects caused by β-adrenoceptor agonists. At present, the levorotatory body is used clinically for the treatment of high blood pressure, angina pectoris and the reduction of intraocular pressure in glaucoma patients. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/10
CPCC07D285/10
Inventor 李远志田单
Owner 成都摩尔生物医药有限公司
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