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A kind of method for preparing (s)-metoprolol succinate

A technology of metoprolol succinate and metoprolol base, applied in the field of production-metoprolol succinate, can solve the problems of reducing the yield of compound 2, achieve low price, convenient regeneration, and increase product yield rate effect

Active Publication Date: 2011-12-28
SHANDONG CHUANGXIN PHARMA RES & DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in this process, the first step of the reaction will be accompanied by a large amount of water, and then under the catalysis of the base, the epoxy bond in the product compound 2 molecule is prone to ring-opening hydrolysis reaction, which finally reduces the yield of compound 2.

Method used

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  • A kind of method for preparing (s)-metoprolol succinate
  • A kind of method for preparing (s)-metoprolol succinate
  • A kind of method for preparing (s)-metoprolol succinate

Examples

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Embodiment 1

[0080] The external circulation water removal system in this embodiment is a single water removal column filled with water removal agent, the size of the water removal column is 1 m×0.12 m inner diameter, and the filling rate of water removal agent is 80%.

[0081] The qualitative and quantitative detection method of reaction substrate and product HPLC is: Alltech Prevail C 18 (250 mm×0.46 mm×5 μm) chromatographic column; mobile phase: methanol:water=50:50; column temperature: 30°C; flow rate: 1 mL / min; injection volume: 20 μL; UV detection wavelength: 280 nm .

[0082] 4-Hydroxyphenethyl methyl ether and ( R )-epichlorohydrin with a molar ratio of 1:1, 4-hydroxyphenethyl methyl ether and catalyst sodium hydroxide are mixed with a molar ratio of 1:1.5 to prepare a reaction substrate for subsequent use. Pump 2.45 kg of the mixed reaction substrate into a 3 L reactor, heat to 90 °C and vigorously stir the reaction. During the reaction, the reaction feed liquid is passed into t...

Embodiment 2

[0084] The external circulation water removal system in this embodiment is a parallel combination of two water removal columns filled with water removal agents. The size of the water removal columns is 1 m×0.12 m in inner diameter, and the filling rate of water removal agents is 80%.

[0085] Reaction substrate and product HPLC qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing catalyst dewatering agent and each operating parameter are as follows:

[0086] 4-Hydroxyphenethyl methyl ether and ( R )-epichlorohydrin in a molar ratio of 1:2, 4-hydroxyphenethyl methyl ether and catalyst potassium hydroxide are mixed in a molar ratio of 1:2 to prepare a reaction substrate for subsequent use. Pump 2.45 kg of the mixed reaction substrate into a 3 L reactor, heat to 60 °C and vigorously stir for reaction. The water system is returned to the reactor, and the reaction is stopped after 1 h, and the discha...

Embodiment 3

[0088] The external circulation water removal system in this embodiment is a series combination of three water removal columns filled with water removal agents. The size of the water removal columns is 1 m×0.12 m in inner diameter, and the filling rate of water removal agents is 80%.

[0089] Reaction substrate and product HPLC qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing catalyst dewatering agent and each operating parameter are as follows:

[0090] 4-Hydroxyphenethyl methyl ether and ( R )-epichlorohydrin with a molar ratio of 1:4.5, 4-hydroxyphenethyl methyl ether and catalyst potassium carbonate mixed with a molar ratio of 1:1 to prepare a reaction substrate for subsequent use. Pump 2.45 kg of the mixed reaction substrate into a 3 L reactor, heat to 45 °C and vigorously stir the reaction. During the reaction, the reaction feed liquid is passed into the external circulation water remov...

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Abstract

Belonging to the field of pharmaceutical chemistry, the invention specifically relates to a method for preparing (S)-metoprolol succinate. The method comprises the steps of: pumping hydroxyphenylethyl methyl ether and (R)-chloropropylene oxide into a reaction vessel, and during the reaction process, pumping a reaction feed liquid into an external circulating dewatering system loaded with a dewatering agent for circulating dewatering, reacting the prepared (S)-3-[4-(2-methoxyethyl) phenoxyl]-1, 2-epoxypropane with isopropylamine so as to obtain an (S)-metoprolol base; mixing the (S)-metoprolol base with succinic acid, thus obtaining (S)-metoprolol succinate. During the first step of reaction in the invention, water generated in the reaction process can be effectively removed through the external circulating dewatering device, and the loss of (S)-3-[4-(2-methoxyethyl) phenoxyl]-1, 2-epoxypropane is reduced, thus realizing simple and fast production of low energy consumption. By the method of the invention, the conversion rate of the first step product (S)-3-[4-(2-methoxyethyl) phenoxyl]-1, 2-epoxypropane is over 90%, the final yield of (S)-metoprolol succinate is greater than 75%, and the utilization rate of the reaction substrate is obviously enhanced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a preparation ( S )-Metoprolol succinate method, particularly a kind of 4-hydroxyphenethyl methyl ether and ( R )-epichlorohydrin as starting material production ( S )-metoprolol succinate method. Background technique [0002] The chemical name of Metoprolol is 1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol. Its chemical structural formula is as follows: [0003] [0004] Metoprolol is the world's first selective beta 1 - Adrenergic receptor blockers, ie cardioselective drugs. It is widely used clinically in the treatment of patients with various cardiovascular diseases such as hypertension and ischemic heart disease, chronic stable heart failure, and arrhythmia. It is the drug of choice for the treatment of hypertension in the world in recent years, and it is also an essential drug in my country. [0005] The drug was successfully developed in Sweden's Has...

Claims

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Application Information

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IPC IPC(8): C07C217/32C07C213/08
Inventor 卢定强赵娴凌岫泉吴永平欧阳平凯江鸿
Owner SHANDONG CHUANGXIN PHARMA RES & DEV
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