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Preparation method of carvedilol phosphate hemihydrate

A technology of carvedilol phosphate and phosphoric acid, applied in the direction of organic chemistry, etc., can solve the problems affecting product purity and high dimer content, and achieve the effects of high purity and yield, simple synthesis method and high total yield

Active Publication Date: 2016-10-26
佛山市隆信医药科技有限公司
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Problems solved by technology

[0010] US4503067 first reported that 4-(2,3-epoxypropoxy) carbazole was obtained as a starting material by condensation with epichlorohydrin, and then with 2-(2-methoxyphenoxy base) ethylamine reaction to obtain carvedilol, and then react the obtained carvedilol with phosphoric acid to obtain phosphate, the synthetic route is relatively simple, but the method results provided by this patent show that the dimer content is high, which affects the product purity

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  • Preparation method of carvedilol phosphate hemihydrate
  • Preparation method of carvedilol phosphate hemihydrate
  • Preparation method of carvedilol phosphate hemihydrate

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preparation example Construction

[0032] The invention provides a kind of preparation method of carvedilol phosphate, comprising:

[0033] 1) Mixing and reacting a compound having a structure of formula (II) with 2-(2-methoxyphenoxy)ethylamine to obtain a reaction solution containing a compound having a structure of formula (III);

[0034]

[0035] 2) adding phosphoric acid to the reaction solution obtained in step 1) to obtain 2-(2-methoxyphenoxy)ethylamine phosphate and filtrate,

[0036] The molar ratio of the 2-(2-methoxyphenoxy)ethylamine to the phosphoric acid is 1:(0.70~0.90);

[0037] 3) adding phosphoric acid to the filtrate obtained in step 2) to obtain carvedilol phosphate.

[0038] According to the present invention, the present invention mixes the compound having the structure of formula (II) with 2-(2-methoxyphenoxy)ethylamine to obtain a reaction solution containing the compound of formula (III); wherein, the The molar ratio of the compound having the structure of formula (II) to the 2-(2-m...

Embodiment 1

[0045] Preparation of 4-(2,3-epoxypropoxy)-carbazole (formula (II))

[0046] Add ethanol (300mL), water (300mL) and sodium hydroxide (13.2g, 0.33mol) to a 1000mL three-necked flask with mechanical stirring and stir to dissolve, then cool down to room temperature, 4-hydroxycarbazole (54.96g, 0.3mol) Add and stir for 60 minutes, add epichlorohydrin (30.53g, 0.33mol), stir and react at room temperature for 20 hours, filter, wash with 50% ethanol / water (100ml), and dry to obtain tan solid 4-(2,3 -Glycidyloxy)-carbazole (50.24g), the yield was 70%, and its purity was greater than 96% as detected by HPLC.

[0047] Preparation of carvedilol (formula (III))

[0048] Add absolute ethanol (800mL), 4-(2,3-epoxypropoxy)-carbazole (47.86g, 0.20mol) and 2-(2-methoxybenzene Oxy)ethylamine (167.09 g, 1.00 mol) was refluxed for 6 hours to obtain a reaction solution, which was then cooled and used directly in the next step.

[0049] Preparation of Carvedilol Phosphate

[0050] At room tempe...

Embodiment 2

[0054] The preparation of 4-(2,3-epoxypropoxy)-carbazole (formula (II)) is consistent with the examples.

[0055] Preparation of carvedilol (formula (III))

[0056] Add absolute ethanol (800mL), 4-(2,3-epoxypropoxy)-carbazole (47.86g, 0.20mol) and 2-(2-methoxybenzene Oxy)ethylamine (133.67 g, 0.80 mol) was refluxed for 6 hours to obtain a reaction liquid, which was then cooled and used directly in the next step.

[0057] Preparation of Carvedilol Phosphate

[0058] At room temperature, slowly add 80% phosphoric acid (88.17g, 0.72mol) dropwise (88.17g, 0.72mol) to the carvedilol ethanol solution obtained in the previous step at room temperature. Stir at room temperature for 1 hour, then filter, wash the filter cake with absolute ethanol (100 mL), and combine the filtrates for the next reaction. The filter cake is 2-(2-methoxyphenoxy)ethylamine phosphate.

[0059] Add water (45mL) to the obtained filtrate, slowly (3 hours) dropwise add 80% phosphoric acid (24.49g, 0.2mol) to ...

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Abstract

The invention provides a preparation method of carvedilol phosphate hemihydrates. The preparation method comprises the following steps: carrying out mixing reaction on a compound with a structure as shown in a formula (II) and 2-(2-methoxy phenoxy) ethylamine to obtain reaction liquid containing a compound with the structure as shown in a formula (III); directly adding phosphoric acid in the reaction liquid obtained in the step (1) so that 2-(2-methoxy phenoxy) ethylamine phosphate and filtrate can be obtained; adding phosphoric acid in the filtrate obtained in the step (2) to obtain the carvedilol phosphate hemihydrates. The reaction liquid obtained in the step (1) is not required to be treated, the phosphoric acid is added in the same reaction system in two steps, excessive 2-(2-methoxy phenoxy) ethylamine is recycled and can be continued to be used for reaction, and furthermore, the purity and the yield of the prepared carvedilol phosphate hemihydrates as a target product are quite high. In addition, preparation of the compound with the structure as shown in the formula (II) and the carvedilol phosphate hemihydrate as the target product is realized through a one-pot method, and a synthesis method is simple.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of carvedilol phosphate. Background technique [0002] Carvedilol phosphate hemihydrate, structural formula as shown in (I), chemical name is 1-(9H-carbazole-4-oxyl)-3-[2-(2-methoxyphenoxy) ) Ethylamino]-2-propanol phosphate hemihydrate. [0003] [0004] Carvedilol Phosphate is a third-generation beta-blocker jointly developed by GSK and Flamel Technologies, which can slow down the heart rate and reduce the load on the heart. It has a good curative effect on symptoms such as heart failure, myocardial infarction and hypertension accompanied by diabetes. [0005] At present, there are many reports about the preparation method of carvedilol phosphate, such as: WO2004113296A reports the reaction of 4-hydroxycarbazole with epichlorohydrin to obtain intermediate 2-(2-methoxyphenoxy)ethylamine ( Intermediate II) is then reacted with benzyl-protected 2-(2-methoxy...

Claims

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Application Information

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IPC IPC(8): C07D209/88
CPCC07D209/88
Inventor 石磊
Owner 佛山市隆信医药科技有限公司
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