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Azilsartan intermediate and preparation method thereof

An intermediate and reaction technology, which is applied to the intermediate of synthesizing antihypertensive drug azilsartan and the field of preparation thereof, can solve the problems of many impurities, low process yield, long reaction time and the like

Inactive Publication Date: 2014-03-26
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The technical problem to be solved by the present invention is to provide a kind of azilsartan intermediate and its preparation in order to overcome the defects of low process yield, many impurities and long reaction time in the preparation method of azilsartan in the prior art. method

Method used

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  • Azilsartan intermediate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0084] Preparation of compound (3B)

[0085] 15.2 g of the raw material (compound 2B) was placed in a reaction flask, 150 ml of ethanol, 3.6 g of triethylamine, and 28 ml of 50% aqueous hydroxylamine solution were added, reacted for 7 hours, cooled and crystallized to obtain 14.1 g (86.0%) of a white solid. The main amide impurity (compound 6B) in the reaction solution was detected by HPLC at the end of the reaction: the product was 2.55%: 97.44% (that is, the ratio of impurity to product was 1:38.2), see figure 1 .

[0086] Table 1: figure 1 Analysis of HPLC detection data

[0087]

[0088] The mass spectrum shows: the molecular ion peak [M+1] is 459.

[0089] 1 HNMR spectrum (DMSO-d6): δppm 1.1-1.3 (3H, t), 1.3-1.4 (3H, t), 3.2-3.3 (2H), 4.1-4.3 (2H, q), 4.5-4.7 (2H, q ), 5.4-5.5 (1H, s), 5.5-5.6 (2H, s), 6.9-7.8 (11H, m).

[0090] Melting point: 210-212°C.

[0091] Impurity 6B

[0092] Mass spectrum shows: molecular ion peak [M+1] is 444.

[0093] Melting point:...

Embodiment 2

[0095] Preparation of compound (3B)

[0096] 15.0 g of raw material (compound 2B) was placed in a reaction flask, 150 ml of ethanol, 1.8 g (2.5 mL) of triethylamine, and 30 ml of 50% aqueous hydroxylamine solution were added, reacted for 10 h, cooled and crystallized, and 15.4 g (95.2%) of a white solid was obtained. . The main amide impurity (compound 6B) in the reaction solution was detected by HPLC at the end of the reaction: the product was 2.55%:97.44% (that is, the ratio of impurities to product was 1:38.2), and the purity of the product detected by HPLC after cooling and crystallization was 98.49%.

Embodiment 3

[0105] Preparation of compound (3B)

[0106] 7.5 g of the raw material (compound 2B) was placed in a reaction flask, 50 ml of ethanol and 15 ml of 50% aqueous hydroxylamine solution were added, reacted for 10 h, cooled and crystallized to obtain 6.2 g (76.0%) of a white solid. The main amide impurity (compound 6B) in the reaction solution was detected by HPLC: the product was 12.16%: 87.83%.

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Abstract

The invention discloses an azilsartan intermediate and a preparation method thereof. The preparation method comprises the following step: in a solvent, mixing a compound 3B with chloroformate to react under the action of alkali to obtain a compound 4B. The preparation method has the advantages of fewer impurities, short reaction time, higher technical yield and higher product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an intermediate for synthesizing antihypertensive drug Azilsartan (Azilsartan compound 1) and a preparation method thereof. Background technique [0002] Azilsartan is the latest antihypertensive drug on the market, developed by Takeda Pharmaceutical, and was approved in Japan on January 28, 2012. Azilsartan is a selective angiotensin Ⅱ receptor antagonist, which can competitively and reversibly block the combination of angiotensin and AT1 receptors to lower blood pressure. The affinity for AT1 receptors is More than 10,000 times the AT2 receptor, because it does not inhibit ACE, it will not affect the level of bradykinin, nor will it bind to and block other receptors or ion channels related to vascular regulation. Azilsartan's ability to bind to human AT1 receptors is 2 times and 30 times that of olmesartan and angiotensin II, respectively. Clinical studies have shown that a...

Claims

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Application Information

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IPC IPC(8): C07D235/26C07D413/10
CPCC07D235/26C07D413/10
Inventor 王小梅隋强唐超刘帅欧阳群香时惠麟
Owner SHANGHAI INST OF PHARMA IND
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