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Intermediate and method for preparing naproxcinod
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A naprocino and system technology, applied in the field of medicinal chemistry, can solve the problems of incomplete reaction, severe reaction conditions, complicated operation, etc., and achieve the effects of good product quality, simple operation and high purity
Inactive Publication Date: 2012-05-09
TIANJIN INSTITUTE OF PHARMA RESEARCH
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[0004] WO95 / 09831 discloses a method for preparing naproxen, including naproxen made into sodium salt, and then reacting with 1-bromo-4-chlorobutane to synthesize (S)-2-(6-methoxy-2-naphthyl ) 4-chlorobutyl propionate, and then react with silver nitrate to prepare the product. The disadvantage is that the activity of butyl chloride is poor, and the reaction conditions with silver nitrate are severe, and it is easy to produce racemic products
And the reaction is not complete, affecting the yield and product quality
[0005] WO01 / 10814 discloses a method for preparing naproxen, including naproxen or its acid chloride and 4-nitrooxybutan-1-ol through DCC condensation to obtain the product. The disadvantage is that nitrooxyalkyl alcohol is very unstable and easy to decompose , not suitable for industrial production, and when naproxen is condensed with DCC or prepared into an acid chloride, the chiral configuration is prone to racemization during the reaction process, thereby affecting the chiral purity of the final product
[0006] WO03 / 08698 discloses a method for preparing naproxen, including the condensation of naproxen and 4-bromobutyl nitroester under alkali catalysis to obtain the product. The disadvantage of this method is that 4-bromobutyl nitroester needs to be prepared in advance, and it is not easy save
Disadvantages The reaction time of each step of this method is relatively long, and the intermediate must be separated by column chromatography, which is cumbersome to operate
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Embodiment 1
[0024] Example 1 (S)-2-(6-Methoxy-2-naphthyl)propanoic acid 4-bromobutyl ester
[0025] In a 1L flask equipped with stirring and a thermometer, add naproxen (23g, 0.1mol) and DMF300ml, stir to dissolve and add KHCO 3 (10g, 0.1mol), react at room temperature for 4h, then add dibromobutane (43.2g, 0.2mol) and continue to react at room temperature for 48h. After the reaction, 200ml of water was added, extracted with dichloromethane, dried, and distilled to obtain a light yellow oil, which was crystallized by adding isopropanol to obtain 25g of a white solid with a yield of 70%, mp32-36°C, HPLC≥82%.
[0027] Example 2 (S)-2-(6-Methoxy-2-naphthyl)propanoic acid 4-bromobutyl ester
[0028] In a 1L flask equipped with stirring, a thermometer, and a reflux condenser, add naproxen (23g, 0.1mol) and 200ml of acetone, stir to dissolve and add dibromobutane (64.8g, 0.3mol) and 5ml of triethylamine , 55 ~ 60 ℃ reaction 8h. The solvent and excess dibromobutane were distilled off under reduced pressure to obtain a light yellow oil, which was crystallized by adding isopropanol to obtain 27 g of a white solid with a yield of 75%, mp32-36°C, HPLC≥85%.
Embodiment 3
[0029] Example 3 (S)-2-(6-Methoxy-2-naphthyl)propanoic acid 4-bromobutyl ester
[0030] In a 1L flask equipped with stirring, a thermometer, and a reflux condenser, add naproxen sodium (23g, 0.1mol) and 300ml of acetonitrile, stir and dissolve, then add K 2 CO 3 (13.8g, 0.1mol), dibromobutane (216g, 1.0mol) was refluxed for 4h. The solvent and excess dibromobutane were distilled off under reduced pressure to obtain a light yellow oil, which was crystallized by adding isopropanol to obtain 32 g of a white solid with a yield of 89%, mp32-36°C, HPLC≥92%.
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Abstract
The invention provides an intermediate and a method for preparing naproxcinod. The method comprises the following steps: reacting naproxen or pharmaceutical acceptable salts thereof with dibromobutane to obtain (S) - 2 - (6 - methoxy - 2 - naphthyl) - propionic acid -4 - bromo butyl, and then preparing the naproxcinod by nitrate esterification. According to the method, the raw materials are easy to obtain, the operation is simple and convenient, the product yield is high and the purity is good. The method is suitable for mass production.
Description
technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to an intermediate and a method for preparing a non-steroidal anti-inflammatory drug naproxenol. Background technique [0002] Naproxinod (naproxcinod), chemical name (S)-2-(6-methoxy-2-naphthyl) propionate 4-nitrooxybutyl ester, is naproxen ((+)-α -Methyl-6-methoxy-2-naphthaleneacetic acid), the first COX inhibitornitric oxide donor compound of Nicox, France. Naproxen is a non-steroidal anti-inflammatory analgesicdrug with good anti-inflammatory, antipyretic and analgesic effects. It has been widely used in the world and has become one of the main antipyretic analgesics and best-selling over-the-counter drugs in the world. However, in recent years, the cardiovascular side effects of non-steroidal anti-inflammatory drugs have been paid more and more attention. In 2004, the U.S. FDA issued a warning about the anti-inflammatory drugnaproxen, claiming that ...
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