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Preparation method of lansoprazole intermediate

A technology for lansoprazole and intermediates, applied in the field of preparation of lansoprazole intermediates, can solve problems such as low product yield, large purification difficulty, and increased product cost, and achieve high yield and good industrial application , The effect of safety improvement

Inactive Publication Date: 2012-12-26
SHOUGUANG FUKANG PHARMA
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  • Description
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Problems solved by technology

The method needs to use column chromatography to purify the product, which is difficult to purify and the product yield is low, which limits the expansion of industrial scale to a certain extent; meanwhile, potassium tert-butoxide reacts with trifluoroethanol to produce tert-butanol, The boiling point of tert-butanol (82.5°C) is similar to the boiling point of trifluoroethanol (73°C), so the recovered trifluoroethanol is mixed with tert-butanol and cannot be directly applied to the next reaction, resulting in an increase in product cost

Method used

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  • Preparation method of lansoprazole intermediate
  • Preparation method of lansoprazole intermediate

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preparation example Construction

[0024] The invention provides a kind of preparation method of Lansoprazole intermediate, comprises the following steps:

[0025] a) After mixing trifluoroethanol, 2,3-dimethyl-4-halopyridine-N-oxide and inorganic basic compound, carry out reflux reaction to obtain 2,3-dimethyl-4-trifluoroethane Oxypyridine-N-oxide.

[0026] In the present invention, 2,3-dimethyl-4-halopyridine-N-oxide and trifluoroethanol are used as raw materials, and reflux reaction is carried out in the presence of inorganic basic compounds to obtain 2,3-dimethyl-4-tris Fluoroethoxypyridine-N-oxide can directly carry out the preparation of lansoprazole in the next step without complicated post-treatments such as column chromatography purification and catalyst recovery. Wherein, trifluoroethanol is not only used as a reaction raw material, but also as a reaction solvent, which avoids the introduction of other solvents, and does not require fractional distillation to recover the complicated post-treatment of...

Embodiment 1

[0057] Dissolve 2,3-dimethyl-4-nitropyridine-N-oxide 48.3g (0.287mol) in 100mL ethanol to obtain 2,3-dimethyl-4-nitropyridine-N-oxide Ethanol solution, start stirring, add 500mL 25% hydrochloric acid ethanol solution to it and reflux for 3 hours to obtain a mixture of 2,3-dimethyl-4-chloropyridine-N-oxide, and then evaporate the mixture under normal pressure ethanol in the ethanol-free 2,3-dimethyl-4-chloropyridine-N-oxide mixture, to the ethanol-free 2,3-dimethyl-4-chloropyridine-N-oxide mixture After adding 200mL of water, extract with 300mL dichloromethane three times, collect the organic phase and distill off the dichloromethane in the organic phase to obtain pure 2,3-dimethyl-4-chloropyridine-N-oxide 43g, yield 95%. The product is a white solid with a melting point of 103°C~105°C. 1 H NMR (CDCl 3 , 600MHz) δ: 2.39 (s, 3H, Me), 2.55 (s, 3H, Me), 7.13 (d, 1H, Py-H), 8.08 (d, 1H, Py-H).

[0058] 150mL trifluoroethanol and 60g K 2 CO 3 (0.415moL) was mixed in a 100mL fo...

Embodiment 2

[0060] Dissolve 2,3-dimethyl-4-nitropyridine-N-oxide 48.3g (0.287mol) in 100mL ethanol to obtain 2,3-dimethyl-4-nitropyridine-N-oxide ethanol solution, start stirring, add 500mL 25% hydrobromic acid ethanol solution to it and reflux for 3 hours to obtain a mixture of 2,3-dimethyl-4-bromopyridine-N-oxide, and then evaporate it under normal pressure Ethanol in the mixture gives ethanol-free 2,3-dimethyl-4-bromopyridine-N-oxide mixture, to ethanol-free 2,3-dimethyl-4-bromopyridine-N-oxide After adding 200mL of water to the mixture, extract with 300mL dichloromethane in 3 times, collect the organic phase and distill off the dichloromethane in the organic phase to obtain 2,3-dimethyl-4-bromopyridine-N-oxide pure Product 54g, yield 93%. The product is a white solid with a melting point of 97.6°C~99.5°C.

[0061] 150mL trifluoroethanol and 45g K 2 CO 3 (0.324moL) was mixed in a 100mL four-necked flask, and the stirring was started, and 50g of 2,3-dimethyl-4-bromopyridine-N-oxide ...

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Abstract

The invention provides a preparation method of a lansoprazole intermediate. The preparation method comprises the following steps of: mixing trifluoroethanol with 2, 3-dimethyl-4-chloropyridine-N-oxide and inorganic alkali compounds, and conducting reflux reaction to obtain 2, 3-dimethy-4-trifluoroethyoxyl-pyridine-N-oxide. Since the 2, 3-dimethyl-4-chloropyridine-N-oxide is used as raw materials, the trifluoroethanol not only is used as a reaction raw material, but also is used as a reaction solvent and other solvents are not needed to be introduced, the complex post-treatment of recovering the trifluoroethanol through fractionation is avoided and the step of post-reaction treatment is simplified; and since cheap and easy-to-obtain industrial alkali compounds such as potassium carbonate and potassium hydroxide are used, not only can the reaction be conducted smoothly and is the yield high, but also catalysts for catalysis are not needed, the step of complex catalyst recovery is not needed, the post-reaction treatment becomes simple, the degree of safety is high, the cost is lower and the yield is high.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of a lansoprazole intermediate. Background technique [0002] Lansoprazole (Lansoprazole) is the second proton pump inhibitor after Omeprazole (Omeprazole), developed by Takeda Corporation of Japan, and launched in France in 1991. Flowing esophagitis has obvious therapeutic effect. At present, lansoprazole is mainly synthesized by the following route, wherein, 2,3-dimethyl-4-trifluoroethoxypyridine-N-oxide is the key intermediate of synthetic lansoprazole, namely the following Compound (4) in the synthetic route: [0003] [0004] The prior art discloses a variety of preparation methods of 2,3-dimethyl-4-trifluoroethoxypyridine-N-oxide, mainly by 2,3-dimethyl-4-nitropyridine-N - Obtained by reaction of oxide with trifluoroethanol. For example, the researchers disclosed that 2,3-dimethyl-4-nitropyridine-N-oxide and trifluoroethanol were reacted at a la...

Claims

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Application Information

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IPC IPC(8): C07D213/89
Inventor 宋伟国高东圣董良军杨磊夏艳吕伟香田梅王伟刘东
Owner SHOUGUANG FUKANG PHARMA
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