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Preparation process of 3-[2-(3-chlorphenyl)ethyl]-2-pyridinecarboxylic acid

A preparation process, picolinic acid technology, applied in the direction of organic chemistry, etc., can solve the problems of unfavorable industrial production, increase the number of reaction steps, expensive methanesulfonic acid, etc., and achieve the effect of eliminating production hidden dangers, mild reaction conditions, and reducing by-products

Active Publication Date: 2016-05-11
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Methanesulfonic acid is more expensive in this method, and the cost is higher
[0012] In summary, the existing preparation technology of 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxylic acid (II) either has low yield, or needs to convert the substrate into cyano group first and then carry out Hydrolysis preparation, although the yield is improved, but the number of reaction steps is increased, which is not conducive to industrial production

Method used

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  • Preparation process of 3-[2-(3-chlorphenyl)ethyl]-2-pyridinecarboxylic acid
  • Preparation process of 3-[2-(3-chlorphenyl)ethyl]-2-pyridinecarboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0035] Embodiment 1. Preparation of compound I

[0036] The preparation process of compound I can be found in references, Zhang Guang, Chen Min, Zhuang Shouqun, etc. 8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridine- Synthesis of 11-ketone[J]. Chinese Journal of Pharmaceutical Industry, 2013, 44(12): 1215-1216, 1231

[0037]

[0038] 1) Preparation of compound IX

[0039] Add compound VIII (250 g, 2.12 mol), tert-butanol (650 ml, 6.90 mol), formic acid (750 ml, 10.49 mol) into the dry reactor, and stir at room temperature for 5 min. Concentrated sulfuric acid (100ml, 1.84mol) was slowly added dropwise within 30 minutes to complete, gradually warming up to 90°C for 8 hours, then cooling to room temperature, distilling off the solvent under reduced pressure, dissolving the residue in water (1L), adding concentrated ammonia water ( about 750ml) to adjust the pH to 9 to 10. Extracted with toluene (2.1L), evaporated the solvent under reduced pressure to obtain whi...

Embodiment 2

[0042] Example 2. Preparation of 3-[2-(3-chlorophenyl) ethyl]-2-pyridinecarboxylic acid

[0043] Add 3-[2-(3-chlorophenyl)ethyl]-N-tert-butyl-2-pyridinecarboxamide (25.00g, 78.91mmol) to the dry reactor, slowly add 68% (w / w) 50.0ml of sulfuric acid. After the dropwise addition was completed, the mixture was stirred at room temperature for 0.5 h, and then heated to reflux. After the reaction was refluxed for 7 h, the reaction solution was cooled to room temperature. Add 40% (w / w) aqueous sodium hydroxide solution to adjust the pH to 9-10. Then, add toluene and stir. After a period of time, the resulting solution is filtered, and the filtrate is transferred to a separatory funnel. After the layers were separated, the toluene phase was washed once with an appropriate amount of water, and the washing liquid was combined with the water phase and the filter cake. Then, the pH of the solution was adjusted to 4-5 using 2.4M aqueous hydrochloric acid solution, and then ethyl acet...

Embodiment 3

[0044] Example 3. Preparation of 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxylic acid

[0045] Add 3-[2-(3-chlorophenyl)ethyl]-N-tert-butyl-2-pyridinecarboxamide (25.00g, 78.91mmol) to the dry reactor, slowly add 60% (w / w) 50.0ml of sulfuric acid. After the dropwise addition was completed, the mixture was stirred at room temperature for 0.5 h, and then heated to reflux. After the reaction was refluxed for 13 h, the reaction solution was cooled to room temperature. Add 40% (w / w) aqueous sodium hydroxide solution to adjust the pH to 9-10. Then, add toluene and stir. After a period of time, the resulting solution is filtered, and the filtrate is transferred to a separatory funnel. After the layers were separated, the toluene phase was washed once with an appropriate amount of water, and the washing liquid was combined with the water phase and the filter cake. Then, the pH of the solution was adjusted to 4-5 using 2.4M aqueous hydrochloric acid solution, and then ethyl acet...

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Abstract

The invention provides a preparation process of 3-[2-(3-chlorphenyl)ethyl]-2-pyridinecarboxylic acid (as shown in formula II). The reaction equation is as shown in the description, wherein substituent R is hydrogen, tertiary butyl, phenyl or substituted phenyl; the method comprises the step of carrying out reaction on a reaction substrate, namely a 3-[2-(3-chlorphenyl)ethyl]-N-R substituted-2 pyridine carboxamide compound I, and a 50%-70% sulfuric acid aqueous solution at proper temperature, so as to obtain 3-[2-(3-chlorphenyl)ethyl]-2-pyridinecarboxylic acid. The preparation process has the following positive and progressive effects: the 50%-70% sulfuric acid aqueous solution is directly used as a hydrolytic reagent and a solvent as well; the sulfuric acid aqueous solution with the concentration of 50%-70% has no oxidability, so that the generation of by-products during the feeding period is reduced; at the same time, not only is intense heat release produced by reaction of concentrated sulfuric acid with water in the existing report avoided, but also influences on reaction due to excess local temperature of the reaction liquid as well as latent troubles in production are eliminated; the preparation process is mild in reaction condition, simple and convenient to operate, high in product yield, and quite suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation process of a pharmaceutical intermediate-3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxylic acid. Background technique [0002] 3-[2-(3-chlorophenyl) ethyl]-2-pyridinecarboxylic acid (II) is the main intermediate of synthetic tricyclic ketone shown in formula III, and this tricyclic ketone (III) is synthetic Important intermediates of second-generation antihistamines such as loratadine (IV), desloratadine (V), and rupatadine (VI). [0003] [0004] Prior Art In the synthesis of 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxylic acid (II), the corresponding 2-pyridine carboxamides (formula I) are directly hydrolyzed into carboxylic acid , the reaction is difficult to carry out; therefore, the compound of formula II is usually first converted to 3-[2-(3-chlorophenyl) ethyl] by the compound of 2-pyridine carboxamides (formula I) -2-cyanopyridine, followed by cyano hy...

Claims

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Application Information

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IPC IPC(8): C07D213/803C07D213/79
Inventor 张广庄守群王国平周后元王宏博陈敏
Owner SHANGHAI INST OF PHARMA IND
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