AU2018101133A4

AU2018101133A4 - 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method

Info

Publication number: AU2018101133A4
Application number: AU2018101133A
Authority: AU
Inventors: Yida Yan
Original assignee: Chengdu Ao Ka Te Technology Co Ltd
Current assignee: Chengdu Ao Ka Te Technology Co Ltd
Priority date: 2017-09-17
Filing date: 2018-08-12
Publication date: 2018-09-13
Anticipated expiration: 2026-08-12
Also published as: CN108238907A; GB201715090D0; IES20180294A2

Abstract

2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method Abstract 5 The present invention discloses 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method, comprises the following steps: 2-(4-isobutylphenyl) propanol and biphenyl solution are added to the reaction vessel, the temperature of the solution is raised, the aqueous solution is added, potassium peroxydisulfate is added, continues to react; tetrabutoxy zirconium powder is added in batches, then potassium 10 sulfate solution is added, raises the temperature, controls the stirring speed, reacts, lowers the temperature, potassium chloride solution is added, the solution layers, separate the oil layer, adjusts the pHwith the formic acid solution, washed with hexyl ether solution, recrystallizes from 2-ethyl butanol solution, dehydrated with dehydration, gets the finished product 2-(4-isobutyl phenyl) propionic acid. Figure 1 | ' I ' I ' |I I ' I 14 12 10 8 6 4 2 0 ppm Figure 1 Ic0 (G) cT] (E) (G) c NNCH2 (D) (B) (B) (A) (A) a (C) (F) H CooH Figure 2

Description

The present invention discloses 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method, comprises the following steps: 2-(4-isobutylphenyl) propanol and biphenyl solution are added to the reaction vessel, the temperature of the solution is raised, the aqueous solution is added, potassium peroxydisulfate is added, continues to react; tetrabutoxy zirconium powder is added in batches, then potassium sulfate solution is added, raises the temperature, controls the stirring speed, reacts, lowers the temperature, potassium chloride solution is added, the solution layers, separate the oil layer, adjusts the pHwith the formic acid solution, washed with hexyl ether solution, recrystallizes from 2-ethyl butanol solution, dehydrated with dehydration, gets the finished product 2-(4-isobutyl phenyl) propionic acid.

Figure 1

1/1

2018101133 12 Aug 2018

ppm

Figure 1

Figure 2 ί

2018101133 12Aug2018

2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method

FIELD OF THE INVENTION

The present invention relates to a method for preparing a pharmaceutical 5 intermediate which belongs to the field of organic synthesis, more particularly, relates to 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method.

GENERAL BACKGROUND

2-(4-isobutylphenyl) propionic acid drugs is used as PG synthesis inhibitors and cyclooxygenase (COX) inhibitors, and the inhibitory activity against COX-1 is greater than that of against COX-2, it has thermal analgesic and antiinflammatory effects. Treatment of rheumatism and rheumatoid arthritis is less curative than acetyl salicylic acid and phenylbutazone. It is suitable for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and neuritis. Most of the existing synthesis methods are using condensation, hydrolysis, elimination, oxidation and neutralization of isobutylacetophenone. Most of the synthesis methods are as follows: isobutyl acetophenone, ethanol, silver nitrate, potassium hydroxide and other compounds as raw materials, the silver nitrate raw materials used in this synthesis method have corrosion and convergence on the skin and mucous membranes, the skin contact with silver nitrate after the light becomes dark, and prone to inflammation, which will endanger the health of synthesis operators, which is not conducive to safety production. One of the raw materials potassium hydroxide has a burning effect on the organization, it can dissolve the protein, generates the alkaline denatured protein. Solution or dust splashed on the skin, especially splashed into the mucosa, can produce soft scab. The higher solution the concentration, the higher the temperature, the stronger of the effect. If it splashing into the eye, not only can damage the cornea, but also make the deep tissue damage, so the use of potassium hydroxide as raw materials will increase the risk of synthesis process, harm the health of the operator, which is not conducive to safe production; and potassium hydroxide is corrosive, corrosion resistance of production equipment becomes higher, resulting in increased production equipment manufacturing costs, rising production costs, which is

2018101133 12 Aug 2018 not conducive to cost control, therefore, it is necessary to propose a new synthesis method.

SUMMARY

Based on the technical problems of the background technology, the purpose of the present invention is to provide 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method, comprises the following steps:

A: 2-(4-isobutylphenyl) propanol and biphenyl solution are added to the reaction vessel, the temperature of the solution is raised to 40-46 °C, the aqueous solution is added for 30-50 min, potassium peroxydisulfate is added, continues to react for 90-120 mm;

B: tetrabutoxy zirconium powder is added in batches in 40-60 min, then potassium sulfate solution is added, raises the temperature to 50-54 °C, controls the stirring speed at 310-330 rpm, reacts for 3-4 h, lowers the temperature to 5-9 ° C, potassium chloride solution is added, the solution layers, separate the oil layer, adjusts the pH to 3-4 with the formic acid solution, washed with hexyl ether solution for 20-30 min, recrystallizes from 2-ethyl butanol solution, dehydrated with dehydration, gets the finished product 2-(4-isobutyl phenyl) propionic acid.

Preferably, the biphenyl solution has a mass fraction of 20-27%. Preferably, the mass fraction of the potassium sulfate solution is 15-22%. Preferably, the potassium chloride solution has a mass fraction of 10-16%. Preferably, the formic acid solution has a mass fraction of 30-35%. Preferably, the mass fraction of hexyl ether solution is 50-56%.

Preferably, the 2-ethyl butanol solution has a mass fraction of 70-77%. Throughout the reaction process can be the following reaction formula:

CH

cn₂on

COOH

2018101133 12Aug2018

Compared with the synthesis method disclosed in the background art, the invention provides 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method, it is unnecessary to use silver nitrate, potassium hydroxide as a synthesis raw material, avoiding the raw materials silver nitrate harm to the health of synthesis operators, which is conducive to safe production. But also avoiding cauterization of potassium hydroxide on the organization, and its solution or dust splashed on the skin, especially splashed into the mucosa, resulting in the risk of soft scab, thereby reducing the risk factor of the synthesis process, which is conducive to the health of operators. At the same time, avoiding the strong corrosive potassium hydroxide improving corrosion resistance requirements of the production equipment, reducing the production equipment manufacturing costs, lowering production costs, which is conducive to cost control, reducing intermediate links reaction, decreasing the reaction time and improving the reaction yield, at the same time, the present invention provides a new synthetic route which has laid a good foundation for further enhancing the yield of the reaction.

DESCRIPTION OF THE DRAWINGS

Figure 1 is the *HNMR analysis spectrum of finished product 2-(4-isobutylphenyl) propionic acid.

Figure 2 is a H atom mark map of the finished product 2-(4-isobutylphenyl) propionic acid molecule.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples with reference to specific embodiments of the present invention are further illustrated:

Embodiment 1

2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method, comprises the following steps:

A: 2mol 2-(4-isobutylphenyl) propanol and 800ml biphenyl solution with a mass fraction of 20% are added to the reaction vessel, the temperature of the solution is raised to 40 °C, 4 mol aqueous solution is added for 30 min, 4 mol potassium peroxydisulfate is added, continues to react for 90 min;

2018101133 12Aug2018

B: 3 mol tetrabutoxy zirconium powder is added in 3 times in 40 min, then 1.2L potassium sulfate solution with a mass fraction of 15% is added, raises the temperature to 50 °C, controls the stirring speed at 310 rpm, reacts for 3h, lowers the temperature to 5 °C, 700ml potassium chloride solution with a mass fraction of 10% is added, the solution layers, separate the oil layer, adjusts the pH to 3 with the formic acid solution with a mass fraction of 30%, washed with hexyl ether solution with a mass fraction of 50% for 20 min, recrystallizes from 2-ethyl butanol solution with a mass fraction of 70%, dehydrated with anhydrous magnesium sulfate dehydration, gets the finished product 2-(4-isobutyl phenyl) propionic acid 400.464g, yield of 97.2%.

Embodiment 2

A: 2mol 2-(4-isobutylphenyl) propanol and 800ml biphenyl solution with a mass fraction of 23% are added to the reaction vessel, the temperature of the solution is raised to 43 °C, 5 mol aqueous solution is added for 40 min, 5 mol potassium peroxydisulfate is added, continues to react for 100 min;

B: 4 mol tetrabutoxy zirconium powder is added in 4 times in 50 min, then 1.2L potassium sulfate solution with a mass fraction of 18% is added, raises the temperature to 52 °C, controls the stirring speed at 320 rpm, reacts for 3.5h, lowers the temperature to 7 ° C, 700ml potassium chloride solution with a mass fraction of 13% is added, the solution layers, separate the oil layer, adjusts the pH to 3.5 with the formic acid solution with a mass fraction of 32%, washed with hexyl ether solution with a mass fraction of 53% for 25 min, recrystallizes from 2-ethyl butanol solution with a mass fraction of 74%, dehydrated with anhydrous magnesium sulfate dehydration, gets the finished product 2-(4-isobutyl phenyl) propionic acid 401.7g, yield of 97.5%.

Embodiment 3

A: 2mol 2-(4-isobutylphenyl) propanol and 800ml biphenyl solution with a mass fraction of 27% are added to the reaction vessel, the temperature of the solution is

2018101133 12Aug2018 raised to 46 °C, 6 mol aqueous solution is added for 50 min, 6 mol potassium peroxydisulfate is added, continues to react for 120 min;

B: 5 mol tetrabutoxy zirconium powder is added in 5 times in 60 min, then 1.2L potassium sulfate solution with a mass fraction of 22% is added, raises the temperature to 54 °C, controls the stirring speed at 330 rpm, reacts for 4h, lowers the temperature to 9 °C, 700ml potassium chloride solution with a mass fraction of 16% is added, the solution layers, separate the oil layer, adjusts the pH to 4 with the formic acid solution with a mass fraction of 35%, washed with hexyl ether solution with a mass fraction of 56% for 30 min, recrystallizes from 2-ethyl butanol solution with a mass fraction of

77%, dehydrated with anhydrous magnesium sulfate dehydration, gets the finished product 2-(4-isobutyl phenyl) propionic acid 404.172g, yield of 98.1%.

Infrared analysis of finished product l-methyl-2-quinolinone, infrared spectrum is shown in figure 1, the analysis of data is shown in table 1.

Figure 1 is *HNMR analysis spectrum of the finished product 2-(4-isobutyl 15 phenyl) propionic acid.

Figure 2 is a H atom mark map of the finished product of 2-(4-isobutylphenyl) propionic acid molecule.

Table 1 is the *HNMR analysis data of the finished product 2-(4-isobutylphenyl) propionic acid.

The parameters of the *HNMR analysis of 2-(4-isobutylphenyl) propionic acid are set as follows:

399.65 MHz, Ci₃Hi₈O₂, 0.047 g: 0.5 ml, CDCfi Table 1 1HNMR data chemical shift atomic type (PPm)

A 7.213

B 7.094

C 3.695

D 2.438

E 1.835

2018101133 12Aug2018

1.486

0.889

F

G

The embodiments of the present invention are merely preferred embodiments of the present invention, but the range of the present invention is not limited this, and any person who is familiar with those skilled in the arts, within the technical range of the present invention. It is intended that the technical solution and its inventive concept be replaced or modified equivalently with reference to the range of the invention.

2018101133 12Aug2018

Claims

Claims

1. 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method, comprises the following steps:

5 A: 2-(4-isobutylphenyl) propanol and biphenyl solution are added to the reaction vessel, the temperature of the solution is raised to 40-46 °C, the aqueous solution is added for 30-50 min, potassium peroxydisulfate is added, continues to react for 90-120 min;

B: tetrabutoxy zirconium powder is added in batches in 40-60 min, then 10 potassium sulfate solution is added, raises the temperature to 50-54 °C, controls the stirring speed at 310-330 rpm, reacts for 3-4 h, lowers the temperature to 5-9 ° C, potassium chloride solution is added, the solution layers, separate the oil layer, adjusts the pH to 3-4 with the formic acid solution, washed with hexyl ether solution for 20-30 min, recrystallizes from 2-ethyl butanol solution, dehydrated with

15 dehydration, gets the finished product 2-(4-isobutyl phenyl) propionic acid.
2. 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method according to claim 1 wherein the biphenyl solution has a mass fraction of 20-27%.
3. 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method according to claim 1 wherein the mass fraction of the potassium sulfate solution is

20 15-22%.
4. 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method according to claim 1 wherein the potassium chloride solution has a mass fraction of

10-16%.
5. 2-(4-isobutylphenyl) propionic acid drug intermediates synthesis method 25 according to claim 1 wherein the formic acid solution has a mass fraction of 30-35%.

1/1

2018101133 12 Aug 2018 ppm

Figure 1

Figure 2