AU2018101139A4

AU2018101139A4 - P-methoxyphenylacetic acid drug intermediates synthesis method

Info

Publication number: AU2018101139A4
Application number: AU2018101139A
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: CN108238896A; IE20180288U1

Abstract

P-methoxphenylacetic acid drug intermediates synthesis method Abstract 5 The present invention discloses p-methoxyphenylacetic acid drug intermediates synthesis method, comprises the following steps: 4-methoxy-6-methyl-benzaldehyde and sodium nitrate solution is added to the reaction vessel, controls the temperature of the solution, controls the stirring speed, ethylene glycol solution and aluminum isopropoxide is added, continues to react; then cobalt chloride powder is added, raises 10 the temperature, continues to react, reduces the temperature, oxalic acid solution is added to adjust the pH, washed with potassium sulfate solution, washed with tri-pentylbenzene solution, recrystallized in triethylene glycol solution, dehydrated with dehydration, gets the finished product p-methoxyphenylacetic acid. 15 Figure 1 so I 4000 S500 SOOO 20 2000 1500 1000 5oo Figure 1

Description

The present invention discloses p-methoxyphenylacetic acid drug intermediates synthesis method, comprises the following steps: 4-methoxy-6-methyl-benzaldehyde and sodium nitrate solution is added to the reaction vessel, controls the temperature of the solution, controls the stirring speed, ethylene glycol solution and aluminum isopropoxide is added, continues to react; then cobalt chloride powder is added, raises the temperature, continues to react, reduces the temperature, oxalic acid solution is added to adjust the pH, washed with potassium sulfate solution, washed with tri-pentylbenzene solution, recrystallized in triethylene glycol solution, dehydrated with dehydration, gets the finished product p-methoxyphenylacetic acid.

Figure 1

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Figure 1 ί

2018101139 12Aug2018

P-methoxyphenylacetic 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 p-methoxyphenylacetic acid drug intermediates synthesis method.

GENERAL BACKGROUND

P-methoxyphenylacetic acid is mainly used for organic synthesis and is used as an intermediate for puerarin drugs. Puerarin drugs can be used to dilate blood vessels, improve blood circulation; reduce myocardial oxygen consumption, inhibit cancer cells; increase coronary flow, adjust the blood microcirculation; treatment for sudden deafness at all ages; reduce cardiovascular and cerebrovascular disease risk. The existing synthesis methods are mostly using p-methoxyacetophenone as raw materials, ethanol, sulfur and hexahydrate piperazine are put into the reaction pot for 4h, and then steamed for ethanol. The resulting sulfated piperazine and p-methoxyacetophenone react for 20h in 135-140 ° C, then sodium hydroxide is added to reflux for 20h. After completion of the reaction, the mixture is cooled to below 35 °C and the pH is adjusted to 8-9 with hydrochloric acid. After the separation of sulfur with the centrifuge, and then neutralized to pH 3-4, cooling, centrifugal dehydration, the resulting crude refined to get p-methoxyphenylacetic acid. This synthesis method requires the use of sulfur, sodium hydroxide as reactant, sulfur is flammable, sulfur dust can cause explosion in the air or easy to be explosive or burning when mixed with the oxidant, sulfur storage tank space is easy to form hydrogen sulfide explosion concentration, and cause the explosion or poisoning, therefore, as a reactant, sulfur will increase the risk coefficient of synthesis process, which is not conducive to the health of production operators. Reactive raw materials sodium hydroxide is highly corrosive, its solution or dust splashed on the skin, especially splashed into the mucosa, can produce soft scab, and can penetrate deep tissue. Strong corrosive sodium hydroxide will raise requirements of corrosion resistance to equipment, resulting in equipment manufacturing costs increase, which

2018101139 12Aug2018 is not conducive to cost control. And the temperature required for the synthesis process is high, it needs to be maintained at 130 °C for more than 20h, which will lead to higher energy consumption in the synthesis process, which will not reduce the engineering cost, and the whole process is complicated, 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 p-methoxyphenylacetic acid drug intermediates synthesis method, comprises the following steps:

A: 4-methoxy-6-methyl-benzaldehyde and sodium nitrate solution is added to the reaction vessel, controls the temperature of the solution to 40-47 ° C, controls the stirring speed at 150-180 rpm, ethylene glycol solution and aluminum isopropoxide is added, continues to react for 70-90 min;

B: then cobalt chloride powder is added, raises the temperature to 50-56 °C, continues to react for 2-3 h, reduces the temperature to 10-16 °C, oxalic acid solution is added to adjust the pH to 5-6, washed with potassium sulfate solution for 30- 40 min, washed with tri-pentylbenzene solution for 50-60 min, recrystallized in triethylene glycol solution, dehydrated with dehydration, gets the finished product p-methoxyphenylacetic acid.

Preferably, the sodium nitrate solution has a mass fraction of 15-22%.

Preferably, the mass fraction of the ethylene glycol solution is 20-26%.

Preferably, the oxalic acid solution has a mass fraction of 10-17%.

Preferably, the potassium sulfate solution has a mass fraction of 10-15%. Preferably, the mass fraction of tri-pentylbenzene solution is 30-37%.

Preferably, the triethylene glycol solution has a mass fraction of 60-65%.

Throughout the reaction process can be the following reaction formula:

2018101139 12Aug2018

Compared with the synthesis method disclosed in the background art, the invention provides p-methoxyphenylacetic acid drug intermediates synthesis method, it is unnecessary to use sulfur, sodium hydroxide as a reactant, avoiding the risk of sulfur is flammable, and the sulfur dust can cause the risk of explosion, and the risk of explosion or poisoning caused by that sulfur storage tank space is easy to form the concentration of hydrogen sulfide explosion, reducing the risk factor of synthesis process, which is conducive to the production operator's health, but also avoiding the strong corrosive effect sodium hydroxide as a reactant on the corrosion resistance requirements of the equipment, reducing equipment manufacturing costs, which is conducive to cost control. And the reaction does not need to be maintained at 130 °C for more than 20h, greatly reducing the energy required lor the reaction, 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 OFTHE DRAWINGS

Figure 1 is the infrared analysis spectrum of finished product p-methoxyphenylacetic acid.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples with reference To specific embodiments of the present invention are tint her illustrated;

Embodiment 1

P-methoxyphenylacetic acid drug intermediates synthesis method, comprises the following steps:

A: 2 mol 4-methoxy-6-methyl-benzaldehyde and 800 ml sodium nitrate solution with a mass fraction of 15% is added to the reaction vessel, controls the temperature of

2018101139 12Aug2018 the solution to 40°C, controls the stirring speed at 150 rpm, 4 mol ethylene glycol solution with a mass fraction of 20% and 4 mol aluminum isopropoxide is added, continues to react for 70 min;

B: then 4 mol cobalt chloride powder is added, raises the temperature to 50 °C, 5 continues to react for 2 h, reduces the temperature to 10 °C, oxalic acid solution with a mass fraction of 10% is added to adjust the pH to 5, washed with potassium sulfate solution with a mass fraction of 10% for 30 min, washed with tri-pentylbenzene solution with a mass fraction of 30% for 50 min, recrystallized in triethylene glycol solution with a mass fraction of 60%, dehydrated with activated alumina dehydration, gets the finished product p-methoxyphenylacetic acid 326.024g, yield of 98.2%.

Embodiment 2

A: 2 mol 4-methoxy-6-methyl-benzaldehyde and 800 ml sodium nitrate solution 15 with a mass fraction of 18% is added to the reaction vessel, controls the temperature of the solution to 44°C, controls the stirring speed at 160 rpm, 5 mol ethylene glycol solution with a mass fraction of 23% and 5 mol aluminum isopropoxide is added, continues to react for 80 min;

B: then 5 mol cobalt chloride powder is added, raises the temperature to 53 °C, 20 continues to react for 2.5 h, reduces the temperature to 13 °C, oxalic acid solution with a mass fraction of 14% is added to adjust the pH to 5.5, washed with potassium sulfate solution with a mass fraction of 13% for 35 min, washed with tri-pentylbenzene solution with a mass fraction of 34% for 55 min, recrystallized in triethylene glycol solution with a mass fraction of 63%, dehydrated with activated alumina dehydration, gets the finished product p-methoxyphenylacetic acid 327.02g, yield of 98.5%.

Embodiment 3

A: 2 mol 4-methoxy-6-methyl-benzaldehyde and 800 ml sodium nitrate solution 30 with a mass fraction of 22% is added to the reaction vessel, controls the temperature of

2018101139 12Aug2018 the solution to 47°C, controls the stirring speed at 180 rpm, 6 mol ethylene glycol solution with a mass fraction of 26% and 6 mol aluminum isopropoxide is added, continues to react for 90 min;

B: then 6 mol cobalt chloride powder is added, raises the temperature to 56 °C, 5 continues to react for 3 h, reduces the temperature to 16 °C, oxalic acid solution with a mass fraction of 17% is added to adjust the pH to 6, washed with potassium sulfate solution with a mass fraction of 15% for 40 min, washed with tri-pentylbenzene solution with a mass fraction of 37% for 60 min, recrystallized in triethylene glycol solution with a mass fraction of 65%, dehydrated with activated alumina dehydration, gets the finished product p-methoxyphenylacetic acid 328.348g, yield of 98.9%.

Infrared analysis of finished product p-methoxyphenylacetic acid, infrared spectrum is shown in figure 1, the analysis of data is shown in table 1.

Table 1 Analysis data

Serial	Peak position	Transmittance	Half width	Peak difference
number	(cnf¹)	(%)	(cm'¹)	(%)
1	382	69	21	23
2	520	58	14	29
3	554	52	31	23
4	676	26	16	69
5	770	51	9	42
6	816	16	25	68
7	897	35	47	14
8	923	26	30	22
9	1026	9	25	81
10	1106	45	9	48
11	1182	18	26	57
12	1242	13	42	56
13	1299	29	16	32
14	1313	35	14	27
15	1406	19	24	40
16	1425	48	16	9

2018101139 12Aug2018

17	1444	54	14	16
18	1465	46	22	29
19	1514	13	18	70
20	1583	49	13	33
21	1613	31	18	41
22	1707	9	94	66
23	2645	64	183	7
24	2834	43	169	8
25	2965	20	139	23

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.

2018101139 12Aug2018

Claims

Claims

1. P-methoxyphenylacetic acid drug intermediates synthesis method, comprises the following steps:

5 A: 4-methoxy-6-methyl-benzaldehyde and sodium nitrate solution is added to the reaction vessel, controls the temperature of the solution to 40-47 ° C, controls the stirring speed at 150-180 rpm, ethylene glycol solution and aluminum isopropoxide is added, continues to react for 70-90 min;

B: then cobalt chloride powder is added, raises the temperature to 50-56 °C, 10 continues to react for
2-3 h, reduces the temperature to 10-16 °C, oxalic acid solution is added to adjust the pH to 5-6, washed with potassium sulfate solution for 30- 40 min, washed with tri-pentylbenzene solution for 50-60 min, recrystallized in triethylene glycol solution, dehydrated with dehydration, gets the finished product p-methoxyphenylacetic acid.

15 2. P-methoxyphenylacetic acid drug intermediates synthesis method according to claim 1 wherein the sodium nitrate solution has a mass traction of 15-22%.
3. P-methoxyphenylacetic acid drug intermediates synthesis method according to claim 1 wherein the mass fraction of the ethylene glycol solution is 20-26%.
4. P-methoxyphenylacetic acid drug intermediates synthesis method according to 20 claim 1 wherein the oxalic acid solution has a mass fraction of 10-17%.
5. P-methoxyphenylacetic acid drug intermediates synthesis method according to claim 1 wherein the potassium sulfate solution has a mass fraction of 10-15%.

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Figure 1