AU2018101143A4

AU2018101143A4 - 2,3-dihydroxy-succinic acid drug intermediates synthesis method

Info

Publication number: AU2018101143A4
Application number: AU2018101143A
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: GB201719123D0; CN108285413A; IE20180284U1

Abstract

2,3-dihydroxy-succinic acid drug intermediates synthesis method Abstract 5 The present invention discloses drug intermediates 2,3-dihydroxy-succinic acid drug intermediates synthesis method, comprises the following steps: 1,4-dibromo-2,3-dimethoxy-butyl dialdehyde, heptane solution was added to the reaction vessel, controlled the stirring speed, raised the temperature of the solution, added the aqueous solution, added dimethyl sulfoxide, added sebacic acid dioctyl 10 ester solution in batches, continued to react; raised the temperature of the solution, added potassium bromide solution, added zinc acetate powder, continued to react, reduced the temperature, standed, added sodium nitrate solution, the solution is layered, the oil layer was separated, washed with 3-hexanol solution, recrystallized in cyclic valerate solution, dehydrated with dehydration, got the finished product 15 2,3-dihydroxy-succinic acid. Figure 1 )'0 4000 3500 3000 2500 2000 1500 1000 500 Figure 1

Description

The present invention discloses drug intermediates 2,3-dihydroxy-succinic acid drug intermediates synthesis method, comprises the following steps:

1,4-dibromo-2,3-dimethoxy-butyl dialdehyde, heptane solution was added to the reaction vessel, controlled the stirring speed, raised the temperature of the solution, added the aqueous solution, added dimethyl sulfoxide, added sebacic acid dioctyl ester solution in batches, continued to react; raised the temperature of the solution, added potassium bromide solution, added zinc acetate powder, continued to react, reduced the temperature, standed, added sodium nitrate solution, the solution is layered, the oil layer was separated, washed with 3-hexanol solution, recrystallized in cyclic valerate solution, dehydrated with dehydration, got the finished product

2,3-dihydroxy-succinic acid.

Figure 1

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Figure 1

2018101143 12 Aug 2018

2,3-dihydroxy-succinic acid drug intermediates synthesis method

FIELD OF THE INVENTION

The present invention relates to a method for preparing a pharmaceutical intermediate which 5 belongs to the field of organic synthesis, more particularly, relates to drug intermediates l-methyl-2-quinolinone synthesis method.

GENERALBACKGROUND

2,3-dihydroxy succinic acid is mainly used in medicine, food, leather, textile and other industries, used as antioxidant synergist, retarder, tanning agents, chelating agents, pharmaceuticals; 0 2,3-dihydroxy-succinic acid is very important chiral ligands and chocolates that can be used to prepare many famous chiral catalysts and as chiral sources to synthesize complex natural product molecules. Most of the existing synthesis methods from glyoxal with hydrocyanic acid and then acid hydrolysis reaction, this synthesis method used in the reaction material glyoxal by inhalation, ingestion or by skin absorption is harmful to the human body; it has a stimulating effect on the skin, 5 can cause dermatitis; vapor or fog has a stimulating effect on the eyes, mucous membranes and upper respiratory tract; factors above will lead to the reaction material glyoxal harm to the health of the operation personnel. Glyoxal is harmful to the environment, can cause pollution to the atmosphere, increasing the disposal cost of pollutants later. The reaction raw material hydrocyanic acid is a highly toxic substance, which inhibits the respiratory enzyme, resulting in intracellular A) asphyxia; acute hydrogen cyanide severe poisoning shows a deep coma, shallow breathing, paroxysmal convulsions, and even tonic spasm. Therefore, the use of hydrocyanic acid as a raw material will harm to the health of the operation personnel, which is not conducive to safe production. Therefore, the above synthesis method has many shortcomings, it is necessary to propose a new synthesis method.

SUMMARY OF THEINVENTION

Based on the technical problems existing in the general background technology, the invention proposed 2,3-dihydroxy-succinic acid drug intermediates synthesis method, including the following steps:

A: 1,4-dibromo-2,3-dimethoxy-butyl dialdehyde, heptane solution was added to the reaction 30 vessel, controlled the stirring speed at 170-190 rpm, raised the temperature of the solution to 40-46°C, added the aqueous solution, added dimethyl sulfoxide, added sebacic acid dioctyl ester

2018101143 12 Aug 2018 solution in batches within 20-40 min, continued to react for 50-80 min;

B: raised the temperature of the solution to 55-62 °C,added potassium bromide solution, added zinc acetate powder, continued to react for 2-3 h, reduced the temperature to 10-16°C, standed for 30-50 min, added sodium nitrate solution, the solution is layered, the oil layer was separated, washed with 3-hexanol solution for 30-50 min, recrystallized in cyclic valerate solution, dehydrated with dehydration, got the finished product 2,3-dihydroxy-succinic acid.

Preferably, the heptane solution has a mass fraction of 15-21%.

Preferably, the sebacic acid dioctyl ester solution has a mass fraction of 20-26%.

Preferably, the potassium bromide solution has a mass fraction of 10-15%.

Preferably, the sodium nitrate solution has a mass fraction of 20-26%.

Preferably, the 3-hexanol solution has a mass fraction of 40-45%.

Preferably, the cyclic valerate solution has a mass fraction of 60-67%.

Throughout the reaction process can be the following reaction formula:

\\

H.CO X.

v:h + + C₂H₆OS + H,0 + Zn(CH,COO)i sir

1.J \\ .CH

ILCO

-Br

IIO

-OH

Compared with the synthesis method disclosed in the background art, the invention provides drug intermediates 2,3-dihydroxy-succinic acid synthesis method, it is unnecessary to use glyoxal and hydrocyanic acid as the reaction raw materials, avoiding glyoxal as raw materials harm to the health of the operation personnel, and the pollution to the environment, reducing the disposal cost of pollutants later. Moreover, avoiding hydrocyanic acid belonging to the highly toxic substances as reactants, which is conducive to the production of the health of the operator, reducing the risk coefficient of synthesis process, reducing intermediate links reaction, decreasing the reaction time and improving the reaction yield, while providing a new synthesis method of the invention, laying a good foundation to further improve the reaction yield.

DESCRIPTION OF THE DRAWINGS

Figure 1 is the infrared analysis spectrum of finished product 2,3-dihydroxy-succinic acid.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

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

2018101143 12 Aug 2018 further illustrated:

Embodiment 1:

2,3-dihydroxy-succinic acid drug intermediates synthesis method, comprises the following steps:

A: 3mol 1,4-dibromo-2,3-dimethoxy-butyl dialdehyde, 900ml heptane solution with a mass fraction of 15% was added to the reaction vessel, controlled the stirring speed at 170 rpm, raised the temperature of the solution to 40 °C, added 6mol aqueous solution, added 6mol dimethyl sulfoxide, added 6mol sebacic acid dioctyl ester solution with a mass fraction of 20% twice within 20 min, continued to react for 50 min;

B: raised the temperature of the solution to 55 °C,added 1.3L potassium bromide solution with a mass fraction of 10%, added 3mol zinc acetate powder, continued to react for 2 h, reduced the temperature to 10°C, standed for 30 min, added 700mol sodium nitrate solution with a mass fraction of 20%, the solution is layered, the oil layer was separated, washed with 3-hexanol solution with a mass fraction of 40% for 30 min, recrystallized in cyclic valerate solution with a mass fraction of

60%, dehydrated with magnesium sulfate anhydrous dehydration, got the finished product 2,3dihydroxy-succinic acid 439.65g, yield of 97.7%.

Embodiment 2:

2,3-dihydroxy-succinic acid drug intermediates synthesis method, comprises the following steps: A: 3mol 1,4-dibro mo-2,3-dimethoxy-butyl dialdehyde, 900ml heptane solution with a mass

A) fraction of 18% was added to the reaction vessel, controlled the stirring speed at 180 rpm, raised the temperature of the solution to 43 °C, added 7mol aqueous solution, added 7mol dimethyl sulfoxide, added 7mol sebacic acid dioctyl ester solution with a mass fraction of 23% 3 times within 30 min, continued to react for 70 min;

B: raised the temperature of the solution to 58°C,added 1.3L potassium bromide solution with a mass fraction of 13%, added 4mol zinc acetate powder, continued to react for 2.5 h, reduced the temperature to 13°C, standed for 40 min, added 700mol sodium nitrate solution with a mass fraction of 23%, the solution is layered, the oil layer was separated, washed with 3-hexanol solution with a mass fraction of 43% for 40 min, recrystallized in cyclic valerate solution with a mass fraction of 64%, dehydrated with magnesium sulfate anhydrous dehydration, got the finished product 2,330 dihydroxy-succinic acid 441.45g, yield of 98.1%.

2018101143 12 Aug 2018

Embodiment 3:

2,3-dihydroxy-succinic acid drug intermediates synthesis method, comprises the following steps: A: 3mol 1,4-dibromo-2,3-dimethoxy-butyl dialdehyde, 900ml heptane solution with a mass fraction of 21% was added to the reaction vessel, controlled the stirring speed at 190 rpm, raised the temperature of the solution to 46 °C, added 8mol aqueous solution, added 8mol dimethyl sulfoxide, added 8mol sebacic acid dioctyl ester solution with a mass fraction of 26% 4 times within 40 min, continued to react for 80 min;

B: raised the temperature of the solution to 62°C,added 1.3L potassium bromide solution with a mass fraction of 15%, added 5mol zinc acetate powder, continued to react for 3 h, reduced the temperature to 16°C, standed for 50 min, added 700mol sodium nitrate solution with a mass fraction of 26%, the solution is layered, the oil layer was separated, washed with 3-hexanol solution with a mass fraction of 45% for 50 min, recrystallized in cyclic valerate solution with a mass fraction of 67%, dehydrated with magnesium sulfate anhydrous dehydration, got the finished product 2,3dihydroxy-succinic acid 442.35g, yield of 98.3%.

Table 1 is the infrared analysis data.

Table 1 infrared analysis data

Serial	Peak position	Transmittance	Half peak	Peak difference
number	(cm'¹)	(%)	(cm'¹)	(%)
1	668	63	35	24
2	1086	37	31	40
3	1133	35	35	41
4	1193	42	34	12
5	1223	42	37	9
6	1256	45	51	14
7	1743	9	68	85
8	3337	31	499	11
9	3412	26	90	19

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.

2018101143 12 Aug 2018

Claims

Claims

1. 2,3-dihydroxy-succinic acid drug intermediates synthesis method, comprises the following steps:

5 A: 1,4-dibromo-2,3-dimethoxy-butyl dialdehyde, heptane solution was added to the reaction vessel, controlled the stirring speed at 170-190 rpm, raised the temperature of the solution to 40-46°C, added the aqueous solution, added dimethyl sulfoxide, added sebacic acid dioctyl ester solution in batches within 20-40 min, continued to react for 50-80 min;

10 B: raised the temperature of the solution to 55-62°C,added potassium bromide solution, added zinc acetate powder, continued to react for 2-3 h, reduced the temperature to 10-16°C, standed for 30-50 min, added sodium nitrate solution, the solution is layered, the oil layer was separated, washed with 3-hexanol solution for 30-50 min, recrystallized in cyclic valerate solution, dehydrated with dehydration, got

15 the finished product 2,3-dihydroxy-succinic acid.
2. Drug intermediates l-methyl-2-quinolinone synthesis method according to claim 1 wherein the heptane solution has a mass fraction of 15-21%.
3. Drug intermediates l-methyl-2-quinolinone synthesis method according to claim 1 wherein the sebacic acid dioctyl ester solution has a mass fraction of 20-26%.

20
4. Drug intermediates l-methyl-2-quinolinone synthesis method according to claim 1 wherein the potassium bromide solution has a mass fraction of 10-15%.
5. Drug intermediates l-methyl-2-quinolinone synthesis method according to claim 1 wherein the sodium nitrate solution has a mass fraction of 20-26%.

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Figure 1