Improved preparation method of mannityl nicotinate

A technology of hexanicotinate and reaction, which is applied in the field of preparation of pharmaceutical compounds, can solve the problems affecting the export and sales of hexanicotinate, reduce the batch production capacity of refining equipment, and increase the burden of solvent recovery posts, so as to avoid the problem of product quality Effects of instability, reduction of operation steps and product loss, shortening of production cycle

Active Publication Date: 2013-03-13
HUAZHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned production process has many operating steps, the separation and purification of the intermediate nicotinyl chloride hydrochloride and the property of mannohexonicotinate being easily soluble in acid all cause unnecessary product loss
In addition, a large amount of N,N-dimethylformamide is used as a solvent in the refining process, and there are the following problems: 1. Hexapanoic acid ester has little solubility in N,N-dimethylformamide, so it must be used to ensure the dissolution A large amount of solvent, at the same time, in order to ensure the refining yield, it must be concentrated under reduced pressure to evaporate most of the solvent
This not only increases the solvent consumption, but also reduces the batch production capacity of the refining equipment; 2. N,N-dimethylformamide is a second-class toxic solvent, which is restricted in the production of raw materials and has a negative effect on the liver function of the operator. 1. Kidney function is more toxic, and because the solvent is used in the refining process, it will inevitably affect the export sales of hexanicotinate; 3. In industrial production, in order to reduce production costs, the N,N-dimethyl Distillation, dehydration and other treatment of the formamide mother liquor, after qualified
This increases the burden on solvent recovery posts

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Acyl chloride reaction: Add 200kg of pyridine with a moisture content of no more than 0.3% into a pre-dried 1000L glass-lined reaction kettle, add 100kg of nicotinic acid under stirring, and add 106kg of thionyl chloride dropwise under cooling conditions after stirring evenly. After the addition is completed, control the temperature for more than 1 hour and slowly raise the temperature to 60-65°C, and keep it warm for 6 hours;

[0020] Esterification reaction: Add 27kg of mannitol in batches under cooling conditions, heat up to 85-90°C after adding mannitol, keep the temperature for 3 hours, cool down to below 50°C after the reaction, add a small amount of water dropwise, and wait for the temperature of the system to drop Then continue to add water until the total amount of water added is 100kg, then lower the temperature to below 10°C, and then add dropwise an aqueous solution of sodium hydroxide with a concentration of 10% by mass to adjust the pH to 6.7-7.0. Then cen...

Embodiment 2

[0023] Acyl chloride reaction: Add 200kg of pyridine with a water content of no more than 0.3% into a pre-dried 1000L glass-lined reaction kettle, add 100kg of nicotinic acid under stirring, and add 116kg of thionyl chloride dropwise under cooling conditions after stirring evenly. After the addition is completed, control the temperature for more than 1 hour and slowly raise the temperature to 60-65°C, and keep it warm for 4 hours;

[0024] Esterification reaction: Add 29kg of mannitol in batches under cooling conditions, heat up to 85-90°C after adding mannitol, keep the temperature for 2 hours, cool down to below 50°C after the reaction, add a small amount of water dropwise, and wait for the temperature of the system to drop Then continue to add water until the total amount of water added is 100kg, then lower the temperature to below 10°C, and then add dropwise an aqueous solution of sodium hydroxide with a concentration of 10% by mass to adjust the pH to 6.7-7.0. Then centri...

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PUM

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Abstract

The invention discloses a preparation method of mannityl nicotinate, which takes nicotinic acid, thionyl chloride and mannitol as main raw materials and comprises the steps of acylating chlorination, esterification, refining and the like, wherein the two reactions of acylating chlorination and esterification are finished by a 'one-pot method', and an alkaline neutralization method is adopted to sufficiently precipitate the product after the reaction; and in the refining process, a method of acid solution decoloration and alkaline precipitation taking water as a solvent is adopted to replace the existing traditional technology of adopting a large amount of class-two toxic solvent N,N-dimethylformamide to perform decoloration refining. Through the synthesis method disclosed by the invention, the separation and purification of intermediates are not required, and a crude product can be refined directly without drying, so that the operation steps are reduced, the production period is shortened, and the production cost is lowered, thus the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to an improved preparation method of mannohexonicotinoid ester. Background technique [0002] Hexaponicotinate is a cardiovascular drug that can dilate blood vessels and lower blood lipids. It is clinically used to treat coronary heart disease, cerebral thrombosis, atherosclerosis, hypertension, and hyperlipidemia. Compared with similar drugs - inositol nicotinate and sorbitan nicotinate, mannohexonicotinate is easier to hydrolyze in the body than the other two, and the drug effect is faster, and it can also relieve the strong expansion of the terminal effect of niacin itself. Side effects such as facial flushing and gastrointestinal discomfort. As the aging phenomenon in the world and China becomes more and more serious, hexonicotinate, as a high-efficiency antihypertensive and blood lipid-lowering drug, belongs to the category of anti-tumor drugs, cardiovascula...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/803
Inventor 王勇李新宇付林廖俊薛俊徐勇
Owner HUAZHONG PHARMA
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