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Industrial preparation method of pramiracetam sulfate

A technology of pramiracetam sulfate and hydrochloride, which is applied in the field of compound preparation, can solve the problems of difficult filtration, unsafe process, incomplete reaction, etc., and achieve improved yield, process stability, high process safety, The effect of avoiding generation of water

Active Publication Date: 2020-03-24
BEIJING YUEKANGKECHUANG PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its weak point is to make potassium salt with potassium hydroxide as alkali, and the moisture produced by the reaction after the potassium salt becomes solid is difficult to remove. If the moisture is not removed through drying, the yield of synthetic pramiracetam will be greatly reduced, so The reaction must be carried out in two steps and the drying process of the potassium salt needs to be increased, and react in toluene with two kinds of insoluble solids (potassium salt and hydrochloride) in toluene, the reaction is difficult, the reaction time is longer, and the reaction temperature It will be relatively high, and the yield is not too high
Its deficiency is that in the preparation process, phase-transfer catalyst TBA has been used, and in the reaction process, the temperature is too high, the by-product is too much, the reaction is very incomplete (for reversible reaction), and the product is simple and heterogeneous (1-2%). Pyrrolidone ethyl acetate has no industrial products, the price is very expensive (much more expensive than the final product), the production cost is very high, and it cannot be industrialized
[0013] Synthesis of pramiracetam in CN201210491569 adopts sodium hydride as alkali, a large amount of hydrogen can be produced in the reaction, and under the protection of nitrogen, it is also easy to explode due to the mixing of air during feeding; because there are very fine solid products, filtration is also very difficult, due to excessive The sodium hydride is untreated, and the excessive sodium hydride will spontaneously ignite and cause an explosion when it is exposed to the air during filtration. The process is very unsafe and difficult to industrialize.
[0014] In CN201410591758, chloroacetyl chloride and N,N-diisopropylethylenediamine are used in a toluene-water two-phase reaction system, and sodium carbonate is used as a catalyst to synthesize the intermediate N-[(2-diisopropylamino) Ethyl]-chloroacetamide has many side reactions. After solvent extraction, it is directly used for the next step without refining. There are many impurities in the follow-up reaction. It is difficult to crystallize after salt formation, and it is difficult to obtain qualified products.
The synthesis of pramiracetam uses solid sodium hydroxide as the base. Since the reaction will produce water, the product under the strong base will be hydrolyzed, which will cause the reaction to be incomplete, and the yield will be greatly reduced.

Method used

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  • Industrial preparation method of pramiracetam sulfate

Examples

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Embodiment 1

[0053] This embodiment provides an industrialized preparation method of pramiracetam sulfate, wherein the molar ratio of the free amide, α-pyrrolidone and sodium methoxide is about 1:1.5:1.5, and the specific process is as follows:

[0054] (1) Add 3.6 liters of tetrahydrofuran, 474.4 grams of diisopropylethylenediamine, cool down to zero degrees, dropwise add 421.1 grams of chloroacetyl chloride dissolved in 400mlTHF, drop it at 15 degrees for one hour and forty minutes, and keep warm at 10 degrees to react 3h, filtered, rinsed with a small amount of THF, and air-dried at 60 degrees to obtain 821.0 grams of material (slightly yellow), with a yield of 97.06% and a purity of 96.8%, heated and dissolved with 1.65 liters of absolute ethanol to absorb 50 grams of activated carbon, filtered while hot, Crystallized at 0-5 degrees, filtered and dried to obtain 650.0 g of N-(2-(diisopropyl)ethyl)-2-chloroacetamide hydrochloride, with a yield of 79.17% and a purity of about 99%.

[005...

Embodiment 2

[0060] The difference between this example and Example 1 is that in step (3), the molar ratio of the free amide, α-pyrrolidone and sodium methylate is adjusted to 1:1.5:2.5, and the specific process is as follows:

[0061] (1) Add 3.6 liters of tetrahydrofuran, 474.4 grams of diisopropylethylenediamine, cool down to zero degrees, dropwise add 421.1 grams of chloroacetyl chloride dissolved in 400mlTHF, drop it at 15 degrees for one hour and forty minutes, and keep warm at 10 degrees to react 3h, filtered, rinsed with a small amount of THF, and air-dried at 60 degrees to obtain 821.0 grams of material (slightly yellow), with a yield of 97.06% and a purity of 96.8%, heated and dissolved with 1.65 liters of absolute ethanol to absorb 50 grams of activated carbon, filtered while hot, Crystallized at 0-5 degrees, filtered and dried to obtain 650.0 g of N-(2-(diisopropyl)ethyl)-2-chloroacetamide hydrochloride, with a yield of 79.17% and a purity of about 99%.

[0062] (2) Dissolve 64...

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Abstract

The invention relates to the field of preparation of compounds, in particular to an industrial preparation method of pramiracetam sulfate. The method includes: (1) converting N-(2-(diisopropyl)ethyl)-2-chloroacetamide hydrochloride to obtain free amide, and removing moisture in the free amide; (2) reacting solid alkali with alpha-pyrrolidone in a solvent I under the protection of nitrogen, simultaneously distilling alcohol generated by the reaction, then adding a solution prepared from the free amide and the solvent I dropwise, and carrying out reaction to obtain pramiracetam; and (3) preparing pramiracetam and sulfuric acid into pramiracetam sulfate. According to the method, pramiracetam sulfate with excellent quality can be efficiently obtained, and the method has the characteristics oflow cost, high environmental friendliness, no use of dangerous materials, and high process safety, and is beneficial to popularization and application in industrial preparation.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to an industrial preparation method of pramiracetam sulfate. Background technique [0002] The structural formula of pramiracetam sulfate is as follows: [0003] [0004] It was developed by the Warner-Lambert Company of the United States. It was first launched in Italy in 1993, and has been listed in Argentina, Australia, France, Japan and other countries successively. At present, my country does not import the raw materials and preparations of this product. [0005] Pramiracetam sulfate belongs to the class of pyrrolidone nootropics. It is a high-efficiency, low-toxicity, and well-tolerated cognitive activator. It is a cyclic derivative of ⅹ-aminobutyric acid. It can promote the conversion of ADP into ATP in the brain, promote the synthesis of acetylcholine and enhance the conduction of nerve excitement. It has a strong ability to improve brain function, enhance memory, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
CPCC07D207/27
Inventor 宋更申陈世杰张海燕张婷婷
Owner BEIJING YUEKANGKECHUANG PHARM TECH CO LTD
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