CN1105357A - Process for synthesizing alpha-pyrrolidone acetamide - Google Patents

Abstract

The process for synthesizing alpha-pyrrolidone acetamide used as medicine for nourishing brain and promoting intelligence features that petro-chemical by-product is used as initial material and the synthesis is performed with general chemical apparatus under ordinary pressure.

Description

Process for synthesizing alpha-pyrrolidone acetamide

The present invention relates to the synthetic method of alpha-pyrrolidone acetamide.Belong to the pyrrolidone field.

(α-pyrrolidinoneacetamide) is a kind of Chinese People's Anti-Japanese Military and Political College's cortex anoxic that has to alpha-pyrrolidone acetamide, and the activation brain cell promotes phosphorus matter to absorb and the effect of brain albumen synthetic.Use this compound as a kind of multi-functional brain tonic medicine in medical treatment, commodity " piracetam " by name (piracetam) are used for the treatment of sequela such as cerebral concussion, cerebral trauma, cerebral arteriosclerosis and cerebrovascular sclerosis; Still a kind of promote thinking and memory increase the intelligence medicine, for degradation symptom under old mental deterioration, dementia and the children's intelligence curative effect is preferably arranged also.

Oneself of synthetic above-claimed cpd has method, all need under high temperature, high pressure, high-tension apparatus and suitable conditions such as catalyzer, to carry out [spaeth E.and Litner J.Ber 69 2727(1936); U.S.pat 4181662(1980); U.S.pat.4111952(1978); U.S.pat 3884936(1974)], these exacting terms not only make raw material and facility investment higher, and complicated operating process, and difficulty is big.The main raw material that China produces this compound at present relies on import fully, and costs an arm and a leg, thereby makes the finished product price higher.

The objective of the invention is, a kind of beginning raw material cheap, that be easy to get that adopts is provided, get rid of and under condition of high voltage, react, avoid using the synthetic route of high-tension apparatus, produce alpha-pyrrolidone acetamide, and can reduce its production cost.

Synthetic method of the present invention comprises shown in following reaction formula:

1, the byproduct pentanedioic acid that adopts petrochemical complex makes it in 50-70 ℃ for the beginning raw material, under diacetyl oxide or Acetyl Chloride 98Min. effect, generates Pyroglutaric acid (I).Also can directly use Pyroglutaric acid to make the beginning raw material, in fact, it also is the by product of petrochemical complex.

2, Pyroglutaric acid is bathed under the temperature at 200-230 ℃ and react, generate glutarimide (II) with ammoniacal liquor.This product can be purified and is used for next step reaction.

3, make glutarimide, at 0-5 ℃, reaction is 30-60 minute in sodium hydroxide-hypochlorous acid is received the aqueous solution, is warming up to 50-70 ℃ then and continues reaction 1.5-3 hour.With hydrochloric acid neutralization reaction liquid, make pH equal 7.Filtrate is concentrated into dried, adds 95% ethanol and make solid dissolving, elimination insolubles.Filtrate is concentrated into dried, product 4-aminobutyric acid (III), can purify is used for next step reaction.

4, the 4-aminobutyric acid is dissolved in the toluene in the reflux of water trap is housed, reflux is told the water of generation, and when treating anhydrous steaming, reaction is finished.Decompression steams toluene earlier, steams product alpha-pyrrolidone (IV) again.Calculate from pentanedioic acid, the overall yield of compound (IV) is 45-50%.

5, in the dry toluene of new steaming, add basic metal or its compound, wherein available comprising: lithium, sodium, potassium, lithium hydride, sodium hydride, sodium amide, potassium hydride KH.Heating, reflux, stir, make basic metal or its compound powdering, be chilled to room temperature after, in wherein adding the toluene solution that is dissolved with alpha-pyrrolidone, under agitation, slowly be warming up to 60-75 ℃, reacted 30-40 hour, till having reacted to basic metal or its compound.Then, in the toluene solution that wherein slowly splashes into ethyl chloroacetate, again in 70-80 ℃, stirred 3-6 hour, cooling is filtered.Boil off the toluene in the filtrate earlier, decompression steams alpha-pyrrolidone ethyl acetate (V) again.Boiling point 83-90/40Pa, productive rate 60%.

6, in compound (V), add ammoniacal liquor,, be evaporated to dried at stirring at room 4-6 hour.Get alpha-pyrrolidone acetamide.Fusing point 149.0-150.0 ℃.Productive rate 61%.

More than the starting raw material of each step reaction and the mol ratio of reagent be 1: (1-3).

The advantage of synthetic method of the present invention is:

1, adopts domestic existing petrochemical by-product to make the beginning raw material, need not reimportation expensive desired raw material, save a large amount of foreign exchanges.

2, reaction does not need condition of high voltage, high-tension apparatus and catalyzer, reduces facility investment and productive expense greatly, can produce with general production unit.

3, production, processing ease, wherein the product of some step needn't be purified, and promptly can be used for next step reaction.

4, compare with existing method, can reduce the cost 1/3 of final product approximately.

In order to be illustrated more clearly in the present invention, enumerate following example, but it there is not any restriction to the present invention.

Embodiment:

1. Pyroglutaric acid (I) is synthetic

In the there-necked flask of the 100ml that reflux is housed, add the acetic anhydride of 50ml and the pentanedioic acid of 26.4g(0.2mol, heating is three hours in 50-60 ℃ water-bath, the acetic acid that generates in acetic anhydride that pressure reducing and steaming is excessive and the reaction, cooling back ether wash residual thing, suction strainer, drain, compound (I) 22.2g(97.4%), fusing point 56.5-57 ℃.

2. synthetic (II) of glutarimide

In the matrass of 250ml, add 100ml, 25% ammoniacal liquor, the compound (I) of 22.2g is added wherein in batches, and after making it to dissolve fully, filled with water prolong, reacting by heating in 220-225 ℃ oil bath, constantly there is liquid to steam, when absence of liquid distillates, stop heating, be chilled to after the room temperature in wherein adding 100ml water, the question response thing complete molten after, in the aqueous solution, add the small amount of activated decolouring, filter, concentrating filter liquor gets compound (II) 17.2g, about 140 ℃ of fusing points, this step product need not purifying and can be directly used in the next step.

3.4-aminobutyric acid (III) is synthetic

In the 1000ml there-necked flask, add the water of 713ml and the solid sodium hydroxide of 80g, treat that solution is chilled to room temperature (20 ℃), feed 0.65mol chlorine with conduit, make NaOCl-NaOH solution, this solution is as cold as 0 ℃ after, in wherein add 33.6g(0.3mol in batches) glutarimide (II), stirring also remains on 0-10 ℃, reacts 40 minutes, slowly is warming up to 55-60 ℃ then and reacts 2 hours again.

Reaction solution is adjusted to neutrality (pH=7) with concentrated hydrochloric acid (about 65ml), and distillation is concentrated into driedly then, and cooling back adds the ethanol (95%) of 350ml, filter, remove solid insoluble, get 4-aminobutyric acid crude product after filtrate concentrates, can not purifiedly be directly used in next step reaction.

4. alpha-pyrrolidone (IV) is synthetic

In the reflux of water trap is housed, add 4-aminobutyric acid crude product and 250ml toluene, reflux is also constantly told the water that reaction generates, and then reacts when treating anhydrous steaming and finishes, and steams toluene (recyclable use repeatedly), decompression steams product again, get 12.2g, boiling point, 85 ℃/90Pa, calculate four step overall yields 48% of compound (IV) from pentanedioic acid.

5. alpha-pyrrolidone ethyl acetate (V) is synthetic

In the 250ml there-necked flask, add the 100ml exsiccant and newly steam toluene and 2.3g(0.1ml) sodium Metal 99.5, reflux and vigorous stirring make into the sodium powder.In bottle, add 8.5g(0.1mol after being chilled to room temperature) compound (VI) (with the dissolving of an amount of dry toluene), stir and slowly be warming up to about 75 ℃ reaction down 36 hours, till whole sodium Metal 99.5s have reacted.

With 13ml(0.1mol) the toluene solution of ethyl chloroacetate, slowly be added drop-wise in the above-mentioned reaction solution, about 75 ℃, stirred 5 hours, be chilled to room temperature then, filter, boil off the solvent in the filtrate earlier, decompression steams product again, gets 10.9g, colourless liquid (63.7%), boiling point, 83-90 ℃/40Pa.

6. alpha-pyrrolidone acetamide (VI) is synthetic

In flask at the bottom of the 100ml garden, adding 10.9g(0.63mol) compound (V) and 20ml ammoniacal liquor, at room temperature stirred 5 hours, be evaporated to dried then, get white solid, use the Virahol recrystallization, get white crystals shape target compound (VI) 5.5g(60.8%), fusing point, 149.0-150.0 ℃.

Claims (2)

1, a kind of method of synthetic alpha-pyrrolidone acetamide is characterized in that, described method is to make target compound (VI) by the reaction shown in the following formula, comprising:

(1). make diacetyl oxide or Acetyl Chloride 98Min. 50-70 ℃ and pentanedioic acid effect, producing Pyroglutaric acid (I) or directly using Pyroglutaric acid is the beginning raw material;

(2). make Pyroglutaric acid in 200-230 ℃ of down warm and ammoniacal liquor reaction of bath, generate glutarimide (II), this compound can be purified and is used for next step reaction;

(3). make glutarimide in 0-15 ℃, reaction is 30-60 minute in sodium hydroxide-aqueous sodium hypochlorite solution, then, be warming up to 50-70 ℃, continue reaction 1.5-3 hour, with hydrochloric acid neutralization reaction liquid, make pH equal 7, solution concentration to doing, is added 95% ethanol, make the solid dissolving, leach insolubles.Remove and desolvate, get product 4-aminobutyric acid (III), can purify is used for next step reaction;

(4). in the reflux of water trap is housed the 4-aminobutyric acid is dissolved in the toluene, reflux steams the water of generation, and during anhydrous steaming, stopped reaction boils off solvent, and decompression steams alpha-pyrrolidone (IV);

(5). in anhydrous toluene, add basic metal or its compound, wherein available comprising: lithium, sodium, potassium, lithium hydride, sodium hydride, potassium hydride KH, sodium amide, reflux, stirring make basic metal or its compound be powdery, after being chilled to room temperature, in wherein adding the alpha-pyrrolidone toluene solution.Under agitation, be warming up to 60-75 ℃ of reaction 30-40 hour, till having reacted to basic metal or its compound.Then, in the toluene solution that wherein slowly splashes into ethyl chloroacetate, again in 70-80 ℃ of stirring 3-6 hour, cooling is filtered, and steams solvent, and decompression steams product alpha-pyrrolidone ethyl acetate (V);

(6). with adding ammoniacal liquor in the compound (V), at room temperature stirred 4-6 hour, be evaporated to dried.Get the solid product alpha-pyrrolidone acetamide;

More than each the reaction raw material and the mol ratio of reagent be: 1: (1-3).

2, in accordance with the method for claim 1, it is characterized in that, in the described method:

A. directly make the beginning raw material and carry out the reaction of second step, need not to carry out the first step reaction with Pyroglutaric acid;

B. the basic metal in the reaction of the 5th step is selected sodium Metal 99.5 for use.