CN101928229A - Process method for producing L-2-aminobutanamide hydrochloride serving as intermediate of levetiracetam - Google Patents

Abstract

The invention discloses a process method for producing L-2-aminobutanamide hydrochloride serving as an intermediate of levetiracetam, which solves the problem that the conventional produced product has excessively high impurity content or production cost is too high for an enterprise to bear and the like. The method is characterized by comprising the following steps of: reacting propionaldehyde with ammonia water, ammonium chloride and sodium cyanide to obtain 2-amino butyronitrile; hydrolyzing the 2-amino butyronitrile under an alkali condition to obtain 2-aminobutanamide; and splitting the 2-aminobutanamide with L-tartaric acid to obtain the L-2-aminobutanamide hydrochloride. An L-2-amino amides product of which the content is over 99.5 percent is obtained by removing a byproduct, namely, sodium chloride by recrystallization so as to meet the use requirement of foreign customers. The process has the advantages of high yield, high safety and low cost and can be widely suitable for industrialized production of medium-sized and small enterprises.

Description

Produce the processing method of the intermediate L-2-amino-butanamide hydrochloride of Levetiracetam

One, technical field

The invention belongs to medicine and chemical field, relate to a kind of making method of pharmaceutical intermediate, relate in particular to a kind of processing method of intermediate L-2-amino-butanamide hydrochloride of chemical antiepileptic drug Levetiracetam.

Two, background technology

The L-2-amino-butanamide hydrochloride is antiepileptic drug Levetiracetam (Levet iracetam is an a kind of pyrrolidinone derivatives) important intermediate, and Levetiracetam is the research and development of Belgian UCB company, obtains the FDA approval in April, 2000, goes on the market in the U.S..It is present unique medicine that is used for the treatment of limitation and secondary generalized epilepsy.The characteristics of this product are: 1. therapeutic index height; 2. be the broad-spectrum curing medicine; 3. use with other antiepileptic drug compatibility, do not interact; 4. have and anti-cause epilepsy and two kinds of performances of anti-epileptic, can prevent the generation (not having a kind of generation that can prevent epilepsy in the present commercially available antiepileptic drug) of epilepsy; 5. the safety index height is the highest antiepileptic drug of safety coefficient; 6. the every index of pharmacokinetics is good.Sales volume in 2009 is stood out, and the amplitude of selling with 20% increases at present, and market outlook are good.

The Levetiracetam molecular structure is as follows:

(S)-alpha-ethyl-2-oxygenate-1-ethanamide tetramethyleneimine

The synthetic method of Levetiracetam mainly contains two kinds:

1. XianCheng's cyclization becomes route: be starting raw material with the 2-Pyrrolidone; through salify and replace racemic intermediate (±)-α-ethyl-(2-oxygen-1-pyrrolidyl) acetate (1); be resolving agent with the R-α-Ben Yian again; get intermediate (S)-n-ethyl-(2-oxygen-1-pyrrolidyl) acetate (3); 3 with corresponding ammonia, amine or alcohol acylation reaction take place respectively, obtain Levetiracetam and 9 derivatives thereof.

2. the back becomes cyclization to become route: be reacted into ring by 4-chlorobutanoylchloride and L-2-amino-butanamide and obtain Levetiracetam.Its reactive chemistry equation is as follows:

Synthesize earlier the method that afterwards splits because method 1 adopts, industrial being difficult to realizes producing, and its cost is also higher; And there are several derivatives in the reaction product, extract and separates and have difficulty greatly.Producing at present the production route of basic employing method 2, is the first-selected technology of the synthetic Levetiracetam of raw material with the L-2-amino-butanamide in method 2.

Bibliographical information about the synthetic route of L-2-amino-butanamide mainly contains:

1. aminobutyric acid amidation

The 2-aminobutyric acid is obtained the L-2-aminobutyric acid with the fractionation of L-tartrate, L-2-aminobutyric acid acidylate is got the amino Butyrylation compound of L-2-again, the back obtains the L-2-amino-butanamide under the ammoniacal liquor condition.

1.1. the butyric acid bromination gets the 2-aminobutyric acid

This route is raw material with the butyric acid, and replacing α with bromine is last hydrogen, adds ammoniacal liquor replace bromine atom then, and obtains target product.Generate by product HBr gas in this reaction.And the use bromine, the Workshop Production environment is poor.Because butyric acid has 3 hydrogen atoms at α, Br can replace 2 even 3 hydrogen atoms simultaneously on the α position in addition, causes final product to be difficult to separate, and the purity of product does not reach client's service requirements.

1.2. be that raw material methylates through desulfuration and directly generates the 2-aminobutyric acid with the methionine(Met).

This operational path is simple, but owing to its production cost can not be accepted.

1.3. extra large mattress method Synthetic 2-aminobutyric acid

With positive propionic aldehyde is raw material and bicarbonate of ammonia and sodium cyanide reaction generation Hai Yin, and hydrolysis under the pressurization alkaline condition obtains 2-aminobutyric acid sodium, regulates pH with hydrochloric acid and promptly obtains the 2-aminobutyric acid to point of equivalent.

During this method glycolylurea hydrolysis, temperature and pressure is higher, has potential safety hazard, and emits a large amount of ammonias, and the desalination cost is higher simultaneously.

Three, summary of the invention

Purpose of the present invention is exactly problem and the defective that exists at prior art, provides a kind of method of utilizing chemosynthesis to produce the processing method of the intermediate L-2-amino-butanamide of the production Levetiracetam that quality meets the requirements of the customers.

Technical scheme of the present invention is: mainly may further comprise the steps:

A, with positive propionic aldehyde be raw material and ammoniacal liquor, ammonium chloride, sodium cyanide react the 2-aminobutyronitrile; The temperature of its generation is 50～80 ℃, and the reaction times is 10～14 hours, and the feed ratio of each raw material is positive propionic aldehyde: sodium cyanide: ammonium chloride=1: 1～1.5: 1.5～2.Its reaction equation is as follows:

The sodium hydroxide alkaline solution of B, adding 10% obtains the 2-amino-butanamide to the 2-aminobutyronitrile hydrolysis that generates under the low pressure alkaline condition; The temperature of hydrolysis is controlled at 60～100 ℃, and the caustic lye of soda consumption is the positive propionic aldehyde of 1～1.5g/g, and the reaction times of Fen Xieing is 14～18 hours fully.Its reaction equation is as follows:

C, split with L-tartrate and to obtain the L-2-amino amides, recrystallization is removed and promptly get content behind the by product sodium-chlor above 99.5% L-2-amino amides product.Its chemical reaction mode is as follows:

D, obtain product L-2-amino-butanamide hydrochloride with hcl acidifying.

It is the synthetic route of raw material that positively effect of the present invention is to adopt positive propionic aldehyde, and compares with aminobutyric acid technology that to have a foreign matter content low, optics and chemical purity height, and finished product purity is high to surpass 99.5%, and optical purity also reaches more than 99.5%; Molar yield reaches 45%, and resolution yield is more than 95%, and raw materials cost is low, only is the 60%-70% of the existing bromo technology of using; This technology is easy to control production environment simultaneously, avoids the meeting of bromine to send out and generate bromize hydrogen gas, improves the work situation in workshop; Synthetic route is simple, and synthesis cycle is short, reaction temperature and, equipment requirements, be fit to and medium-sized and small enterprises production

Four, description of drawings

Fig. 1 is a technological process block-diagram of the present invention.

Five, embodiment

With L-2-amino-butanamide hydrochloride lab scale methodology is example:

The first step: with positive propionic aldehyde be raw material and ammoniacal liquor, ammonium chloride, sodium cyanide react the 2-aminobutyronitrile.

1, ratio of components is:

Name of an article consumption (g) specification remarks

Sodium cyanide 610 30%

Ammoniacal liquor 530 25%

Ammonium chloride 280 industry

Propionic aldehyde 160 industry

Ethyl acetate 600 industry are recyclable

2, concrete operations are as follows:

In the 2000ml there-necked flask, add 30% sodium cyanide 610g, suction 25% ammoniacal liquor 530g again, stir the back and add 280g ammonium chloride, stirring and dissolving, cool off with water-bath, normal temperature drips the positive propionic aldehyde of 160g down, drips off in about 1 hour, and 6 lab scales are stirred in 50 ℃ in the back, the vapor detection propionic aldehyde disappears substantially, back 200*200*200g ethyl acetate extraction 3 times, three times extraction liquid concentrates at the 1000ml there-necked flask, and the beginning air distillation arrives 82 ℃ to interior temperature and slips out thing after a little while, close heating, reduced vacuum is pulled to sees that seldom solvent comes out, and the vapor detection solvent is less than 5%, and product is 200g.

Second step: the sodium hydroxide alkaline solution of adding 10% obtains the 2-amino-butanamide to the 2-aminobutyronitrile hydrolysis that generates under the low pressure alkaline condition.

1, ratio of components is:

Name of material consumption g specification remarks

200 self-controls of 2-aminobutyronitrile

The aqueous solution of caustic lye of soda 200 10%

Methyl alcohol 200

2, concrete operations step is as follows:

In the 1000ml there-necked flask, add the 200g2-aminobutyronitrile, hydro-oxidation sodium liquid 200g, being heated to 50 ℃ stirred 2 hours, after vapor detection 2-aminobutyronitrile is less than 3%, 80 ℃ of following vacuum are greater than 0.096Mpa, and approximately decompression was steamed 8-9 hour, hasten to weigh behind the evaporate to dryness water 2-amino-butanamide: 200g, add the dilution of 200g methyl alcohol, pour into then in the 2000ml there-necked flask.

The 3rd step: obtain the L-2-amino amides with the fractionation of L-tartrate.

At first be the synthetic of S (+)-2-amino-butanamide * L-tartrate

1, ratio of components is:

Name of material consumption g specification remarks

2-amino-butanamide 200 50% methanol solutions

Methyl alcohol 1000 industry

80 industry of L-tartrate

2, concrete operations are as follows:

Add the methyl alcohol into 1000g in the methanol solution of suction material 2-amino-butanamide in above-mentioned 2000ml there-necked flask, stir, add L-tartrate 73g, reflux 5 hours is cooled to 20 ℃ then, and suction filtration obtains product: 150g, optical purity: 99.7%.

Be the synthetic of S (+)-2-amino-butanamide then

1, ratio of components

Name of material consumption g specification remarks

S (+)-2-amino-butanamide * L-tartrate 150 self-controls

Ethanol 400

Sodium ethylate 5

2, concrete operations are as follows:

In the there-necked flask of 1000ml, add S (+)-2-amino-butanamide * L-tartrate 140g, ethanol 400g, stirring at room adds the 5g sodium ethylate, refluxed then 1 hour, reduce to room temperature, stirred 2 hours, filter, filtrate elder generation normal pressure steams back evaporated under reduced pressure solvent, obtains S (+)-2-amino-butanamide 80g of chirality.

Be the synthetic of S (+)-2-amino-butanamide hydrochloride at last.

1, ratio of components is:

Name of material consumption g specification remarks

S (+)-2-amino-butanamide 80 self-controls

Concentrated hydrochloric acid 120 contains hydrogenchloride more than 30%

Gac 5

Ethyl acetate 400

2, concrete operations are as follows:

In the 1000ml there-necked flask, add S (+)-2-amino-butanamide, add the 400g ethyl acetate, heating, allow solid dissolve, add the hydrochloric acid soln of 120g30% then, stirring and refluxing 1 hour, filter, filtrate is cooled to below 0 ℃ and stirred 2 hours, filters, and 80 ℃ of following vacuum-drying filter cakes obtain the finished product 98g.

Claims (3)

1. processing method of producing the intermediate L-2-amino-butanamide hydrochloride of Levetiracetam, this method may further comprise the steps:

A, with positive propionic aldehyde be raw material and ammoniacal liquor, ammonium chloride, sodium cyanide react the 2-aminobutyronitrile;

The sodium hydroxide alkaline solution of B, adding 10% obtains the 2-amino-butanamide to the 2-aminobutyronitrile hydrolysis that generates under the normal pressure alkaline condition;

C, split with L-tartrate and to obtain the L-2-amino amides, recrystallization is removed and promptly get content behind the by product sodium-chlor above 99.5% L-2-amino amides product.

D, obtain product L-2-amino-butanamide hydrochloride with hcl acidifying.

2. the processing method of the intermediate L-2-amino-butanamide hydrochloride of production Levetiracetam according to claim 1, it is characterized in that: it is 10～14 hours with the reaction times that the temperature that steps A 2-aminobutyronitrile generates is 50～80 ℃, and the feed ratio of each raw material is positive propionic aldehyde: sodium cyanide: ammonium chloride=1: 1～1.5: 1.5～2.

3. the processing method of the intermediate L-2-amino-butanamide of production Levetiracetam according to claim 1 and 2, it is characterized in that: the temperature of step B hydrolysis is controlled at 60～100 ℃, the caustic lye of soda consumption is the positive propionic aldehyde of 1～1.5g/g, and the reaction times of Fen Xieing is 14～18 hours fully.

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