CN101838211B - Processing method for producing intermediate 2-aminobutyric acid of levetiracetam - Google Patents

Abstract

The invention provides a processing method for producing an intermediate 2-aminobutyric acid of levetiracetam, which solves the problems that the existing products have excessive impurity content or enterprises can not bear production cost, etc. The processing method is characterized by taking n-propanal as a raw material to react with ammonium bicarbonate and sodium cyanide to product heroin; hydrolyzing under a low-pressure alkaline condition to obtain 2-amino-sodium butylate; adjusting pH into an equivalent point with hydrochloric acid to obtain the 2-aminobutyric acid; and recrystallizing to remove a by-product-sodium chloride, and the content of the product exceeds 99%, thus meeting the use requirements of foreign customers, wherein the cost of production materials is a half of the costs of the additional two lines. The processing method can be widely applicable to industrial production of medium and small-sized enterprises.

Description

Produce the processing method of the intermediate 2-amino butyric acid 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 2-amino butyric acid of chemical antiepileptic drug Levetiracetam.

Two, background technology

DL-aminobutyric acid is antiepileptic drug Levetiracetam (Levetiracetam is a kind of pyrrolidinone derivatives) important intermediate, and Levetiracetam is the research and development of Belgian UCB. S.A. (BE) Bruxelles Belgium, obtains FDA approval in April, 2000, goes on the market in the U.S..It is current unique medicine that is used for the treatment of limitation and secondary generalized epilepsy.The feature of this product is: 1. therapeutic index is high; 2. be 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 (there is no a kind of generation that can prevent epilepsy in current commercially available antiepileptic drug) of epilepsy; 5. safety index is high, is the antiepileptic drug that safety coefficient is the highest; 6. the every index of pharmacokinetics is good.The sales volume of 2007 is stood out, and sells and increases with 20% amplitude at present, and market outlook are good.

The synthetic method of Levetiracetam mainly contains two kinds:

1. XianCheng's ring synthetic route: taking 2-Pyrrolidone as starting raw material; through salify with replace to obtain racemic intermediate (±)-α-ethyl-(2-oxygen-1-pyrrolidyl) acetic acid (1); again taking R-α-phenylethylamine as resolving agent; obtain intermediate (S)-n-ethyl-(2-oxygen-1-pyrrolidyl) acetic acid (3); 3 respectively with corresponding ammonia, amine or alcohol generation acylation reaction, obtain Levetiracetam and 9 derivatives thereof.

2. rear one-tenth ring synthetic route: be reacted into ring by 4-chlorobutanoylchloride and L-2-amino-butanamide and obtain Levetiracetam.Its reactive chemistry equation is as follows:

First synthesize because method 1 adopts the method splitting afterwards, industrial being difficult to realized production, and its cost is also higher; And in reaction product, there are several derivatives, extract with separating and have larger difficulty.Produce at present the production line of basic employing method 2, in method 2, taking L-2-amino-butanamide as raw material, and C4H9NO2 is the first-selected technique of synthetic L-2-amino-butanamide.Its retrosynthesis route is as follows:

Can find out that by above reaction 2-amino-butyric acid is that the important intermediate of Levetiracetam has been subject to paying close attention to widely.

The bibliographical information of the current synthetic route about 2-amino-butyric acid mainly contains:

1, butyric acid bromination route is produced 2-amino-butyric acid

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

2, methylate and directly generate aminobutyric acid through desulfuration taking methionine(Met) as raw material.

Although this operational path route is simple, can not be accepted by manufacturing enterprise because its production cost is very expensive.

Three, summary of the invention

Object of the present invention is exactly problem and the defect existing for prior art, provides a kind of method of utilizing chemosynthesis to produce the processing method of the intermediate 2-amino butyric acid of the production Levetiracetam that quality meets the requirements of the customers.

Technical scheme of the present invention is: mainly comprise the following steps:

A, react with bicarbonate of ammonia and sodium cyanide taking positive propionic aldehyde as raw material generate Hai Yin; Sea mattress building-up reactions optimum charging ratio is, positive propionic aldehyde: sodium cyanide: bicarbonate of ammonia=1: 1～1.5: 1.2～1.8, and the optimum temps of its generation is 40～50 DEG C, the reaction times transforming is completely 22～28 hours.

B, add 30% alkaline solution, under low pressure alkaline condition, the Hai Yin generating is hydrolyzed, obtain 2-amino-butyric acid sodium; The temperature of hydrolysis is controlled between 100～130 DEG C, and sodium hydroxide concentration is the positive propionic aldehyde of 0.8～1.2g/g, and the reaction times of decomposing is completely 14～18 hours.

C, become aminobutyric acid hydrochloride with hydrochloric acid regulating rotary, with dissolve with ethanol, remove by filter sodium-chlor.

After D, decolouring, add acid binding agent, adjust between pH to 5.8～7.2 and obtain 2-amino-butyric acid.

E, remove and obtain content after a small amount of by product sodium-chlor and exceed 99% 2-amino-butyric acid product with mixed solvent recrystallization.

Below in conjunction with accompanying drawing, the invention will be further described.

Four, brief description of the drawings

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

Five, embodiment

In 250ml there-necked flask, add bicarbonate of ammonia 125g, add 30% sodium cyanide solution 174g, add 340g, stir 30 minutes, drip propionic aldehyde 60g, temperature is controlled at 50 DEG C, adds rear airtightly, is warmed up to 45 DEG C, react 4 hours, be more slowly warmed up to 80 DEG C, be incubated 4 hours, cool to 50 DEG C, add alkali lye, open exhaust-valve, be warmed up to 95 DEG C, ammonia excretion 4 hours, closes exhaust-valve, slowly be warmed up to 150 DEG C, be incubated 4 hours, cool to below 30 DEG C.

2. slowly drip the about 600g of hydrochloric acid, after adding, concentrating under reduced pressure, after doing, uses respectively 20g ethanol band water 2 times, adds 600g ethanol, refluxes 1 hour, cools to 35 DEG C, centrifugal, and by washing with alcohol, mother liquor is extracted in decolouring still.

3. after mother liquor exhausts, add gac, reflux decolour 1 hour.

4. at normal temperatures, open stirring, drip acid binding agent 90g, between adjust pH to 6.5～～7.0, after mixing up, cool to 10 DEG C of left and right, centrifugal, a small amount of cold ethanol drip washing for filter cake, dries.Mother liquor is collected, and reclaims ethanol.

Solids in mixed solvent after recrystallization 100 DEG C following dry.

Claims (2)

1. a processing method of producing the intermediate 2-amino butyric acid of Levetiracetam, the method comprises the following steps:

A, react with bicarbonate of ammonia and sodium cyanide taking positive propionic aldehyde as raw material generate intermediate product, the best molar ratio of described building-up reactions is, positive propionic aldehyde: sodium cyanide: bicarbonate of ammonia=1:1 ~ 1.5:1.2 ~ 1.8, the optimum temps of its generation is 10 ~ 60 DEG C, the reaction times transforming is completely 10 ~ 28 hours;

B, to add mass percentage concentration be 30% alkaline solution, under low pressure alkaline condition, the intermediate product generating is hydrolyzed, obtain 2-amino-butyric acid sodium, the temperature of hydrolysis is controlled between 100 ~ 130 DEG C, sodium hydroxide concentration is the positive propionic aldehyde of 0.8 ~ 1.2g/g, and the reaction times of decomposing is completely 14 ~ 18 hours;

C, obtain 2-amino-butyric acid to point of equivalent with salt acid for adjusting pH, recrystallization is removed and is obtained mass content after by product sodium-chlor and exceed 99% 2-amino-butyric acid product.

2. the processing method of the intermediate 2-amino butyric acid of production Levetiracetam according to claim 1, is characterized in that: step C forms semicarbazide hydrochloride with salt acid for adjusting pH, separates with sodium-chlor, adds acid binding agent to be again converted into 2-amino-butyric acid.