CN106187809A

CN106187809A - A kind of synthesis technique of levetiracetam intermediate

Info

Publication number: CN106187809A
Application number: CN201610569141.4A
Authority: CN
Inventors: 刘艳琴; 郭威; 宋爱平
Original assignee: NANTONG YABEN CHEMICAL Co Ltd
Current assignee: NANTONG YABEN CHEMICAL Co Ltd
Priority date: 2016-07-20
Filing date: 2016-07-20
Publication date: 2016-12-07

Abstract

The present invention relates to the synthesis technique of a kind of levetiracetam intermediate L 2 amino amides hydrochlorate, with 2 chloro-butyric acids as initiation material, first prepare 2 neoprene acid amide intermediate, 2 neoprene acid amide intermediate generate DL 2 amino-butanamide by reaction again, finally by splitting into salt and realize the synthesis of L 2 amino amides hydrochlorate, synthetic route is as follows:

Description

A kind of synthesis technique of levetiracetam intermediate

Technical field

The invention belongs to pharmaceutical intermediate preparation field, particularly to the synthesis technique of a kind of levetiracetam intermediate.

Background technology

Epilepsy is a kind of chronic recurrent caused by Different types of etiopathogenises of short duration brain function dysregulation syndrome, due to this disease Sick prolonged and repeated outbreak has had a strong impact on quality of life and the social work ability of patient, causes the biggest to individual and society Harm.Levetiracetam, chemical name (s)-a-ethyl-2-oxo-1-pyrrolidine acetamide, is that the exploitation of UCB. S.A. (BE) Bruxelles Belgium of Belgium is ground A kind of new antiepileptic drugs of system, compared with similar drugs, levetiracetam has therapeutic index height, safety index height, can use In being used individually, do not interact with other antiepileptic, side effect is slight, better tolerance, pharmacokinetics are every The features such as index is excellent, are the antiepileptics uniquely with the special performance that prevention epilepsy occurs of report at present.

L-2-amino-butanamide is the important intermediate of synthesis antiepileptic levetiracetam, the most efficiently, economically Preparation L-2-amino-butanamide is to reduce levetiracetam cost, it is achieved the key of the preparation efficient, economic of levetiracetam is asked Topic.

In CN101130504A, it was recently reported that with 2-bromo-butyric acid as initiation material, prepare through ammonification, esterification, ammonolysis, fractionation Target product.2-bromo-butyric acid and ammonia react generation 2-amino-butyric acid, due to generation ammonium bromide and 2-amino-butyric acid in separation Difficulty, so needing refined, reaction yield is low, about 70% molar yield.Additionally in the reaction of ammonolysis, it is by 2-amino fourth Acid first generates 2-amino-butyric acid methyl ester, then reacts with ammonia and obtains DL 2-amino-butanamide, and reaction rate is slow, logical ammonia reaction 24 hours, sometimes lead to ammonia and produce pressure, higher to equipment requirements, process safety is had an impact.Therefore this route also exists Yield is low, the defect that process safety is poor.

For above-mentioned phenomenon, China Patent No. 201010558447.2 proposes in a kind of chiral drug levetiracetam The synthesis technique of mesosome L-2-amino amides hydrochlorate, with 2-bromo-butyric acid as initiation material, first prepares 2-bromine butyramide intermediate, 2-bromine butyramide intermediate generates mixed whirlpool 2-amino-butanamide by reaction again, realizes L-2-aminoacyl finally by splitting into salt The synthesis of amine hydrochlorate.Compared with existing synthesis technique, this synthesis technique reaction condition is gentle, reacts easily controllable, cost Low, yield is higher, but by-product is more, affects the purity of finished product.

Therefore, research and develop a kind of yield that can improve reaction, reduce byproduct of reaction and reduce the levetiracetam of cost The synthesis technique of intermediate L-2-amino amides hydrochlorate is necessary.

Summary of the invention

The technical problem to be solved in the present invention is to provide a kind of yield that can improve reaction, reduces byproduct of reaction and fall The synthesis technique of the levetiracetam intermediate of low cost.

For solving above-mentioned technical problem, the technical scheme is that the synthesis technique of a kind of levetiracetam intermediate, Its innovative point is: with 2-chloro-butyric acid as initiation material, first prepares 2-neoprene acid amide intermediate, and 2-neoprene acid amide intermediate leads to again Cross reaction and generate DL 2-amino-butanamide, finally by splitting into salt and realize the synthesis of L-2-amino amides hydrochlorate, synthesis Route is as follows:

Concretely comprise the following steps:

(1) there is amidation process in 2-chloro-butyric acid and ammonia under thionyl chloride effect, generates 2-chlorobutamide；

(2) 2-chlorobutamide and ammonia react generation DL 2-amino-butanamide；

(3) the DL 2-amino-butanamide method by Resolution, is combined into L-TARTARIC ACID and salts out, and reaches isolated and purified Purpose, remove resolving agent through alkalization and obtain optically active free alkali, and then become salt to obtain optically active L-2-aminoacyl Amine hydrochlorate.

Further, there is amidation process in the 2-chloro-butyric acid described in step (1) and ammonia under thionyl chloride effect, The ether solvent that reaction uses is methyl tertiary butyl ether(MTBE).

Further, the 2-chloro-butyric acid described in step (1), the quality mol ratio of thionyl chloride and ammonia be 1:1:2～ 3, reaction temperature is 0-5 DEG C, and the response time is 5-7 hour, and reaction pressure is normal pressure.

Further, the 2-chlorobutamide described in step (2) and ammonia reaction temperature are 20-40 DEG C, and the response time is 10-15 hour.

It is an advantage of the current invention that:

(1) synthesis technique of levetiracetam intermediate of the present invention, with 2-chloro-butyric acid as raw material, greatly reduces the one-tenth of main material This, and compared with existing synthesis technique, improve reaction yield, and by-product is less, and then improve the purity of finished product；This Outward, in the method, reaction condition is gentle, reacts easily controllable, and process safety is greatly improved, and equipment requirements is low, is adapted to industry Metaplasia is produced；

(2) synthesis technique of levetiracetam intermediate of the present invention, the ether solvent that reaction uses is methyl tertiary butyl ether(MTBE), with biography The ether that system uses is compared, and the injury to human body is greatly reduced, and then further ensure that the safety of technique.

Detailed description of the invention

The following examples can make professional and technical personnel that the present invention is more fully understood, but the most therefore by this Bright it is limited among described scope of embodiments.

(1) synthesis of 2-chlorobutamide

Embodiment one:

In the reaction bulb of 1000ml, adding 82.5g2-chloro-butyric acid, 165g mass concentration is ammonia and the 500ml methyl-tert of 30% Butyl ether, cools to 0 DEG C, slowly drips 82.5g thionyl chloride under stirring, drips off rear insulated and stirred and reacts 5 hours, reaction After completing, layering, organic layer is washed, is concentrated to dryness, obtains 2-chlorobutamide 72g.

Embodiment two:

In the reaction bulb of 1000ml, adding 82.5g2-chloro-butyric acid, 165g mass concentration is ammonia and the 500ml methyl-tert of 30% Butyl ether, cools to 0 DEG C, slowly drips 82.5g thionyl chloride under stirring, drips off rear insulated and stirred and reacts 7 hours, reaction After completing, layering, organic layer is washed, is concentrated to dryness, obtains 2-chlorobutamide 75g.

Embodiment three:

In the reaction bulb of 1000ml, adding 82.5g2-chloro-butyric acid, 247.5g mass concentration is ammonia and the 500ml methyl of 30% Tertbutyl ether, cools to 0 DEG C, slowly drips 82.5g thionyl chloride under stirring, drips off rear insulated and stirred reaction 5 hours, instead After should completing, layering, organic layer is washed, is concentrated to dryness, obtains 2-chlorobutamide 78g.

Table 1 below is to synthesize yield and the comparison or purity table of 2-chlorobutamide in embodiment 1-3.

Table 1 embodiment 1-3 synthesizes yield and the comparison or purity of 2-chlorobutamide

As can be seen from the above table, by this synthesis technique, the yield of 2-chlorobutamide can reach more than 85%, and purity carries the most significantly Gao Liao, up to more than 95%；Meanwhile, each embodiment is compared, and embodiment 3 is most preferred embodiment.

(2) synthesis of DL 2-amino-butanamide

Embodiment one:

In the reaction bulb of 1000ml, add 165g2-chlorobutamide, 500g mass concentration is the ammonia of 30%, cool to 40 DEG C, stirring reaction 15 hours, after reaction completely, it is evaporated to do, residual solids methanol refines, and obtains DL 2- Amino-butanamide 116g.

Embodiment two:

In the reaction bulb of 1000ml, add 165g2-chlorobutamide, 500g mass concentration is the ammonia of 30%, cool to 20 DEG C, stirring reaction 10 hours, after reaction completely, it is evaporated to do, residual solids methanol refines, and obtains DL 2- Amino-butanamide 119g.

Embodiment three:

In the reaction bulb of 1000ml, add 165g2-chlorobutamide, 500g mass concentration is the ammonia of 30%, cool to 30 DEG C, stirring reaction 12 hours, after reaction completely, it is evaporated to do, residual solids methanol refines, and obtains DL 2- Amino-butanamide 121g.

Table 2 below is to synthesize yield and the comparison or purity table of DL 2-amino-butanamide in embodiment 1-3.

Table 2 embodiment 1-3 synthesizes yield and the comparison or purity of DL 2-amino-butanamide

As can be seen from the above table, by this synthesis technique, the yield of DL 2-amino-butanamide can reach more than 70%, and purity is also Substantially increase, up to more than 99%；Meanwhile, each embodiment is compared, and embodiment 3 is most preferred embodiment.

(3) synthesis of L-2-amino amides hydrochlorate

In 1000ml reaction bulb, add the DL 2-amino-butanamide of 80g.450ml mass concentration is the ethanol of 95%, heating To 65 DEG C. adding 55gL-tartaric acid, stir 2 hours, filter, be the washing with alcohol of 95% by mass concentration, filter cake is L-2-ammonia Base butyramide L-TARTARIC ACID salt solid, is suspended in ethanol, is passed through chlorine the most saturated, is stirred at room temperature 7 hours, filters, subtracts Pressure is concentrated into about 200ml, the hydrogen chloride of dropping 30%, and regulation PH is 2, filters, washing with alcohol solid, and vacuum drying obtains L- 2-amino amides hydrochlorate 49g.

Table 3 below is yield and the comparison or purity table of the present invention and conventional synthesis L-2-amino amides hydrochlorate.

Table 3 present invention and the yield of conventional synthesis L-2-amino amides hydrochlorate and comparison or purity

As can be seen from the above table, compared with tradition, synthesis technique of the present invention, the yield of L-2-amino amides hydrochlorate is greatly improved , more than 60% can be reached, purity also substantially increases, and can reach 99.8%.

The ultimate principle of the present invention and principal character and advantages of the present invention have more than been shown and described.The skill of the industry The art personnel simply explanation it should be appreciated that the present invention is not restricted to the described embodiments, described in above-described embodiment and description The principle of the present invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, these Changes and improvements both fall within scope of the claimed invention.Claimed scope by appending claims and Its equivalent defines.

Claims

1. the synthesis technique of a levetiracetam intermediate, it is characterised in that: with 2-chloro-butyric acid as initiation material, first prepare 2- Neoprene acid amide intermediate, 2-neoprene acid amide intermediate generates DL 2-amino-butanamide by reaction again, finally by splitting into Salt realizes the synthesis of L-2-amino amides hydrochlorate, and synthetic route is as follows:

Concretely comprise the following steps:

(2) 2-chlorobutamide and ammonia react generation DL 2-amino-butanamide；

The synthesis technique of levetiracetam intermediate the most according to claim 1, it is characterised in that: described in step (1) 2-chloro-butyric acid and ammonia under thionyl chloride effect, there is amidation process, the ether solvent of reaction employing is methyl tertbutyl Ether.

The synthesis technique of levetiracetam intermediate the most according to claim 1, it is characterised in that: described in step (1) 2-chloro-butyric acid, the quality mol ratio of thionyl chloride and ammonia be 1:1:2～3, reaction temperature is 0-5 DEG C, and the response time is 5-7 Hour, reaction pressure is normal pressure.

The synthesis technique of levetiracetam intermediate the most according to claim 1, it is characterised in that: described in step (2) 2-chlorobutamide and ammonia reaction temperature be 20-40 DEG C, the response time is 10-15 hour.