EP 1517893 A2 (text from WO2004069796A2)
LEVETIRACETAM
(−)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide
A process for preparing (S)- α-ethyl-2-oxo-l -pyrrolidineacetamide which comprises cyclizing (S)-N-[l-(aminocarbonyl)propyl]- 4-chlorobutanamide, in a solvent selected from the group consisting of acetonitrile and methyl tertbutyl ether, in the presence of a strong base, and recovering the crude levetiracetam.
(2S)-2-(4-chlorobutanoylamino)butanamide
(S)-N-[l-(aminocarbonyl)propyl]- 4-chlorobutanamide
- CAS No.: 4635-59-0
- Formula: C4H6Cl2O
Scheme
A process for preparing (S)-α-ethyl-2-oxo-l -pyrrolidineacetamide (levetiracetam) comprising reacting (S)-2-amino-butanamide hydrochloride and 4-chlorobutryl chloride in a solvent selected from the group consisting of acetonitrile and methyl tertbutyl ether, in the presence of a strong base, and recovering the crude levetiracetam.
key intermediate
- CAS Number 7682-20-4
- Linear Formula CH3CH2CH(NH2)CONH2 · HCl
- Molecular Weight 138.60
(S)
2S)-2-Aminobutanoic acid hydrochloride
Example 1
PREPARATION OF CRUDE LEVETIRACETAM FROM L-ABA HCL IN
ACN
Anhydrous sodium sulfate 13.6 g (0.096 M) is added to dry acetonitrile (ACN) (96 ml) under vigorous stirring at 3-5 degrees C. and under a nitrogen blanket. (S)-2- amino-butanamide hydrochloride (L-ABA HC1) 11.08g (0.08 M) is added. The mixture is stirred at 3-5 degrees C. for 30 minutes. Powdered KOH 17.23 g (0.28 M) is added. 4-chlorobutyryl chloride 12.41g (0.088M) in 39 ml dry acetonitrile is added drop-wise over a period of about 30 minutes, while the temperature is kept under 5 degrees C. The reaction mixture is stirred while the temperature is kept under 5 degrees C for a further 5 hrs. The insoluble matter is filtered off and washed with acetonitrile (15 ml). The filtrate and washing are evaporated in vacuo at 35-40 degrees C. The residue is recrystallized from 50 ml ethyl-acetate to give 9.6 g (Yield=70 %) of product displaying 99 % purity (crude product) by capillary GC; 99.65% L-isomer and 0.35 % D-isomer (D-Levetiracetam) by dextrine based chiral capillary GC.
The amount of D-isomer was determined as follows: Column: Beta Dex325 capillary column 30m x 0.25mm+0.25micron thickness. Oven: 160 degrees C; Carry gas: nitrogen, flow lml min.; Detector FID, 230 degrees C; Injection: split. 150:1, 210 degrees C; Sample: 1 microliter of 0.05% levitiracetam solution in methanol; RT of D-isomer: 34.5 min, levitiracetam-33.4 min.
Example 2
PREPARATION OF CRUDE LEVETIRACETAM FROM L-ABA HCL IN ACN USING A DRYING AGENT
L-ABA HC1 69.25 g (0.5 M) and powdered KOH 101.25 g (1.8 M) are added to a vigorously stirred suspension of powdered molecular sieves in 625 ml acetonitrile under nitrogen. The temperature is kept at about 10 degrees C. A solution of 4- chlorobutyryl chloride 77.5 g (0.5M) in acetonitrile 250 ml is added drop-wise. The temperature is kept under 20 degrees C. After 2 hrs, 1.25 liters of acetonitrile are added and the mixture is stirred for 1 hour and then filtered. The solid is washed with acetonitrile (25ml). The combined filtrate and washes are evaporated in vacuo to yield a semi-solid oil 70 g, which upon crystallization from warm ethyl-acetate (150) ml leads to 60.5.5 g (72 %) of levetiracetam 98.2 % purity (crude product).
Example 3 PREPARATION OF CRUDE LEVETIRACETAM FROM L-ABA HCL IN ACN WITH NEUTRALIZATION Anhydrous sodium sulfate 99.6 g is added with stirring into acetonitrile 700 ml under a nitrogen blanket. The temperature is set and maintained at 3-5 degrees during the reaction.
L-ABA HC1 69.25 g (0.5 M), followed by 124 g ground KOH are then introduced into the above mixed suspension. 4-chlorobutyryl chloride 77.6 g (0.55 M.) is added at a rate sufficient to keep the temperature at 3-5 degrees C. The reaction mixture is kept for 5 hrs under these conditions. The mixture is then neutralized with care to about pH 6 using concentrated HC1 (32%). The mixture is filtered and washed twice with acetonitrile (total 400 ml). The filtrate and washes are combined and concentrated to a 500 ml solution which is filtered. Upon cooling, crude levetiracetam crystallizes displaying about 99 % purity (HPLC). Recrystallization from warm ethyl acetate leads to 72 g (84 %) of pure levetiracetam, displaying >99.5% isomeric purity by chiral capillary GC.
Example 4
PREPARATION OF CRUDE LEVETIRACETAM FROM L-ABA HC1 IN MTBE 6.92 g (0.05 M) L-ABA HCL and 10.12 g (0.18 M) ground KOH and 7.53 g
(0.053M) of NaS04 are mixed vigorously in 62 ml methyl tert butyl ether (MTBE). The temperature is kept at 5 degrees C. A solution of 7.75 g (0.05 M) of 4- chlorobutyryl chloride (CBC) is added drop-wise. After 3 hours, the mixture is allowed to return to room temperature during 1 hour. The reaction mix is filtered and the solid is washed with a total of 87 ml MTBE to give a crude solid 6.5 g containing levetiracetam having a purity of 76% as per HPLC.
Example 5 PREPARATION OF (S)-N-[l-(aminocarbonyl)propyl]-4-chlorobutanamide (CBA) FROM ABA BASE IN MTBE
5.1 g (0.05 M) of ABA base and 9.75 g (0.1 M) of 2-hydroxypyridine are mixed vigorously in 60 ml of MTBE at 0-5 degrees C. A solution of 8.45 g (0.06 M) of CBC in 25 ml MTBE is added drop-wise over 30 minutes. The reaction is nearly completed after 2 hours but was left overnight for 17 hours. The reaction mix is filtered and the solid washed with 15 ml acetonitrile. The combined extracts are evaporated to a crude solid residue of 13 g which contains CBA having a purity of 91 % as per HPLC. Example 6
PREPARATION OF LEVETIRACETAM FROM CBA IN THE PRESENCE OF KI IN MTBE
6.2 g (0.03 M) of CBA 2.5 g of ground KOH and 0.33 g (0.002 M) KI catalyst are stirred in MTBE vigorously at room temperature. After 4 hours, the mixture is filtered and the solid is washed twice with hot ethyl acetate. HPLC of the crude mixture indicates a purity of 95.9 % of levetiracetam.
Example 7 (Comparative Example) PREPARATION OF LEVETIRACETAM FROM CBA IN MTBE WITHOUT KI
6.2 g (0.03 M) of CBA 2.5 g of ground KOH are stirred vigorously at room temperature in MTBE. After 4 hours, the reaction mixture is filtered and the solid is washed twice with hot ethyl acetate. HPLC of the crude mix indicates 88.6 % levetiracetam.
Example 8
PURIFICATION OF LEVETIRACETAM FROM VARIOUS SOLVENTS
Experimental Procedure:
A 100 ml flask is charged with 3 g of levetiracetam. Solvent is added in portions under slight reflux until total dissolution. Solutions are left to cool to room temperature for 5 hours and stored at
4 degrees C. for a further 16 hours. The crystalline material is filtered on buchner. The material is dried at 40-45 degrees C. under 100mm vacuum.
Example 9
PURIFICATION OF LEVETIRACETAM FROM A MIXTURE OF TWO SOLVENTS
Experimental procedure: A 100 ml flask is charged with 3 g. levetiracetam and the selected solvent is added in portions at about 40 degrees C, under stirring. The co-solvent is then added in portions until the solution is turbid. The suspension is left to cool under stirring to room temperature for 5 hours and left at 4 degrees C. for a further 16 hours. The crystalline material is filtered on buchner. The material is dried at 40-45 degrees C. l der 100mm vacuum.
Example 10 PREPARATION OF LEVETIRACETAM FROM L-ABA HCL IN ACN USING A DRYING AGENT
27.7 g (0.2 M ) ABA HC1 is added to 80 g (0.56 M) powdered K2CO3 in 500 ml ACN and the mixture is stirred at room temperature for 30 minutes and then cooled to about 0 degrees Celcius. A solution of 4-chlorobutyryl chloride, 31 g (0.22 M ) in 100 ml of ACN is added to the mixture over a period of about 1 hour while the temperature is kept at between about 0-3 degrees Celcius. The reaction mixture is brought to room temperature and stirred for 2 hours. The temperature of the reaction mixture is raised to 30 degrees Celcius and 8.4 g (0.21 M) sodium hydroxide is added. After 90 minutes, another charge of 8.4 g sodium hydroxide is introduced and the mixture is stirred at 30 degrees Celcius for another 150 minutes. The suspension is filtered and the solid is washed with 0.25 liters of ACN. The filtrate and washes are combined and evaporated in vacuo to a solid which is crystallized from about 80 ml of hot ACN leading to a crude 26 g Levetiracetam (77 % purity). Recrystallization of the crude levetiracetam from 170 ml hot ethylacetate gives 23.5 g of the final product.
| Publication number | EP1517893 A2 |
| Publication type | Application |
| Application number | EP20040707805 |
| PCT number | PCT/US2004/003149 |
| Publication date | 30 Mar 2005 |
| Filing date | 3 Feb 2004 |
| Priority date | 3 Feb 2003 |
| Also published as | CA2515090A1, 6 More » |
| Inventors | Ben-Zion Dolitzky, Serguel Finogueev, Jean Hildesheim |
| Applicant | Teva Pharmaceutical Industries Limited |
| Export Citation | BiBTeX, EndNote, RefMan |
| Non-Patent Citations (1), Classifications (6), Legal Events (6) | |
| External Links: Espacenet, EP Register | |
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Levetiracetam is chemically known as (-)-(S)-α-ethyl-2-oxo-1 -pyrrolidine acetamide. It is represented by the Formula I:
Formula I
Levetiracetam is an antiepileptic drug useful for the treatment of epilepsy and is available in the market under the brand name "KEPPRA" in the form of tablet, oral solution and injection.
Gobert et. al. in U.S. Patent No. 4,943,639 disclose levetiracetam, its homologues and pharmaceutical composition thereof. The '639 patent also discloses a process for the preparation of levetiracetam, which is summarized in scheme 1 :
Scheme 1 : Process for preparing levetiracetam per USP 4,943,639
Acharyulu et al., in US 2005182262, describe a process for the preparation of levetiracetam, which is summarized in scheme 2:
Scheme 2: Process for preparing levetiracetam as per US 2005182262
Futagawa et al., in US 6,107,492, disclose a method of resolution of racemic mixture of alpha-ethyl-2-oxo-1-pyrrolidineacetamide through chromatography column packed with optical resolution packing material, that contains silica gel-supported amylose tris (3,5-dimethylphenyl carbamate).
WO 2006/095362 describes a process for the preparation of levetiracetam, which is summarized in scheme 3:
Scheme 3: Process for preparing levetiracetam per WO '362
WO 2006/053441 discloses a process for the preparation of levetiracetam by reacting (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with methane sulfonyl chloride and a stream of ammonia in the presence of triethyl amine.
WO 2006/127300 describes a process for the preparation of levetiracetam by reacting (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid with ditertiary butyl dicarbonate and ammonium bicarbonate in the presence of acetonitrile and pyridine.
Although various processes for preparation of levetiracetam are disclosed in the art, they may suffer from one or more drawbacks. Hence, there is a continuing need for a commercially viable process for preparing levetiracetam. SUMMARY
In one embodiment, there is provided a process for preparing levetiracetam:
and 4-chlorobutyrylchloride:
EXAMPLE-8: PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE (FORMULA I)..
LEVETIRACETAM
S-aminobutyramide hydrochloride (60 g) and dichloromethane (720 ml) were charged into a clean dry round bottom flask and stirred at a temperature of about -10°C for about 10 minutes. Tetra-butyl ammonium bromide (27.8 g) was added and stirred at -10°C for about 10 minutes. Potassium hydroxide (48.5 g) was added at about -10°C and stirred for about 15 minutes followed by addition of mixture of 4-chloro butyrlchloride (30.5 g) and dichloromethane (60 ml) was added slowly at a temperature of about -60C over a period of about 45 minutes. The resultant reaction mixture was stirred for about 45 minutes. Potassium hydroxide (48.5 g) was added at about -10°C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (18.4 g) and dichloromethane (60 ml) slowly over about 30 minutes and stirred for about 45 minutes. A lot of potassium hydroxide (24.2 g) was added at a temperature of about -1O0C and stirred for about 15 minutes followed by the addition of 4-chlorobutyrl chloride (18.4 g of) dissolved in dichloromethane (60 ml) over a period of about 30 minutes. The restιltantHr€aεtionHmxture^/vas stirred at a temperature of about -2°C for about 5 hours. Potassium hydroxide (12.1 g) was added followed by stirring for about 2 hours. pH of the reaction mixture was adjusted to about 7 to about 7.5 by addition of acetic acid (45 ml). The unwanted solid was filtered and the solid was washed with dichloromethane (120 ml). The organic layer was dried over anhydrous sodium sulphate (60 g). The obtained clear organic layer was distilled off completely at about 35°C under vacuum. Ethyl acetate (60 X 2 ml) was added to the residue and distilled completely under vacuum to remove the traces dichloromethane, yielding the title compound as a solid residue. To the obtained residue ethyl acetate (120 ml) was added at a temperature of about 250C to about 300C and stirred for about 30 minutes. The reaction mixture was cooled to a temperature of about O0C followed by stirring for about 30 minutes. The separated solid was filtered and the solid was washed with precooled ethyl acetate (24 ml). The obtained solid was dried at about 40°C under vacuum for about 3 hours to afford 70.5 g of pure title compound. Yield: 95.68% Purity by HPLC: 99.15%. Purity by chiral HPLC: 99.8%.
EXAMPLE-7: PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE AS PER US 4,943,639
Sodium sulfate (25 g) was added to a suspension of (S)-2-amino- butanamide hydrochloride (20 g) in dichloromethane (175 ml) at a temperature of about 25 to about 35°C. The reaction mixture was cooled to about O0C to about - 1O0C followed by the addition of potassium hydroxide (33.1 g) and tetra butylammonium bromide (2.3 g). A solution of 4-chlorobutyrylchloride (22.3 g) in dichloromethane (30 ml) was added to the reaction mixture over a period of 1 hour and stirred for about 2 hours. Potassium hydroxide (8.3 g) was added to the reaction mixture and stirred for about 5 hours 30 minutes. The reaction mixture was filtered and washed with dichloromethane (50 ml). The filtrate was concentrated completely followed by the addition of toluene and then distilled off the solvent completely. Ethylacetate (110 ml) was added to the reaction crude and heating given to a temperature of about 75 to about 800C and stirred for about 20 minutes. Filtered the suspension and washed the solid with ethylacetate (10 ml). The obtained filtrate was distilled completely followed by ethylacetate (80 ml) was added and then stirred for about 15 minutes. The reaction suspension was cooled to about 0°C to about 5°C and stirred for about 1 hour 45 minutes. Acetone (10 ml) was added to the reaction mixture and stirred for about 1 hour 40 minutes. The sususpension was filtered and dried the solid at a temperature of about 600C for about 3 hours 30 minutes to afford 8.5 g of title compound. Purity: 96.7% by HPLC; Yield: 34.61% 16.1% of (S)-2-amino-butanamide hydrochloride, 65% of 4-chlorobutyrylchloride and 7.2% of intermediate of Formula A were not converted to title compound.
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PATENT
PATENT
US 2005182262
(S)-2-aminobutyramide hydrochloride
The compound (S)-2-aminobutyramide hydrochloride is prepared by dissolving 50 grams of (S)-2-aminobutyric acid hydrochloride in 100 mL of methanol, and adding 28.7 mL of thionyl chloride while maintaining the reaction mixture temperature below about 55° C., then stirring until the reaction is complete. A vacuum is applied and maintained until the methanol has been distilled from the mixture. Isopropanol is then added, followed by the introduction of ammonia gas at a pressure about 60 psi (413 kPa) until the reaction is complete. After filtering to remove formed ammonium chloride, the solvent is partially evaporated and isopropanol hydrochloride is added. The mixture is stirred while solid product forms, then the solid is separated by filtration and washed with isopropanol.
The product was characterized by the following 1H NMR data (200 MHz, DMSO-d6): 0.9-1.0(t,3H), 1.8-1.9(Q,2H), 3.7-3.8(t, 1H), 7.5-7.7(Br,NH2), 8.0-8.2(Br,NH2)
The compound (−)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide is prepared by suspending 50 grams of (S)-2-aminobutyramide hydrochloride in 500 mL of dichloromethane at room temperature, then cooling to temperatures between −5 and 0° C. and adding 81.2 grams of potassium hydroxide and 23.3 grams of tetrabutylammonium bromide at those temperatures. A 66.4 gram amount of 4-chlorobutyryl chloride is added at the same temperatures. After completion of the reaction, solids are removed by filtration, the solution is adjusted to pH 7-7.5 with acetic acid, and dichloromethane is partially evaporated by the application of a vacuum. 150 mL of ethyl acetate are added to precipitate the product, which is isolated by filtration and washed with ethyl acetate and then with acetone; the product has a chiral purity of 99.8 percent by high performance liquid chromatography. The final product is purified by recrystallization from ethyl acetate, giving a yield of 60-65 percent.LEVETIRACETAM
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PATENT
ROUTE FROM D-(+)-2-amino butanol
http://www.google.im/patents/WO2006095362A1?cl=en
WO 2006/095362
describes a process for the preparation of levetiracetam, which is summarized in scheme 3:
Thus according to one aspect the present invention relates to a process for the preparation of (S)-(-)-α~ethyl-2-oxo-l-pyrrolidineacetamide of Formula (I), comprising the steps of :
i) condensation of (S)-2-amino butanol of Formula (IΙ)and 4-halobutryl chloride, where halo group can be chloro, bromo or iodo in solvents to form α-ethyl-2-oxo pyrrolidine ethanol of Formula (III)
................(H) ...........................................................................(III)
ii) oxidation of (S)-α-ethyl-2-oxo pyrrolidine ethanol to yield (S)-α-ethyl-2-oxo pyrrolidine acetic acid having the formula (IV)
(IV)
iii) esterification of (S)-α-ethyl-2-oxo pyrrolidine acetic acid (IV) with an alcohol to provide alkyl ester of Formula (V) wherein, R is 1-4 Carbon atom.
(V)
iv) ammonolysis of alkyl esters of formula (V) with ammonia to provide (S)-(-)- α-ethyl- 2-oxo-l -pyrrolidine acetamide of formula (I).
(I)
Acording to another aspect the invention relates to a process for the preparation of (S)-(-)- α~ethyl-2-oxo-l-pyrrolidineacetamide of Formula (I), comprising the steps of : i) condensation of (S)-2-amino butanol of Formula (IΙ)and 4-halobutryl chloride, where halo group can be chloro, bromo or iodo in solvents to form α-ethyl-2-oxo pyrrolidine ethanol of Formula (III)
...........(II)............................................................. (III)
ii) oxidation of (S)-α-ethyl-2-oxo pyrrolidine ethanol to yield (S)-α-ethyl-2-oxo pyrrolidine acetic acid having the formula (IV)
(IV)
iii) reacting (S)-α-ethyl-2-oxo pyrrolidine acetic acid (IV) with alkyl haloformate of formula HaICOOZ in which Hal represents halogen atom and Z an alkyl radical having 1 to 4 Carbon atoms to provide alkyl ester of Formula (V) wherein, R is 1-4 Carbon atom.
(V) iv) ammonolysis of alkyl esters of formula (V) with ammonia to provide (S)-(-)- α-ethyl- 2-oxo-l -pyrrolidine acetamide of formula (I).
(I)
The new process of this invention comprises a sequential series of steps that involve:
Condensation of (S)-2-amino butanol and 4-halobutryl chloride, where halo group can be chloro, bromo or iodo is carried out in the presence of an inorganic as well as tertiary organic base, in solvents, such as, benzene, toluene, xylene, trimethyl benzene, chlorinated solvents, eg, methylene chloride, chloroform, carbon tetrachloride, dichloroethane etc, Dimethyl formamide (DMF), Methyl t-butyl ether and Tetrahydrofuran, to make α-ethyl-2-oxo pyrrolidine ethanol of Formula (III). The temperature of the condentation is in the range of 0 to 400C and preferably 0 to 5°C.
(III)
The step of oxidation of (S)-α-ethyl-2-oxo pyrrolidine ethanol is carried out in the presence of an oxidising agent in acidic, basic and neutral medium, preferably a basic medium, to yield (S)-α-ethyl-2-oxo pyrrolidine acetic acid having the formula (IV) in good yields at -10 to 500C.
(IV)
The oxidizing agent is selected from i) potassium permanganate in water (pH 7.0), in alkaline medium, pH (7-14) and even in acidic medium, pH (4-6), ii) Sodium or potassium dichromate in acidic medium.
The esterification of (S)-α-ethyl-2-oxo pyrrolidine acetic acid (IV) is effected with an alcohol in acidic medium or in presence of cationic ion exchange resin to make alkyl ester of Formula (V). Alternatively, the compound of Formula (V) can be formed by reacting the alkyl ester of Formula (IV) with alkyl haloformate of formula HaICOOZ in which Hal represents halogen atom and Z an alkyl radical having 1 to 4 Carbon atoms. The alkyl haloformate is preferably, commercially readily available, ethyl chloroformate, benzyl chloro formate and the like.
(V)
The ammonolysis of alkyl esters of formula (V) with ammonia in solvents is carried out in accordance with the method described by K. FOLKERS et al in J.Med. Chem, 14, 484- 487 (1971) or under 3.5 to 4 kg of Ammmonia pressure in autoclave , yield (S)-(-)- α- ethyl-2-oxo-l -pyrrolidine acetamide of formula (I).
(I)
Example- 1
4-chlorobutyryl chloride
(S)-2- amino butanol/D-(+)-2-amino butanol
Preparation of (S)-α-ethyl-2-oxo pyrrolidine ethanol (III)
184 g of anhydrous Na2SO4 is added to a suspension of 100 g (1.123 mole) of (S)-2- amino butanol in 800ml of Toluene at ambient temperature. The mixture is cooled to 0 to 5°C. Then, 188 g of powder potassium hydroxide is added to the mixture followed by the addition of 173.4 g of 4-chlorobutyryl chloride in 100 ml of Toluene drop wise at 00C , with vigorous stirring . Ten hrs later, the reaction mixture is filtered over Hyflo-cel and the filtrate evaporated under reduced pressure . The crude product is purified by high vacuum distillation ( 137-14O0C at 2 mm pressure). Yield : 167.8 g ( 95%) [oc]25= -27.46 (C=I, acetone)
Example-2 Preparation of (S)-α-ethyl-2-oxo pyrrolidine acetic acid (IV)
A mixture of 225 g of (S)-α- ethyl -2-oxo pyrrolidine ethanol and a solution of 44.8 g of sodium carbonate in 4500 ml of water placed in a 10 litre round bottomed flask. Then 340 g of potassium permanganate is added to the reaction mixture with vigorous stirring, during 3-4 hours, cooling the mixture to 0°-5°C by immersing in a bath of ice water. Allow the reaction mixture to attain room temperature gradually. 15 hours later, filter off the precipitated manganese dioxide, concentrated the filtrate to about 1000 ml under reduced pressure and acidified with dilute sulphuric acid up to pH 2 followed by the saturation with NaCl. Cover the solution with a layer of dichloromethane. Separate the dichloromethane layer and extract the aqueous layer two to three times with 100 ml portions of dichloromethane and distilled off on rotavapor. Recrystallised the crude acid (209 g) from 210 ml of toluene; filter and wash with toluene . Yield : 130 gm (54 %) ; MP 1240C ; [oc]25= -24.32 (c=l, acetone)
Example-3
Preparation of (S)-α-ethyl-2-oxo pyrrolidine acetic acid methyl ester (V)
R- METHYL
A mixture of 34 g (S)-α-ethyl-2-oxo pyrrolidine acetic acid and 100 ml of methanol was taken in a 250 ml of round bottom flask fitted with reflux condenser and added 3.4 g ion exchange resin 225H^tO the reaction. Allowed to reflux for 12 hours. Filter the resin. The crude product in methanol was taken as such for ammonolysis.
Example-4 Preparation of (S)-(-)-α-ethyl-2-oxo-l-pyrrolidineacetamide (I) LEVETIRACETAM
(S)-α-ethyl-2-oxo pyrrolidine acetic acid methyl ester in MeOH from Example 3 is placed in autoclave under 4 kg of ammonia pressure at 25°C. The reaction mixture was allowed to stir for about 16 hours. The solvent was distilled off under reduced pressure. The crude (S)-(-)-α-ethyl-2-oxo-l-pyrrolidineacetamide 30 g was recrystallised from 240 ml Acetone to get 20.4 g pure product.
Yield : 20.4 (60%); MP : 117°C ; [oc]25= -91.75 (C=I, acetone)
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PATENT
ROUTE FROM D-(+)-2-amino butanol and with the dihydro-furan-2-one/γ-butyrolactone
ROUTE FROM D-(+)-2-amino butanol and with the dihydro-furan-2-one/γ-butyrolactone
Levetiracetam obtained by the process described herein is believed to have less than 0.1% of one or more of the following structural related impurities: 2- Amino butric acid, S-aminobutyramide hydrochloride, chloramide of Formula A and (-)-(S)-alpha-ethyl-2-oxo-1 -pyrrolidine acetic acid of Formula II.
Formula A
Also provided is a process for making levetiracetam by a) reacting the compound of the Formula III:
(III) with an oxidizing agent in the presence of a base and a phase transfer catalyst to provide the compound of the Formula II:
(II) b) reacting the compound of the Formula Il with a chlorinating agent to obtain an intermediate acid chloride of the formula (H-A):
(H-A)
c) reacting the compound of the formula (M-A) with a source of ammonia. The process for the preparation of levetiracetam of Formula I is summarized in the scheme 4.
Scheme-4: Process for preparing levetiracetam.
Also provided is a process for preparing the compound of Formula III by reacting D-(+)-2-amino butanol of the Formula Vl:
Formula Vl with the dihydro-furan-2-one of the Formula IV:
Formula IV to provide (S)-α-ethyl-2-oxopyrrolidine ethanol of the Formula III, which may be then converted to levetiracetam. The process for the preparation of the intermediate III is summarized in the scheme 5:
.....................................................(Vl) .....................(IV)............................................... (III)
Scheme-5: Process for preparing Formula III
EXAMPLE1 : PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1-PYRROLIDINE ACETAMIDE (FORMULA I) levetiracetam
S-aminobutyramide hydrochloride (25 g) and dichloromethane (300 ml) were^harged into a clean dry4 neck round bottom flask and stirred at about
S-aminobutyramide hydrochloride (25 g) and dichloromethane (300 ml) were^harged into a clean dry4 neck round bottom flask and stirred at about
100C for about 10 minutes. Tetra-n-butyl ammonium bromide (1 1.6 g) was added and stirred at a temperature of about -1O0C for about 10 minutes. Potassium hydroxide (20.2 g) was added at a temperature of about -100C and stirred for 15 minutes followed by addition of mixture of 4-chloro butyrlchloride (12.7 g) and dichloromethane (25 ml) was added slowly at a temperature of about -6°C over a period of about 45 minutes. The resultant reaction mixture was stirred for about 45 minutes. Potassium hydroxide (20.2 g) was added at a temperature of about - 1O0C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (7.6 g) and dichloromethane (25 ml) slowly over a period of about 30 minutes and stirred for about 45 minutes. A lot of potassium hydroxide (10.1 g) was added at a temperature of about -100C and stirred for about 15 minutes followed by addition of 4-chlorobutyrl chloride (7.6 g of) dissolved in dichloromethane (25 ml) slowly over about 30 minutes. The resultant reaction mixture was stirred at a temperature of about -2°C for about 5 hours. Potassium hydroxide (5.05 g) was added followed by stirring for about 2 hours. The separated unwanted solid was filtered and the solid was washed with dichloromethane (50 ml). pH of the filtrate was adjusted to about 7 by addition of acetic acid (0.8 ml). The organic layer was dried over anhydrous sodium sulphate. The obtained clear organic layer was distilled off completely at about 35°C under vacuum. Ethyl acetate (25 X 2 ml) was added to the residue and distilled completely under vacuum to remove the traces dichloromethane, yielding the title compound as a solid residue.
To the obtained residue ethyl acetate (10 ml) was added at a temperature of about 25°C to about 300C and cooled to about 0°C followed by stirring for about 30 minutes. The separated solid was filtered and the solid was washed with precooled ethyl acetate (10 ml). The obtained solid was dried at about 400C under vacuum for about 3 hours to afford 27 g of pure title compound. Purity by HPLC: 99.94%. Purity by chiral HPLC: 99.7%.
EXAMPLE 2: PREPARATION OF (S)-α-ETHYL-2-OXO-1-PYRROLIDINE
ETHANOL (FORMULA III)
D-2-amino butanol (50 g) and γ-butyrolactone (62 g) were charged into a clean and dry autoclave containing acetic acid (3.6 g). The reaction mixture was maintained under about 20 kg/cm2 to about 25 kg/cm2 nitrogen pressure at a temperature of about 2200C to about 23O0C for about 15 to about 20 hours. The resultant reaction mixture was cooled to a temperature of about 250C to about 35°C to afford the 109.2 g of title compound as a residue. Purity by HPLC: 91.79%
EXAMPLE 3: PREPARATION OF (S)-α-ETHYL-2-OXO PYRROLIDINE ACETIC ACID (FORMULA II)
Potassium hydroxide (10 g) was dissolved into water (180 ml) and cooled to a temperature of about 1 O0C. Tetra-n-butyl ammonium bromide (2 g) and (S)- α-ethyl-2-oxo pyrrolidine ethanol (10 g) in methylene chloride (18 ml) were charged followed by stirring for about 10 minutes. Potassium permanganate (15 g) was charged followed by stirring at a temperature of about 300C for about 8 hours. The resultant reaction mixture was filtered through a celite bed and the celite was washed with water (100 ml) followed by separation of organic and aqueous layers. The separated aqueous layer was charged into a clean and dry round bottom flask followed by cooling to about 0°C. pH of the reaction solution was adjusted to about 3 by the addition of hydrochloric acid (2 ml) followed by stirring for about 5 minutes. To the resultant reaction mixture sodium phosphate (25 g) was added followed by stirring for about 10 minutes. Toluene (150 ml) was added into the reaction solution and about 50% of the solvent was distilled off. The resultant reaction solution was extracted with dichloromethane (5*50 ml) followed by separation of organic and aqueous layers. The organic layer was dried over anhydrous sodium sulphate (10 g). Organic layer was distilled completely at a temperature of about 300C under vacuum to obtain the title compound as a residue.
To the residue toluene (10 ml) was added and stirred at 0°C for about 30 minutes. The separated solid was filtered and the solid was washed with toluene (5 ml). The obtained solid was dried at a temperature of about 600C under vacuum for about 1 hour to afford the pure 5 3 fj πf title compound.
Purity by HPLC: 97%.
EXAMPLE 4: PREPARATION OF (-)-(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ACETAMIDE (FORMULA I)LEVETIRACETAM
(-)-(S)-α-ethyl-2-oxo-1 -pyrrolidine acetic acid (5 g) of Formula Il and dichloromethane (50 ml) were charged into a clean and dry round bottom flask and stirred for about 20 minutes. The resultant reaction solution was cooled to about -25°C followed by dropwise addition of a mixture of thionyl chloride (4.5 ml) and dichloromethane (10 ml) slowly over a period of about 10 minutes. The resultant reaction mixture was stirred at a temperature of about -15°C for about 90 minutes. After completion of the reaction thionyl chloride was expelled by purging with nitrogen gas at about -100C for about 90 minutes. Dry ammonia gas was passed slowly into the mixture at about -100C for about 3 hours. The separated solid was filtered and the solid was washed with dichloromethane (50 ml). The resultant filtrate was distilled completely under vacuum to afford the title compound as a residue.
To the crude obtained, ethyl acetate (10 ml) was charged followed by stirring at a temperature of about 300C for about 15 minutes. The separated solid was filtered and the solid was dried at about 6O0C under vacuum for about 3 hours to afford 4 g of the title compound. Yield: 80.46% Purity by HPLC: 98.09%. Purity by chiral HPLC: 99.73%.
EXAMPLE-5: PREPARATION OF(S)-α-ETHYL-2-OXO-1 -PYRROLIDINE ETHANOL (FORMULA III)
D-2-amino butanol (0.515 g) and γ-butyrolactone (0.5 g) were charged into a clean and dry TFM liner vessel. The vessel was placed in microwave oven and irradiated radiation for 1 hour at a temperature of about 2000C to give -1-g-of title compound.
Purity: 81.69% by HPLC at 16.56 retention time (RT)
4-hydroxy-N-1-hydroxymethyl-propyl)butyramide intermediate: 8.81% at 6.122 Impurity: 5.71% at 14.32 RT
..............................................
PATENT
Step 1 - Synthesis of methyl (S)-aminobutyrate hydrochloride
.................................(23) .............................................................(24)
5.0g of (S)-amino butyric acid (23) was suspended in 50 ml of methanol and stirred at 0-5°C. 6.35g of thionyl chloride was added dropwise over 45 min to form a clear solution. After stirring for 20 hours at room temperature, the reaction was concentrated under reduced pressure to dryness and the almost colourless residue solidified to give the required product which was dried in an oven at 50°C under vacuum (7.6g; 102% crude yield). The same reaction was scaled-up from 200g of the amino acid and provided 296g (99.5% yield) of product (24). Analysis gave the following results: 1H NMR (DMSO-de) : d 0.94 (3H, t) 1.88 (2H, q) 3.75 (3H, s) 3,9 (1H, m) 8,8
(3H, m). m.p. : 107°C-110°C IR : 2876 cm 1, 1742 cm 1.
TLC : Si02, 20%MeOH/80%EtOAc/ l%NH OH, UV & IR. (TLC is an abbreviation for thin layer chromatography).
Step 4 - Ammonolysis of (S)-PBM to give Levetiracetam.
11.3g of ammonia gas was condensed in 13.2 ml of water at approximately 0°C and the temperature was maintained at 0-5°C. Then 20g of (S)-PBM (26) was added dropwise over a period of 10 min and reaction mixture was maintained at 5°C and stirred for minimum 8 hrs (reaction was complete as indicated by TLC). The reaction mixture was then evaporated to dryness under vacuum and dried by means of toluene (2x50 ml) to give minimum 17g (92%) of crude (S)-pyrrolidinobutyramide (crude Levetiracetam) as an off-white to beige solid. Analysis gave the following results (chiral and achiral HPLC): The extent of racemisation was 0.0%. The extent of hydrolysis was measured to 2.5%. Example 2
17.3g of ammonia gas were condensed in 22 ml of water at 0°C and temperature maintained at 0-5°C. Then 20g of (S)-PBE obtained via SMB separation of the corresponding racemic mixture were added dropwise over a period of 2 min and the reaction mixture was maintained at 5°C and stirred for 96 hrs (reaction was complete as judged by TLC). The reaction mixture was then evaporated to dryness under vacuum and dried by means of toluene (2x100 ml) to give minimum 14.8g (87%) of crude (S)-pyrrolidinobutyramide as a brown orange solid. Analysis gave the following results (chiral and achiral HPLC): The extent of racemisation was 1.6% with 6.6% hydrolysis.
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P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE
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