1 LEVETIRACETAM
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1 LEVETIRACETAM
DRUG SPOTLIGHT…LEVETIRACETAM
LEVETIRACETAM
(-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide
CAS 102767-28-2
Epilepsy is a chronic neurological disorder that consists of repeated occurrences of spontaneous seizures. Levetiracetam, [(S)-a-ethyl-2-oxopyrrolidine acetamide], has recently been approved as an add-on therapy for the treatment of refractory epilepsy . The (S)-enantiomer of etiracetam (levetiracetam) has shown remarkable pharmacokinetic and pharmacological activity which has led to the quick approval of this antiepileptic drug by the FDA. Levetiracetam offers several advantages over traditional therapy, including twice-daily dosing, a wide margin of safety with no requirements for serum drug concentration monitoring and no interactions with other anticonvulsants, and less adverse effects than traditional treatments
Levetiracetam (INN) /lɛvɨtɪˈræsɨtæm/ is an anticonvulsant medication used to treatepilepsy. It is the S-enantiomer of etiracetam, structurally similar to the prototypicalnootropic drug piracetam.
Levetiracetam is marketed under the trade name Keppra. Keppra is manufactured by UCB Pharmaceuticals Inc. Since November 2008 the drug has been available as a genericbrand in the United States.
Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures, or as an adjunctive therapy for partial, myoclonicand tonic-clonic seizures. It is also used in veterinary medicine for similar purposes.
Levetiracetam has potential benefits for other psychiatric and neurologic conditions such as Tourette syndrome, autism, bipolar disorder and anxiety disorder, as well asAlzheimer’s disease. However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.
Along with other anticonvulsants like gabapentin, it is also sometimes used to treatneuropathic pain. It has not been found to be useful for essential tremors.
Levetiracetam (LEV) is a novel antiepileptic drug (AED) which was discovered in early 1980s and soon, in 1999 FDA approved LEV for the management of partial onset seizure. In India, LEV tablet was approved in April 2005. It acts by binding to the synaptic vesicle protein SV2A, which is present on synaptic vesicles and some neuroendocrine cells. Pharmacokinetics of LEV such as, less protein binding and lack of hepatic metabolism makes LEV less susceptible to drug interactions with other anticonvulsants. Evidence also suggests that LEV is much better than other AEDs in the way of broad therapeutic window, convenient dosing and less adverse effect. Besides the pharmacological effects, pharmacoeconomically also, LEV is a beneficial drug. All these valuable pharmacological and pharmacoeconomic aspect makes LEV an important option in management of various types of epilepsy.
- PubMed Health A division of the National Library of Medicine at the National Institutes of Health.
- Keppra (levetiracetam) Final Printed Label April 2009. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Accessed 29 July 2011.
- Keppra UCB (manufacturer’s website)
- NIH MedLine drug information
KEPPRA injection is an antiepileptic drug available as a clear, colorless, sterile solution (100 mg/mL) for intravenous administration.
The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C8H14N2O2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula:
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Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble inchloroform (65.3g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.)
KEPPRA injection contains 100 mg of levetiracetam per mL. It is supplied in single-use 5 mL vials containing 500 mg levetiracetam, water for injection, 45 mg sodium chloride, and buffered at approximately pH 5.5 with glacial acetic acid and 8.2 mg sodium acetate trihydrate. KEPPRA injection must be diluted prior to intravenous infusion
(S)-(−)-α-ethyl-2-oxo-1-pyrrolidine acetamide, which is referred under the International Nonproprietary Name of Levetiracetam, its dextrorotatory enantiomer and related compounds. Levetiracetam is shown as having the following structure:
Levetiracetam, a laevorotary compound is disclosed as a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system in the European patent No. 162036. This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidine acetamide completely lacks activity (A. J. GOWER et al., Eur. J. Pharmacol., 222, (1992), 193-203). Finally, in the European patent application No. 0 645 139 this compound has been disclosed for its anxiolytic activity.
The asymmetric carbon atom carries a hydrogen atom (not shown) positioned above the plane of the paper. The preparation of Levetiracetam has been described in the European patent No. 0162 036 and in the British patent No. 2 225 322, both of which are assigned to the assignee of the present invention. The preparation of the dextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidine acetamide has been described in the European patent No. 0165 919.
- Levetiracetam was first disclosed in EP 162036 indicating particular therapeutic properties distinguishing it from the racemic form.
- Several processes for obtaining levetiracetam have been disclosed. One promising approach is the reaction of (S)-2-aminobutyramide (5) with an alkyl 4-halobutyrate or with a 4-halobutyryl halide followed by cyclization as outlined in EP 162036 . Clearly, said (S)-2-aminobutyramide (5) is a key intermediate in the preparation of levetiracetam and given the importance of the correct stereochemistry of levetiracetam also the correct stereochemistry in the key intermediates is of importance.
- The separation of stereoisomers is considered to be one of the difficult tasks in chemistry since chiral compounds exhibit identical physical properties in non-chiral environments. Although several approaches for the preparation of optically pure (S)-2-aminobutyramide (5) have been reported, many of these are related to resolution of racemic (R,S)-2-aminobutyramide (e.g. WO 2006/103696 ), optionally using catalytic amounts of an aldehyde such as described in JP 2007/191470 . However, an approach directly starting from the Schiff base of racemic (R,S)-2-aminobutyramide (i.e. compound (1)) is unavailable whereas there is a need for this as said Schiff bases are highly suitable from a preparative point of view as these compounds may be conveniently isolated from the aqueous media that they are usually prepared in. This is in contrast with the parent 2-aminobutyramide which is highly soluble in water and consequently difficult to obtain in sufficient purity.
British Pat. No. 1,309,692 describes the compound α-ethyl-2-oxo-l- pyrrolidineactamide (melting point 122 degrees C.) and states that compounds of this type can be used for therapeutic purposes, for example for the treatment of motion sickness, hyperkinesia, hypertonia and epilepsy.
- Several processes for obtaining levetiracetam have been disclosed in the art. Patent application EP 162,036-A1 discloses obtaining levetiracetam by reacting (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid with an alkyl haloformate and subsequently with ammonia, as summarized in the following scheme:
- The same document discloses obtaining levetiracetam by reacting (S)-2-aminobutanamide with an alkyl 4-halobutyrate or with a 4-halobutyryl halide, and subsequent cyclization of alkyl (S)-4-[[1-(aminocarbonyl)propyl]amino]butyrate or of (S)-N-[1-(aminocarbonyl)propyl]-4-halobutanamide thus obtained, as summarized in the attached scheme:
- The two previous processes have the drawback of operating at temperatures between -10°C and -60°C and the drawback of using intermediates for cyclization that are not readily obtained.
- Patent application GB 2,225,322-A1 discloses a process for obtaining levetiracetam by hydrogenolysis of (S)-α-[2-(methylthio)ethyl]-(2-oxo-1-pyrrolidine)acetamide by means of a desulfurizing reagent such as Raney nickel or NaBH4.NiCl2.6H2O, according to the following scheme:
- A drawback of this industrial-scale process is that it requires special equipment and special precautions for handling the products.
- Other processes are known (for example US patents No 6,107,492 and6,124,473 ) in which levetiracetam is obtained by means of optical resolution of racemic etiracetam of formula (I). InUS patent No 6,107,492 resolution is performed by means of preparative high performance liquid chromatography or by means of a continuous simulated fluid bed chromatographic system with a chiral stationary phase. US patent No 6,124,473 discloses a continuous simulated fluid bed chromatographic system consisting of at least three chiral stationary phase columns. These industrial-scale resolution processes are affected by drawbacks related to using chromatography.
- Patent applications WO 01/64,637-A1 and WO 02/26,705-A2 disclose processes for preparing levetiracetam by asymmetric hydrogenation of intermediates with a double bond, the hydrogenation of which gives the levetiracetam ethyl group, according to the following scheme:
- The industrial-scale difficulties and hazard of hydrogenation can be mentioned in relation to these processes.
- Finally, patent application ES 447,346 describes a process for the preparation of a pyrrolidone derivative, in particular the 2-oxo-1-pyrrolidinylacetamide, which comprises first reacting pyrrolidone with formaldehyde and a secondary amine, then reacting the compound obtained with an alkylating agent such as dimethyl sulfate, followed by treating the compound obtained with sodium or potassium cyanide, and finally reacting the compound obtained with hydrogen peroxide in basic medium.
Moreover, it also mentions that these compounds can be applied in the field of memory disorders in normal or pathological conditions.
It is also known that α-ethyl-2-oxo-l-pyrrolidineacetamide possesses a protective activity against aggressions of the central nervous system caused by hypoxias, cerebral ischemia, etc. (Pharmazie, 37/11, (1982), 753-765).
U.S. patent 4,969,943 discloses the levorotatory isomer of α-ethyl-2-oxo-l- pyrrolidineacetamide, which has the absolute S configuration, a method for making the isomer and pharmaceutical compositions containing the same. U.S. patent 4,696,943 discloses that the levorotatory isomer has a 10 times higher protective activity against hypoxia and a 4 times higher protective activity against ischemia compared to the known racemic form.
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Compound (I) can also be condensed with 4-chlorobutyryl chloride (IV) either directly in the presence of tetrabutylammonium bromide (TBAB) in dichloromethane, followed by in situ treatment with potassium hydroxide, or via the isolation of intermediate (S)-N-[1-(carbamol)propyl]-4-chlorobutyramide (V).
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An alternative procedure involves hydrolysis of racemic ethyl 2-(2-oxopyrrolidin-1-yl)burytate (VI) with sodium hydroxide to produce racemic 2-(2-oxopyrrolidin-1-yl)butyric acid (VII), which is resolved by fractional crystallization with (R)-(+)-alpha-methylbenzylamine in benzene, followed by acid-base treatment to give (S)-2-(2-oxopyrrolidin-1-yl)butyric acid (VIII). Compound (VIII) is finally treated with ethyl chloroformiate and ammonia in dichloromethane
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US Patent 8,338,621
J. Surtees and co-inventors disclose alternative processes for making active pharmaceutical ingredients (APIs) that are used to treat epilepsy and seizures. One compound that can be prepared by their processes is the established drug levetiracetam (1, Figure 1), marketed under the trade name Keppra. Because 1 is now off-patent, there is obvious interest in new drugs.
The inventors also claim that seletracetam (2) and brivaracetam (3) (Figure 2) can be prepared by their processes. These drugs are apparently much more active than 1.
All of the drugs are used as single isomers, so a stereoselective synthesis is desirable. The inventors describe two routes for preparing the molecules; the first, shown in Figure 1, is the synthesis of 1 by the reaction between pyrrolidone (4) and chiral bromo amide 5 in the presence of a base. GC analysis showed that the conversion is 40.3% and that the product contains 51% of the (S)-enantiomer and 49% of the (R)-isomer. No details of their separation are given, although the use of chiral HPLC is discussed.
The same reaction is used to prepare derivative 6 of 1. Compound 7 is prepared from the corresponding hydroxy ester and then condensed with 4 to give 6. Chiral HPLC showed that the product is a mixture of 89.3% (S)-enantiomer 6and 10.7% of its (R)-isomer.
The inventors do not describe the detailed preparation of 2, but they report that acid 8 is prepared in 41% yield from pyrrolidone 9 and acid 10 in the presence of NaH (Figure 2). Ammonolysis of 8 produces 2; no reaction details are provided.
In a reaction similar to the preparation of 8, acid 11 is prepared from 10 and pyrrolidone 12. The product is isolated in 77% yield and can be converted to 3by ammonolysis. Again, no details are provided for this reaction.
The second route for preparing the substituted pyrrolidones does not start with simple pyrrolidones and is the subject of additional claims. The route involves a cyclization reaction, shown in Figure 3. The preparation of enantiomer 13 begins with the reaction of racemic salt 14 and optically pure bromo ester 15. This step produces intermediate 16, isolated as a yellow oil. The crude material is treated with 2-hydroxypyridine (2-HP) to cyclize it to 17. This ester is hydrolyzed to give acid 18. Conversion to 13 is carried out by adding ClCO2Et, followed by reaction with liquid NH3 in the presence of K2CO3. The overall yield of 13 is 32%.
This route is also used to prepare levetiracetam (1) by treating 5 with the HCl salt of amino ester 19 to give 20, recovered as its HCl salt in 49% yield. The salt is basified with Et3N and treated with 2-HP to cyclize it to 1, initially isolated as an oil. GC analysis showed 100% conversion, and chiral HPLC showed that the product contains 98.6% (S)-isomer and 1.4% (R)-isomer.
The inventors also prepared 1 and its (R)-enantiomer 21 by using a similar reaction scheme with alternative substrates to 5. Figure 4 outlines the route, which starts from protected hydroxy amide 22 and amino ester 23. When the reaction is carried out in the presence of Cs2CO3, the product is (R)-enantiomer24, which is used without purification to prepare 21 by treating it with 2-HP. Chiral HPLC showed that the product is 94% (R) and 6% (S).
When the reaction between 22 and 23 is run with K2CO3, the product is (S)-enantiomer 25. This is used to prepare 1, but the product contains only 79% (S)-isomer.
The inventors do not comment on the apparent stereoselectivity of the carbonate salts in the reaction of 22 with 23. This is an intriguing finding and worthy of investigation. (UCB S.A. [Brussels]. US Patent 8,338,621,
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Journal of Chemistry Volume 2013 (2013), Article ID 176512, 5 pages http://dx.doi.org/10.1155/2013/176512
Research Article
Enantioselective Synthesis of Antiepileptic Agent, (−)-Levetiracetam, through Evans Asymmetric Strategy
1Department of Research and Development, Inogent Laboratories Private Limited, 28A, IDA Nacharam, Hyderabad 500 076, India
2Centre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India
3R&D Centre, Orchid Chemicals and Pharmaceuticals Ltd., 476/14, Sholinganallur, Chennai 600 119,
2Centre for Pharmaceutical Sciences, Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500 072, India
3R&D Centre, Orchid Chemicals and Pharmaceuticals Ltd., 476/14, Sholinganallur, Chennai 600 119,
A practical and efficient enantioselective synthesis of antiepileptic drug, (−)-Levetiracetam, has been described in five steps (33.0% overall yield) and high optical purity (99.0% ee), using Evans asymmetric strategy for -alkylation of carbonyl functionality as the key step. The simplicity of the experimental procedures and high stereochemical outcome make this method synthetically attractive for preparing the target compound on multigram scales.
white solid. Mp: 113–114°C.
S ROT= −95.0 [c = l.0, acetone].
1H NMR , 400 MHz):
δ 6.50 (br s, 1H),
5.70 (br s, 1H),
4.50 (t, J = 8.7, 6.8 Hz, 1H),
3.48 (m, 2H), 2.50 (m, 2H),
1.98–2.20 (m, 3H),
1.70 (m, 1H),
0.98 (t, J = 7.7 Hz, 3H) ppm; CH2-CH3
13C NMR , 75 MHz): δ175.9, 172.7, 55.9, 43.7, 31.0, 21.2, 18.0, 10.4 ppm;
IR : 3200, 1731, 1620 cm−1;
ESI-MS: m/z 171.0 [M++1].
Anal. calcd. for C8H14N2O2: C, 56.45; H, 8.29; N, 16.46; O, 18.80. Found: C, 56.76; H, 8.52; N, 16.87; O, 19.26.
Chiral HPLC purity 99% ee. The enantiomeric excess was determined by HPLC analysis in comparison with authentic racemic material and HPLC conditions: Chiral OD-H column; hexane: i-PrOH (90 : 10 v/v); flow rate 1.0 mL/min; UV −210 nm; column temperature 25°C; CHIRAL HPLC purity: = 14.4 min (S)-isomer (major enantiomer) and 9.3 min (R)-isomer (minor enantiomer).
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