MXPA06003024A - Process for preparing 2-oxo-1-pyrrolidine derivatives - Google Patents

Abstract

The present invention relates to a new process for preparing 2-oxo- I -pyrrolidine derivatives of general formula (I) wherein the substituents are as defined in the specification.

Description

PROCESS FOR PREPARING 2-OXO-1-PYROLYLIDINE DERIVATIVES DESCRIPTION OF THE INVENTION The invention relates to a process for preparing 2-oxo-l-pyrrolidine derivatives. (S) - (-) -a-ethyl-2-oxo-l-pyrrolidin acetamide, which is referred to under the International Non-Proprietary Name of Levetiracetam, Levetiracetam is described as a protective agent for the treatment and prevention of hypoxic and ischemic aggressions of the central nervous system in European Patent No. 0 162 036.

This compound is also effective in the treatment of epilepsy. The preparation of Levetiracetam has been described in European Patent No. 0 162 036 and in British Patent No. 2 225 322. Other 2-oxo-pyrrolidine derivatives and their synthesis have been described in WO 01/62726. This patent application specifically describes the synthesis of (2S) -2- (2-oxo-4-n-propyl-1-pyrrolidinyl) butanamide using a two-step reaction, wherein, in the first step, the 4-n -propyl- Ref. 170771 Hydroxyfuranone is reacted with S-2-aminobutyramide in the presence of NaBH 4 to form and isolate the corresponding unsaturated pyrrolidone, followed by a second reaction step, wherein the unsaturated pyrrolidone is hydrogenated with NH 4 COOH in the presence of a catalyst of Pd / C. The present invention relates to a more economical and simple process for the preparation of 2-oxo-1-pyrrolidine derivatives. The invention provides a process for the preparation of 2-oxo-l-pyrrolidine derivatives of the general formula (I), and salts thereof, wherein: R1 is Ra or Rb; R3 or R4 are the same or different and each is independently hydrogen, hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, Ra, Rb, alkylsulfonyl, aryisulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, acyl, ester, amido, acyloxy, steroxy or idooxi; X is -CONR5R6, -COOR7 or -CN; R5, R6, R7 are the same or different, and each is, independently, hydrogen, Ra or R; Ra is Cl-20 alkyl or Cl-20 alkyl substituted by one or more hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, Rb, alkylsulfonyl, aryisulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide , acyl, ester, amido, acyloxy, steroxy and / or amidooxy; Rb is aryl, heteroaryl, heterocycloalkyl or the same substituted by one or more Ra, hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, aryl, alkylsulfonyl, aryisulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, heterocycloalkyl, heteroaryl, acyl, ester, amido, acyloxy, steroxy and / or amidooxy; comprising the reaction of a furan derivative of the formula (II) or (III) wherein R and R are the same or different and each is Cl-10 alkyl or the same substituted by aryl, with a compound of the formula (IV) and with H2 in the presence of a catalyst.

The term "alkyl", as used herein, is defined as including saturated monovalent hydrocarbon radicals having straight, branched or cyclic portions or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 atoms of carbon for non-cyclic alkyl and 3-8 carbon atoms for cycloalkyl. The term "aryl" as used herein, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl, naphthyl. The term "heterocycloalkyl", as used herein, represents a cyclic alkyl (cycloalkyl), having at least one O, S and / or N atom that disrupts the carbocyclic ring structure such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl groups , piperazinyl, morpholino and pyrrolidinyl. The term "heteroaryl", as used herein, represents an "aryl" as defined above, having at least one O, S and / or N that interrupts the carbocyclic ring structure, such as pyridyl., furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl. The term "halogen", as used herein, includes an atom of Cl, Br, F, I. The term "hydroxy," as used herein, represents a group of the formula -OH. The term "thiol", as used herein, represents a group of the formula -SH. The term "cyano", as used herein, represents a group of the formula -CN. The term "carboxy", as used herein, represents a group of the formula -COOH. The term "sulfonic acid", as used herein, represents a group of the formula -SO 3 H. The term "sulfonamide", as used herein, represents a group of the formula -S02NH2 in which one or both of the hydrogens may be optionally replaced by "alkyl", "aryl", "heteroaryl" and / or " heterocycloalkyl "or the same substituted as defined above. The term "acyl", as used herein, represents a group of the formula RCO-, wherein R represents an "alkyl", "aryl", a "heterocycloalkyl" portion or "heteroaryl", or the same substituted as defined above.

The term "ester", as used herein, represents a group of the formula -COOR wherein R represents an "alkyl", "aryl", a "heterocycloalkyl" portion or "heteroaryl", or the same substituted as defined above. The term "alkoxy", as used herein, includes -OR groups in which R represents an "alkyl" or a "heterocycloalkyl" portion, or itself substituted as defined above. The term "aryloxy", as used herein, includes -OR groups in which R represents an "aryl" or a "heteroaryl" portion, or substituted same as defined above. The term "alkylthio", as used herein, includes -SR groups wherein R represents an "alkyl" or a "heterocycloalkyl" portion, or substituted same as defined above. The term "arylthio", as used herein, includes -SR groups wherein R represents an "aryl" or a "heteroaryl" portion, or substituted same as defined above. The term "acyl-coxy", as used herein, represents a group of the formula RCOO-, wherein R represents an "alkyl", "aryl", a "heteroaryl" or "heterocycloalkyl" portion, or the same substituted as It was defined earlier. The term "alkylsulfonyl", as used herein, represents a group of the formula -S02R wherein R represents an "alkyl" or a "heterocycloalkyl" portion, or substituted same as defined above. The term "arylsulfonyl", as used herein, represents a group of the formula -S02R wherein R represents an "aryl" or a "heteroaryl" portion, or substituted same as defined above. The term "alkylsulfinyl", as used herein, represents a group of the formula -SO-R wherein R represents an "alkyl" or a "heterocycloalkyl" portion, or substituted thereof as defined above. The term "arylsulfinyl", as used herein, represents a group of the formula -SO-R wherein R represents an "aryl" or a "heteroaryl" portion, or substituted same as defined above. The term "steroxy", as used herein, represents a group of the formula -OCOOR, wherein R represents an "alkyl", "aryl", a "heteroaryl" or "heterocycloalkyl" portion, or the same substituted as It was defined earlier. The term "amido", as used herein, represents a group of the formula -CONH2 in which one or both of the hydrogen atoms may optionally be replaced by "alkyl", "aryl", "heteroaryl" and / or "heterocycloalkyl" or the same substituted as defined above. The term "amidoxy", as used herein, represents a group of the formula -OCONH2 in which one or both of the hydrogen atoms may optionally be replaced by "alkyl", "aryl", "heteroaryl" and / or "heterocycloalkyl" or the same substituted as defined above. In the process according to the present invention, Ra is preferably Cl-20 alkyl or Cl-20 alkyl substituted by one or more hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, aryl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, heterocycloalkyl, heteroaryl, acyl, ester, amido, acyloxy, steroxy and / or amidoxy; and Rb is preferably aryl, heteroaryl, heterocycloalkyl or the same substituted by one or more alkyl, hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, aryl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, heterocycloalkyl, heteroaryl, acyl, ester, amido, acyloxy, steroxy and / or amidoxy. In the compounds of the formula (I) and (IV), X is preferably -CONR5R6, more preferably - CONH2. R1 is preferably Cl-6 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl; most preferably methyl, ethyl or n-propyl, especially ethyl. A furan derivative of the formula (II) is preferably used in the process of the present invention. In the compounds of the formula (I), (II) and (III), R3 is preferably hydrogen, halogen or a Cl-4 alkyl. More preferably R3 is hydrogen. When a furan derivative of the formula (III) is used, R4 is preferably Ra or hydrogen, more preferably Cl-6 alkyl or Cl-6 alkyl substituted by one or more halogens. Most preferably, R 4 is n-propyl. When a furan derivative of the formula (III) is used, R3 and R4 are preferably the same. In this case, R3 and R4 are more preferably selected from hydrogen, halogen or an alkyl of Cl-4. Most preferably, R3 and R4 are hydrogen. In the furan derivatives of the formula (III), R2 and R2 'are preferably Cl4 alkyl or benzyl, most preferably methyl. The compounds of the formulas (II) and (III) used in the process according to the invention can be obtained by any process suitable for this. The compounds of the formula (II) are preferably obtained by reaction of an aldehyde of the formula (V) with a keto acid of the formula (VI) in the presence of a base such as a cyclic secondary amine, preferably morpholine, followed by hydrolysis in acid conditions. The reaction is generally conducted at a temperature between 25 ° C and 100 ° C, preferably between 30 ° C and 60 ° C. More preferably, the reaction production is purified by extraction, particularly with an ether, especially diisopropyl ether.

The present invention therefore also relates to the preparation of compounds of the formula (II) by the process mentioned hereinabove. The compound of the formula (IV) used in the process according to the invention can be obtained by any means suitable for this. Preferably it is obtained by neutralization of the corresponding salts, more preferably of the corresponding hydrochloride or salt of tartaric acid, most preferably of the corresponding hydrochloride salt. The process according to the invention is generally conducted in the presence of solvent. Preferred solvents are selected from alcohols, water, esters such as ethyl acetate and aromatic solvents such as toluene and mixtures thereof. The most preferred solvents are alcohols. More preferred is isopropanol. Preferred catalysts according to the invention are metal-based catalysts, such as catalysts based on Pd, Pt and Ni. More preferred are Pd-based catalysts, most preferably Pd on C such as Pd on 5% carbon. The reaction is generally carried out at a temperature of 25 ° C to 100 ° C, preferably 30 ° C to 60 ° C, most preferably 40 ° C. The process according to the invention is conducted in the presence of hydrogen. The process according to the invention is generally conducted under hydrogen pressure in the range of 0.1 to 10 bar, preferably 0.2 to 5 bar and most preferably 0.2 to 0.5 bar, in a closed reactor. The process according to the present invention is also applicable to the preparation of pharmaceutically acceptable salts of the compound (II). The term "pharmaceutically acceptable salts" according to the invention includes non-toxic, therapeutically active acid and base addition salt forms which the compounds of the formula (I) are capable of forming. The process according to the invention relates to the preparation of all stereoisomeric forms of the compounds of the formula (I) and mixtures (including racemates) thereof. The compounds of the formula (I) and (IV) have at least one stereogenic center in their structure, the carbon atom being attached to the nitrogen atom of the pyrrolidine ring. This stereogenic center is indicated by an asterisk (*) in the compounds of the formula (I) and (IV). This stereogenic center may be present in an R or S configuration, the notation R and S is used in accordance with the rules described in Mash. Appl. Chem., 45 (1976) 11-30. The process according to the invention is preferably applied to the preparation of compounds of the formula (I) in the form (S) or (R). The term "form (S)", as used herein, means that the compound in question is composed of more than 50%, preferably more than 90% of the enantiomer having the stereogenic carbon atom indicated by an asterisk in the S configuration. The term "form (R)", as used herein, means that the compound in question is composed of more than 50%, preferably more than 90% of the enantiomer having the stereogenic carbon atom indicated by an asterisk in the R configuration. The process according to the invention is particularly suitable for the preparation of compounds of the general formula (I) in the form (S). In this case, the process according to the invention is preferably conducted using a compound of the formula (IV) in the (S) or in the (R) form. It was surprisingly found that racemization does not occur during the process of the present invention. When R3 and / or R4 are different from hydrogen, the compounds of the formula (I) have at least one stereogenic center complementary in structure, ie the carbon atom to which such R3 and R4 are attached. In this case, the process may contain an additional step wherein the diastereoisomers are separated. Such separation can be given by any suitable means for this. Preferably it is given by chromatography, in particular using a chiral stationary phase. The process according to the invention particularly applies to the preparation of compounds of the formula (I) in the form (2S, 4S) and (2S, 4R). The term (2S, 4S) [respectively (2S, 4R)] as used herein means that the compound in question is composed of more than 50%, preferably more than 90% of the diastereomer having the stereogenic carbon atom indicated by an asterisk in the S configuration and the carbon atom to which R4 joins in the R configuration [respectively The following examples are provided for illustrative purposes only and are not intended, nor should be constructed, as limiting the invention in any way. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.

Example 1: Synthesis of (2S) -2- ((4R) -2-oxo-4-n-propyl-l-pyrrolidinyl) butanamide 1. 1 Synthesis of free base (2S) -2-aminobutyramide NH, NH2 NH, HOX? H NH '° amOH. ^ Y "* OH O 1800 ml of isopropanol were introduced into a 5L reactor. 1800 g of (2S) -2-aminobutyramide tartrate were added under stirring at room temperature. 700 ml of a 25% aqueous solution of ammonium hydroxide were added slowly while maintaining the temperature below 25 ° C. The mixture was stirred for an additional 3 hours and then the reaction was allowed to complete at 18 ° C for 1 hour. The ammonium tartrate was filtered. Performance: 86% 1. 2 Synthesis of 5-hydroxy-4-n-propyl-furan-2-one Heptane (394 ml) and morpholine (127.5 ml) were introduced into a reactor. The mixture was cooled to 0 ° C and glyoxylic acid (195 g, 150 ml, 50% by weight of water) was added. The mixture was heated at 20 ° C for 1 hour, and then valeraldehyde (148.8 ml) was added. The reaction mixture was heated at 43 ° C for 20 hours. After cooling to below 20 ° C, a 37% aqueous solution of HCl (196.9 ml) was slowly added to the mixture, which was then stirred for 2 hours. After removal of the heptane phase, the aqueous phase was washed three times with heptane. Diisopropyl ether was added to the aqueous phase. The organic phase was removed, and the aqueous phase was further extracted with diisopropyl ether (2x). The diisopropyl ether phases were combined, washed with brine and then dried by azeotropic distillation. After filtration and evaporation of the solvent, 170 g of 5-hydroxy-4-n-propyl-furan-2-one was obtained as a brown oil. Performance: 90.8%. 1. 3 Synthesis of (2S) -2- ((4R) -2-oxo-4-n-propyl-l-pyrrolidinyl) butanamide and (2S) -2- ((4S) -2-oxo-4-n-propyl -l-pyrrole (S, TU) (S, S) The solution of (2S) -2-aminobutyramide in isopropanol containing 250 g, obtained as described hereinabove was dried by azeotropic distillation under vacuum. To the solution of dry (2S) -2-aminobutyramide was added 5-hydroxy-4-n-propyl-furan-2-one (290 g) between 15 ° C and 25 ° C; The mixture was heated to 30 ° C and maintained for at least 2 hours at this temperature. Then acetic acid (1.18 eq.), Pd / C catalyst was added. (5% w / w; Johnson Matthey 5% Pd on carbon - type 87L) and hydrogen was introduced into the system under pressure. The temperature was maintained at 40 ° C maximum and the H2 pressure was kept between 0.2 bar and 0.5 bar followed by stirring at least 20 hours after the initial reaction. The solution was then cooled between 15 ° C and 25 ° C and filtered to remove the catalyst. The product solution in isopropanol is solvent switched to a product solution in isopropyl acetate by azeotropic distillation with isopropyl acetate. The organic solution was washed with aqueous sodium bicarbonate followed by a wash with brine and then filtered. After recrystallization, 349 g of (2S) -2- ((4R) -2-oxo-4-n-propyl-1-pyrrolidinyl) utanamide and (2S) -2- ((4S) -2- were obtained oxo-4-n-propyl-l-pyrrolidinyl) butanamide (Yield: 82.5%). 1. 4 Preparation of (2S) -2- ((4R) -2-oxo-4-n-propyl-l-pyrrolidinyl) utanamide The chromatographic separation of the two diastereomers obtained in 1.3 was performed using chiral stationary phase (CHIRALPAK AD 20 μl ) and a 45/55 mix (volume / volume) of n-heptane and ethanol as eluent at a temperature of 25 ± 2 ° C. The crude (2S) -2- ((4R) -2-oxo-4-n-propyl-l-pyrrolidinyl) -butanamide thus obtained was recrystallized from isopropylacetate, yielding (2S) -2- ((4R) -2- Pure oxo-4-n-propyl-1-pyrrolidinyl) butanamide (Total yield: 80%).

Example 2: Synthesis of (2S) -2- ((4R) -2-oxo-4-n-propyl-l-pyrrolidinyl) butanamide (SR) (S, S) Example 1 was repeated except that in step 1.1 a solution of (2S) -2-aminobutyramide.HCl in isopropanol was used (27.72 g, 1.2 equivalent), which was neutralized with a solution NH3 / isopropanol (3.4-3.7 mol / L). The resulting ammonium chloride was removed from this solution by filtration and the solution was used directly for the reaction with 5-hydroxy-4-n-propyl-furan-2-one (23.62 g, 1.0 equivalent) without intermediate drying of the solution of (2S) -2-aminobutyramide. Yield after separation of the two diastereoisomers and recrystallization: about 84%.

Example 3: Synthesis of (S) - (-) - -ethyl-2-oxo-l-pyrrolidine acetamid The free base (2S) -2-aminoburamide (2 g) was dissolved in water (80 ml) and 2,5-dimethoxy-2,5-dihydro furan (2.4 ml, 1 eq.) Was added. Aqueous HCl (2.4 ml, 1.5 eq.) Was added at room temperature and the reaction mixture was stirred for 1.5 hours. Then, sodium carbonate was added until the pH of the mixture reached 8-9. Then, a Pd / C catalyst (5%) in a mixture of water and ethanol (20 ml) was added together with H2 and kept for 35 minutes. The solution was cooled between 15 ° C and 25 ° C and filtered to remove the catalyst. The ethanol was removed under vacuum and the desired compound was extracted with ethyl acetate, the organic solution was then washed with brine, dried over magnesium sulfate and evaporated to yield the (S) - (-) -a-ethyl- 2-oxo-l-pyrrolidin acetamide (Yield: 13%).

Example 4: Synthesis of methyl 1- [(1S) -1- (aminocarbonyl) propyl] -5-oxo-3-pyrrolidinecarboxylate 2-Hydroxy-5-oxo-2,5-dihydro-furan-3-carboxylic acid methyl ester (3.08 g) in methanol (40 ml) was added to a solution of (2S) -2-aminobutyramide (2.0 g). in methanol (30 ml) in a hydrogenation reactor and the mixture was maintained for at least 2 hours at room temperature. Then Pd / C catalyst (10% w / w, Johnson Matthey Pd on 5% carbon - type 87L) was added and hydrogen was introduced into the system under pressure. The temperature was maintained at 40 ° C maximum and the hydrogen pressure between 4 bar and 5 bar, followed by agitation for at least 20 hours after the initial reaction. The solution was then cooled between 15 ° C and 25 ° C and filtered to remove the catalyst. The solvent was evaporated under vacuum and the resulting yellow product was purified by preparative liquid chromatography (eluent: dichloromethane / methanol (95: 5)) (yield 43%).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (18)

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. Process for the preparation of 2-oxo-1-pyrrolidine derivatives of the general formula (I), and salts thereof, characterized in that: R1 is Ra or Rb; R3 and R4 are the same or different and each is independently hydrogen, hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, Ra, Rb, alkylsulfonyl, ariisulfonilo, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, acyl, ester, amido, acyloxy, steroxy or amidooxi; X is -CONR5R6, -COOR7 or -CN; R5, R6, R7 are the same or different, and each is, independently, hydrogen, R or Rb; Ra is alkyl of Cl-20 alkyl or Cl-20 substituted or one or more hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, Rb, alkylsulfonyl, ariisulfonilo, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide , acyl, ester, amido, acyloxy, steroxy and / or amidooxy; Rb is aryl, heteroaryl, heterocycloalkyl or the same substituted by one or more Ra, hydroxy, thiol, halogen, cyano, carboxy, sulfonic acid, aryl, alkylsulfonyl, ariisulfonilo, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkoxy, aryloxy, sulfonamide, heterocycloalkyl, heteroaryl, acyl, ester, amido, acyloxy, steroxy and / or amidooxy; comprising the reaction of a furan derivative of the formula (II) or (III) wherein R2 and R2 'are the same or different and each is Cl-10 alkyl or the same substituted by aryl, with a compound of the formula (IV) and with H2 in the presence of catalyst.

2. Process according to claim 1, characterized in that a furan derivative of the formula (II) is used.

3. Process according to claim 1 or 2, characterized in that R3 is hydrogen.

4. Process according to any of claims 2 to 3, characterized in that R4 is Ra or hydrogen.

5. Process according to claim 4, characterized in that R4 is Cl-6 alkyl or Cl-6 alkyl substituted by one or more halogens.

6. Process according to claim 5, characterized in that R4 is n-propyl.

7. Process according to any of the preceding claims, characterized in that X is -CONR5R6.

8. Process according to claim 7, characterized in that X is -CONH2.

9. Process according to any of claims 1 to 8, characterized in that R1 is Cl-6 alkyl.

10. Process according to claim 9, characterized in that R1 is ethyl.

11. Process according to any of claims 2 to 10, wherein the compound of formula (II) is obtained by reacting an aldehyde of formula (V) with a ketoacid of formula (VI), wherein R3 and R4 are as defined in claim 1, in the presence of a base.

Process according to any of the preceding claims, characterized in that the compound of the formula (IV) is obtained by neutralization of the corresponding hydrochloride salt.

13. Process according to any of the preceding claims, characterized in that the catalyst is a catalyst based on Pd, Pt or Ni.

14. Process according to claim 13, characterized in that the catalyst is a catalyst based on Pd.

15. Process according to any of the preceding claims, characterized in that the compounds of the formula (I) are in the form (S) or in the form (R).

16. Process according to claim 15, characterized in that the compounds of the formula (I) are in the form (S).

17. Process according to any of the preceding claims, wherein when R3 and / or R4 are different from hydrogen diastereoisomers obtained are separated further.

18. Process according to any of the preceding claims, characterized in that it applies to the preparation of (2S) -2- ((4R) -2-oxo-4 ~ n-propyl-l-pyrrolidinyl) butanamide.