PROCEDURE FOR THE PREPARATION OF 1-CARBAMOYLMETHYL DERIVATIVES OF 4-HYDROXY-2-OXO-PYRROLIDINE AS WELL AS INTERMEDIATES FOR OBTAINING SUCH COMPOUNDS.

Description

2nd ed. Eng. Fernando GARRONE from INTERNAZIONALE BREVETTI a.rl deprotected at the 4-hydroxy group and then subjected to aminols to obtain the compound (i). DESCRIPTION The present invention relates to a process for the preparation of pyrrolidone derivatives having pharmaceutical activity, as well as intermediates for obtaining such drugs. More specifically, the present invention relates to a process for preparing 4-hydroxy-2-oxo-1-pyrrolidinacetamide and its N-derivatives having pharmacological properties and also relates to a process for preparing alkyl 4-hydroxy-2-oxo-1-pyrrolidinacetate useful as an intermediate in obtaining the aforementioned drugs. 4-Hydroxy-2-oxo-1-pyrrolidinacetamide and its N-alkyl derivatives are valuable psychotropic drugs that restore cognitive functions damaged by various pathologies in animals, as well as in humans. 4-hydroxy-2-oxo-1-pyrrolidinacetamide itself, also known by the common name oxiracetam, is particularly preferred. There are currently various processes for preparing oxiracetam and its analogues, which differ mainly in the starting materials used and therefore in the sequence of reactions followed in the synthesis. Thus, a process starting from gamma-amino-beta-hydroxybutyric acid is described in Italian patent application No. 20226 A / 77 of the same Applicant. Dr. Fernando GARRONE of INTERNAZIONALE BREVETTI s.r.l. Another method using protected glycinamide and an epoxybutanoate as starting materials is described in Italian patent application No. 19802 A / 84 of the same Applicant. Despite the existence of the aforementioned known methods, there is a need for new processes for the preparation of the valuable drugs oxiracetam and its analogues, especially those that respond to the ever-changing availability of starting products on the market. Therefore, the main aim of the present invention is to provide a process for preparing oxiracetam and its N-alkyl analogues starting from starting materials available at economically attractive costs. Another goal is to develop a process for the production of oxiracetam and its analogues that can be easily implemented without any special handling. A further object of the present invention is to provide a process for preparing intermediates useful for the production of oxiracetam and its analogues. These and other objects which will become clearer hereinafter are achieved, according to one aspect of the present invention, by a process for preparing 4-hydroxy-2-oxo-1-pyrrolidineacetate esters of the formula 4 ar. ing. Fernando GARRONE of INTERNAZIONALE BREVE77 / srl CHiCOOft 00 as intermediates for the preparation of pharmaceutically active compounds, wherein R is alkyl with 1 to 3 carbon atoms, consisting of reacting diketene with a selected halogen between chlorine and bromine, and a glycine ester NH^CH^COOR, at a temperature of -78°C to +10°C, to obtain an alkyl 4-halo-3-oxobutanamidoacetate 0 XCHj,- C-Crt4-COHH-CH4COOR (lv) then reducing compound (IV) in the presence of a reducing agent at a temperature of -10°C to +30°C to obtain the corresponding 3-hydroxy derivative, protecting the 3-hydroxy group by reaction with a hydroxy protecting agent, cyclizing the protected derivative in the presence of a base at a temperature of -10°C to +30°C to obtain the respective derivative 4“i <Arossiprotetto di 2-osso-1-pirrolidinacetato GB 5,000 R (Vl1^ in cui Z e un gruppo protettore di idrossi, e deproteggere (VII)per ottenere il composto (il). According to a further aspect of the invention, a process is provided for preparing oxiracetam or its analogues 5 ér. Ing. Fernando GARRONE dalli INTERNAZIONALE BULVETTI s.rl of the formula: wherein R^ and R^ are the same or different and are each hydrogen or an alkyl having from 1 to 3 carbon atoms, this process comprising the steps set forth above for the preparation of alkyl 4-hydroxy-2-oxo-1-pyrrolidineacetate, and then the aminolysis of this intermediate by reaction with HNR R^ wherein R^ and R^ have the meanings given above to obtain the desired compounds of oxiracetam or its analogues. When preparing oxiracetam, aminolysis with ammonia is performed, while for its analogues an appropriate amine is used. The process according to the invention comprises, in the first step, the reaction of diketene with a halogen and a digliein ester. The reaction is carried out at low temperatures from -78°C to +10°C, preferably from -50°C to -20°C, in an anhydrous environment in a solvent selected from methylene chloride, chloroform, tetrahydrofuran, or toluene. Preferably, the halogen is added to the diketene dissolved in the chosen solvent as such or in the form of a solution or by bubbling it in the gaseous state through the diketene solution, and then the glycine ester is added as such or possibly released in situ from one of its salts, for example hydrochloride. It is preferable to use an equimolar ratio between reagents, although it is possible to use an excess of one of them. The resulting 4-halo-3-oxobutanamido alkyl (IV) acetate is reduced to the respective 3-hydroxy (V) derivative with a suitable reducing agent. Compounds of the hydride class are generally used as reducing agents, with NaBH^ being preferred. The reduction is carried out from -10°C up to +30°C, preferably at 0°C, in a solvent chosen for example from dimethoxy-tanOj tetrahydrofuran, ethyl ether, 2-methoxyethanol, ethanolmethanol, isopropanol, water. The 3-hydroxy derivative (V) is protected by the 3-hydroxy group. Dihydropyran is advantageously used as the protecting agent according to the invention, although alternative protecting groups such as methoxymethylene, ethylvinyl ester, and trimethylsilyl are also useful. The reaction with dihydropyran is carried out at room temperature, in a solvent chosen for example from methylene chloride, chloroform, tetrahydrofuran, toluene, benzene, etc., and in the presence of an acid catalyst, preferably pyridinoparatoluenesulfonate (PPTS). Preferably, a quantity of PPTS of 10% by weight with respect to compound (V) is used. The 3-hydroxyprotected derivative (Vi) obtained is cyclized in the presence of a base such as NaH, tBuONa, NaNH^ or NaQH η ér. eng. Fernando GARRONE from INTERNAZIONALE BREVETTI srl of which sodium hydride is preferred. The reaction occurs at a temperature of -10°C to +30°C, preferably at 0°C, in a suitable solvent such as THF, toluene, CH Cl„, dioxane. zz Alkyl(VII) 4-hydroxy-2-oxo-1-pyrrolidineacetate protected on the hydroxy group is obtained and deprotected by heating, for example at 20-70°C, in a solvent such as ethanol, methanol, isopropanol, water and in the presence of a suitable acid catalyst, preferably PPTS. The intermediate 4-hydroxy-2-oxo-1-pyrrolidineacetate obtained (II) is then transformed into the desired final product (i), i.e. oxiracetam or its analogues, by aminolysis carried out in a solvent such as water, methanol, ethanol, at a temperature of -10°C to +50°C. The sequence scheme of the synthesis reactions, according to a preferred embodiment of the process, is reported below: CH? - C — 0I 1CH 2TC =° (in A Xj, ---a»- Z) NHjtH^COOR CH-OH CH*, CONH - CH^COOfi. (t) ♦ CH^X i C =0 __ cwe CONH -CH^COOR (S) C Hi* CH - O No, BR4 -0 CHz COHH-CH^COOR ffia / ) i (vTi ou) HO \ ΝιΛ> CH^COOR Dr. Fernando GARRONE of the INTERNATIONAL PATENTS sti IVO, \ / N '0 CU^-CO - NH^ ( I 0^) The following examples are given by way of non-limitative illustration of the invention. EXAMPLE 1 2-(4-bromo-3-oxobutanamido)methyl acetate In a multi-necked flask equipped with magnetic stirrer, thermometer, dropper, and CaCl2 valve, dissolve 4.8 ml of diketene in 30 ml of methylene chloride. Cool to -50°C and add a solution of 3.24 ml of bromide dissolved in 20 ml of methylene chloride dropwise over 30 minutes. Stir for 2 minutes at room temperature. At -40°C, add a finely ground, intimate mixture of 20 g of NaCO2 and 7.9 g of glycine methyl ester hydrochloride all at once. Stir for 90 minutes, allowing to cool to room temperature. The salt is quickly filtered off, and the filtrate is concentrated under vacuum at room temperature. The residual oil is purified by silica chromatography. Fernando GARRONE de / laiINTERNAZ / ONALE BREVETTI s.rl lice, eluting with ethyl acetate. The desired product is obtained as a white powder with mp 7^~77°C. EXAMPLE 2 2-(4-bromo-3-hydroxybutanamido)methyl acetate In a 100 ml flask with magnetic stirring, dissolve 1.5 g of 2-(4-bromo-3-oxobutanamide)methyl acetate in 15 ml of dimethoxyethane. Cool to 0°C and add 60 mg of NaBH. After 5 minutes, the solvent is evaporated under vacuum and the residue is chromatographed on silica, eluting with ethyl acetate. The title product is obtained as a white powder with mp 60-61°C. EXAMPLE 3 2-(4-bromo-3-hydroxybutanamide)methyl acetate In a 50-ml flask equipped with a magnetic stirrer, thermometer, dropper, and CaCl2 valve, dissolve 0.76 ml of ketene in 3.5 ml of methylene chloride. Cool to -30°C, slowly add a solution of 0.5 ml of bromine into 3.5 ml of methylene chloride, stirring at -30°C for 10 minutes. This solution is quickly added dropwise into a gliein methyl ester solution prepared by suspending 1.25 ml of gliein methyl ester hydrochloride in 20 ml of methylene chloride containing 2.8 ml of triethylamine, stirred for 30 minutes, and cooled to -30°C. The mixture is stirred and brought to room temperature. It is filtered and evaporated under vacuum at room temperature, the residual oil is dissolved in 20 ml of ethanol, cooled to 0°C and treated with 100 mg of NaBKL.After 5 minutes, the excess hydride is destroyed with acidulated water, the ethanol is evaporated and the solution is dissolved in ethyl acetate. It is washed with brine, amidated over MgSO4, evaporated, and purified by silica chromatography, eluting with ethyl acetate. The title product is obtained as a white powder with a mp of 60-61°C. EXAMPLE: 2-(4-bromo-3-hydroxybutanamido)ethyl acetate. The reaction is carried out as previously described using 1.4 g of glycine ethyl ester hydrochloride. A white powder with a mp of 59.6ΐ°0 is obtained. EXAMPLE 5 2~^4-bromo-3-(tetrahydropyran-2-yloxy)butanamide / methyl acetate To a solution of 300 mg of 2-(4-bromo-3-hydroxybutanamide)methyl acetate in 50 ml of methylene chloride, 30 mg of pyridinium paratoluenesulfonate and 1 ml of dihydropyran are added. The mixture is stirred at room temperature for 20 hours, evaporated under vacuum, and chromatographed on silica, eluting with ether. A colorless oil Rf 0.33 is obtained (silica gel plates, layer thickness 0.25 mm, eluting with ethyl ether). EXAMPLE 6 2-[4-bromo-3-(tetrahydropyran-2-yloxy)butanamide / ethyl acetate To a solution of 1 g of 2-(4-bromo-3”hydroxybutanamido)acetate in 30 ml of methylene chloride, add 100 mg of pyridinium paratoluenesulfonate and 1 ml of dihydropyran, The mixture is stirred at room temperature for 3 hours, evaporated under vacuum, and chromatographed on silica gel, eluting with ether. A straw-colored oil with a Rf of 0.5 is obtained (silica gel plate, layer thickness 0.25 min), eluting with ethyl acetate. EXAMPLE 7 2-(4-chloro-3-oxobutanamido)ethyl acetate In a multi-necked flask equipped with magnetic stirrer, thermometer, and CaCl2 valve, dissolve 5.08 ml of diketene in 40 ml of CH2Cl. The solution is cooled to -30°C and a current of chlorine is passed for 1 hour. After the addition of chlorine, the solution is rapidly dropped into a diglycein ethyl ester solution prepared by suspending 9.30 g of diglycein ethyl ester hydrochloride in 160 ml of methylene chloride containing 18.6 ml of triethylamine, stirred for 30 minutes, and cooled to -30°C. The solution is left under stirring for 30 minutes, the solvent is evaporated under vacuum and dissolved in ethyl acetate, the salts are filtered, the solution is evaporated, and the sample is photographed on silica, eluting with ethyl acetate. The product is obtained as a white powder with a mp of 96-97°C. EXAMPLE 8 2-(4-chloro-3-hydroxybutanamido)ethyl acetate In a multi-necked flask equipped with magnetic stirrer, thermometer, and CaCl^ valve, dissolve 5.08 ml of diketene - 1 2 - by Dr. Fernando GARRONE from INTERNAZIONALE BREVETTI srl in 40 ml of CH4Cl. The solution is cooled to ~30°C and a stream of chlorine is passed for 90 minutes. After the addition of chlorine, the solution is rapidly dropped into a solution of glycine ethyl ester in 160 ml of CP4Cl prepared as in the previous example. The solution is stirred for 30 minutes, the solvent is evaporated under vacuum, dissolved in ethyl acetate, and the salts are filtered again. The solution is evaporated again, the oily residue is dissolved in 150 ml of ethanol, cooled in ice, and 1.26 g of NaBH^ added portionwise. After 30 minutes, a few drops of acidulated water are added, the solvent is evaporated, the solution is dissolved in ethyl acetate, washed with brine, and the solution is midified over MgSO4. The solution is evaporated and chromatographed on silica, eluting with ethyl acetate. The product is obtained as a white powder with a mp53~54°C. EXAMPLE 9 B”Z4ziì2r2iJzi^eÌrfiÌ£°Pii!^ni2“iìox:Ì)butanamido)ethyl acetate In a 50 ml flask, dissolve 1 g of 2-(4-chloro-3-hydroxybutanamido)ethyl acetate in 10 ml of CH Cl 2. 100 mg of pyridinium paratoluenesulfonate and 0.5 ml of hydropyran are added. Leave under stirring for 7 hours. The solvent is evaporated and the chromatograph is carried out, eluting with ethyl acetate. A colourless oil Rf 0.5 is obtained (silica gel plates, layer thickness 0.25 mm) eluting with ethyl acetate. EXAMPLE 10 Ethyl 2-oxo-4-(tetrahydropyran-2-yl)-1-pyrrolidineacetate U - Ór. ing. Fernando GARRONE dellaNTFRNAZIONALE BREVETTI srl 150 mg of Null is suspended in 20 ml of tetrahydrofuran and cooled on ice. A solution of 2.5 g of 2-[4-1-Γοιηο-3-(tetrahydropyran-2-yloxy)butanamide / ethyl acetate in 30 ml of tetrahydrofuran is added to the suspension. Stir for 40 minutes. The reaction mixture is poured, under stirring, into a solution of acetic acid (1 cc) in water (10 cc) at 0°C. It is extracted with ether, the organic phase is washed with a saturated NaHCO3 solution, then washed in brine and siamidified and evaporated. The crude oil obtained is purified by chromatography on silica, eluting with ethyl acetate. A colorless oil with Rf 0.32 is obtained (silica gel plates, layer thickness 0.25 mm) with ethyl acetate as eluent. EXAMPLE 11 2-oxo-4-(tetrahydropyran-2-yl)-1-pyrrolidine ethyl acetate The reaction is carried out as previously described using 2.24 g of 2-[4-chloro-3-(tetrahydropyran-2-yloxy)butanamido / ethyl acetate. A colorless oil Rf 0.32 is obtained (silica gel slab, layer thickness 3.25 mm) eluted with ethyl acetate. EXAMPLE 12 4-Hydroxy-2-oxo-1-pyrrolidine_ethyl_acetate A solution of 0.16 g of ethyl 2-oxo-4-(tetrahydropyran-2-yl)-1-pyrrolidineacetate is dissolved in 5 ml of ethanol with 16 mg of pyridinium paratoluenesulfonate. It is heated for 4 hours at 35°C, the ethanol is evaporated and the residue is chromatographed on silica. The product is obtained as a colorless oil. EXAMPLE 11 A solution consisting of 7.1 g of ethyl 4-hydroxy-2-oxo-1-pyrrolidineacetate obtained in Example 12 in 7.1 ml ammonium hydrate (d 0.90) is stirred at room temperature for 15 hours. It is diluted with 140 ml acetone and the mixture is stirred at room temperature until the gummy precipitate solidifies into white crystals. By filtration under vacuum and drying, 4-hydroxy-2-oxo-1-pyrrolidineacetamide is obtained, melting at 100-162°C, Rf 0.32 silica gel (eluent: water: acetonitrile 4:1).

Claims

15 dr. ing. Fernando GARRONE Agile ΜΤΜναϊΙΟΝΑΙΪ HpFvrrr, tr, CLAIMS 1. Process for preparing 1-carbamoylmethyl derivatives of 4-hydroxy-2-oxo-pyrrolidine of the formula »0 'i N° (lì CH^tONR^ in which R and R„ are the same & different and are each hydrogen o1 A an alkyl radical with from 1 to 3 carbon atoms^ consisting in reacting diketene with a halogen selected from chlorine and bromine and a glycine ester NH^CH^COOR in which R is an alkyl with from 1 to 3 C atoms, at a temperature of from ~78°C to +10°C, to obtain a 4-halo-3-oxobutanamido alkyl acetate.0 XCH -c!-CH -CONH-CH COOR (IV) M ié 4* reduce compound (IV) in the presence of a reducing agent at a temperature of -10°C to +30°C to obtain the corresponding 3-hydroxy derivative, protect the 3-hydroxy group by reaction with a hydroxy protecting agent, cyclize the protected derivative in the presence of a base at a temperature of -10°C to +30°C to obtain the respective 4-hydroxy-2-oxo-1-pyrrolidineacetate derivative protected on the hydroxy group. 2-0. ^ 0 i CH^COOR. (wì dr. Ing. Fernando C / .P.OGNG detta-16- ^TERNAZIONALE BREVETTI srL where Z is a hydroxy protecting group, deprotect (VII) to obtain 4-hydroxy-2-oxo-1-alkylpyrrolidineacetate and subject the latter to aminolysis by reaction with HNRjI^ to obtain the compound (1).

2. Process for preparing 4-hydroxy-3-oxo-1-pyrrolidineacetate esters of the formula H0V ϋ (ni CH^COOR as intermediates for the preparation of pharmaceutically active compounds, wherein R is an alkyl with 1 to 3 carbon atoms, consisting of reacting diketene with a halogen selected from chlorine and bromine and a glycine ester Nt^CH^COOR, at a temperature of -78°C to +10°C, to obtain a 4-halo-3-oxobutanamidoalkyl acetate XCH -C-CH -CONH-CH COOR (IV) M * then reducing compound (IV) in the presence of a reducing agent at a temperature of ~10°C to +30°C to obtain the corresponding 3-hydroxy derivative, protecting the 3-hydroxy group by reaction with a hydroxy protecting agent, cyclizing the protected derivative in presence of a base at a temperature from -10°C to +30°C to obtain the respective derivative 4-hydroxy-2-oxo-1-pyrrolidineacetate protected on the hydroxy group 2-0 1 ι 7 - ér. ìng. providing GARRONE of INTERNAZIONALE BREVETTI srL where Z is a hydroxy protector, and deprotect (Vii) to obtain compound (il).

3. Process according to claim 1 or 2 wherein the reduction of (IV) is carried out with sodium borohydride in a solvent selected from dimethoxymethane, tetrahydrofuran, ethers, alcohols and mixtures thereof.

4. Process according to any of the preceding claims wherein the protection of the 3-hydroxy group is achieved by reacting 4-halo-3-hydroxybutanamido dialkyl acetate with dihydropyran in the presence of pyridino paratoluenesulfonate (PPTS) at room temperature, 5. Process according to any of the preceding claims wherein said cyclization step is carried out in the presence of a base selected from NaH, tBuONa, NaNH^ and NaOH.

6. Process according to claim 4 wherein the deprotection of the 3-hydroxyl is carried out by heating in alcohols or water at 20-70°C in the presence of PPTS.

7. A process according to claim 1 wherein the aminolysis is carried out with ammonia at room temperature to obtain 4-hydroxy-2-oxo-1-pyrrolidinacetamide.

8. 4-hydroxy-2-oxo-1-pyrrolidinacetamide obtained by the process according to any of claims 3 to 7.