HK1181382A - Process for the preparation of dimiracetam - Google Patents

Description

Process for the preparation of dimiracetam

Technical Field

The present invention relates to a novel process for the manufacture of dimiracetam which gives the compound in high purity and good yield.

Background

WO 93/09120 describes a process for the preparation of dimiracetam (2, 5-dioxohexahydro-1H-pyrrolo [1,2-a ] imidazole) 1 and related compounds. 5-ethoxy-2-pyrrolidone reacts with benzyl carbamate and catalytic amount of p-toluenesulfonic acid to obtain 5-benzyloxy carbonyl amino-2-pyrrolidone. This compound is then deprotonated at the pyrrolidine nitrogen with sodium hydride in acetonitrile and reacted with ethyl bromoacetate to give 5-benzyloxycarbonylamino-2-oxo-1-pyrrolidine-acetic acid ethyl ester 2. Subsequent cyclization can be carried out after isolation of the ethyl ester and/or benzyloxycarbonyl protecting groups in the presence of various cyclizing agents.

The synthesis and pharmacological activity of dimiracetam is described in M, Pinza et al, J, Med, chem. 36:4214-20 (1993). Dimiracetam 1 contains a 2-pyrrolidone and 4-imidazolidinone core that has been considered important for cognition enhancing activity. In addition, the structure maintains the backbone of piracetamide (2-oxo-1-pyrrolidinyl-acetamide) and oxiracetam (4-hydroxy-2-oxo-1-pyrrolidinyl-acetamide) with acetamide side chains constrained to a folded conformation. The ability to reverse scopolamine-induced amnesia was evaluated in a one-time trial, dark avoidance (step through), passive avoidance paradigm. The main feature observed was a potent anti-amnestic activity after intraperitoneal administration. The delacetam completely retains the activity when orally taken, and is 10-30 times more effective than a reference medicament, namely oxiracetam.

The use of dimiracetam for the treatment of chronic pain is disclosed in WO 2008/125674. At doses higher than those reported for cognitive enhancing activity, dimiracetam is able to fully restore hyperalgesia or allodynia associated with several chronic pain patterns, for example in iatrogenic neuropathies associated with antiviral and chemotherapeutic drug treatments and in pain symptoms caused by osteoarthritis.

Methods for treating, preventing and/or delaying the progression of neuropathic pain are disclosed in US 2010/0125096, based on a new and inventive dosing regimen.

The obtaining of dimiracetam by condensation of isobutyl 4-oxobutyrate 3 with glycylamine hydrochloride 4, the pH being adjusted to pH 9.5 after glycinamide is dissolved in water and before addition of isobutyl oxobutyrate, is reported in EP 0335483 (example 9) and in m. Pinza et al, j. med. chem.36: 4214-20 (1993).

Crude dimiracetam obtained from this synthesis was purified by column chromatography and isolated from glycylamine with an overall yield of 19.1%.

Summary of The Invention

The present invention relates to the synthesis of dimiracetam 1, characterized in that a 4-oxo-butanoic acid ester (I), wherein R is lower alkyl, is condensed with glycinamide (II) or an acid addition salt thereof in a one-pot reaction with controlled pH. The reaction can be carried out in aqueous solution or in anhydrous lower alcohol solution.

Detailed Description

The present invention relates to a new efficient process for the synthesis of dimiracetam, characterized in that a 4-oxo-butanoic acid ester (I) is condensed with glycinamide (II) or an acid addition salt thereof in a one-pot reaction with controlled pH.

In a first particular embodiment of the invention, 4-oxo-butanoic acid ester (I) is heated with glycinamide (II) or an acid addition salt thereof in aqueous solution, maintaining the pH constant during the reaction. In another particular embodiment, the 4-oxobutanoic acid ester is condensed with glycinamide or an acid addition salt thereof in anhydrous lower alcohol and the intermediate 4-oxo-imidazolidin-2-yl-butanoic acid ester (III) is further treated with a base to obtain dimiracetam of formula 1.

Lower alcohols as understood herein are alcohols having from 1 to 5 carbon atoms, in particular methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, n-pentanol or isopentanol, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol or sec-butanol, in particular n-propanol.

The esters of 4-oxobutanoic acid are preferably lower alkyl esters having from 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl esters, in particular methyl or ethyl esters, preferably ethyl esters.

Glycinamide is preferably provided in the form of an acid addition salt, for example in the form of the hydrochloride or bisulfate salt, in particular the hydrochloride salt. However, it can also be used in the form of the free base.

As a specific example, the 4-oxo-butanoic acid ester is ethyl ester, the 4-oxo-butanoic acid ethyl ester of formula 5, and the glycinamide is provided as the glycylamine hydrochloride of formula 4. In a particular embodiment of the condensation reaction in aqueous solution, the pH is kept at a pH of 5.5 to 7.5, in particular about 6.6. In another particular embodiment, the condensation reaction in aqueous solution is carried out at 90 to 100 ℃ for 0.5 to 10 hours, preferably 1 to 3 hours, in particular about 1.5 hours.

It has surprisingly been found that one of the key factors of the one-pot aqueous condensation reaction, which is very different from the prior art, is to maintain a constant and selected pH as the reaction proceeds. From a pure technical point of view, a constant selected pH is necessary to avoid rapid degradation of the 4-oxobutanoate ester (which has an ester moiety that is readily hydrolyzed by water at high pH). The selected pH value is critical for the yield of the one-pot reaction in water, as it is a compromise between the basic pH necessary to form the glycylamine base for reaction with the aldehyde group and the acidic pH to reduce hydrolysis of the ester group of the 4-oxobutyrate ester.

The pH control is preferably carried out by an automated system which constantly measures the pH of the reaction solution and is connected to a distributor for the alkaline solution. The alkaline solution may be an aqueous hydroxide solution, e.g. potassium hydroxide or sodium hydroxide solution, or a carbonate solution, e.g.Such as potassium carbonate or sodium carbonate, preferably sodium carbonate solution, such as 20% w/v Na in water₂CO₃. Although a pH in the range of pH 5.5 to 7.5 was found to be suitable, the best results of the reaction were obtained when the pH was set to 6.6.

No pH control with the reaction is reported in the prior art, only at the beginning of the reaction, the pH is adjusted to pH 9.5 before the addition of the aldehyde. Following the prior art procedure and starting from pH 9.5, the ethyl 4-oxobutyrate 5 was hydrolyzed and the pH was lowered very quickly until a pH value below pH 5 was reached. At this pH, the reaction is almost stopped, since glycinamide is protonated and can no longer react with aldehyde functions that may remain.

According to the invention, the 4-oxobutanoic acid ester is used in molar excess with respect to the amount of glycinamide, for example in an amount of 1 to 3 molar equivalents. The aldehyde functionality degrades in an aqueous reaction environment.

The key factor for an alternative embodiment in which the one-pot reaction is carried out in a lower alcohol as solvent and is very different from the prior art is the anhydrous condition. Under the reaction conditions selected, the 4-oxobutanoic acid ester (I) is not degraded and can therefore react with the glycinamide (II) over the course of the reaction time. Although a molar excess of 4-oxobutanoate is necessary for the reaction in aqueous solution, such excess is not required for the reaction in anhydrous lower alcohols. pH control is desirable because a constant apparent pH, obtained by gradual addition of a suitable base, is necessary to control the equilibrium of the free base of glycinamide with its protonated form.

Under anhydrous conditions, automated systems that maintain a constant pH by addition of a base produce results that are as important as in aqueous solutions. However, in contrast to aqueous solutions, the determination of the value of the preferred range of the pH is of no significance, since pH measurements are only reliable in aqueous solutions. For example, an apparent pH of 5.5 was found to be optimal in n-propanol solution. Those skilled in the art will readily find the appropriate apparent pH for the corresponding anhydrous lower alcohol solvent. The same type of equipment for measuring alkalinity and acidity as in aqueous solution is used, which can then be used for constant addition of base to compensate for the formation of acid during the course of the reaction. As examples, use is made of solutions of amine bases or alkoxides in the particular lower alcohols used as reaction solvents, for example sodium or potassium alkoxides, such as methoxide, ethoxide or tert-butoxide, sodium hydride, butyllithium, sodium or sodium carbonate or potassium carbonate, in particular potassium tert-butoxide.

In the reaction of 4-oxobutanoic acid ester (I) with glycinamide (II) or an acid addition salt thereof in anhydrous lower alcohol, the intermediate 3- (4-oxoimidazolidin-2-yl) -propanoate (III) does not spontaneously cyclize to the desired dimiracetam. A suitable base must be added to effect the cyclization.

Suitable bases are ammonia, strong organic amines, such as triethylamine, diisopropylethylamine, pyridine, lutidine (lutidine), collidine or 4-N, N-dimethylaminopyridine, alkoxides, such as tert-butoxide, for example sodium tert-butoxide or potassium tert-butoxide, or methoxide or ethoxide, inorganic bases, such as solid potassium or sodium carbonate, or ammonium carbonate. The preferred base is ammonia.

In a particularly preferred embodiment, the lower alcohol is n-propanol. The molar yield of ethyl 3- (4-oxoimidazolidin-2-yl) propionate of formula 6 to glycylamine hydrochloride 4 as determined in the n-propanol reaction mixture was about 80% or greater, and the conversion of ethyl 3- (4-oxoimidazolidin-2-yl) propionate to dimiracetam during the reaction with ammonia was nearly quantitative.

In a particular embodiment, the reaction temperature is from 90 to 120 ℃, preferably about 100 ℃, and the reaction time is from 2 to 10 hours, preferably about 4 hours. After the intermediate product of formula (III) is formed (e.g. in the form of compound 6), a base, e.g. ammonia, is added and the reaction temperature after the addition of ammonia is maintained at 30 to 90 ℃ for 10 to 24 hours, in particular at 60 to 70 ℃ for 16 to 20 hours, such as 18 hours.

When the reaction is carried out in a low boiling alcohol, such as methanol, ethanol or isopropanol, the reaction is preferably carried out under pressure in a closed system to achieve the desired optimum reaction temperature of about 100 ℃.

The reaction, although referred to as "one pot", may also be carried out using continuous reactor technology.

After the reaction, the desired dimiracetam is isolated from the aqueous reaction mixture or the anhydrous lower alcohol reaction mixture by standard procedures, such as extraction, precipitation, filtration and recrystallization. The product is obtained in high purity by recrystallization from isopropanol.

Examples

Example 1: preparation in aqueous solution

A solution of 2.56 g (22.7 mmol) glycinamide hydrochloride (98% pure) in 200 ml water was heated to 95 ℃ and treated with 20% w/v Na in water₂CO₃The pH was adjusted to 6.6. Ethyl 4-oxobutyrate (97% pure) (7.60 g, 56.6 mmol) was then added dropwise over the course of four hours, the temperature being maintained at 95 ℃, by automatic addition (pHstat) of 20% w/v Na in water₂CO₃The pH was maintained at 6.6. The solution was stirred at 95 ℃ for 1.5 hours and then concentrated under vacuum to a small volume. The suspension obtained is treated with 50 ml of isopropanol and the solvent is evaporated at atmospheric pressure. This operation is repeated once more. The residue was diluted with 50 ml of isopropanol and the resulting suspension was heated to 60 ℃ and subsequently filtered. The filtrate was concentrated to about 15 ml, cooled to room temperature, and stirring was continued for about 2 hours. The white precipitate was collected by suction filtration, washed with 4 ml of isopropanol and dried under vacuum at 60 ℃ for 12 hours to give 1.8 g of crude dimiracetam (12.8 mmol, 55.5%). Recrystallization from isopropanol (10 vol.) gives 1.6 g (50%) of pure dimiracetam (determined by area% HPLC)>99.5%）。

Melting point: 154 deg.C

¹H-NMR (in CD)₃OD 1.90-2.05 (1H, m), 2.33-2.44 (1H, m), 2.48-2.60 (1H, m), 2.64-2.78 (1H, m), 3.55 and 4.02 (2H, AB q, J =15.9 Hz), 4.76 (s, H)₂O), 5.34 (1H, t, J=6.12 Hz)。

¹³C-NMR (CD₃OD): 30.8 (CH₂), 32.4 (CH₂), 47.7 (CH₂), 74.0 (CH), 175.2 (C=O), 180.1 (C=O)。

FT-IR: 3280 cm^-1 (NH), 1678-1698 cm^-1 (C=O), 1222-1284 cm^-1。

MS: m/z 141 (MH⁺)。

HPLC conditions: column: zorbax SB-AQ, 250 mm x 4.6 mm x 5 mm; and (3) detection: UV 200 nm; mobile phase A: HPLC grade water; mobile phase B: acetonitrile/water (50: 50).

Example 2: preparation in n-propanol

A suspension of 90.0 g (0.798 mol) of glycinamide hydrochloride (purity 98%) in 7.2 l of n-propanol was heated to reflux and 250 ml of solvent were distilled off. A solution of 15% w/v sodium tert-butoxide in n-propanol (260 ml, 0.35 mol) was added and the apparent pH was measured to be 5.5. The apparent pH was maintained at 5.5 by the automatic addition of a 15% w/v solution of sodium tert-butoxide in n-propanol, ethyl 4-oxobutyrate (97% pure) (262.3 g, 1.955 mol) was added dropwise over the course of four hours while maintaining the reaction mixture at reflux, the solvent was distilled off continuously at about 400 ml/h, and n-propanol was added continuously to the reaction mixture at about 400 ml/h. A total of 363 ml (0.476 mol) of a 15% w/w solution of sodium tert-butoxide in n-propanol was added. The mixture was stirred under reflux for an additional 1.5 hours and then cooled to 65 ℃. A solution of 7.5% w/w ammonia in n-propanol (800 g) was added to the mixture over the course of 6 hours and heating continued at 65 ℃ for an additional 18 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off. The clear solution was concentrated under vacuum to a small volume (approximately 0.5 l) and stirred at 0 ℃ for 2 hours. The white precipitate was collected by suction filtration, washed with 50 ml of n-propanol and dried under vacuum at 60 ℃ for 12 hours to give pure dimiracetam (65 g, 58.1%) which melted at 154 ℃. HPLC purity: 99.7 percent.

Claims (15)

1. A process for the manufacture of dimiracetam of formula 1, characterized in that a 4-oxo-butanoic acid ester of formula (I), wherein R is lower alkyl, is condensed with glycinamide of formula (II) or an acid addition salt thereof in a one-pot reaction with controlled pH.

2. The method of claim 1, wherein the 4-oxo-butanoic acid ester (I) is condensed with glycinamide (II) or an acid addition salt thereof in aqueous solution.

3. The method of claim 1, wherein the 4-oxo-butanoic acid ester (I) is condensed with glycinamide (II) or an acid addition salt thereof in an anhydrous lower alcohol solution.

4. The method of any one of claims 1 to 3, wherein the 4-oxo-butanoic acid ester (I) is ethyl 4-oxobutanoate.

5. The method of any one of claims 1 to 4, wherein the glycinamide (II) acid addition salt is glycinamide hydrochloride.

6. The method of claim 2, 4 or 5, wherein the pH is maintained at a pH of 5.5 to 7.5.

7. The process of claim 2, 4, 5 or 6 wherein the reaction temperature is maintained at about 100 ℃ for 0.5 to 10 hours.

8. The process of claim 7, wherein the reaction temperature is maintained at about 100 ℃ for 1 to 3 hours.

9. The process of claim 2, 4, 5, 6, 7 or 8, wherein 1 to 3 molar equivalents of 4-oxobutanoic acid ester (I) are used for one molar equivalent of glycinamide (II).

10. The process of claim 3, 4 or 5 wherein the lower alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, n-pentanol and isopentanol.

11. The process of claim 10, wherein the lower alcohol is n-propanol.

12. The process of any one of claims 3, 4, 5, 10 or 11, wherein ammonia is added in the final step of the reaction.

13. The process of any one of claims 3, 4, 5, 10, 11 or 12, wherein the reaction temperature is maintained at 90 to 120 ℃ for 2 to 10 hours.

14. The process of claim 12, wherein the reaction temperature after the addition of ammonia is maintained at 30 to 90 ℃ for 10 to 24 hours.

15. The process of claim 12, wherein the reaction temperature after the addition of ammonia is maintained at 60 to 70 ℃ for 16 to 20 hours.