DE2759297B1 - Process for the preparation of 2-oxo-1-pyrrolidine-acetamide - Google Patents

Description

It is known that 2-oxo-i-pyrrolidine-acetamide is produced by reaction of 2-oxo-pyrrolidine-Na (produced from 2-oxo-pyrrolidine and Na or NaOtI) with 2-chloroacetamide, and also by the action of NH ₃ adf 2-Oxo-1-pyrrolidine-acetic acid ester or chloride (GB 10 39 113) or by thermal decomposition of Sires ammonium salt (GB 13 09 692) can be prepared. The compound mentioned shows, for example, a therapeutic effect in the treatment of chronic disorders of the brain function. It is known by the "genetic" name pyracetam.

It has now been found that the compound of formula 1 in a simple manner according to the the following reaction scheme can be produced:

2H ₂ N-CH ₂ -CONH ₂ + (H)

(IH)

ClCH ₂ -CH ₂ -Ch ₂ -CONH-CH ₂ -CONH ₂ (IV)

HCl H ₂ N-CH ₂ -CONH ₂

(V) ⁱ

CH ₂ CONH ₂
(H

According to the invention, glycine amide is converted into Ν, Ν-Dknethylacetamid dissolved and gradually cooled down Solution of the chloride of 4-chlorobutyric acid in one aprotic organic solvent added. The resulting precipitate of Gh / cinamidatzes of Formula V is used to regenerate Glydnamide nitrated while the volatile solvent is off the filtrate is removed under reduced pressure. The product is made with the addition of a suitable Solvent in which the product is insoluble, precipitated from the residue. The 4-Chkwbutyrylglycinatnid obtained is then dissolved in alcohol and in the presence of sodium hydroxide or one Sodium alcohol, or basic anion exchange Scher's Dowex 1 converted into 2-oxo-l-pyrrondine acetamide, which from the reaction solution after Removing the solvent is isolated.

The advantage of the method according to the invention is that the use of sodium or Sodium hydride and the process with the intermediate ammonium salt is avoided, so that the The process according to the invention is easy to carry out. Furthermore, the starting materials are easily accessible.

Preparation of the starting compound
4-chlorobutyrylglycine amide of the formula IV

11.1g (0.15MoI) glycine amide are dissolved in 5OnU Ν, Ν-dimethylacetamide with gentle warming and then 10.55 g (0.075MoI) chloride of 4-chk> rbutyric acid in 50 ml anhydrous dioxa tmter Bskahking are gradually added to the solution the reaction solution is stirred for a further 10 minutes at room temperature and the precipitate formed is filtered off. 8 g of glycinamide HCl are obtained. The Dkwcan solvent is removed by distillation in vacuo and the product is separated from the backwater using ether. This gives 103 g (78%) of product, Fj t23 - \ 25 ° C

The product shows in thin-layer chromatography on SBicagel mk methylene chloride-acetone-methanol = 5: 5: 1 only one spot at Rf 0.43 (detection by spraying with iodine).

For analytical purposes, the product is made from a mixture of acetone with hexane or ethyl acetate recrystallized, giving colorless platelets be, mp 28-130 ° C

Analysis: CeHi IN ₂ O ₂ Cl (17 $ 62)

Calculated: C 4034, H 421. N 15.68%;
Found: C 40.46, H 5.97, N 15.54%.

IR spectrum (cm- ^J ):

340Θ, 3310, 3200 (NH ₂ , NH),

1680-1620 (C-0, prim. + Sec. Amide).

1550-153O (sec. Amide)

The inventive method is based on the following examples are explained in more detail:

example 1

2-Oxo-1-pyrrolidine-acetamide by cyclization
of 4-chlorobutyrylglycine amide with NaOH.

10 g (0.056 mol) of 4-chlorobutyrylglycine amide are ^{dissolved in 100 ml of anhydrous ethanol with heating up to 50 °} C. and 5.9 ml of 1 η sodium hydroxide in ethanol (0.056 mol) are added dropwise with stirring. The reaction solution is refluxed for 10 minutes and heated to boiling. After cooling, the sodium chloride formed (2.9 g, 89%) is separated off by filtration. After removing the solvent, adding isopropanol to the oily residue gives 63 g (86%) of the white, crystalline product, _mp 145 - 147 ° C.

Example 2

2-Oxo-1-pyrrolidine-acetamide by cyclization
with sodium tert-butoxide.

15th

20th

4 g (0.022 mol) of 4-chlorobutyrylglycine amide are dissolved in 80 ml of dioxane with heating. A suspension of 0.022 mol of sodium tert-butoxide in 20 ml of anhydrous dioxane is added to the solution with stirring. The mixture is stirred at room temperature for one hour, and the precipitate (1.2 g, (94%)) is separated off by filtration. The mother liquor is evaporated to dryness and the crude product crystallized from isopropanol to give 2.24 g (72%) of the product, M _p 146-149 ° C.

The ring closure reaction of 4-chlorobutyrylglycine amide with sodium methylate can be carried out in an analogous manner or ethylate.

Example 3

2-Oxo-1-pyrrolidine-acetamide by cyclizing 4-chloro-butyrylglycine amide using a Anion exchange ^.

2.2 g (0.0124MoI) of 4-chlorobutyrylglycine amide will be used dissolved in 15 ml of anhydrous ethanol and to one Added suspension of the ion exchanger Dowex 1 in ethanol. The suspension contains 20mI of the dry Ion exchanger Dowex 1 in the OH form in 30 ml of anhydrous EthanoL The reaction mixture is a Stirred at a temperature of 20-25 ° C. for an hour. The exchanger is then decanted and washed with 20 ml of ethanol. All of the ethanol is then evaporated from the solid residue 1.25 g (71%) of the product are obtained by recrystallization from isopropanol, melting point 145 ° -147 ° C.

In an analogous way one obtains a much purer crude product after recrystallization from isopropanol in 85% yield with a F _p of 148-150 ⁰ C, when working with a column filled with the exchanger.

Claims (1)

Claim: »Process for the preparation of 2-oxo-l-pyrrolidine acetamide of the formula CH ₂ -CONH ₂ characterized in that 4-chloro-butylrylglycine amide in an organic Solvent dissolves and in the presence of a sodium alcoholate or a basic ion exchanger of the Dowex 1 type cyclized at a temperature from Iff C. «