DE2759297C2 - Process for the preparation of 2-oxo-1-pyrrolidine-acetamide - Google Patents

Description

It is known that 2-oxo-l-pyrro! Idine acetamide by reaction of 2-oxo-pyrrolidine-Na (prepared 2-oxo-pyrrolidine and Na or NaOH) with

2-chloroacetamide, also by the action of NHj 2-Oxo-t-pyrrolidine acetic acid ester or chloride (GB 10 39 113) or by thermal decomposition of their ammonium salt (GB 13 09 692) can. The compound mentioned shows, for example, a therapeutic effect in the treatment of chronic ones Disorders of brain function. It is known by the generic name of pyracetam.

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

2H ₂ N CH ₂ CONH, + CICH ₂ CH, CH ₂ COCl (II) (III)

CICH, C ^- H. CH ₂ CONH CH ₂ CONH ₂ (IV)

HC ^- IH ₂ N CH ₂ CONH ₂ (V)

N ^w

CH ₂ CONH ₂
(I)

According to the invention, glycinamide is converted into N.N-dimelhylacetamide dissolved and gradually the cooled solution of the chloride of 4-chlorobutyric acid in one aprotic organic solvents added. The resulting precipitate of the glycinamide salt Formula V is filtered to regenerate the glycinamide, while the volatile solvent is removed the fillrate 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-chlorobutyrylglycine amide obtained is then dissolved in alcohol and in the presence of sodium hydroxide or one Sodium alcohol. or the basic anion exchanger Dowex I in 2-oxo-l-pyrrolicJin-acetamide vice versa converts, which is isolated from the reaction solution after removal of the solvent.

The advantage of the method according to the invention is that the use of sodium b / w Sodium h> drid and the procedure with the intermedia ren ammonium salt is avoided, so that the Effective procedure is easy to carry out. Furthermore are! the starting materials easily accessible,

Preparation of the starting compound
4-Chlorbuiyrylglycifiamid of the formula IV

11.1 g (0.15 mol) of glycinamide are dissolved in 50 ml of NN-dimelhylacetäifiid with gentle warming and 1055 g (0.075 mol) of chloride of 4-chlorobutyric acid in 50 ml of anhydrous dioxane are added to the solution with ice cooling. The reaction solution is then stirred for a further 10 minutes at room temperature and the precipitate formed is filtered off. 8 g of glycinamide · HCl are obtained. The solvent dioxane is removed by distillation in vacuo and the product is separated off from the residue with ether. One obtains 10.5 g (78%) of the product. F _n 123-125 "C.

In the thin-layer chromatogram on silica gel, the product shows methylene chloride-acetone-methanol = 5: 5: 1 only one spot at Rf 0.43 (detection by spraying with iodine).

For analyzes / awakening, the product is made from a mixture of acetone with hexane or ethyl acetate recrystallized, whereby colorless platelets are resurrected. M.p. 128-130 "C.

Analysis: C ₆ H ₁₁ NjO ₂ Ci (178.62)

Calculated: C 4034, H 6.21, N 15.68%;
found: C 40.46, 1-15.97, N 15.54%.

IR-SpeklfUm (crh '):

3400,3310,320Ö (NH _2i NI I),
1680-1620 (C = O, priili. + Sck. Amide),
⁶ S 1550-1530 (sec. Amide)

The process according to the invention is explained in more detail using the following examples:

55

example 1

2-Oxo-1-pyrrolidine-acetamide by cyclization
of 4-chlorobutyryIgIycinamide 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 sodium hydroxide in ethanol (0.056 mol) are added dropwise to the solution with stirring. The reaction solution is refluxed for 10 minutes and heated to boiling. After cooling, the sodium chloride formed (2 ^ 5 g, 89%) is separated off by filtration. After removal of the solvent, by the addition of isopropanol to the oily residue 6.9 g (86%) of white crystalline product, mp _p 145-147 ° C.

Example 2

2-Oxo-1-pyr-olidine-acetamide by cyclization
only sodium tert-butoxide

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, the precipitate (1.2 g, (94%)) separated by filtration. The mother liquor is evaporated to dryness and the crude product is crystallized from isopropanol, giving 224 g (72%) of the product are F _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-l-pyrrolidine-acetamide by cyclizing

ίο 4-chloro-butyryIglycinamid using a Anion exchanger.

2.2 g (0.0124MoI) of 4-chlorobutyrylglycine amide are dissolved in 15 ml of anhydrous ethanol and * .u one Suspension of the ion exchanger Dowex 1 in ethanol

given π. The suspension contains 20 ml of the dry Ion exchanger Dowex 1 in the OH form in 30 ml of anhydrous ethanol. The reaction mixture becomes a Stirred for an hour at a temperature of 20-25 ° C The exchanger is then decanted and

»U washed with 20 ml of ethanol. The whole is then evaporated Athanui is obtained from the solid residue by recrystallization from isopropanol 1.25 g (71%) of product, F _p 145- 147 ° C.

In an analogous manner, a much purer crude product is obtained after recrystallization from isopropanol in yields of 85% with an _mp of 148-150 ³ 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, -CONH ₂ characterized in that 4-chloro-butyIrylgIycinamid is dissolved in an organic solvent and cyclized in the presence of NaOH, a sodium alcoholate or a basic ion exchanger of the Dowex 1 type at a temperature from 20 ⁰ C "