RU2032668C1 - Method for preparing 1-alkoxycarbonylmethylpyrrolidones-2 - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: desired products are prepared of pyrrolidone-2. Said compounds interact with sodium alcoholate NaOCH₃ or NaOC₂H₅ in the medium of dry nonpolar aprotic solvent followed by removing thus prepared alcohol by azeotropic distillation. Then triethylbenzyl ammonium chloride, or tetrabutyl ammonium iodide is added into reaction mass which contains sodium salt of pyrrolidone-2, content of said reagents is 0.5-5 mol % of pyrrolidone-2 quantity. Thus prepared reaction mixture containing appropriate quaternary ammonium salt of pyrrolidone-2 is treated by methyl or ethyl ester of monochloroacetic acid, the process is carried out at room temperature. Thus prepared sodium chloride as macrocrystalline precipitate is then removed by filtration. Desired products as dark-red liquid are then distilled. Yields of desired products are 74 % and 72-84 %, their boiling points are 127-131 C/5 mm Hg and 120- 135 C/2 mm Hg. EFFECT: improves efficiency of the method.

Description

где AlK метил (Ia), этил (Iб).The invention relates to the chemistry of pyrrolidones and relates to an improved method for producing known alkoxycarbonylmethylpyrrolidone-2 compounds of the general formula I

where AlK is methyl (Ia), ethyl (Ib).

Пирацетам родоначальник и наиболее важный представитель нового класса психотропных препаратов ноотропов (I).Compounds are key compounds in the synthesis of the known drug piracetam (1-carbamidomethylpyrrolidone-2) of formula II

Piracetam is the ancestor and the most important representative of a new class of psychotropic drugs nootropics (I).

 There are two main methods for producing compounds of general formula I.

A known method of obtaining compound IB (2), which consists in the fact that pyrrolidone-2 (III) is alkylated with dimethyl sulfate in benzene during boiling, the resulting methyl sulfate complex (IV) is treated with aqueous potash, resulting in 0-methylbutyrolactim (V), without isolation or isolation , subjected to alkylation with ethyl acetate of chloroacetic acid at 150-160 ^about With according to the scheme.

CH₃SO $\genfrac{}{}{0ex}{}{\text{-}}{\text{4}}$

Целевой продукт Iб перегоняют в вакууме.Scheme of the method analogue (2)

CH ₃ SO $\genfrac{}{}{0ex}{}{\text{-}}{\text{4}}$

Target product IB is distilled in vacuo.

Ib is obtained with a yield of: 57% counting on starting III (product V is not isolated), 73% counting on V (with isolating product V). The content of the main substance is not indicated, t. 110-125 ^{° C} (at 3 mm Hg).

 The main disadvantages of the analogue method: a relatively low yield (57%) of the target product I; the use of highly toxic dimethyl sulfate; the need for disposal of the resulting toxic gaseous methyl chloride, which requires the use of expensive equipment for its disposal.

 A known method for the synthesis of compounds of general formula I, which is based on the preparation of a metal salt of pyrrolidone-2 with its subsequent alkylation (3).

This method is the closest in technical essence and the achieved result is an analog of the proposed method (i.e., prototype) and that pyrrolidone-2 (III) is treated with sodium alcoholate of formula VI
NaOAIK where AIK is methyl, ethyl, in dry toluene in an inert gas stream (followed by removal of the alcohol by azeotropic distillation). The resulting reaction mass containing the resulting sodium salt of pyrrolidone-2, is treated with methyl or ethyl ether of chloroacetic acid of the formula VII
ClCH ₂ wherein COOAIK AIK methyl, ethyl at 0-5 ^{° C,} followed by aging at room temperature (20 ° ^C) for 15-20 hours.

+NaOAlk _____→

Na⁺

где AIK метил, этил.The scheme of the prototype method (3)

+ NaOAlk _____ →

Na ⁺

where AIK is methyl, ethyl.

 The target product is isolated as follows. To the reaction mass, which is a toluene solution of the target product, in which the finely dispersed sodium chloride formed during the reaction is suspended, water is added in the amount necessary to completely remove sodium chloride from the toluene layer, the washed toluene fraction is evaporated and distilled.

Get the target products, counting on starting III, with the release of: Ia-70% t. Bales. 118-123 ^{° C} (5 mmHg), Ib b.p. 72-75%. 144-148 (16 mmHg).

 The content of the main substance in the target product is not indicated.

During the reproduction of this method by the authors of the application, the product Ib was obtained with a yield of 67% content of the basic substance 71% bp 122-123 ^about C (3 mm RT.article 3).

 The main disadvantages of the prototype method.

 The complexity of the selection of the target product. This is due to the fact that during the reaction, along with the target product, sodium chloride is also formed, in the form of a fine powder, the removal of which from the reaction mass, which is a toluene solution of the target product, by conventional filtration is impossible, and therefore, to isolate the target product from such a reaction mass it is subjected to repeated washing with a large volume of water (400 ml of water per 1 mol of sodium salt), which causes hydrolysis of the target product (the ester moiety is saponified in the compound I) leads to the formation of non-utilizable waste water. The duration of the process (exposure of the reaction mass 20 h).

 These disadvantages make it difficult to create domestic industrial production of compounds of the general formula I.

 The aim of the invention is to simplify the process.

R_″
а) где R=R_'=R_" есть (хлорид триэтил- С₂Н₅-группа,R_"' есть бензиламмония СН₂С₆Н₅ группа, ТЭБАХ) Х атом хлора,
или
б) R=R_' есть СН₃-группа, R_" есть СН₂С₆Н₅-группа, (катамин АБ) R_"'-смесь углеводородов С₁₀-С₁₈, Х-атом хлора,
или
в) R=R_'=R_"=R_"' есть С₄Н₉-группа, Х-атом иода (иодид тетрабутиламмония)
взятой по отношению к пирролидону-2 в количестве 0,5-5 мол. (предпочтительно 1 мол.), полученную реакционную массу, содержащую соответствующую четвертичную аммонийную соль пирролидона-2, подвергают обработке метиловым или этиловым эфиром монохлоруксусной кислоты при комнатной температуре с последующей выдержкой при той же температуре.This goal is achieved by the claimed method for producing 1-alkoxycarbonylmethylpyrrolidone-2 of the general formula I, which consists in the fact that pyrrolidone-2 (III) is reacted with an sodium alcoholate of the formula VI
NaOAIK where AIK is methyl, ethyl, in a medium of dry non-polar aprotic solvent, for example toluene (followed by removal of the resulting alcohol by azeotropic distillation), to the resulting reaction mass containing the sodium salt of pyrrolidone-2, add a quaternary ammonium salt of formula A
R-

R _″
a) where R = R _' = R _" is (triethyl chloride - C ₂ H ₅ group, R _"" is benzylammonium CH ₂ C ₆ H ₅ group, TEBAH) X is a chlorine atom,
or
b) R = R _' is a CH ₃ group, R _" is a CH ₂ C ₆ H ₅ group, (catamine AB) R _{" is a} mixture of hydrocarbons C ₁₀ -C ₁₈ , X is a chlorine atom,
or
c) R = R _' = R _" = R _"' is a C ₄ H ₉ group, the X-atom of iodine (tetrabutylammonium iodide)
taken in relation to pyrrolidone-2 in an amount of 0.5-5 mol. (preferably 1 mol.), the resulting reaction mass containing the corresponding Quaternary ammonium salt of pyrrolidone-2, is subjected to treatment with methyl or ethyl ester of monochloracetic acid at room temperature, followed by exposure at the same temperature.

 Sodium chloride formed during the reaction, precipitated as a coarse-crystalline precipitate, is filtered off, the filtrate is evaporated and the obtained technical target product is distilled in the form of a dark red liquid.

The expected products are obtained in the form of light yellow liquids with a yield, counting on starting III:
Ia- 74% b.p. 127-131 ^about C / 5 mm Hg

Ib 72-84% b.p. 120-135 ^about C / 2 mm Hg

_{______→}
где AIK, R-R_"'. Х имеют указанные значения.The scheme of the proposed method

_{______ →}
where AIK, RR _" '. X have the indicated meanings.

 The use of a quaternary ammonium salt of formula A in an amount less than 0.5 mol. (example 6, table) or more than 5 mol. (example 7), leads in the first case to a decrease in the yield of the target products, and in the second case does not lead to an increase in the yield and quality of the products.

 The novelty of the proposed method is the addition to the reaction mass containing the corresponding sodium salt of pyrrolidone-2, a quaternary ammonium salt of formula A, and in an amount of 0.5-5 mol. with respect to the starting pyrrolidone-2; alkylating the resulting reaction mass containing the corresponding quaternary ammonium salt of pyrrolidone-2 at room temperature with chloroacetic acid methyl or ethyl ester; removing formed in the form of large crystals of sodium chloride by filtration from the reaction mass containing technical product 1.

 The combination of these differences of the proposed method unexpectedly allowed a more focused and complete process and thus: to simplify the selection of target products; get high quality target products (with a basic substance content of 91-96%).

Simplification of the isolation of the target product lies in the fact that in the claimed conditions, as described above, as well as in the prototype, sodium chloride is formed along with the technical product, but unlike the prototype, it is formed in the form of large crystals that are easily removed from the reaction mass by conventional filtration, which greatly facilitates the isolation of product 1, eliminates the need for washing the reaction mass with water and, thus, the formation of large volumes of unused waste water. In addition, there is a reduction in the duration of exposure of the reaction mass at the last stage to 2 hours (in the prototype 15-20 hours) and the simplification of maintaining the temperature regime (in the prototype 0 - (- 5) ^about C, in the present method at room temperature).

 The literature describes the alkylation of pyrrolidone-2 in the aqueous alkali-benzene-quaternary ammonium salt system (10). However, these conditions turned out to be absolutely unsuitable for synthesis 1 due to the presence of aqueous alkali, which easily hydrolyzes both the starting chloroacetic ester to glycol ether, glycolic acid, chloroacetic acid, and the target product to the sodium salt of 2-oxopyrrolidinoacetic acid.

 Based on the literature reviewed on the alkylation of lactams (3-10), in particular, pyrrolidone-2, we state that the conditions for its alkylation described in this application are offered for the first time.

 It should be noted that the synthesis of piracetam in our country is based on a scarce feedstock of pyrrolidone-2, which does not allow the production of piracetam in the amount necessary for domestic health care (≈ 100 t).

 The proposed method allows to solve the problem of obtaining an intermediate for the production of a valuable drug of the nootropic action of piracetam, which is currently being purchased abroad.

 PRI me R 1. Obtaining 1-methoxycarbonylmethylpyrrolidone-2 (Ia).

To a suspension of 2.06 g (0.09 mol) sodium metal in 20 ml of dry toluene was added dropwise a mixture of 5 ml (0.12 mol) of methanol and 7 ml of dry toluene at 96-100 ^{° C} with vigorous stirring for 0.5 h The mixture is stirred at 97-98 ^about C for 1 h until the sodium is completely dissolved and 7.73 g (0.0909 mol) of pyrrolidone-2 are added to it at the same temperature. To the mixture was added 50 ml of toluene and stirring was distilled off an azeotropic mixture of alcohol and toluene in the vapor to a temperature ^of 109-110 C. Next reaktsonnuyu weight representing a toluene suspension of the sodium salt of 2-pyrrolidone was cooled to room temperature, was added 0.61 g of (2 , 7 mmol) and TEBAH thereto comprising a quaternary ammonium salt of 2-pyrrolidone was added dropwise 9.86 g (0.0909 mole) of methyl chloroacetate at 20-24 ^{° C,} kept at this temperature and stirred for 2 hours formed sodium chloride filter they are washed, washed with 100 ml of toluene, the toluene is distilled off and the resulting dark red reaction mass is distilled in vacuum.

10.4 g (73.6%) of 1-methoxycarbonylmethylpyrrolidone-2 are obtained in the form of a light yellow liquid with so on. 127-131 (5 mmHg and a basic substance content of 91.0%
PRI me R 2. Obtaining 1-ethoxycarbonylmethylpyrrolidone-2 (IB).

To a suspension of 10.3 g (0.45 mol) sodium metal in 105 ml of dry toluene was added dropwise a mixture of 32 ml (0.55 mol) of absolute ethanol and 37 ml of dry toluene at 98-101 ^{° C} and vigorous stirring for 1- 1.5 hours. the mixture was stirred at ¹⁰⁰ ° C for 1 hour until complete dissolution of sodium and poured thereto 38.25 g (0.45 mol) of 2-pyrrolidone at the same temperature. To the mixture was added 150 ml of dry toluene and stirring was distilled off an azeotropic mixture of alcohol and toluene in the vapor to a temperature ^of 109-110 C. The reaction mixture, which is a toluene suspension of the sodium salt of 2-pyrrolidone, cooled to room temperature, was added 1.02 g (4.5 mmol) of triethylbenzylammonium chloride (TEBAH) and to the reaction mixture containing the quaternary ammonium salt of pyrrolidone-2, 55.12 g (0.45 mol) of monochloracetic acid ethyl ester are added dropwise with stirring at such a rate that the temperature of the reaction mass did not exceed 26 ^{° C} and then stirred for a further 2 hours.

The precipitate of sodium chloride is filtered off, washed with 250 ml of dry toluene, the latter is evaporated. The resulting reaction mass is distilled at a temperature in pairs of 120-135 ^about C / 2 mm RT.article

64.25 g (83.5% of theory, based on pyrrolidone-2) of 1-ethoxycarbonylmethylpyrrolidone-2 are obtained, with a basic substance content of 94.9%
PRI me R 8. In conditions similar to example 2, but using tetrabutylammonium iodide in an amount of 1 molar, the desired product Ib is obtained with a yield of 72.2% and a basic substance content of 95.0%
Example 9. Under conditions similar to example 2, but using catamine AB in an amount of 1 mol. get the target product IB with a yield of 74.9% and a basic substance content of 95.6%
PRI me R 10. In conditions similar to example 2, but using methyl alcohol, get the target product IB with a yield of 79.0% and a basic substance content of 91.4%
PRI me R 11. In conditions similar to example 2, but using dry xylene as a solvent, get the target product IB with a yield of 74.2% and a basic substance content of 94.6%

Claims (1)

METHOD FOR PRODUCING 1-ALCOXICARBONILMETHYLPYRROLIDONE-2 of the general formula

where Alk is methyl or ethyl, including the interaction of pyrrolidone-2 with sodium alcoholate of the general formula NaOAlk, where Alk has the indicated meanings in a dry non-polar aprotic solvent, followed by removal by azeotropic distillation of the alcohol formed during the reaction, treatment of the reaction mixture containing the corresponding sodium pyrrolidone-2 salt, alkylation of the resulting reaction mass with chloroacetic acid methyl or ethyl ester and its subsequent exposure at room temperature, isolation of the target product the distillation of the obtained technical product, characterized in that to the reaction mass containing the corresponding sodium salt of pyrrolidone-2, add a quaternary ammonium salt of the General formula

where R = R '= R''C ₂ H ₅ group,
R '''CH ₂ C ₆ H ₅ group,
X chlorine atom (TEBAH triethylbenzylammonium chloride)
or
R = R 'CH ₃ group; R ″ CH ₂ C ₆ H ₅ group;
R ″ ″ hydrocarbon mixture C _{1 0} C _{1 8} ;
X chlorine atom (catamine A)
or
R = R '= R''= R _k ''' C ₄ H ₉ group;
X iodine atom (tetrabutylammonium iodide),
taken in an amount of 0.5 to 5 mol. in relation to pyrrolidone-2, and the resulting reaction mass containing the corresponding corresponding quaternary ammonium salt of pyrrolidone-2 is alkylated with chloroacetic acid methyl or ethyl ester at room temperature, followed by removal of the resulting sodium chloride from the reaction mass by filtration.

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