CS225847B2 - The production of new 4-polyalkoxyphenyl/-2-pyrrolidone - Google Patents

Description

A process for the preparation of racemic and optically active 4- (polyalkoxyphenyl) -2-pyrrolidones of the general formula i 'is known.

(d) where

R 1 and R 8 are the same or different and are hydrocarbon groups of up to 18 carbon atoms which are substituted by at least one halasene atom, hydroxy, carboxyl, alkoxy, carboxyamido or optionally substituted amino groups, or

R 1 and R 8 together denote an alkylene group with up to 3 carbon atoms,

R ₃ is hydrogen or methoxy,

X represents an oxygen or sulfur atom, and

R1 represents a hydrogen atom, an alkyl group, an aryl group or an ethyl group.

Said compounds of formula (I ') are valuable neuropsychotropic substances.

We have now discovered novel 4- (polyalkoxyphenyl) -2-pyrrolidones, which are similar to the aforementioned compounds of formula (I ').

The present invention relates to a process for the preparation of such novel 4- (polyelkoxyphenyl) -2-pyrrolidones of formula (I)

where

R, ε Rg · which may be the same or different denote alkyl groups having 1 to 5 carbon atoms or cycloalkyl groups having 5 or 6 carbon atoms, and

R 1 denotes amino, NH-alkyl, NH-aryl, NH-aralkyl, N-alkylg, N-arylg and alkyl /

N, wherein the alkyl group has up to 5 carbon atoms and the aryl group has up to aryl carbon atoms.

These compounds are either in racemic or optically active form.

It has now been found that the novel 4-lpolyalkoxyphenyl) -2-pyrrolidones of formula I wherein Sj is NHg-, NH-alkyl, NH-aryl, NH-aralkyl, N-alkylg, N-arylg and eryl

N, with the same phermacologically active spectrum, still have a pronounced counter-functional effect compared to the compounds of the formula I *.

The compounds of the formula I have an asymmetric carbon atom and can therefore exist as racemates as well as optical antipodes.

Suitable hydrocarbon groups R 1 and R 8 are saturated or unsaturated, straight or branched alkyl groups having 1 to 5 carbon atoms and longer cycloalkyl groups having 5 or 6 carbon atoms.

Suitable alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2-methyl-butyl and 2,2-dimethylpropyl. The alkyl groups may also be unsaturated and may be, for example, vinyl, 1-propenyl, 2-propenyl, 2-propynyl, 3-methyl-2-propenyl and the like.

When R 1 and / or R 1 in the compound of formula (I) are cycloalkyl groups, these groups contain 5 or 6 carbon atoms. Preferred are, for example, cyclopentyl and cyclohexyl groups.

Preferred are compounds of formula 1 wherein R 8 is methyl.

Racemic and optically active compounds of formula I are valuable neuropsychotropic drugs. The novel compounds have a centrally depressing, apomorphine antagonistic e entinociceptive effect and thus are somewhat similar to chlorpromazine (Modern Problem of Pharmacopsychiatry, Vol. 5, pp. 33-44: PAY Jansen, Chemical and Pharmacologiol Classification of Neuroleptics, ed. DP Bobon et al. S. Karger Verlag Basel,

Munchen, Paris, New York (1970). In contrast, however, the compounds of the invention differ from chlorpromazine by less pronounced reflex shortening, less pronounced sedative and narcotic properties, and by other kinds of influencing biogenic amines. Thus, for example, 4- (3,4-dimetexyphenyl) -2-pyrrolidone has about a 20-fold weaker barbitile effect of prolonging sleep time against chlorpromazine.

In particular, the compounds of the present invention which are substituted on the nitrogen atom of the heterocyclic ring by a carbonyl group substituted on an oxygen or nitrogen atom exhibit a marked prolonged action, with the same spectrum of action.

The beneficial properties of the novel compounds of the present invention are unexpected because, as the experiments show, the corresponding per-substituted or metasubstituted phenyl-2-pyrrolidones have a different spectrum of action, or have little effect.

For example, 4- (4-chlorophenyl) -2-pyrrolidone described in Japanese Patent No. 70 16 692 has an anti-seizure effect. The unsubstituted phenyl-2-pyrrolidones are only very poorly active.

Based on the above-described effects, the compounds of the invention can be used in the form of pharmaceutical preparations for the treatment of various neurological and psychological disorders. The pharmaceutical preparations are prepared using carriers customary for enteral or parenteral administration such as water, alcohol, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyethylene glycol and the like. The preparations may be prepared in solid form as tablets, capsules, dragees or suppositories, or in liquid form as solutions, suspensions or emulsions.

The novel compounds of the formula I are prepared by the process according to the invention by reacting 4-polyalkoxyphenyl-2-pyrrolidone of the formula II

where

R @ ₁ and R @ 8 denote either R @ ₃ and R @ 8 or hydrogen atoms, in a manner known per se, acylated by treatment with an isocyanate of the formula

RNCO where

R is chlorosulfonyl, alkyl of up to 5 carbon atoms, aryl or aralkyl of up to 8 carbon atoms, at a temperature between room temperature and the boiling point of the reaction mixture; and optionally the free amino group is alkylated, aralkylated or aryl-treated with up to 5 carbon, aralkyl halide with up to 8 carbon atoms or aryl halide with up to 8 carbon atoms in the presence of sodium hydride at a temperature between -10 ° C and room temperature.

The compounds obtained by the process according to the invention in which R @ 1 or R @ 8 are hydrogen must finally be converted by O-alkylation to the final products of formula I. The alkylation is preferably carried out with the corresponding R @ 1 -halogen or R @ 8 -halogenide; -tosylethy in a manner known per se. Suitable halides are chlorides, bromides or iodides. In alkylation, the starting compound is dissolved, for example, in a polar solvent, and heated in the presence of a base with an eluting agent at a temperature in the range of 30 to 50 ° C. Suitable bases are, for example, sodium hydroxide, potassium carbonate, an alkali metal alkoxide such as sodium ethoxide, potassium butoxide and potassium tert-butoxide. Suitable polar solvents are dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ketones such as acetone and methyl isobutyl ketone, as well as alcohols such as ethanol, butanol and tert-butanol.

The starting compound of formula (II) may be prepared by methods known per se, for example by treating the starting benzaldehyde substituted with R (and Rg) with an alkyl malonic ester to form the corresponding benzalmalonate dialkyl ester. tetramethylguenidine via dialkyl ester, - (substituted phenyl) -2-nitroethyl malonic acid, and then pressurized hydrogenation using Raney nickel to 4- (substituted phenyl) -2-pyrrolidone-3-carboxylic acid alkyl ester of formula II.

The reaction starting from the substituted benzaldehyde leading to the compound of formula II is illustrated by the following reaction scheme:

njo.

(II)

The following explanation is given in relation to the examples.

Conventional work-up means extraction with the solvent, washing of the organic phase with saturated sodium chloride solution, drying over anhydrous calcium sulphate and evaporation in vacuo at a bath temperature of 40 to 45 ° C. Particular reference is made to post-treatment of the organic phase, such as acid washing or with a hydroxide solution.

The reported yields are not optimal values because optimization tests have not been performed.

Temperatures are always given in degrees Celsius.

Substances used as crude products shall be tested by thin-layer chromatography, in at least two systems, and by means of IR spectra, not of satisfactory purity. All other substances are analytically pure (determination of carbon, hydrogen, nitrogen; iC, UV, NMR spectra; thin-layer chromatography; partly by titration e by gas chromatography).

From the melting point determined in the Kofler block, the solvents used for recrystallization are indicated in brackets.

For example, the compounds of formula (II) may be prepared as follows:

A. Benzalmalonic acid diethyl ester of the correspondingly substituted benzaidehyde is heated with 1 60 g (1 mol) of diethyl melonate, 30 ml of glacial acetic acid and 3 ml of piperidine in one liter of benzene until 1 mole of water is removed on a water separator. The benzene solution is worked up in a conventional manner.

The 3-isobutoxymethoxybenzeldehyde not yet described in the literature is prepared as follows:

108 g (710 mol) of 3-hydroxy-4-methoxybenzeldehyde are heated with 40.5 g (723 mol) of potassium hydroxide and 120 g (675 mol) of isobutyl bromide in 250 ml of ethanol, with stirring and boiling for 26 hours. After distilling off the alcohol in vacuo, the residue was treated with ethyl acetate in the usual manner, but additionally washed with 2N sodium hydroxide. 35 g of starting material are obtained from the alkaline extract by acidification. The yield of 3-isobutoxy-4-methoxybenzaldehyde is 40 g. Melting point: 70 ° C (heptene).

The yield and boiling points and melting points of some compounds are summarized in the following table.

ORi R ₂ ⁼ ^, COOC ₂ H ₅ ^C ₂ H ₅ COOC *and R ' Yield ($ theory) Boiling point (° C / Pa) Melting point (recrystallizing agent) and -CHj -ch ₃ 70 188-189 ° C / 67 Pa b -CHj- 53 172 ° C / 53 mbar C -CHgCHg- 88 227-289 ° C / 133 Pa d -ch ₂ ch (ch ₃ ) ₂ -ch ₃ 95 190-192 ° C / 13 Pe E -H -ch ₃ 78 213 to 215 ° C / 133 Pa mp 86 ° C (diisopropyl ether) F -ch ₃ -H 77 mp 121 ° C (diisopropyl ether)

B. (- (substituted phenyl) -2-nitroethyl malonic acid diethyl ether)

500 mmol of the corresponding benzalmalonic acid diethyl ester (see A) are dissolved in 250 ml of nitromethene and 12.7 ml of tetramethylguanidine are added under stirring at 0 ° C. After the exothermic reaction subsided, the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was treated with ethyl acetate in a conventional manner, but additionally washed with 2 N-hydrochloric acid.

The acetoxymethoxybenzelmalonic acid ester required for Examples Bb) and Bc) is prepared as follows:

150 g (510 mol) of (3-hydroxy-4-methoxybenzyl) malonic acid diethyl ester (see Ae) are dissolved in 450 ml of pyridine and 57 ml (604 mmol) of acetic anhydride are added dropwise under ice-cooling. After standing at room temperature for 16 hours, pyridine was removed in vacuo. Usual work-up with ethyl acetate gave 163 g (95% of theory) of (3-acetoxy-4-methoxybenzal) malonic acid diethyl ester. Mp 75-77 ° C (diisopropyl ether).

(4-Hydroxy-3-methoxybenzal) malonate (see Af) is analogy to the corresponding 4-ethyl-3-methoxy derivative. The yield is 95 DEG C., m.p. 5.00 DEG C. (diisopropyl ether-petroleum ether).

OFtj

2 ° - <0 ° -CHCH

CH,

In no ₂ / COOC ₂ H ₅ • COOC ₈ H ₈

^R í ^S 2 Yield (S5 theory) Melting point (recrystallizing agent) (B) -ch ₃ -CH ₃ 59 75 ° C (methylene chloride diiso-, propyl ether) b -coch ₃ -ch ₃ 95 Crude product (thin film, iC) O -CH ₃ -COCH ₃ 95 Crude product (thin layer, whip)

C. 4- (Substituted-phenyl) -2-pyrrolidone-3-carboxylic acid ethyl ester

300 mmol of the corresponding 1-phenyl-2-nitroethylmalonic acid diethyl ester are dissolved in 700 ml of methanol and hydrogenated with approximately 10 g of Raney nickel at 60 ° C and 9.5 MPb until 3 moles of hydrogen are taken up. The catalyst is filtered off, the filtrate is evaporated under vacuum and the oily residue is recrystallized.

^K í ^R 2 Yield (IT theory) Melting point (recrystallizing agent) and -CH ₃ -ch ₃ 84 106 ° C (ethyl acetate) b -H -CH ₃ 70 125 ° C (ethyl acetate-diisopropyl ether). (removal of the acetyl group in acetylic acid and treatment) C -ch ₃ -coch ₃ 62 172 ° C (ethyl acetate)

D. 4- (Substituted phenyl) -2-pyrrolidone

This compound is obtained in a manner known per se by saponifying the ethyl 4- (substituted phenyl) -2-pyrrolidone-3-carboxylic acid ethyl ester at the 3-position of the pyrrolidone ring and de7 carboxylating it from the removal of the COOC3H3 group. The compound produced is used as the starting material of formula II.

The invention is illustrated by the following examples.

Example 1

0.221 g of 4- (3,4-dimethoxyphenyl) -2-pyrrolidone was mixed with 3 ml of chlorosulfonylisocyanate and the reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was further treated with common methylene chloride and purified by chromatography on a silica gel column using chloroform-acetone (1: 1). 0.026 g of 4- (3,4-dimethoxyphenyl) -2-pyrrolidone-1-carboxylic acid amide, m.p. 125 DEG-127 DEG C. (methanol), is obtained.

Example 2

Amides, 4- (3,4-dimethoxyphenyl) -2-pyrrolidone-1-carboxylic acid

2.21 g of 4- (3,4-dimethoxyphenyl) -2-pyrrolidone are mixed with an excess (about ten-fold) of the isocyanate of formula R-NCO and the reaction mixture is heated at reflux for 2.5 hours. The reaction mixture was then evaporated in vacuo.

Depending on the isocyanate used, the following 1-carboxylic acid amides are obtained

R Yield Melting point ° C (recrystallize begin means) -CHj 1,47 g 95 to 98 (ethyl acetate-diisopropyl ether) cn ₃ -CH 1.53 g 105 to 107 (ethyl acetate-petroleum ether) ch ₃ - <2> 2.62 g 110 to 112 (ethyl acetate-petroleum ether) -ch ₂ - <@> 2.8 g oil product

SUBJECT OF THE INVENTION

Claims (1)

Process for the preparation of novel 4- (polyalkoxyphenyl) -2-pyrrolidones of the general formula I (I) 225647 where Ri and _R2, which may be the same legs it different, represent an alkyl radical containing 1 βϊ 5 carbon atoms or cykloelkylové groups with 5 or 6 carbon atoms e R 6 denotes amino, NH-alkyl, NH-eryl, NH-alkyl, N-alkyl, N-eryl and alkyl N, wherein the alkyl group has up to 5 carbon atoms and the aryl group has up to 5 aryl 8 carbon atoms, characterized in that 4- (polyalkoxyphenyl) -2-pyrrolidone of the general formula XI wherein: R @ 1 and R @ 2 denote either R @ 1 and R @ 3 or hydrogen atoms, silylated by the action of an isocyanate of the formula RNCO where R represents a chlorosulfonyl group, an alkyl of up to 5 carbon atoms, an aryl or eralkyl of up to 8 carbon atoms, at a temperature between room temperature and the boiling point of the reaction mixture and optionally the free amino group is alkylated, aralkylated or , an alkyl halide of up to 8 carbon atoms or an aryl halide of up to 8 carbon atoms in the presence of sodium hydride at a temperature between -10 ° C and room temperature.