CS268274B1 - Process for preparing heterocyclic lactam esters - Google Patents

Abstract

Heterocyclic lactam esters of the general formula I represent important intermediates in the synthesis of biologically active substances for the pharmaceutical industry. These compounds are newly prepared by reacting acid esters of the formula II with acid chlorides, for example oxalyl chloride or thionyl chloride, in an aromatic hydrocarbon, such as benzene or toluene, and then with a tryptamine salt of the formula III in a two-phase mixture of a chlorinated hydrocarbon, for example methylene chloride or chloroform, and an aqueous solution of sodium or potassium carbonate or bicarbonate. The tryptamine esters of the formula IV obtained are then cyclized by the action of an acid in an organic solvent at boiling temperature, in particular p-toluenesulfonic acid in toluene or xylene, or hydrogen chloride in an alkanol.

Description

The invention relates to a process for the preparation of heterocyclic lactam esters of the general formula I.

in which R represents an alkyl group having 1 to 4 carbon atoms.

The compounds of the formula I are known and are important intermediates in the production of biologically active substances for the pharmaceutical industry.

By a method known from the literature (Czech Patent No. 224980), the compounds of general formula I are prepared by condensing ryptamine with dialkyl-4-oxoheptanedioates in a high-boiling organic solvent. According to a second process known from the literature (Czech Patent Certificate No. 224981), the compounds of formula I are prepared by heating tryptamine first with hydrochelidonic anhydride and then with an alcohol in the presence of an acid. The disadvantage of both processes lies in the long reaction time at high temperatures and the need for chromatographic purification of the products.

The essence of the process according to the invention lies in the fact that the ester acids of the general formula II

R-OOC.CH ₂ .CH ₂ . CO.CH 2 .CH 2 .COOH (II), in which R represents an alkyl group having 1 to 4 carbon atoms, are reacted with acid chlorides, and then with a tryptamine salt of general formula III

(III).

in which HX denotes an inorganic acid, for example hydrochloric or sulfuric acid, in the presence of an acid scavenger, and the tryptamide esters of formula IV obtained

(IV).

in which R is as defined above, are cyclized by the action of H ⁺ as a catalyst in an organic solvent at the boiling point of the mixture.

For example, oxalyl chloride or thionyl chloride in an aromatic hydrocarbon medium such as benzene or toluene, at a temperature of 15 to 70 ° C, is used to react the compounds of the formula II with acid chlorides.

The conversion of the tryptamine salt of formula III to the tryptamide ethers of formula IV, which are novel, is carried out at 0-25 ° C in a biphasic mixture of a chlorinated aliphatic hydrocarbon, such as methylene chloride or chloroform, and an aqueous solution of an inorganic base such as carbonate or bicarbonate. metal, in particular

CS 268274 B1 potassium carbonate or sodium bicarbonate.

In the cyclization of tryptamide esters of the formula IV, organic sulfonic acids, in particular p-toluenesulfonic acid, in an aromatic hydrocarbon, for example toluene or xylene, or inorganic acids, in particular hydrochloric or sulfuric acid, in an alkanol having 1 to 4 carbon atoms, for example in ethanol or butanol.

According to a preferred embodiment of the process according to the invention, the tryptamide esters of the formula IV are not isolated but are directly cyclized.

The process according to the invention is variable in that tryptamine base (III, HX electron pair) can be used instead of the tryptamine salts of the formula III.

The advantage of the process according to the invention is that it uses a tryptamine salt of the formula III, which eliminates the need to pre-release tryptamine from the salt of the formula III in comparison with previous processes for the preparation of the compounds of the formula I. It has been found that the compounds of the formula I can be prepared under milder conditions and in a simple manner a high purity of the reaction products can be obtained without the need to purify these chromatographs.

Alternatively, the compounds of formula IV can also be prepared by using tryptamine and working in an anhydrous solvent. The disadvantage of this process, while providing comparable yields, is the need to dry the solvent, and in addition to the use of tertiary organic bases, such as triethylamine or pyridine, as the scavenger of hydrogen chloride.

The following examples illustrate, but do not limit, the generality of the production method according to the invention.

Example 1

a) Type of tamid-ethyl ester (compound of formula IV, where R - CgHg) ^{Ke 3, n} ® ^si 9 (38.3 mmol) ethyl ester (II, R · C ₂ H ₅ ) and benzene (42 ml) 3.95 ml (i.e. 1.2 equivalents) of oxalyl chloride are added. After the turbulent foaming subsided (approx. 1.5 h), the reaction mixture was cooled to 15 ° C, slowly (approx. 1 h) heated to 50 ° C and maintained at this temperature for 1 h. The reaction mixture was evaporated on a rotary evaporator 25 ml of toluene are added to the residue and the solution is again evaporated in vacuo. The residue is dissolved in 10 ml of methylene chloride and added dropwise over 10 minutes to a biphasic mixture of 7.37 g (37.5 mmol) of tryptamine hydrochloride (III, HX · HCl), 6.35 g (46 mmol) of potassium carbonate and 150 ml of methylene chloride. and 100 ml of water at 0 ° C. The cooling bath was removed and the reaction mixture was stirred for an additional 35 minutes while warming to 20 ° C. The organic phase is then separated and washed successively with 100 ml of 3% hydrochloric acid solution, 30 ml of water and 30 ml of brine. After drying over sodium sulfate, the methylene chloride is concentrated on a rotary evaporator in vacuo and the residue is crystallized from ethyl acetate or benzene. 7.1 g (55.1%) of crystals with a melting point of 99.5-100.5 DEG C. are obtained, which are homogeneous according to thin-layer chromatography.

b) Lectam ethyl ester (compound of formula I, where R · CgHg) 0.69 g (2 mmol) of tryptamide ethyl ester (IV, R »CgHg), ^m 9 of p-toluenesulphonic acid and 9 ml of xylene are heated to gentle boiling, kept at this temperature it cools down. To the reaction mixture were added 15 ml of chloroform and 10 ml of 2% sodium hydroxide solution, and after shaking, the organic phase was separated. After washing with 10 ml of water and drying over magnesium sulphate, the organic phase is evaporated in a water pump vacuum. The residue is recrystallized from benzene or ethyl acetate. 0.57 g (88.4%) of crystals with a mp of 196-198.5 ° C are obtained.

Example 2

To a solution of 2.3 g (10 mmol) of butyl ester (II, R · C 2 Hg) in 20 mL of toluene at 20 ° C was added 2.3B g of thionyl chloride. The solution is heated to 70 DEG C. for 1.5 hours and maintained at this temperature for 0.5 hours. The reaction mixture is then evaporated in vacuo, the residue is not diluted with 15 ml of toluene and again evaporated on a rotary evaporator. A solution of the residue in 5 ml

CS 26-274 B1 chloroform ββ is added dropwise over 5 minutes to a biphasic mixture of 1.97 g (10 mmol) of tryptamine hydrochloride (III, HX »HCl), 2.52 g (30 mmol) of sodium bicarbonate, 30 ml of chloroform and 50 ml of water at 25 ° C. After 30 minutes, stirring was stopped and the reaction mixture was worked up as in Example 1a. 38.7% (1.44 g) of a glassy tryptemide butyl ester (IV, R <1> Hg) are obtained, which is homogeneous according to thin-layer chromatography.

Example 3

Following the procedure of Example 1a, except that instead of tryptamine hydrochloride, t-typt amine hydrosulfate (111, HX &lt; + &gt; crude tryptamide methyl ester (IV, R · CH 2), which does not crystallize but directly dissolves in methanol containing 5% hydrogen chloride. The solution was heated to reflux for 2 h and evaporated on a vacuum evaporator. The crystalline residue was recrystallized from ethyl acetate to give 49.8% of lactam methyl ester (1, R 2 CH 2), m.p. 179-180.5 ° C.

Example 4

Following the procedure of Example 1a, except that toluene was used instead of benzene at 25-60 ° C, a glassy tryptamide propyl ester (IV, R, C ?) in a yield of 53.3%; The product is uniform by thin layer chromatography.

Example 5 '

To a solution of tryptamide 1-propyl ester (IV, R 2 Cl 2 H 2 O) in propanol was added 1% v / v concentrated sulfuric acid and the mixture was heated to reflux for 0.5 h. sodium hydroxide uses sodium carbonate. 89.1% of a glassy lactampropyl ester (I, R &lt; + &gt;

Example 6 ·

Following the procedure of Example 1b, except that methanesulfonic acid was used instead of p-toluenesulfonic acid, lactam-butyl ester (I, R < , 0% in the form of transparent glass.

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of heterocyclic lactam esters of the general formula I in which R represents an alkyl group having 1 to 4 carbon atoms, characterized in that the ester acids of the general formula II R-00C.CH ₂ .CH ₂ .CO.CH ₂ .CH ₂ .COOH (II). in which R is as defined above, are reacted with acid chlorides, and then with tryptamine salts of formula III CS 26Θ274 Bl (HI). in which HX represents an inorganic acid, for example hydrochloric or sulfuric acid, in the presence of a scavenger, and the tryptamide esters of formula IV in which R is as defined above are cyclized by treatment with H as a catalyst in an organic solvent at the boiling point of the mixture. 2. A process as claimed in claim 1, wherein, for example, oxalyl chloride or thionyl chloride in an aromatic hydrocarbon medium, such as benzene or toluene, is used to react the ester acids in the formula II with acid chlorides at a temperature of 15 to 70 ° C. 3. A process according to claim 1, wherein the conversion of the tryptamine salt of formula III to tryptamide esters of formula IV is carried out at 0 to 25 ° C in a biphasic mixture of a chlorinated aliphatic hydrocarbon such as methylene chloride or chloroform, and an aqueous solution of an inorganic base, for example an alkali metal carbonate or bicarbonate, in particular potassium carbonate or sodium bicarbonate. 4. The process according to claim 1, wherein in the cyclization of the tryptamide esters of the formula IV, for example, organic sulfonic acids, in particular p-toluenesulfonic acid, in an aromatic hydrocarbon, for example toluene or xylene, or an inorganic acid are used as source H. in particular hydrochloric or sulfuric acid, in an alkanol having 1 to 4 carbon atoms, for example in ethanol or butanol. 5. The process according to items 1 to 4, characterized in that the tryptamide esters of the general formula IV are directly cyclized.