CS231956B2 - Manufacturing process of oktahydrooxazolo(3,2-a)porrolo(2,1-c)pyrazine derivatives - Google Patents

Abstract

Title cpds of formula (I) (where R1 is cyano or -COX; X is amino or lower alkoxy; R2 is lower alkyl;: R3 is H or lower alkyl; R4 is H, lower alkyl, phenyl or benzyl opt. substd by 1 lower alkoxy, and R5 is H or lower alkyl) are prepd by the intramolecular condensation of (II) (where R6 is a gp. readily eliminated under the reaction conditions). (I) are inters for ergot alkaloids having activity on the central and peripheral circulation.

Description

The present invention relates to a process for the preparation of octahydrooxazolo [3,2-a] pyrrolo [2,1-c] pyrazine derivatives.

The only synthesis so far for the preparation of compounds with a backbone corresponding to formula I is described by A. Hofmann et al in Helv. Chim. Acta 46, 2306 (1963). This synthesis proceeds through a series of steps, in particular the acylation of the corresponding diketopiperazines and subsequent cyclization to the cycloesters have proved critical.

The cyclization of the invention has not been described in the literature. The only known cyclization method, which is approximately comparable to that of the present invention, is described by G. Lucent in Chemical Communications (1971) 1605. It allows the preparation of azocyclols, but only when the amino group of the starting material is activated.

The 2-hydroxy group of the compounds of formula II which are used as starting materials according to the invention need not be activated. The cyclization of the present invention yields the desired compounds of formula I in yields greater than 70%.

Another advantage of the process according to the invention is that the compounds of formula II are easy to purify, which is not possible with the starting materials (acylated diketopiperazines) used in the process described by A. Hofmann.

The present invention provides a process for the preparation of octahydrooxazolo [3,2-a] pyrrolo [2,1-c] pyrazine derivatives of the general formula I

in which

R 1 is cyano or -COX, wherein X is amino or C 1 -C 6 alkoxy,

R 2 represents an alkyl group having 1 to 5 carbon atoms,

R 3 is hydrogen or C 1 -C 5 alkyl,

R 4 is C 1 -C 6 alkyl, benzyl or C 1 -C 4 alkoxy monosubstituted benzyl; and

R 5 is hydrogen or C 1 -C 5 alkyl.

The alkoxy group in the —COX group, which is defined by the meaning of the symbol R1, content

319-5 is 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and especially 1 or 2 'carbon atoms.

The alkyl groups R @ 2, R @ 5 and R @ 6 contain from 1 to 5 and 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. carbon.

When R3 and R5 are alkyl, these are preferably methyl.

The alkyl group R 4 may contain 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Alkoxy as a possible substituent of the benzyl group R @ 4 preferably contains 1 to 4 carbon atoms and is especially methoxy.

According to the invention, the compounds of formula (I) are obtained by the compound of formula (II)

in which

R 1, R 2, R 3, R 4 and R 5 are as defined above and

R6 is pentafluorophenoxy or pentachlorophenoxy, N-succinimidoxy, phenylthio or p-chlorophenylthio, or optionally a nitro- or / or methyl- or chloro-mono- or disubstituted nitrophenoxy group, subjected to intramolecular condensation.

The cyclization according to the invention is largely dependent on the solvent used, the temperature, the degree of dilution as well as the strength of the base; these factors interact.

Thus, the choice of bases or the intensity of the bases is dependent in particular on the solvent chosen: while strong bases can be used in the anhydrous, aprotic medium, cyclization in the aqueous medium is expediently carried out under gentle conditions. compounds. of formula I wherein R 1 is a carboxyl group and these acids can be very difficult to isolate from the reaction mixture.

The cyclization according to the invention is conveniently carried out in a polar solvent.

Suitable aprotic polar solvents are, for example, dimethylsulfoxide, hexamethylphosphoric triamide, acetonitrile, organic carboxylic acid di- (lower alkylamides) such as dimethylformamide, and the like.

The strong bases which can be used in cyclization in anhydrous aprotic media are bases which can deprotonate the nitrogen atom adjacent to the \

CR3R4

And which do not react with carboxyl groups such as alkali metal hydrides such as sodium hydride, alkali metal alkoxides such as sodium ethoxide, etc.

When an alkali metal alkoxide is used as the base, when X is a lower alkoxy group, an alkoxide corresponding to the alcohol HX is expediently used (otherwise, esterification occurs). For a similar reason [reaction R 1 = COO- (lower) alkoxy to R 1 = CONH 2], alkali metal amides are also expediently not used as the base. In this embodiment of the process, preferably 1 to 1.5 mol of strong base per 1 mol of compound II is used.

Auxiliary solvent is expediently used in aqueous cyclization.

Suitable solvents which are inert under the reaction conditions and which are miscible with water are, for example, dimethylsulfoxide, dimethoxyethane, open-chain or cyclic ethers, such as dioxane or tetrahydrofuran, difunctional organic carboxylic acid alkylamides, such as dimethylformamide, etc.

For the above reasons, the cyclization according to the invention is carried out in an aqueous medium under weakly basic conditions, in particular at pH values of 8 to 10.

A suitable buffer solution is, for example, a borate, carbonate or phosphate buffer with hydroxyl ions. Particularly suitable is the use of borate buffer (pH = 9) with the addition of a catalytic amount of 2-hydroxypyridine.

Good results are obtained at a reaction temperature between about 0 and 30 ° C. Suitably, the reaction is carried out at room temperature, and if the reaction is carried out in an anhydrous environment, it is suitable to work with stirring.

The reaction temperature is dependent on the other reaction conditions and the importance of the substituents in Formula II. It can vary from 1 to 10 hours.

Working up the obtained reaction mixture to isolate the desired reaction products. may be carried out in a manner known per se. for example by extraction and optionally subsequent chromatography.

The starting materials of formula (II) are novel and their preparation also forms part of the invention.

The compounds of formula II are obtained by reacting the acid of formula III

U < ^00H

R.-C-OH R, 7V ¹¹

C-NH-C o

1I in which

R 1 to R 5 are as defined above, with a compound of formula IV

Re-H (IV) wherein

R e is as defined above, or - a compound of formula IVa

O

II

Re-S-Re (IVa) wherein

R6 is as defined above.

The reaction of compounds of formula III with compounds of formula IV or IVa can be carried out by methods known per se. The reaction with the compound of formula (IV) is carried out, for example, in the presence of dicyclohexylcarbodiimide. Preferably an excess of the compound of formula IV is used. The reaction with a compound of formula IVa is carried out, for example, in the presence of a weak tertiary organic base such as pyridine or its homologues.

The compounds of formula II thus obtained can be isolated from the reaction mixture in a manner known per se.

Compounds of formula III are also novel, according to the invention obtained by d6b6деy) l ^and TO, THE Formula V [-1 ,, (: 00 (¾¾

R @ + _- R @ R @ 7

1I

(PhytV) in which

R1 to R5 are as defined above and

R 7 is hydrogen or benzyl.

The debenzylation of the compounds of formula V can be carried out by methods known per se. The hydrogenolytic cleavage of the benzyl group (s) is preferably carried out by hydrogenation in the presence of a noble metal catalyst, preferably palladium, on a suitable support such as carbon. Suitable solvents are, for example, glacial acetic acid or ethanol or a mixture of the two, but preferably ethyl acetate, in particular for the debenzylation of compounds of formula V in which R2 is an isopropyl group.

Compounds of formula V can be obtained, for example, as follows:

The tartronic acid derivative of the formula knows

R2

AND

R1-C-OH

COOH (VI) in which

R 1 and R 2 are as defined above or of formula VII

R2

R1 — C — OCH2C6H5 (VII)

I c — z <II o

in which

R 1 and R 2 are as defined above - a

Z is an active acid component, for example halogen, preferably chlorine, is condensed with an amino acid benzyl ester of formula VIII

Rs

H2N — C — COOCH2C6H5 (VIII)

AND

R4 in which

R 3 and R 4 are as defined above, according to methods customary in peptide chemistry, for example by carbodiimide synthesis to give compounds of formula VI or preferably in the presence of N-ethyldiisopropylamine, in the presence of a suitable solvent, such as. for example mixtures of methylene chloride and dioxane or dimethoxyethane. Thereafter, from the compound of formula IX obtained

R2

AND

R1 — C — OR7 R3 (IX)

C-NH-C-COOCH 2 C 6 H 5

About R4 in which

R1 to R4 and R7 are as defined above, cleaving the benzyl group or benzyl groups as capping groups, i.e. optionally the esterbenzyl group and the optionally present ether-benzyl group simultaneously or optionally selectively only the esterbenzyl group by hydrogenolytic methods known per se, preferably catalytic by hydrogenation with palladium on carbon, for example in glacial acetic acid or ethanol or in a mixture of both solvents, but preferably in ethyl acetate, especially for a compound of formula IX in which R2 is an isopropyl group and the free acid of formula X obtained

R2

R1 — C — OR7 R3 I I

C — NH — C — СООН

O Ré (X) in which

R1 to R4 and R7 are as defined above, condensed with a compound of formula XI

соосн ^ с ₆ ин ₅

R ₅ in which

R 5 is as defined above, by methods customary in peptide chemistry, for example by carbodiimide synthesis, in the presence of a suitable solvent such as methylene chloride, dioxane or dimethoxyethane at room temperature, preferably 1-hydroxybenzotriazole may be added in at least equimolar amounts to avoid possible racemization. .

Part of the compounds of formula I produced by the process of the invention is novel. These new compounds are listed in the following table:

H (XIII

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The synthesis of compounds of formula I is significant with respect to the synthetic preparation of ergot-type peptide alkaloids. In the compounds of formula I, it is possible to:. the residue R 1 = COO (lower) alkyl can be converted to the amino group by known methods. Conversion of compounds of formula I wherein R 1 is carboxamido or cyano to the corresponding amino derivatives can also be carried out by methods known per se. Also, the reaction of the salts of the 2-amino derivatives of the compounds of formula I with lysergic acid or derivatives thereof can be carried out by methods known per se.

As far as the pharmacodynamic effects are concerned, these peptide alkaloids have known effects on the central nervous system and affect both the central,. as well as the peripheral circulatory system. Thus, for example, they exhibit both serotoninantagonist activity and further have a vascular toning effect and block α-receptor activity.

The starting materials are either known or can be prepared by methods known per se or analogously to the methods described herein or analogously known per se.

In the following examples, which illustrate the process of the invention in more detail, all temperatures are in degrees Celsius.

Example 1

2-ethoxycarbonyl-2-methyl-5-benzyl-10b-hydroxy-3,6-dioxooctahydro-8H-oxazolo [3,2-a] pyrrolo [2,1] pyrazine

To 10.54 g (20 mmol) of N- [- 2R-2-liyroxy-2-ethoxycarbonylpropionyl) -L-phenylailainyl-L-proline p-nitrophenyl ester in 250 ml of absolute dimethylformamide is added 5 g at room temperature. Linde molecular sieve and the mixture is stirred for 1515 minutes. Sodium hydride (25 mmol, for example 950 mg (63% oily suspension)) is then added and the reaction mixture is stirred for 2 hours at room temperature with the exclusion of moisture, and most of the solvent is distilled off under vacuum. After cooling, about 50 ml of ethanol are added to decompose and the mixture is immediately poured into cooled 1 N sodium carbonate solution, the reaction mixture is well extracted with chloroform and washed twice with 1 N sodium carbonate solution. m.p. 134 DEG-136 DEG C., [ _.alpha .] _D @ 20 = -25.2 DEG (c = 1.5 in ethanol).

The N- (2R-2-hydroxy-2-ethoxycarbonylpropionyl) -L-phenylanynyl-L-proline p-nitrophenyl ester used as starting material is prepared, for example, as follows:

(a) N- (2R-2-benzyloxy-2-ethoxycarbonylpropionyl) -L-phenylalanine benzyl ester

To 12.75 g (50 mmol) of L-phenylalanine benzyl ester in 25 ml of absolute methylene chloride was added at 0 ° C. 12.9 ml (75 mmol) of N-ethyldiisopropylamine. A solution of 13.5 g (50 mmol) of S- (+) - methylbenzyloxymalonic acid monoethyl ester chloride in 50 ml of absolute methylene chloride is then added dropwise with stirring, and the mixture is stirred at 0 [deg.] C. for 1 hour. For working-up, the reaction mixture is washed cold with saturated sodium bicarbonate solution. Subsequent extraction with methylene chloride, drying over sodium sulfate and evaporation of the solvent gave the title compound as an oily residue, which was further processed immediately. [ _.alpha. ] _{D @} 20 = + 39 DEG (c = 2, chloroform).

b) N- (2R-2-hydroxy-2-ethoxycarbonyl) -L-phenylalanine

In order to cleave the benzylic capping groups, the oily residue obtained in step a) is dissolved in 450 ml of ethyl acetate and hydrogenated using 10 g of palladium on carbon catalyst (10% palladium) at atmospheric pressure and at room temperature. After 8 to 16 hours about 2.2 liters of hydrogen are consumed. The mixture was filtered and the filtrate was concentrated to give the title compound as a colorless resin.

brucine salt:

110 DEG-112 DEG C., [ _.alpha. ] _D @ ²⁰ = + 29.8 DEG (c = 1, chloroform).

c) N- (2R-2-hydroxy-2-ethoxycarbonylpropionyl) -L-phenylalanyl-L-proline benzyl ester g of the resin obtained in step b) is dissolved in 300 ml of ethyl acetate at room temperature and after addition of 13.5 g ( 0.1 mol) of 1-hydroxybenzotriazole (dried or moisture content) was stirred for 10 minutes. 10.3 g (50 mmol) of dicyclohexylcarbodimide are then added to the almost clear solution and the mixture is stirred for a further 10 minutes. Finally, 10.3 g (50 mmol) of L-proline benzyl ester in 50 ml of ethyl acetate are added dropwise over 5 minutes and the mixture is stirred for a further 90 minutes. After filtering off the precipitate, the filtrate was evaporated and the residue taken up in ether to remove the last traces of dicyclohexylcarbodiimide by crystallization. The filtrate was washed with cold 1 N hydrochloric acid solution, sodium bicarbonate solution - and ice water. After drying over sodium sulfate and distilling off the solvent, the title compound remains as a gummy residue.

d) N-- (2R-2-hydroxy-2-thoxycarbonylpropionyl) -L-phenylalanyl-L-proline

The above ester (c) is dissolved in 300 ml of ethyl acetate and the solution is hydrogenated as described in step b) with 5 g of palladium on carbon catalyst (10% palladium). After the same treatment, a colorless resin is obtained which is further processed as such in the next step.

e) N-2R-hydroxy-2-ethoxycarbonylpropionyl) -L-phenylalanyl-L-proene p-nitrophenyl ester

16/5 g of the acid obtained in step c) are dissolved in 403 ml of ethyl acetate as obtained, 13.9 g (C11 mol) of p-nitrophenol and 10.3 g (0.05 mol) of dicyclohexylcarbodiimide are added successively. After stirring at room temperature for 1 hour, the mixture was filtered and the filtrate was evaporated. The residue was dissolved in chloroform, and the chloroform solution was washed thoroughly with 1N sodium bicarbonate solution. After drying over sodium sulfate, and after evaporation of the solvent, the oil crystallized first. the title compound from a mixture of methylene chloride and ether. Yellow crystals are obtained which are dissolved in ethyl acetate for further purification. The insoluble components are filtered off, the filtrate is gently evaporated and the residue is recrystallized again from isopropyl ether. After drying at 60 ° C under high vacuum to obtain slightly yellow crystals, mp 121-123 ° C, [a] at ²⁰ - 60 ° с ~ 1 chloroform-un.] ..

Example 2

2-ethoxycarbonyl-2-methyl-5-benzyl-10b-hydroxy-3,6-dioxooctahydro-8H-oxazolo [3,2-a] pyrrolo [2,1-c] pyrazine

The procedure is analogous to Example 1 and cyclization of N- [2R-2-hydroxy-2-ethoxycarbonylpropionyl] -L-phenylanynyl-L-proline 2,4-dinitrophenyl ester [mp 125-155 ° C from ether; [ _.alpha. ] _D @ ²⁰ = -64 DEG (c = 1, chloroform) to give the title compound, m.p. 134-136 DEG C., [ _.alpha. ] _D @ ²⁰ = -25.2 DEG (c = 1.5, in ethanol) .

The ester used as the starting material is obtained in an analogous manner to that described in step e) of Example 1 by reacting the acid with 18.4 g (0.1 mol) of 2,4-detrtrophenol.

Example 1 a d 3

2-ethoxycarbonyl-2-methyl-5-benzyl-10b-hydroxy-3,6-dioxoctahydro-8n-oxazolo [3,2-a] pyrrolo [2 _; 1c] -pyrazine

The procedure is analogous to Example 1 and the cycling of N- (2H-2-hydroxy-2-ethoxycarbonylproplonyl) -L-phenylalanyl-L-proline (mp 140-141 degrees Celsius from ether). [a] _D ²⁰ - -38 ° (c ~ = 1, chloroform)] gave the title compound, mp 134-136 ° C; [a] _D ²⁰ = -25.2 ° (c = 1.5 in ethanol).

The ester used as starting material was obtained in an analogous manner to that described in step e) of Example 1 by reaction of the acid with 19.8 g (0.1 mol) of 4,6-dmitro-o-cresol.

Example 4

2-ethoxycarbonyl-2-methyl-5-benzyl-10b-hydroxy-3,6-dioxooctahydro-8H-oxazolo [3,2-a] pyrrolo [2,1-c] pyrazine

The procedure is analogous to Example 1 and cyclization of N- (2R-2-hydroxy-2-ethoxycarbonylpropionyl) -L-phenylanynyl-L-proline pentachlorophenyl ester [t. 1.140-142 ° C from a mixture of ether and isopropyl ether); [ _.alpha. ] _D @ ²⁰ = -27 DEG (c = 1. chloroform)] yields the title compound, m.p. 134-136 DEG C., [ _.alpha. ] _D @ ²⁰ = -25.2 DEG (c = 1.5, in ethanol).

The ester used as starting material is obtained analogously to step e) of Example 1 by reaction of the acid with 26.6 g of pentachlorophenol.

Example 5

2-ethoxycarbonyl-2-isopropyl-5-benzyl-10b-hydroxy-3,6-dioxoooctahydro-8H-oxazolo [3,2-a] pyrrolo [2,1-c] pyrazine

By the method described in Example 1, the title compound is obtained by crystallization of N-N- (K-2-oxo-2-sdoxycarbonylisovaleryl) -L-proline p-nitrophenyl ester by crystallization in a non-analytical manner. The title compound is obtained after crystalline silica chromatography on silica gel. mp 152-154 ° C; [ _.alpha. ] _D @ ²⁰ = -17 DEG (c = 1, ethano)).

N- (2R-2-hydroxy-2-ethoxycarbonylisovaleryl) -L-phenylalanyl-L-proline is obtained in an analogous manner to that described in step d) and its p-n-thienyl elaster is obtained analogously to p in step e) of Example 1. In step S-(+) -isopropylbenzyloxymalanic acid methyl ester stearate is used as the reactant. The intermediates produced in the individual steps could not be obtained in the crystalline state, and the proline obtained in (d) and the p-nitrophenyl ester obtained in (e) were further processed as a crude product.

EXAMPLE 1 and Cl 6? -Othoxycarbonyl-2 _? 5-Isopropyl-10b-Nydrexy-1 H -dioxoociddro-BH-Oxazolo [3,2-a]] N -olo [2,1-c] pyrazine

The method described in Example 1 was completely avoided; Cyclic litters of N- (-κ-7-hydroxy-γ-2-e-arbivorosoraloryl) -L-varying p -benzyme of pure pure compound having a melting point of 103-104 ^° C; [a] _n ²⁰

4-6 ° C (c 1, ethanol-ol).

The N- (2R-hydroxy-2-ethoxycarbonylisovaleryl) -L-valyl-L-proline used as starting material is obtained analogously to step d) and its p-nitrophenyl ester analogously to step e) of Example 1.

In step a), S- (+) - isopropylbenzyloxymalonic acid monoethyl ester chloride and L-valine benzyl ester are condensed as reactants.

The following compounds of formula I can also be prepared analogously by the method described in Example 1 by cyclizing a compound of formula

II. The melting points given in the table apply to compounds of formula I which crystallize from isopropyl ether.

Compounds of formula III used as starting materials in an analogous manner to that described in step d) and compounds of formula II in an analogous manner to that described in step c) of Example 1 can also be obtained using a compound of formula VIII and a compound of formula VII in step (a) as starting materials.

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Example 24

2-ethoxycarbonyl-2-methyl-4-benzyl-10b-hydroxy-3,6-dioxooctahydrooxazolo [3,2-a] pyrrolo [2,1-c] pyrazine

527 mg of N- (2R-2-hydroxy-2-ethoxycarbonylpropionyl) -L-phenylalanyl-L-proline p-nitrophenyl ester are dissolved in 40 ml of dioxane at 20 DEG C. and 10 ml of an aqueous solution of the mixture are added to this solution. sodium bicarbonate and sodium carbonate (pH = 10). After 3 hours, the mixture was diluted with 100 mL of methylene chloride and 50 mL of 2 N sodium carbonate solution and extracted three times with 50 mL of methylene chloride. The organic phase was washed with 3X 2 N sodium carbonate solution, dried over sodium sulfate and evaporated. The residue is chromatographed on a 50-fold amount of silica gel, eluting with 1% methanol in methylene chloride. The title compound crystallized from isopropyl ether as colorless needles, m.p. 134-136 ° C. [α] 20 = 34 ° ( _c = -0.5, pyridine).

The N- (2R-2-hydroxy-2-ethoxycarbonylpropionyl) -L-phenylanyl-L-proline p-nitrophenyl ester used as starting material is prepared as follows:

(a) N- (2R-2-benzyloxy-2-ethoxycarbonylpropionyl) -L-phenylalanyl-L-proline benzyl ester

4.47 g (10 mmol) of L-phenylalanyl-L-proline benzyl ester hydrobromide are dissolved in 100 ml of absolute methylene chloride, and 2.5 g (10 mmol) of S- (+) - monoethyl ester chloride are added at -40 ° C with stirring. methylbenzyloxymalonone and then 20 ml of absolute pyridine. After warming to 0 ° C, the mixture was maintained at this temperature for 15 hours. For working-up, the reaction mixture is shaken well with 50 ml. saturated sodium carbonate solution and then washed with water. After extraction with 100 ml of methylene chloride, the combined organic phases are dried and evaporated in vacuo. The title compound crystallizes upon removal of the residue with ether, m.p. 120-121 ° C, [α] ²⁰ D -12 ° (c = 1, pyridine).

b) N- (2R-2-Hydroxy-2-ethoxycarbonylpropio) -4- (1) -L-phenylanynyl-L-proline

2.2 g of the ester obtained in (a) are hydrogenated in 50 ml of glacial acetic acid and 50 ml of ethanol using 1 g of palladium on carbon (10% palladium) at room temperature at atmospheric pressure. After filtration, the filtrate was evaporated and the last glacial acetic acid residue was removed using xylene.

c) N- (2R-2-b-hydroxy-2-ethoxycarbonylpropionyl) -L-phenylalanyl-L-proline p-n-itrophenyl

406 mg (1 mmol) of the foam thus obtained were dissolved in 50 ml of methylene chloride and 0.8 ml of absolute pyridine (10 mmol) and 325 mg of di-p-nitrophenylsulfite were added. The mixture is allowed to stand overnight at 0 ° C and then extracted in a conventional manner with a mixture of sodium bicarbonate and methylene chloride. After evaporation of the sodium sulfate-dried extract, the title compound crystallizes directly from a mixture of methylene chloride and isopropyl ether. Mp 122-123 ° C, [α] 54620 = -67.8 ° (c = 0.4, chloroform).

Claims (5)

object of the invention A process for the preparation of octahydrooxazolo [3,2-a] pyrrolo [2,1-c] pyrazine derivatives of the general formula I wherein: R 1 is cyano or -COX, wherein X is amino or C 1 -C 6 alkoxy, R2 represents a lower alkyl radical having 1 to 5 carbon atoms, R3 is hydrogen or (C1-C5) -alkyl, R d represents a C 1 -C 6 alkyl group, a benzyl group or a C 1 -C 4 lower alkoxy group a monosubstituted benzyl group, and R 5 is hydrogen or (C 1 -C 5) -alkyl, characterized in that the compound of formula (II): wherein: R1, R2, R3. Rd and R5 are as defined above and Re represents pentafluorophenoxy or pentachlorophenoxy, N-succinimidoxy, phenylthio or p-chloro 231936 nylthio or optionally nitro and / or methyl or chloro monosubstituted or disubstituted nitrophenoxy, undergoes intramolecular condensation in the presence of a base. 2. The process of item 1 for producing compounds of formula I wherein R1 is as defined in item 1, R2 is methyl, ethyl or isopropyl, R5 is hydrogen, R4 is isopropyl, sec-butyl, isobutyl or benzyl and R 5 is hydrogen, characterized in that compounds of formula II are cyclized wherein R 1, R 2, R 3, R 4 and R 5 are as defined above and R 6 is optionally nitro and / or methyl a mono- or chloro-substituted or unsubstituted nitrophenoxy, phenylthio or p-chlorophenylthio group. 3. A process according to claim 2, wherein the compound of formula (II) wherein R @ 1 to R @ 5 are as defined in point 2 and R @ 8 is p-nitrophenoxy, o, p-dinitrophenoxy, o-methyl-o 'is cyclized. p-dinitrophenoxy. 4. Process according to claim 1, 2 or 3, characterized in that the cyclization is carried out in a polar solvent. 5. The process of claim 1, wherein the cyclization is carried out under anhydrous conditions in the presence of a strong base in an aprotic polar solvent.