EP2318379A1

EP2318379A1 - Method for preparation of piperazindione derivates

Info

Publication number: EP2318379A1
Application number: EP09781280A
Authority: EP
Inventors: Thomas Zierke; Eike Hupe; Michael Rack; Liliana Parra Rapado; Timo Frassetto
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2008-08-13
Filing date: 2009-07-30
Publication date: 2011-05-11
Also published as: CN102119153A; AR073036A1; JP2011530559A; BRPI0916949A2; US20110144336A1; WO2010018067A1

Abstract

Method for preparation of piperazindione derivates of formula I, wherein R¹ stands for hydrogen, alkyl, alkenyl, alkinyl and alkylcarbonyl, R² stands for hydrogen, alkyl, alkenyl, C₃-C₄-alkinyl and C(=O)R¹¹, R³,R⁴ stand for hydrogen, alkyl and halogen-alkyl, wherein the groups can be substituted, characterized in that amines of formula II, in which R¹ stands for hydrogen and alkyl, which likewise can be substituted, are reacted under basic conditions in an aqueous solvent with N-acylated amino acid derivates of formula II, wherein X stands for halogen, Y halogen, alkoxy or phenyloxy, which can be substituted, and R², R³ and R⁴ have the meaning above.

Description

Process for the preparation of piperazinedione derivatives

description

The present invention relates to a process for the preparation of piperazinedione derivatives of the formula I,

wherein

R ¹ , hydrogen, C ¹ -C ₈ -alkyl, C ₃ -C ₄ -alkenyl, C ₃ -C ₄ -alkynyl and C ₁ -C ₈ -alkylcarbonyl, R ² denotes hydrogen, C ₁ -C ₆ -alkyl, C ₃ - C ₄ alkenyl, C ₃ -C ₄ alkynyl and C (= O) R ¹¹ ,

R ¹¹ is hydrogen, _Ci-C4 -alkyl, Ci-C ₄ haloalkyl, _Ci-C4-alkoxy and CrC ₄ -HaIo- alkoxy; R ^3, R ⁴ are independently hydrogen, Ci-C ₈ alkyl and _{Ci-C8-haloalkyl,} where the groups by halogen, OH, CN, _NO2, Ci-C ₈ -alkyl, C ₂ -C ₈ - alkenyl, C ₂ -C ₈ - alkynyl, C ₃ -C ₈ cycloalkyl, _{Ci-C8-haloalkyl,} _{Ci-C8-alkoxy,} _{Ci-C8-halo-alkoxy,} 0-C (O) R ^12, Phenyl, phenoxy and benzyloxy, which cyclic groups may be unsubstituted or substituted by 1 to 5 groups R ^a ,

R ^{a is} halogen, CN, _NO2, Ci-C ₈ -alkyl, C ₈ haloalkyl, C ₂ -C ₄ alkenyl, C ₈ -

Alkoxy and C 1 -C ₈ haloalkoxy; R ¹² is d-Cβ-alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl and C ₃ -C ₈ -cycloalkyl; mean,

characterized in that amines of formula II,

H ₂ NR ¹ M in the R ^{1 is} hydrogen and Ci-C ₈ alkyl, which may be optionally substituted, means

N-acylated amino acid derivatives of the formula III

wherein

X halogen,

Y is halogen, C 1 -C 6 -alkoxy or phenyloxy, which may be unsubstituted or partially or completely substituted by groups R ^a and R ² , R ³ and R ^{4 have} the meaning given initially, are reacted under basic conditions in an aqueous solvent. Piperazinedione derivatives of the formula I are valuable intermediates, for example for the preparation of pharmaceutical and herbicidal active compounds of the formula IV.

In formula IV, a single or a double bond, A is an optionally substituted. mono- or bicyclic carbo- or heteroaromatic ring, RJ-R ³ , are as defined above and R ⁵ has one of the meanings given for R ¹ -R ³ ,

R ^41, R ⁴² is hydrogen, Ci-C ₈ alkyl and Ci-C ₈ alkoxy, where the groups by halogen, OH, CN, d-Cs-alkyl, Ci-C ₈ haloalkyl, C ₃ -C ₈ - Cycloalkyl, C 1 -C ₈ -alkoxy,

R ^{a is} halogen, CN, NO _2, C -C alkyl ₄ -alkyl, C ₂ -C ₄ alkenyl, C ₂ -C kinyl ₄ -alkyl, Ci-C ₄ alkoxy, 0-C (O) R ^12, Phenoxy and benzyloxy, which are cyclic groups by 1 to 5

R ^a groups such as halogen, CN, _NO2, Ci-C ₄ -alkyl, C ₈ haloalkoxy, C ₈ - haloalkyl groups; R ^{12 is} C ₁ -C ₈ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl and C ₃ -C ₈ -cycloalkyl; n is O, 1, 2, 3, 4 or 5.

These drugs are from Journal of Antibiotics 49 (10), 1996, pp. 1014-1021; J. Agric.

Food Chem. (2001) 49, p.2298-2301; WO 99/48889; WO 01/53290; WO 2005/01 1699;

WO 2007/077201 and WO 2007/077247.

Cyclizations of amino acid derivatives with ammonia, or amines to Piperazindi- onen are, for example, in Tetrahedron Lett. 1971, p.2499; J. Bull. Chem. Soc. Jpn. 1975, Vol. 48, p.2584; Int. J. Prept. Prot. Res. 28 (6), p.579-585 (1986); Heterocycles 2000, Vol. 52 (3), p.1231-1239; Tetrahedron Vol. 58 (6), pp. 1173-1183 (2002); Synth. Commun. 2004, Vol. 34 (22), p. 41 11 -18; Arch. Pharm. 2005, Vol. 338 (5), pages 281-90.

The well-known synthesis routes come because of z. T. expensive starting materials, long reaction times, the use of catalysts, complex purification steps, and moderate yields for economical industrial production of piperazinedione derivatives out of the question.

The object of the invention was to provide a process for preparing the piperazinedione derivatives of the formula I, which is suitable for industrial use and proceeds from commercially readily available starting materials.

Accordingly, the method described above was found. It is based on cheap, commercially available chemicals, such as α-amino acid esters, chloroacetyl chloride and benzyl halides.

This reaction is usually carried out at temperatures of 2O ⁰ C to 14O ⁰ C, preferably 4O ⁰ C to 12O ⁰ C, in an inert organic solvent in the presence of a base and optionally a catalyst [see. Arch. Pharm. 2005, Vol. 338 (5), pp. 281-90].

Suitable solvents are water, aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, ethylbenzene, mesitylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, dichlorobenzene, benzotrifluoride, Ether like

Diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, anisole and tetrahydrofuran (THF), nitriles such as acetonitrile and propionitrile, ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols such as methanol, ethanol, n-propanol, isopropanol , n-butanol and tert-butanol, as well as dimethyl sulfoxide (DMSO), sulfolane, dimethylformamide (DMF), dimethylacetamide (DMA), dimethylethyleneurea (DMI), dimethylpropyleneurea (DMPU), trimethyl ethyleneurea (TMI) and cyclic ureas, particularly preferred Mixtures of water and alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, especially methanol, ethanol, n-propanol and isopropanol. Other of the solvents mentioned, such as water and e.g. Toluene can be used. In this case, a phase transfer catalyst can be used for the cyclization. In the reaction of volatile amines, e.g. Ammonia, especially aqueous ammonia, the reaction can be carried out in a closed apparatus. When using an aqueous amine solution, the addition of a solvent can be dispensed with.

In one embodiment, the cyclization with aqueous ammonia may be carried out under pressure without organic solvent in the presence of a phase transfer catalyst. Alternatively, the cyclization with aqueous ammonia may be conducted under pressure without organic solvent in the absence of a phase transfer catalyst.

Bases used are generally the amines II used, and inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, Potassium carbonate and calcium carbonate, as well as alkali metal bicarbonates, such as sodium bicarbonate, alkylmagnesium halides, such as methylmagnesium chloride, and also suitable organic bases, for example tertiary amines such as trimethylamine, triethylamine, tri-butylamine, di-isopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyridine and bicyclic amines. Particularly preferred are amines of the formula II, alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide.

The bases are generally used in catalytic amounts, but they can also be used equimolar, in excess or optionally as solvent.

In one embodiment of the process according to the invention, phase transfer catalysts are used. They are known to the person skilled in the art [cf. WO 2006/11 1583]. Tetraalkyl- or tetraarylammonium and phosphonium halides, tetrakis (dialkyl or diarylamino) phosphonium halides and alkylguanidinium halide derivatives are usually suitable.

The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous for the yield to use II in an excess based on III.

In one embodiment of the process according to the invention, ammonia (R ¹ = H) is used as compound of the formula II.

In another preferred embodiment of the process according to the invention, the compounds of the formula II used are C 1 -C 4 -alkylamines.

The compounds of the formula III are obtainable, for example, from the reaction of α-amino acid derivatives of the formula III.1 with α-haloacetic acid derivatives of the formula III.2, in which the variables X are halogen, preferably chlorine, Y is halogen or C 1 -C ₄ -alkoxy C 1 -C ₄ -alkoxy, such as methoxy or ethoxy, in particular ethoxy, and Y 'is halogen or C 1 -C 4 -alkoxy, preferably halogen, in particular chlorine. One

III

This reaction is usually carried out at temperatures from -1O ⁰ C to 40 ⁰ C, preferably O ⁰ C to 2O ⁰ C, in an inert organic solvent in the presence of a base [see. J. Org. Chem. 2004, 69 (5); 1542-47].

Suitable solvents are water, aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, ethylbenzene, mesitylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, dichlorobenzene, benzotrifluoride, ethers such as diethyl ethers, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, anisole and THF, nitriles such as acetonitrile and propionitrile, ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, and DMSO, sulfolane, DMF, DMA, N-methylpyrrolidone (NMP), DMI, DMPU TMI, cyclic ureas, particularly preferably mixtures of water with said solvents, in particular with aromatic hydrocarbons, such as toluene. It is also possible to use mixtures of the solvents mentioned.

Suitable bases are generally inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides such as lithium oxide, sodium oxide, calzium oxide and magnesium oxide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, potassium carbonate and calcium carbonate and Alkali metal hydrogencarbonates such as sodium bicarbonate, also organic bases, for example tertiary amines such as trimethylamine, triethylamine, tributylamine, di-isopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyridine and bicyclic amines into consideration. Particularly preferred are alkali metal and alkaline earth metal hydroxides such as NaOH, KOH and Ca (OH) ₂ .

The bases are generally used in catalytic amounts, they are preferably used equimolar, in excess or optionally as a solvent.

In one embodiment of the process according to the invention, phase transfer catalysts are used. They are known to the skilled person. Usually, those mentioned in WO 2006/11 1583 come into question. For practical reasons, tetraalkyl or tetraarylammonium and phosphonium halides, tetrakis (dialkyl or diarylamino) phosphonium halides and alkylguanidinium halide derivatives are preferred.

The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous for the yield to use III.2 in an excess relative to III.1.

In a preferred embodiment of the process according to the invention, the preparation of the compounds of the formula I takes place in a one-pot process from the compounds III.1, which are first aeylated with compounds III.2 and the resulting compounds III are reacted without isolation with the amine II.

Easy access for compounds of the formula III.1 in which R ^{2 is} hydrogen is the reaction of an N-protected amino acid derivative of the formula III.3a with a halide of the formula III.4 in which X is halogen, preferably Chlorine or bromine, in particular bromine. In another embodiment of the process, chlorides of the formula III.4, for example benzyl chloride, are used. In formula III.3a have the variables are as defined for formula III and SG is an acid-cleavable protecting group, such as an aromatic aldehyde or ketone (see Green, Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999). For practical reasons, acetophenone, benzaldehyde, benzophenone and pivalyl aldehyde, especially benzaldehyde, are preferred as protecting group SG and Y is preferably alkoxy. By acidification, the protective group is split off and

(R ² = H)

Compounds of the formula III.1 in which R ^{2 is} other than hydrogen are accessible via an analogous reaction sequence, it being understood that the blocking of nitrogen by other monovalent protective groups (see Green, Wuts, ibid), for example by Boc-, Fmoc , Cbz, acetyl, pivalyl, trifluoroacetyl or benzyl protecting groups. Introduction and removal of the protective groups are familiar to the person skilled in the art.

The reaction of III.3a (or III.3a ") with III.4 is usually carried out at temperatures of from -1 O ⁰ C to 4O ⁰ C, preferably ⁰ ° C to 2O ⁰ C in an inert organic solvent in the presence of a Base [see Synth.Commun., 2005, 35 (8), 1 129-34].

Suitable solvents are water, aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, ethylbenzene, mesitylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, dichlorobenzene, benzotrifluoride, ethers such as Diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, anisole and THF, nitriles such as acetonitrile and propionitrile, ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and DMSO, sulfolane, DMF, DMA, NMP, DMI, DMPU, TMI, cyclic ureas, particularly preferred are aromatic and halogenated hydrocarbons such as toluene, ethylbenzene and chlorobenzene. It is also possible to use mixtures of the solvents mentioned.

Bases generally include inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides such as lithium oxide, sodium oxide, calcite oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, Alkali metal amides such as lithium amide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, potassium carbonate and calcium carbonate, and alkali metal hydrogencarbonates such as sodium hydrogencarbonate, organometallic compounds, in particular alkali metal alkyls such as methyllithium, butyl lithium and phenyl lithium, alkyl magnesium halides such as methyl magnesium chloride and alkali metal and alkaline earth metal alkoxides such as sodium methoxide. Sodium ethoxide, potassium ethoxide, potassium tert-butoxide and Dimethoxymagnesium, also organic bases, for example tertiary amines such as trimethylamine, triethylamine, tributylamine, di-isopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyridine and bicyclic amines into consideration. Particularly preferred are alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates and tertiary amines.

The bases are generally equimolar, but can also be used in excess or optionally as a solvent.

The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous for the yield to use III.4 in an excess based on III.3a or 111.3a ".

Suitable acids for cleaving the protective groups are, for example, inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and perchloric acid, Lewis acids such as boron trifluoride, aluminum trichloride, ferric chloride, tin IV chloride, titanium IV chloride and zinc II chloride, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid and trifluoroacetic acid. Preference is given to inorganic acids, aromatic sulfonic acids, in particular sulfuric acid and hydrochloric acid.

The acids are generally used in catalytic amounts, but they can also be used equimolar, in excess or optionally as a solvent.

In one embodiment of the process according to the invention, the cyclization to the piperazinedione ring takes place with compounds of the formula III in which R ^{2 is} hydrogen. Compounds of the formula I 'are obtained. The introduction of the group R ² different from hydrogen can in this case take place at the level of formula I.

The alkylation of I 'to compounds of the formula I in which R ^{2 is} an alkyl, alkenyl or alkynyl group, in the alkylating agents R ² -X X is a nucleophilic cleavable group such as halogen or alkyl sulfate. Preferred alkylating agents are Dialkyl sulfates, dialkyl carbonates, alkyl chlorides and alkyl bromides, preferably dimethyl sulfate, dimethyl carbonate, methyl chloride and methyl bromide, is usually carried out at temperatures of ^{0 0} C to 12O ⁰ C, preferably 2O ⁰ C to 8O ⁰ C, in an inert organic solvent in the presence of a base [see. Bioorg. Med. Chem. Lett. 2001, 11 (19), 2647-9].

Diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, anisole and THF, nitriles such as acetonitrile and propionitrile, ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols such as methanol, ethanol, n-propanol, Isopropanol, n-butanol and tert-butanol, and also dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide, NMP, DMI, DMPU TMI, cyclic ureas. Preference is given to dipolar aprotic solvents, such as DMF, NMP, DMI and dimethylacetamide.

Suitable bases are generally inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and Calcium hydride, alkali metal amides such as lithium amide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, potassium carbonate and calcium carbonate, and alkali metal hydrogencarbonates such as sodium hydrogencarbonate, organometallic compounds, in particular alkali metal alkyls such as methyllithium, butyl lithium and phenyl lithium, alkylmagnesium halides such as methylmagnesium chloride and alkali metal and alkaline earth metal alkoxides, such as sodium methoxide, sodium ethanolate, potassium ethanolate, potassium tert-butoxide and dimethoxy magnesium, as well as organic bases, eg tertiary amines such as trimethylamine, triethylamine, tributylamine, di-isopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyridine and bicyclic amines into consideration. Particular preference is given to alkali metal amides, such as lithium amide, sodium amide and potassium amide, and also alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide.

The acylation of compounds I ', to give compounds of the formula I, ² in which R stands for alkyl carbonyl, is usually carried out at temperatures of 5O ⁰ C to 22O ⁰ C, preference Example 100 ⁰ C to 18O ⁰ C, in substance or an inert organic solvent in the presence of a base or a catalyst [see. THL 1995, 36 (24), 4295-8].

Suitable solvents are aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether, aromatic hydrocarbons such as toluene, o-, m- and p-xylene, ethylbenzene, mesitylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, dichlorobenzene, benzotrifluoride, ethers such as diethyl ether, Diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, dioxane, anisole and THF, nitriles such as acetonitrile and propionitrile, ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, as well as DMSO, sulfolane, DMF, DMA, NMP, DMI, DMPU, TMI, cyclic ureas, more preferably DMF, NMP and DMA. In another preferred embodiment, the acylation is carried out without solvent in an excess of the acylating agent. It is also possible to use mixtures of the solvents mentioned.

Suitable bases are generally inorganic compounds such as alkali metal and alkaline earth metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal acetates such as lithium acetate, sodium acetate, potassium acetate and calcium acetate, alkali metal and alkaline earth metal oxides such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal amides such as lithium amide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates such as lithium carbonate, potassium carbonate and calcium carbonate and alkali metal hydrogen carbonates such as sodium bicarbonate, as well as organic bases, eg tertiary amines such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidine and 4-dimethylaminopyridine and bicyclic amines into consideration. Particularly preferred are sodium acetate and potassium acetate. The bases are generally used in catalytic amounts, but they can also be used equimolar, in excess or optionally as solvent.

Acidic catalysts include inorganic acids such as hydrofluoric acid, acetic acid, hydrobromic acid, sulfuric acid and perchloric acid, Lewis acids such as boron trifluoride, aluminum trichloride, ferric chloride, tin IV chloride, titanium IV chloride and zinc II chloride , and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid and trifluoroacetic acid use. Preference is given to boron trifluoride, ferric chloride, tin IV chloride, titanium (IV) chloride and zinc (II) chloride, toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, in particular boron trifluoride, iron (III) chloride, toluenesulfonic acid, trifluoroacetic acid. The acids are generally used in catalytic amounts, but they can also be used equimolar, in excess or optionally as a solvent.

The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous for the yield to employ R ² -X in an excess relative to I '.

In a further embodiment of the process according to the invention for the preparation of piperazinediones in which R ¹ and R ^{2 are the} same, ammonia (formula II with R ¹ = H) with compounds of formula III in which R ^{2 is} hydrogen becomes the piperazinedione of the formula If hydrogen groups R ¹ and R ^{2 are} desired, their introduction can be carried out at the level of formula I.

In the alkylating agents R ¹ -X, or R ² -X, X is a nucleophilic cleavable

Group, such as halogen or alkyl sulfate. Preferred alkylating agents are dialkyl sulfates, dialkyl carbonates, alkyl chlorides and alkyl bromides, preferably dimethyl sulfate, dimethyl carbonate, methyl chloride and methyl bromide.

In the acylating agents R ¹ -X, or R ² -X, X is a nucleophilic cleavable

Group such as halogen and R ¹ -OH, or R ² -OH. Preferred acylating agents are carboxylic acid anhydrides and carboxylic acid chlorides, preferably acetic anhydride and acetyl chloride.

In this embodiment of the process according to the invention, R ¹ and R ² preferably denote alkylcarbonyl, such as acetyl, or alkyl, such as methyl, ethyl, allyl, propargyl and

Methylpropargyl, in particular methyl and acetyl.

The alkylation or acylation of the compounds I "is usually carried out under the conditions mentioned above for the analogous reactions of the compounds I '.

The starting materials are generally reacted with one another in equimolar amounts. It may be advantageous for the yield to use R ¹ -X or R ² -X in an excess based on I ".

The reaction mixtures are worked up in a customary manner, for example by mixing with water, separating the phases and optionally chromatographic purification of the crude products. Some of the intermediate and end products are in the form of colorless or pale brownish, viscous oils which are obtained under reduced pressure and moderately elevated temperature of volatile fractions freed or cleaned. If the intermediate and end products are obtained as solids, the purification can also be carried out by recrystallization or trituration.

The starting materials required for the preparation of the compounds I are z.T. commercially available, known in the literature or can be prepared according to the literature.

If individual compounds I are not accessible in the above-described ways, they can be prepared by derivatization of other compounds I.

The naturally occurring α-amino acids or their alkyl esters of the formula III.1 are preferably used in the process according to the invention. For example, the following amino acids are suitable as compounds of the formula III.1:

Alanine, arginine, asparagine, aspartine, cyctein, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and

Valine.

Preferred compounds of the formula III.1 are the alkyl esters, in particular the methyl or ethyl esters of the abovementioned amino acids.

In the definitions of the symbols given in the above formulas, collective terms have been used that are generally representative of the following substituents:

Halogen: fluorine, chlorine, bromine and iodine;

Alkyl: saturated, straight-chain or branched hydrocarbon radicals having 1 to 4, 6, 8 or 10 carbon atoms, for example C ₁ -C ₆ -alkyl, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methyl-propyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1 Methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3- Dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl;

Haloalkyl: straight-chain or branched alkyl groups having 1 to 2, 4 or 6 carbon atoms (as mentioned above), in which groups the hydrogen atoms may be partially or completely replaced by halogen atoms as mentioned above: in particular C 1 -C 2 -haloalkyl, such as chloromethyl, bromomethyl, Dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoro ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2- Trichloroethyl, pentafluoroethyl or 1,1,1-trifluoroprop-2-yl; 1, 1, 2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 1,1,1,3,3,3-hexafluoroisopropyl, 1,1,3,3,3,3-hexafluoroisopropyl, 2-chloro 1, 1, 2-trifluoroethyl and heptafluoroisopropyl.

Alkenyl: unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 4, 6, 8 or 10 carbon atoms and one or two double bonds in any position, e.g. C2-C6 alkenyl such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1 - Methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3 Methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl 3-Butenyl, 1, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl , 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1 pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3 Methyl 3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, 1 Dimethyl 2-butenyl, 1, 1-dimethyl-3-butenyl, 1, 2-dimethyl 1-butenyl, 1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 1, 3 Dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3, 3-Dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1 butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl 1-propenyl and 1-ethyl-2-methyl-2-propenyl;

Haloalkenyl: unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 10 carbon atoms and one or two double bonds in any position (as mentioned above), wherein in these groups, the hydrogen atoms partially or completely replaced by halogen atoms as mentioned above, in particular fluorine, chlorine and bromine could be;

Alkynyl: straight-chain or branched hydrocarbon groups having 2 to 4, 6, 8 or 10 carbon atoms and one or two triple bonds in any position, for example C ₂ -C ₆ alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2 Butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl 3-butynyl, 3-methyl-1-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl , 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3 Methyl 4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1, 1-dimethyl-2-butynyl, 1, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3 -butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl -1-methyl-2-propynyl; Cycloalkyl: mono- or bicyclic, saturated hydrocarbon groups having 3 to 6 or 8 carbon ring members, for example Cs-Cs-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;

5- to 10-membered saturated, partially unsaturated or aromatic heterocycle containing one to four heteroatoms from the group O, N or S:

5- or 6-membered heterocyclyl containing one to three nitrogen atoms and / or one oxygen or sulfur atom or one or two oxygen and / or sulfur atoms, e.g. 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5- isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2- Pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1, 3-dioxane-5 yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl and 2-piperazinyl;

5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom: 5-membered heteroaryl groups, which besides carbon atoms can contain one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom as ring members. eg 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, and 1, 3,4-triazol-2-yl;

6-membered heteroaryl containing one to three or one to four nitrogen atoms: 6-membered ring heteroaryl groups, which in addition to carbon atoms may contain one to three or one to four nitrogen atoms as ring members, e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl;

The preferred embodiments of the intermediates with respect to the variables correspond to those of the groups of formula I.

With regard to their use of the piperazinediones of the formula I, the following meanings of the substituents, in each case alone or in combination, are particularly preferred:

Compounds I are preferred in which R ^{1 is} hydrogen or methyl or ethyl, in particular methyl. Equally preferred are compounds I in which R ^{2 is} C 1 -C ₄ -alkyl, in particular methyl.

Particular preference is given to compounds I in which R ^{3 is} C 1 -C ₄ -alkyl, in particular methyl.

Furthermore, compounds of the formula I are preferred in which R ^{4 is} phenyl-C 1 -C ₄ -alkyl, in particular benzyl, where the ring is substituted by one to five, especially one to three groups R ^a and

R ^{a is} halogen, CN, NO _2, C -C alkyl ₄ -alkyl, C ₂ -C ₄ alkenyl, C ₂ -C kinyl ₄ -alkyl, Ci-C ₄ alkoxy,

0-C (O) R ^11, phenoxy and benzyloxy which cyclic groups by groups such as halogen, CN, _NO2, Ci-C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₂ -C ₈ - Al kynyl, C ₃ -C ₈ - cycloalkyl, Ci-C ₈ -haloalkyl, Ci-C ₈ alkoxy, Ci-C ₈ haloalkoxy may be substituted;

R ¹¹ is C ₁ -C ₆ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl. In another embodiment, R ^{4 is} unsubstituted benzyl.

A particularly preferred embodiment of the process according to the invention relates to the preparation of compounds of the formula I which fall under the formula LA:

wherein

R ¹ , R ² , R ³ , R ⁴ , R ⁵ independently of one another are hydrogen and C 1 -C ₄ -alkyl, and R ⁴¹ , R ^{42 are} hydrogen, C 1 -C ₈ -alkyl and C 1 -C ₈ -alkoxy, where the groups gene by halo-, OH, CN, Ci-C ₈ alkyl-Al, C ₈ haloalkyl, C ₃ -C ₈ cycloalkyl, Ci-C ₈ alkoxy,

R ^{a is} halogen, CN, _NO2, Ci-C alkyl ₄ -alkyl, C ₂ -C ₄ alkenyl, C ₂ -C kinyl ₄ -alkyl, Ci-C ₄ alkoxy,

0-C (O) R ¹¹ , phenoxy and benzyloxy, which contain cyclic groups by groups such as halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₂ -C ₈ -alkynyl, C ₂ -C ₈ - Al kynyl, C ₃ -C ₈ - cycloalkyl, Ci-C ₈ -haloalkyl, Ci-C ₈ alkoxy, Ci-C ₈ haloalkoxy may be substituted;

R ¹¹ is C ₁ -C ₆ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl, n is O, 1, 2, 3, 4 or 5.

synthesis Examples

The instructions given in the Synthesis Examples below were used with appropriate modification of the starting compounds to obtain further compounds I. Preparation of N-protected compounds of formula III.1

Example 1: Ethyl 2- (1-phenylmethylidene) amino-propionate

353,3g alanine ethyl ester hydrochloride and 150g of benzaldehyde were suspended in 2 l CH2Cl2 and then added dropwise at 0 ⁰ C with 232,7g triethylamine. The suspension was warmed to 20-25 ⁰ C and stirred for 5 hours. The precipitate was filtered off and discarded after washing with CH 2 Cl 2. The organic phase was washed with water, dried and freed from the solvent. There were obtained 632.7 g of the title compound. Purity 97% (GC); Yield: 92.2%.

¹ H-NMR (CDCl ₃ ): 1, 3ppm (t, 3H, CH ₃ ); 1, 55ppm (s, 3H, CH _3); 4.15 ppm (d, 1H, CH); 4.2ppm (m, 2H, OCH2); 7.4 ppm (m, 3H, arom. H); 7.8ppm (m, 2H, arom. H); 8.3 ppm (s, 1 H ₁ CH = N).

Example 2: Ethyl 2- (1-phenylmethylidene) amino-propionate

75g alanine ethyl ester hydrochloride and 52,8g of benzaldehyde were suspended in 400ml of toluene and then added dropwise at 0 ⁰ C with 195,2g of 10% NaOH. The suspension was warmed to 20-25 ⁰ C and stirred for 5 hours. The aqueous phase was separated and the organic phase washed with water. The solvent was in vac. distilled off. There were obtained 91.2g of the title compound. Purity 82.5% (GC); Yield: 75%.

Introduction of R ⁴ into compounds of the formula III.1

Example 3: 2-Amino-2-methyl-3-phenylpropionic acid ethyl ester

173.6 g of diisopropylamine were in 2I tetrahydrofuran (THF) presented under N2 atmosphere and then treated at -55 ° C with 688 ml of 2.5 M n-butyllithium (n-BuLi) solution in hexane.

In a second reactor, 330 g of 2- (1-phenyl-methylidene) amino-propionic acid ethyl ester in 500 ml of THF at -60 ⁰ C were submitted and then at this temperature described in the preceding paragraph freshly prepared lithium diisopropyl-amine (LDA ) Solution within one hour. After stirring for 20 minutes, 266.8 g of benzyl bromide were added over the course of 40 minutes. The reaction mixture was heated to 15 ° C within 70 min and treated with cooling with 1, 51 10% HCl. After stirring for 1 h, 2 l of methyl tert-butyl ether (MTBE) was added, the phases separated, the organic phase extracted with 5% HCl. The organic phases were discarded. The combined aqueous phases were made alkaline with cooling with 40% NaOH and then extracted with MTBE. The combined organic phases were washed with sat. NaCI solution from liberated. There remained 266.8 g of the title compound in the form of a yellow oil. Purity 94.8% (GC); Yield 78.2%.

¹ H-NMR (DMSO-de): 1.2 ppm (t, 3H, CH ₃ ); 1, 25 ppm (s, 3H, CH _3); 1, 8ppm (s, 2H, NH ₂ , broad), 2.3ppm (d, 1H, CH), 2.4ppm (d, 1H, CH), 4.05ppm (t, 3H, CH ₃ ); 7.15ppm (d, 2H, arom. H); 7.2ppm (m, 3H, arom. H).

Example 4: 2-Amino-2-methyl-3- (3-fluorophenyl) -propionic acid methyl ester

53.3 g of diisopropylamine were initially charged in 11% THF under an N 2 atmosphere and subsequently at -55 ° C. with 21 l of a 2.5 M n-BuLi solution. in hexane.

In a second reactor, 97.5 g of 2- (1-phenyl-methylidene) amino-propionic acid methyl ester in 500 ml of THF at -60 ⁰ C and at this temperature the freshly prepared LDA solution described in the preceding paragraph was added within one hour , After stirring for 20 minutes, 99.6 g of 3-fluorobenzyl bromide were added over a period of 40 minutes. The reaction mixture was heated to 15 ° C within 70 min and added under cooling 1, 51 10% HCl. After one hour of stirring, 2L of MTBE was added, the layers separated, the organic phase extracted with 5% HCl. The organic phases were discarded. The combined aqueous phases were made alkaline with cooling with 40% NaOH and extracted with MTBE. The combined organic phases were washed with sat. NaCl solution freed from solvent. There remained 75.5 g of the title compound as a yellow oil. Purity 90% (GC); Yield 67.3%.

¹ H-NMR (CDCl ₃ ): 1, 4ppm (s, 3H, CH ₃ ); 1.65ppm (s, 2H, NH ₂ , broad), 2.8ppm (d, 1H, CH), 3.15ppm (d, 1H, CH), 3.75ppm (s, 3H, OCH ₃ ); 6.85ppm (m, 1H, arom.H): 6.9ppm (m, 1H, arom.H); 7.25ppm (m, 1H, arom. H).

Example 5: 2-Amino-2-methyl-3-phenylpropionic acid ethyl ester

100g of 2- (1-phenyl-methylidene) -amino-propionic acid ethyl ester and 80,8g of benzyl bromide were initially introduced and 11 in toluene at 0 ⁰ C, then add ₂ ms at this temperature 33.8g NaOC. After warming to 20-25 ⁰ C, the reaction mixture was stirred for about 15 hrs. The mixture was then acidified with 250 ml of 10% HCl and stirred for 30 min. The organic phase was separated and extracted with 5% HCl. The combined aqueous phases were made alkaline with 40% NaOH, extracted with toluene, the combined organic phases were washed with water, then the solvent was distilled off in vacuo. There remained 61, 2g of the title compound in the form of a light oil. Purity 88.2% (GC); Yield 55.1%.

Example 6: 2-Amino-2-methyl-3-phenylpropionic acid ethyl ester

5g of 2- (1-phenyl-methylidene) -amino-propionic acid ethyl ester 4g benzyl bromide were placed in 50 ml of THF at -10 ⁰ C and then at this temperature with 1, 74g KOCH release. ₃ After stirring for 40 minutes, the reaction mixture was heated to 20-25 ⁰ C ER- warm and stir for a further 30 minutes. The mixture was then acidified with 10% HCl and stirred for 30 min. The organic phase was separated and extracted with 5% HCl. The combined aqueous phases were made alkaline with 40% NaOH, extracted with MTBE, the combined organic phases were washed with water and freed from the solvent. There remained 3.1 g of the title compound as a light oil. Purity 67.6% (GC) ethyl ester and 20.4% methyl ester; Yield 56.7%

Preparation of compounds of the formula III from III.1

Example 7: Ethyl 2- (2-chloroacetylamino) -2-methyl-3-phenylpropionate

190 g of 88% 2-amino-2-methyl-3-phenylpropionäureethylester and 1, 2g tetrabutyl ammonium chloride were initially charged at 5 ° C in 1000 ml of toluene, 387.2g 10% NaOH and then at 5-7 ° C 109, 3g chloroacetyl chloride added dropwise. The re- action mixture was stirred for one hour at 10 ⁰ C and one hour at 20-25 ⁰ C, then treated with water. The organic phase was separated, the aqueous phase extracted with toluene, the combined organic phases washed with water and the solvent distilled off in vacuo. There remained 232.5 g of the title compound as a yellow oil. Purity 90% (GC); Yield 91, 5%. 1 H-NMR (DMSO-de): 1.2 ppm (t, 3H, CH ₃ ); 1, 25 ppm (s, 3H, CH _3); 3.0 ppm (d, 1H, CH); 3.3ppm (d, 1H, CH); 4.1 ppm (t, 4H, CH ₂ O, CH ₂ Cl); 7.1 ppm (d, 2H, arom.-H); 7.25ppm (m, 3H, arom. H); 8.4 ppm (s, 1H, NH).

Example 8: Ethyl 2- (2-chloroacetylamino) -2-methyl-3-phenylpropionate

50 g of 75% 2-amino-2-methyl-3-phenylpropionäureethylester was initially charged at 5 ° C in 200 ml of toluene, 87g 10% NaOH and then added dropwise at 5-7 ° C 24g chloroacetyl chloride. The reaction mixture was stirred for one hour at 10 ⁰ C and one hour at 20-25 ⁰ C, then made alkaline with NaOH, the organic phase was separated, the aqueous phase extracted with toluene, the combined organic phases washed with water and the solvent in Vacuum distilled off. There remained 54 g of the title compound as a yellow oil. Purity 89% (GC); Yield 94%.

Example 9: 2- (2-Chloroacetylamino) -2-methyl-3- (3-fluorophenyl) -propionic acid methyl ester

70 g of 90% 2-amino-2-methyl-3- (3-fluorophenyl) -propionic acid methyl ester and 0.3 g of tetrabutylammonium chloride were initially charged at 5 ° C in 300 ml of toluene, 325g 10% NaOH and then added at 5-7 ° C. 37.5% chloroacetyl chloride added dropwise. The reaction mixture was stirred for one hour at 10 ⁰ C and one hour at 20-25 ⁰ C, then added with 500ml of water. The organic phase was separated, the aqueous phase was extracted three times with 200 ml of toluene, the combined organic phases with Washed water and the solvent distilled off in vacuo. There remained 70 g of the title compound as a yellow oil. Purity 80% (GC); Yield 66.4%.

¹ H-NMR (DMSO-de): 3.2 ppm (d, 1 H, CH); 3.6ppm (d, 1H, CH); 3.8ppm (s, 3H, OCH ₃ ); 4.0 ppm (s, 2H, CH ₂ Cl); 6.75ppm (d, 1H, arom. H); 6.75ppm (d, 1H, arom. H); 6.8 ppm (d, 1H, arom.-H); 7.25ppm (d, 1H, arom. H).

Example 10: Ethyl 2- (2-chloroacetylamino) propionate

62.1 g of alanine ethyl ester hydrochloride were dissolved in 160 ml of water. The solution was cooled by ice bath and treated in several portions with 79.9 g NaHCO ₃ . The reaction mixture was added dropwise with a solution of 66.9 g of chloroacetyl chloride in 140 ml of toluene, then vigorously stirred at 20-25 ⁰ C for 3 hrs. After phase separation, the aqueous phase was extracted with toluene. The combined organic phases were freed from the solvent. There were obtained 82.3 g of the title compound as a colorless oil. Purity 90%; Yield 96%.

¹ H-NMR (CDCl ₃ ): 1, 32 (t, 3H, CH ₃ ); 1, 47 (d, 3H, CH _3); 4.10 (s, 2H, CH ₂ CI); 4.24 (q, 2H, CH ₂ ); 4.59 (quin, 1H, CH); 7.25 (br, 1H, NH).

Preparation of compounds of the formula I from II and III

Example 11: 3-Benzyl-3-methyl-piperazine-2,5-dione

10 g of ethyl 2- (2-chloroacetylamino) -2-methyl-3-phenylpropionate were dissolved in 50 ml of ethanol and 100 ml of 25% aqueous NH ₃ solution. dissolved and 4 hrs. At 50 ⁰ C stirred. The reaction mixture was cooled to 0 ^° C. and admixed with 50 ml of water, the precipitate was filtered off. The residue was washed with water and dried. The mother liquor was concentrated by 2/3 and crystallized at 0 ⁰ C. The total amount of the title compound isolated was 6.8 g. Purity 90% (NMR). Yield: 88.4%.

¹ H-NMR (DMSO-de): 1, 4ppm (t, 3H, CH ₃ ); 2.5 ppm (d, 1 H, CH); 2.7ppm (d, 1H, CH); 3.1 ppm (d, 1 H, CH); 3.35ppm (d, 1H, CH); 7.15ppm (d, 2H, arom. H); 7.3ppm (m, 3H, arom. H); 7.8 ppm (s, 1H, NH); 8.25ppm (s, 1H, NH).

Example 12: 3-Benzyl-3-methyl-piperazine-2,5-dione

1 l of 2- (2-chloroacetylamino) -2-methyl-3-phenylpropionic acid ethyl ester and 1 g of tetrabutylammonium bromide were dissolved in 20 ml of toluene and 90 ml of 25% aqueous NH ₃ solution. dissolved and stirred at 118 ° C for 4 hrs. The reaction mixture was cooled to 0 ^° C. and admixed with 50 ml of water, the precipitate was filtered off. The residue was washed with water and dried. The total amount of the title compound isolated was 6.9 g. Purity 98% (NMR). Yield: 89.3%. Example 13: 3-Benzyl-3-methylpiperazine-2,5-dione

1 l of 2- (2-chloroacetylamino) -2-methyl-3-phenylpropionic acid ethyl ester were dissolved in 60 ml of 25% aqueous NH 3 sol. dissolved and stirred for 4 hrs. At 118 ° C. The reaction mixture was cooled to 0 ^° C. and admixed with 50 ml of water, the precipitate was filtered off. The residue was washed with water and dried. 6.3 g. Purity 98% (NMR). Yield: 81%.

Example 14: 3- (3-Fluorobenzyl) -3-methyl-piperazine-2,5-dione

69 g (217 mmol) of 2- (2-chloroacetylamino) -2-methyl-3- (3-fluorophenyl) -propionic acid methyl ester were dissolved in 250 ml of methanol and 500 ml of 25% aqueous NH 3 sol. solved and 4

Std. At 50 ⁰ C stirred. The reaction mixture was cooled to 0 ^° C. and admixed with 50 ml of water. The precipitate was filtered off, then washed with water and dried. The isolated amount of the title compound was 42 g.

Purity 98% (NMR). Yield: 80.3%.

¹ H-NMR (DMSOd ₆ ): 1, 4ppm (s, 3H, CH ₃ ); 2.5 ppm (s, 3H, CH ₃ ); 2.7ppm (d, 1H, CH);

2.8ppm (d, 1H, CH); 3.1 ppm (d, 1 H, CH); 3,35ppm (s, 3H, CH _3); 3.5ppm (d, 1H, CH); 6.95ppm (m, 1H, arom. H); 7.0ppm (m, 1H, arom. H); 7.1 ppm (m, 1H, arom.H);

7.3ppm (m, 1H, arom. H); 7.9ppm (s, 1H, NH); 8.3ppm (s, 1H, NH).

Example 15: 3-Benzyl-1,3-dimethyl-piperazine-2,5-dione

323 g of 90% ethyl 2- (2-chloroacetylamino) -2-methyl-3-phenylpropionate were dissolved in 700 ml of ethanol and 239 g (3.08 mol) of 40% aqueous methylamine solution. dissolved and stirred for 1, 5 hrs. At 55 ° C. The reaction mixture was evaporated to dryness in vacuo and the residue was recrystallized from toluene. The solid was washed with water and dried in vacuo. The mother liquor was distilled in a vacuum to about 2/3 and crystallized at 0 ⁰ C. 205.5 g of the title compound were isolated.

Purity 95% (NMR); Yield: 85%.

¹ H-NMR (CDCl ₃ ): 1, 6ppm (s, 3H, CH ₃ ); 2.4 ppm (d, 1 H, CH); 2,7ppm (s, 3H, CH _3); 2.75ppm (d, 1H, CH); 3.3ppm (d, 1H, CH); 3.4 ppm (d, 1 H, CH); 7.2ppm (d, 2H, arom.-H); 7.3ppm (m, 3H, arom. H); 8.0 ppm (s, 1H, NH).

Example 16: 3-Methyl-piperazine-2,5-dione

215.1 g of ethyl 2- (2-chloroacetylamino) propionate were dissolved in 1 150 ml of ethanol, and 409 g of 25% aqueous NH ₃ solution were added. The reaction mixture was stirred for 5 hours at 70 ⁰ C, then cooled to 20 ⁰ C and the precipitate was filtered off. The mother liquor was concentrated to dryness, the residue digested in a little water and filtered off the remaining precipitate. Both solids Fractions had a purity> 98% (HPLC). They were combined and dried in vacuo. There were obtained 133.4 g (95% yield) of the title compound, which could be used despite low residual moisture for subsequent acetylation (Example 20). 1 H NMR (CDCl ₃ / DMSOd ₆ ): 1, 44 (d, 3H, CH ₃ ); 3.87 (s, 2H, CH ₂ ); 3.94 (q, 1H, CH); 7.84 (br, 1H, NH); 8.02 (br, 1H, NH).

Example 17: 3-Benzyl-3-methyl-piperazine-2,5-dione

1 1g 92% 2-amino-2-methyl-3-phenylpropionäureethylester and 0.24g tetrabutyl ammonium chloride were initially charged at 5 ° C in 100 ml of toluene, 19.1g 10% NaOH and then added at 5-7 ° C. 6 , 47g chloroacetyl chloride added dropwise. The reaction mixture was stirred for one hour at 10 ⁰ C and one hour at 20-25 ⁰ C, adjusted with NaOH to pH 12 and 2g chloroacetyl chloride added. Thereafter, 100 ml of 25% aqueous NH ₃ -L-Sg. and 150ml of ethanol was added and the reaction mixture stirred for 48 hrs. at 50 ⁰ C, then cooled to 0 ⁰ C and filtered. The residue was dried after washing with water. The isolated amount of the title compound was 6.8 g. Purity 98% (NMR). Yield: 89.2% over two steps of synthesis.

Introduction of R ¹ / R ² into compounds of the formula I

Example 18: 1,4-Diacetyl-3-benzyl-3-methyl-piperazine-2,5-dione

205.2 g of 3-benzyl-1,3-dimethyl-piperazine-2,5-dione were initially charged in 1700 g of acetic anhydride and then heated to 155.degree. Over 24 hours, 1000 g of distillate were removed. Thereafter, the residual acetic anhydride was distilled off in vacuo. There were obtained 245 g of the title compound as a crystal mass. Purity 90% (NMR). Yield: 95%

¹ H-NMR (CDCl ₃ ): 1.85ppm (s, 3H, CH ₃ ); 2.3 ppm (d, 1 H, CH); 2.45 ppm (s, 3H, CH ₃ ); 2.55 ppm (s, 3H, CH ₃ ); 3.3ppm (d, 1H, CH); 3.85ppm (d, 1H, CH); 4.2ppm (d, 1H, CH); 7.05ppm (d, 2H, arom. H); 7.25ppm (m, 3H, arom. H).

Example 19: 1,4-Diacetyl-3- (3-fluorobenzyl) -3-methyl-piperazine-2,5-dione

42g 3- (3-fluorobenzyl) -3-methyl-piperazine-2,5-dione were charged in 800g acetic anhydride and then heated to 155 ° C. Over 24 hours, 1000 g of distillate were removed. Thereafter, the residual acetic anhydride was distilled off in vacuo. There were obtained 42 g of the title compound as a crystal mass. Purity 87% (NMR); Yield: 71.3% 1 H-NMR (DMSO-de): 1.85ppm (s, 3H, CH ₃ ); 2.45 ppm (s, 3H, CH ₃ ); 2.55 ppm (s, 3H, CH ₃ ); 2.7ppm (d, 1H, CH); 2.35 ppm (d, 1H, CH); 3.8ppm (d, 1H, CH); 4.25ppm (d, 1H, CH); 6.8ppm (m.sup.1 H, arom.-H); 6.85ppm (m, 1H, arom. H); 7.0ppm (m, 1H, arom. H); 7.25ppm (s, 1H, arom. H). Example 20: 4-Acetyl-3-benzyl-1,3-dimethyl-piperazine-2,5-dione

205.2 g of 3-benzyl-1,3-dimethyl-piperazine-2,5-dione were initially charged in 1700 g of acetic anhydride and then heated to 155.degree. Over 24 hours, 1000 g of distillate were removed. Thereafter, the residual acetic anhydride was distilled off in vacuo. There were obtained 245 g of the title compound as a crystal mass. Purity 90% (NMR); Yield: 95%

¹ H-NMR (DMSO-de): 1. 8 ppm (s, 3H, CH ₃ ); 2.15 ppm (d, 1H, CH); 2.5 ppm (s, 3H, CH ₃ ); 2.75 ppm (s, 3H, CH ₃ ); 3.2ppm (d, 1H, CH); 3.45ppm (d, 1H, CH); 3.75ppm (d, 1H, CH); 7.1 ppm (d, 2H, arom.-H); 7.3ppm (m, 3H, arom. H).

Example 21: N, N'-Diacetyl-3-methyl-piperazine-2,5-dione

2.5 g of 3-methyl-piperazine-2,5-dione (from Ex. 15) were dissolved in 50 ml of acetic anhydride and refluxed for 4 hours, then excess acetic anhydride was removed in vacuo. The residue was dissolved in CH 2 Cl 2 and the solution washed with sat. Washed NaHCO ₃ solution. After removal of the solvent, 3.3 g of the title compound were obtained as a colorless solid. Purity It. HPLC>98%; Yield 80%.

¹ H-NMR (CDCl ₃ ): 1, 55 (d, 3H, CH ₃ ); 2.57 (s, 3H, COCH ₃ ); 2.59 (s, 3H, COCH ₃ ); 4.05 (d, 1 H, CH _2); 5.14 (d, 1H, CH ₂ ); 5.26 (q, 1H, CH).

Claims

claims

1. A process for the preparation of piperazinedione derivatives of the formula I,

wherein

R ^{1 is} hydrogen, C ¹ -C ₈ -alkyl, C ₃ -C ₄ -alkenyl, C ₃ -C ₄ -alkynyl and C ₁ -C ₈ -

Alkylcarbonyl, R ^{2 is} hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₄ -alkenyl, C ₃ -C ₄ -alkynyl and C (= O) R ¹¹ ,

R ¹¹ is hydrogen, _Ci-C4 -alkyl, Ci-C ₄ haloalkyl, _Ci-C4-alkoxy and Ci-C ₄ - haloalkoxy;

R ^3, R ⁴ are independently hydrogen, Ci-C ₈ alkyl and _{Ci-C8-haloalkyl,} where the groups by halogen, OH, CN, _NO2, Ci-C ₈ -alkyl, C ₂ -C ₈ - alkenyl, C ₂ -C ₈ -alkyl kinyl, C ₃ -C ₈ cycloalkyl, _{Ci-C8-haloalkyl,} _{Ci-C8-alkoxy,} _{Ci-C8-haloalkoxy,} 0-C (O) R ^12, phenyl , phenoxy and benzyloxy, unsubstituted or cyclic groups which may be substituted by 1 to 5 groups R ^a, R ^{a is} halogen, CN, _NO2, Ci-C ₈ -alkyl, C ₈ haloalkyl, C ₂ -C ₄ alkenyl,

_Ci-C8-alkoxy and _{Ci-C8-haloalkoxy;}

R ^{12 is} C ₁ -C ₈ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl and C ₃ -C ₈ -cycloalkyl; mean, characterized in that amines of formula II,

H ₂ NR ¹ M in the

R ^{1 is} hydrogen and C 1 -C ₈ -alkyl, which may optionally be substituted, with N-acylated amino acid derivatives of the formula III

wherein

X halogen,

Y is halogen, C 1 -C 6 -alkoxy or phenyloxy, which may be unsubstituted or partially or completely substituted by groups R ^a and

R ² , R ³ and R ^{4 have} the meaning given, are reacted under basic conditions in an aqueous solvent.

2. The method of claim 1, wherein the compounds of formula III are prepared by reacting amino acid derivatives of the formula III.1 R ² O

R ³ R ⁴ in which R ² , R ³ and R ^{4 have} the meaning according to claim 1 and Y is halogen or C 1 -C ₄ -alkoxy, with α-haloacetic acid derivatives of the formula III.2,

° in the

X is halogen, and Y 'is halogen or C 1 -C ₄ -alkoxy.

3. The method of claim 2, wherein the preparation of the compounds of the formula is carried out in a one-pot process without isolation of the compound of formula III.

4. The method according to any one of the preceding claims, wherein Y in formula III, or III.1 is Ci-C ₄ alkoxy.

5. The method according to any one of the preceding claims, wherein Y 'in formula III.2 is halogen.

6. The method according to any one of the preceding claims, wherein R ^{2 is} hydrogen.

7. The method according to any one of the preceding claims for the preparation of piperazinedione derivatives of the formula I, which correspond to the formula I "

8. A process for the preparation of piperazinedione derivatives of the formula I in which R ¹ and R ^{2 are the} same, by reaction of the compound obtained according to claim 7 düng of the formula I "with alkylating, or acylating R ¹ -X, or R ² -X, where X is halogen.

9. The method according to any one of the preceding claims, wherein R ^{3 is} CrC ₄ -AlkVl.

10. The method according to any one of the preceding claims, wherein R ^{4 is} optionally subst. Benzyl stands.

1 1. Use of the compounds of formula I produced by a process of the preceding claims as an intermediate.

12. Use according to claim 11 for the preparation of active compounds of the formula IV

wherein a single or double bond,

A is a subst. mono- or bicyclic carbo- or heteroaromatic

Ring,

R ¹ -R ³ independently of one another have the meaning according to claim 1, R ^{5 has} one of the meanings given for R ¹ -R ³ , R ⁴¹ , R ^{42 is} hydrogen, C 1 -C ₅ -alkyl and C 1 -C ₈ -alkoxy, where the Groups through

Halogen, OH, CN, Ci -C ₈ -alkyl, C ₈ haloalkyl, C ₃ -C ₈ cycloalkyl, C d ₈ Al koxy, R ^{a is} halogen, CN, _NO2, _Ci-C4- -alkyl, C ₂ -C ₄ alkenyl, C ₂ -C kinyl ₄ -alkyl, Ci-C ₄ alkoxy,

0-C (O) R ¹² , phenoxy and benzyloxy, which contain cyclic groups by 1 to 5 groups R ^a , such as halogen, CN, NO ₂ , C 1 -C ₄ -alkyl, C 1 -C ₈ -haloalkoxy, C i -C ₈ haloalkyl may be substituted; R ^{12 is} C ₁ -C ₈ -alkyl, C ₃ -C ₈ -alkenyl, C ₃ -C ₈ -alkynyl and C ₃ -C ₈ -cycloalkyl; n is O, 1, 2, 3, 4 or 5.