EP2152703A2

EP2152703A2 - Method for producing scopine esters

Info

Publication number: EP2152703A2
Application number: EP08759488A
Authority: EP
Inventors: Waldemar Pfrengle; Werner Rall; Jörg Brandenburg; Rolf Herter
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2007-05-25
Filing date: 2008-05-09
Publication date: 2010-02-17
Also published as: US20100174067A1; WO2008145504A2; WO2008145504A3; JP2010527953A; US8101763B2; EP1997819A1; CA2686872A1

Abstract

The invention relates to a novel method for producing scopine esters of the general formula (1), wherein X -, R, R1 , R2 , R3, R4, R3',R4', R6 and R6' can have the meanings indicated in the claims and in the description.

Description

Process for the preparation of scopin esters

The invention relates to a novel process for preparing scopin esters of the general formula Λ_

wherein X - and the groups R, R ¹ , R ² , R ³ , R ³ ', R ⁴ and R ⁴ ', R ⁶ and R ^{6 '} may have the meanings given in the claims and in the description.

Background of the Invention Anticholinergics can be therapeutically useful in a variety of diseases. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease). For the treatment of these diseases, for example, WO 92/16528 proposes anticholinergics which have a scopin, tropenol or tropine skeleton. WO 92/16528 also mentions processes for the preparation of these anticholinergics. Further processes for the preparation of esters of scopin are disclosed in EP 418 716 A1.

The scopin esters of the general formula Λ_ are already known from WO 03/064419 A1. Furthermore, WO 03/064419 A1 also discloses processes for preparing the scopine esters of the general formula Λ_.

In addition to the synthesis processes disclosed in WO 92/16528 for the preparation of scopin esters, processes for the preparation of esters of scopin are also disclosed, for example, in EP 418 716 A1. The preparation processes known from WO 92/16528 and from EP 418 716 A1 and from WO 92/16528 can also be used for the preparation of the compounds of the formula Λ_. However, these synthetic approaches are sometimes very complex, consisting of several synthetic steps. It is therefore an object of the present invention to provide a synthesis process for the preparation of the scopine esters of Formula 1, which allows a simpler synthetic approach to the compounds of the general formula Λ_, preferably a one-step synthesis process.

DETAILED DESCRIPTION OF THE INVENTION It has surprisingly been found that compounds of the formula Λ_

wherein X - and the groups R, R ¹ , R ² , R ³ , R ³ ', R ⁴ , R ⁴ ', R ⁶ and R ^{6 'have} the meanings given below, can be obtained in a single reaction step, if Starting material Compounds of the formula 2

to be used.

Accordingly, the present invention relates to a process for the preparation of compounds of formula 1.

wherein

X ^'is a singly negatively charged anion, preferably an anion selected from the group consisting of chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate;

R is hydrogen, hydroxy, methyl, ethyl, -CF 3, CHF 2 or fluorine;

R1 and R2 are identical or different, -Ci-Cs-alkyl, which may optionally be substituted by -C3-C6-cycloalkyl, hydroxy or halogen, or R1 and R2 together a -C3-C5-alkylene bridge;

R ³ , R ⁴ , R ³ 'and R ⁴ ', same or different, represent hydrogen, -C- | -C 4 alkyl,

C- | C 4 alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2 or halogen, R ⁶ and R ^{6 are} hydrogen or together are a single bond, characterized in that a compound of formula 2

wherein

Y ^'is a singly negatively charged anion, preferably chlorine, bromine, iodine,

Methanesulfonate or trifluoromethanesulfonate, and R1 and R2 may have the meanings given above,

in one step with a compound of formula 3 wherein

R ^{5 is} a radical selected from the group consisting of hydroxy, methoxy, ethoxy,

ON-succinimide, ON-phthalimide, phenyloxy, nitrophenyloxy, Fluorophenyloxy, pentafluorophenyloxy, vinyloxy, 2-allyloxy, -S-methyl, -S-ethyl and -S-phenyl and wherein R, R ^, R3 ', R4 R4 _J ' _J R ⁶ _unc | R ^{6 '} dj _e have the meanings given above, is reacted.

The present invention preferably relates to a process for the preparation of compounds of the formula λ_

wherein X ^'is an anion selected from the group consisting of chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate;

R is hydroxy, methyl, CF ₃ or fluorine

R1 and R2 are identical or different, methyl or ethyl, preferably methyl

R3, R4 _; R3 ' _unc | R4 '_; are identical or different, hydrogen, -CF3, -CHF2 or fluorine, preferably hydrogen or fluorine, wherein Rβ, Rβ ', R4 and R4' are identical or different, hydrogen, methyl, methoxy, hydroxy, -CF3, -CHF ₂ or halogen and

R ⁶ and R ^{6 are} each hydrogen or together a single bond; mean. characterized in that a compound of formula 2, wherein

Y ^'may denote chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate and R1 and R2 may have the meanings given above,

in one step with a compound of formula 3

wherein

R ^{5 is} a radical selected from the group consisting of hydroxy, methoxy, ethoxy, ON succinimide, ON-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, 2-allyloxy, -S-methyl, -S-ethyl and -S -Phenyl andR ⁶ and R ^{6 are} each hydrogen or together a single bond and wherein R, Rβ, Rβ ', R ^ and R ^' may have any of the above meanings.

The present invention particularly preferably relates to a process for preparing compounds of the formula Λ_

wherein

X ^'is bromine, methanesulfonate or trifluoromethanesulfonate;

R is hydroxy or methyl R 1 and R 2 are identical or different, methyl or ethyl, preferably methyl

R3, R \ R4 _unc | R4 'the same or different, hydrogen, methyl,

Methoxy, hydroxy, -CF3, or fluoro, preferably hydrogen or fluoro, and

R ⁶ and R ^{6 are} each hydrogen or together denote a single bond, characterized in that a compound of formula 2,

wherein

Y ^' may mean bromine, methanesulfonate or trifluoromethanesulfonate and

R1 and R2 may have the meanings given above,

in one step with a compound of formula 3 wherein

R is a radical selected from among hydroxy, ON-succinimide, ON-phthalimide, vinyloxy and 2-allyloxy, preferably vinyloxy and 2-allyloxy, and the radicals R, R ³ , R ⁴ , R ³ , R ⁴ , R ⁶ and R ^{6 may have} one of the meanings given above, is reacted.

In a particularly preferred embodiment, the present invention relates to a process for the preparation of compounds of the formula Λ_

wherein

X ^'is a singly negatively charged anion, preferably chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate, in particular bromine; R methyl,

R ¹ and R ^{2 are} each methyl R ³ , R ³ ', R ⁴ and R ⁴ ' are each hydrogen and

R ⁶ and R ⁶ together represent a single bond,

characterized in that a compound of formula 2 wherein

Y ^'is a singly negatively charged anion, preferably chlorine, bromine, iodine,

Methanesulfonate or trifluoromethanesulfonate, especially bromine; and

R1 and R2 may have the meanings given above,

in one step with a compound of formula 3

wherein

ON succinimide, ON-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, 2-allyloxy, -S-methyl, -S-ethyl and -S-phenyl and the radicals R, R ³ , R ⁴ , R ^{3 '} , R ^4' , R ⁶ and R ^{6 'have} one of the meanings given above, is reacted.

In a particularly preferred embodiment, the present invention relates to a process for the preparation of compounds of formula 1.

wherein X - is a single negatively charged anion, preferably chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate, in particular bromine;

R methyl,

Ri and R2 are each methyl and R ³ , R ⁴ , R ^{3 '} and R ^{4' are} each hydrogen and

R ⁶ and R ^{6 are} each hydrogen,

characterized in that a compound of formula 2

wherein Y - is a single negatively charged anion, preferably chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate, in particular bromine; and

R ¹ and R ^{2 are} each methyl,

in one step with a compound of formula 3 wherein

R ^{5 is} a radical selected from among hydroxy, methoxy, ethoxy, ON-succinimide, ON-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy,

Pentafluorophenyloxy, vinyloxy, 2-allyloxy, -S-methyl, -S-ethyl and -S-phenyl means and

R methyl and

R ³ , R ⁴ , R ^{3 '} and R ^{4' are} each hydrogen and R ⁶ and R ^{6 are} each hydrogen, is reacted.

For carrying out the process according to the invention, the procedure can be as described below.

In a first step, the compound of formula 3 is taken up in a suitable organic solvent, preferably in a polar organic solvent, more preferably in a solvent selected from the group consisting of acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethylsulfoxide and dimethylacetamide , Of the aforementioned solvents, dimethylformamide, N-methylpyrrolidinone and dimethylacetamide are particularly preferred. Of particular importance according to the invention are dimethylformamide and N-methylpyrrolidinone, the latter being particularly preferred.

Preferably, between 0.5 and 2 L, more preferably between 0.75 and 1.5 L of said solvent are used per mole of compound of formula 3.

Depending on the choice of the compound of formula 3, it may be appropriate to activate them before implementation with the compound of formula 2. Are used as the compound of formula 3 such derivatives in which R = hydroxyl, for example, the use of appropriate activating reagents such as carbonyldiimidazole, carbonyldi-1, 2,4-triazole, Dicyclohexylcarbodiimid or ethyl dimethylaminopropylcarbodiimide preferred according to the invention, in which context the use of carbonyldiimidazole is particularly preferred. Between 1 and 2 moles of the coupling reagent are used per mole of compound 3 with R = hydroxy. Preferably, 1 to 1.5 moles of the coupling reagent are used. Get the above mentioned

Coupling reagents, as preferred in the case of R = hydroxy, is used for the reaction mixture then preferably in a temperature range of 15-35 ° C, preferably bwi 20-25 ⁰ C over a period of 1-8 hours, preferably 3-7 hours stirred before being further reacted as described below.

The reaction mixture of 3 in the abovementioned solvent, if appropriate after addition of one of the abovementioned coupling reagents in the case of R = hydroxyl, is then at a temperature of less than 30 ⁰ C, preferably at a temperature between -20 ° C and 20 ⁰ C, especially preferably on one

Temperature set between -10 ° C and 5 ° C and mixed with the compound of formula 2. Based on originally used compound 3, stoichiometric amounts of compound of formula 2 can be added. According to the invention, however, 3 is present in excess compared to 2. According to the invention, between 0.5 and 1 mol, preferably between 0.7 and 0.95 mol, particularly preferably between 0.75 and 0.9 mol 2, are used per mole of compound 3 employed.

The above-mentioned reaction mixture is then treated with a suitable base dissolved in one of the abovementioned solvents. In this case, organic or inorganic bases can be used. As organic bases, preference is given to using alkali metal imidazolides which can be generated, for example, in situ from the alkali metals and imidazole or the alkali metal hydrides and imidazole, or alkali metal tertiary amylates which are commercially available. As Akaliimidazolide are preferably imidazolides of lithium, sodium or potassium, with sodium or lithium imidazolide being preferred according to the invention. Particular preference is given to using lithium imidazolide. The alkali metal tertiary amylates used are preferably sodium tertiary amylate and potassium tertiary amylate, but especially sodium tertiary amylate. Suitable inorganic bases are preferably hydrides of lithium, sodium or potassium. Particular preference is given to using sodium hydride as the inorganic base. Of all the abovementioned bases, lithiumimidazolide is particularly preferably used. If compounds of the formula Λ - be obtained in which R is hydroxy, instead of the above base-catalyzed reaction, a transesterification under milder reaction conditions may appear advantageous. Here, zeolites can advantageously be used as catalysts.

If the reaction is carried out with one of the abovementioned bases, at least stoichiometric amounts of base are used per mole of compound 2 used. 2 to 1, 5 moles, preferably 1, 1 to 1, 3 moles of base are preferably used per mole of compound used. If the base is added in the form of a solution, which is the case in particular in the case of the lithiumimidazolide base, which is preferred in accordance with the invention and is generated in situ, the solvent which is already used to carry out the abovementioned steps is preferably used for this purpose. Preferably, between 0.3 and 1.3 L, more preferably between 0.5 and 1 L of said solvent are used per mole of base. After completion of base addition is in a temperature range of 15-35 ° C, preferably bwi 20-25 ⁰ C over a period of 4-48 hours, preferably stirred for 8-36 hours.

An acid HX is added to the resulting suspension at constant temperature. The choice of acid is determined by the anion X ^' in the desired end product of the general formula λ_. Insofar as in the context of the present invention, those compounds of the general formula Λ_ are preferably synthesized in which X ^'is bromide, the following procedure for the preparation of the inventively preferred bromide-containing end products of formula 1 is described. It will be apparent to those skilled in the art that a similar approach can be used by selecting the appropriate reagent HX in an analogous manner for preparing such compounds in which X ^'is not bromide.

For the preparation of compounds of formula 1 with X = bromide, based on the compound of formula 3, preferably 2 to 4 mol, preferably 2 to 3 mol, more preferably 2.2 to 2.6 mol of hydrogen bromide are added at constant temperature. The hydrogen bromide used here can be added either in gaseous form or in the form, preferably saturated, solutions. According to the invention, the addition of hydrogen bromide preferably takes place in glacial acetic acid form. Particular preference is given to using a 33% hydrogen bromide solution in glacial acetic acid. After completion of the addition is at constant temperature, if appropriate also stirred with ice-cooling (between 0.5 and 6 hours)

Finally, the resulting solution with a non-polar organic solvent, preferably with a solvent selected from the group consisting of acetone, toluene, n-butyl acetate, dichloromethane, diethyl ether, tetrahydrofuran and dioxane, particularly preferably toluene or acetone.

After thorough mixing, the crystallized product is separated and washed with the above-mentioned non-polar solvent. For separation of water-soluble impurities, the crude product may be treated with aqueous bromide solutions, e.g. Be treated with sodium or potassium bromide solution.

Further purification of the compounds of formula 1 thus obtained, if necessary, by chromatography on silica gel or by means of

Recrystallization from suitable solvents, e.g. Water or lower alcohols, such as isopropanol done.

The use of the compounds of the formula 2 which are known in the prior art as starting materials for the synthesis of the structures of the formula 1 makes it possible to access these structures having anticholinergic activity in only one reaction step.

Accordingly, another aspect of the present invention relates to the use of compounds of formula 2

+ Me

Me-N ^'

Y

OH ₂ in which

Y ^' denotes chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate as starting material for the preparation of compounds of the formula Λ_

wherein

X is chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate;

R is hydroxy, C 1 -C 4 -alkyl, C 1 -C ⁴ -alkoxy, CF 3 or fluorine and R ³ , R ⁴ , R ³ 'and R ⁴ ', identical or different, are hydrogen, -C- | -C 4 alkyl,

-Ci-C ^ alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen and R ⁶ and R ^{6 are} each hydrogen or together are a single bond.

The present invention preferably relates to the use of compounds of the formula 2

wherein Y ^'is bromine, methanesulfonate or trifluoromethanesulfonate as starting material for the preparation of compounds of the formula Λ_

wherein

X ^'is bromine, iodine, methanesulfonate or trifluoromethanesulfonate;

R is hydroxy, methyl, CF3 or fluorine and R3, R4, R3 'and R ^ ¹ , identical or different, are hydrogen, methyl, methoxy,

Hydroxy, -CF3, -CHF2 or halogen and

R ⁶ and R ^{6 are} each hydrogen or together are a single bond.

More preferably, the present invention relates to the use of

Compounds of the formula 2

wherein

Y ^' bromine, methanesulfonate or trifluoromethanesulfonate mean as starting material for the preparation of compounds of formula 1.

wherein

X ^'is bromine, methanesulfonate or trifluoromethanesulfonate;

R is hydroxy or methyl; R3, R4, R3 'and R ^ ¹ , same or different, hydrogen, methyl, methoxy,

Hydroxy, -CF3 or fluorine and R ⁶ and R ^{6 are} each hydrogen or together a single bond

mean.

In a particularly preferred embodiment, the invention relates to the use of a compound of formula 2

wherein

Y ^'is chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate,

as starting material for the preparation of compounds of the formula Λ_ wherein

X is chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate;

R is hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, CF 3 or fluorine; preferably methyl

-C 1 -C 4 alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2 or halogen, preferably in each case hydrogen, and R ⁶ and R ⁶ together denote a single bond, preferably in the presence of an alkali metal salt of tertiary amylate as the base, in particular in the presence of Nathum tertiary amylate as the base.

The following examples serve to illustrate examples of synthetic methods carried out. They are to be understood merely as possible, exemplarily illustrated procedures, without restricting the invention to their content.

In a particularly preferred embodiment, the present invention relates to the use of compounds of the formula 2

wherein Y is bromine, as starting material for the preparation of compounds of formula 1,

wherein

X - bromine,

R methyl and

R3, R4 R3 ' _and R4' are hydrogen.

Example 1: Q-Methyl-fluorene-Q-carboxylic acid copinester methobromide

To a solution consisting of 710.8 g (4.384 mol) of 1, 1-carbonyldiimidazole in 8.43 liters of N-methylpyrrolidone are added 900.0 g (4.013 mol) of 9-methyl-fluorene-9-carboxylic acid and the reaction mixture is stirred. 2 , 5-3.0 hours at room temperature. Subsequently, 843.4 g (3.372 mol) of scopine methobromide and 408.4 g (3.709 mol) of sodium tert-amylate are added in portions. The reaction mixture is heated for 3.0-3.5 hours at 40-45 ⁰ C. Subsequently, the reactor contents are cooled to 0- 3 ° C and slowly added at a temperature of 0-7 ⁰ C 1, 38 liters of HBr, 33% in glacial acetic acid. After the end of the addition is for 15 minutes stirred and then added 9.64 liters of isopropanol. The suspension is stirred overnight at 0-3 ⁰ C, filtered, the filter cake washed with 1, 5 liters of isopropanol and then dried in vacuo at 45 ° C. The crude product thus obtained is then dissolved in 7.39 liters of G water at 60 ⁰ C. By addition of hydrobromic acid 48%, the pH of the solution is adjusted to a value in the range of pH 3.0 to 4.0. The solution is clarified by filtration over activated charcoal, the filtrate is cooled to 0-3 ⁰ C whereby the product crystallizes. The suspension thus obtained is stirred for 4-5 hours at 0-3 ° C, filtered off with suction, washed with 1, 5 liters of water and dried in a vacuum oven at 45 ° C.

In an analogous manner can be obtained in a synthesis step:

Example 2: g-fluoro-fluorene-g-carboxylic acid copoester methobromide

Example 3: 2,2-Diphenylpropionic acid copinester methobromide 1. Preparation of: 2,2-diphenylpropionic acid copopropene methobromide (crude product):

10.53 kg (64.97 mol) of 1,1-carbonyldiimidazole are dissolved in 101.8 l of N-methylpyrrolidone. At a product temperature of 25 ° C 14.70 kg (64.97 mol) of 2,2-diphenylpropionic acid are added in portions. The reactor contents are stirred for 2 hours at 25 ° C and then cooled to 2 ° C. 12.50 kg (49.79 mol) of BEA 2180 alcohol and 6.54 kg (59.37 mol) of sodium tert-amylate are added successively at a maximum of 7 ° C. The funnel is rinsed with 8.9 L of N-methylpyrrolidone. The resulting suspension is stirred for 20 minutes at 7 ° C. The reactor contents are heated to 25 ° C and stirred at this temperature for 5 hours. Then 125 L isopropyl alcohol are added at 16 ° C and the reaction mixture at 16 - 21 ⁰ C with 28.59 kg (116.59 mol) of hydrogen bromide 33% in acetic acid. The feed vessel is rinsed with 17.9 L isopropyl alcohol. The suspension is at 23 ° C Stirred for 14 hours. The reactor contents are cooled to 2 ° C. within 30 minutes and stirred at this temperature for 3 hours. The crude product is centrifuged off, washed twice with 35.7 l of isopropyl alcohol and dried in a vacuum oven under vacuum with nitrogen as a trailing gas at 45 ° C.

2. Recrystallization from isopropanol:

8.00 kg (17.45 mol) of the 2,2-diphenylpropionic acid copopro- ester methobromide crude product are dissolved in 168 L isopropyl alcohol at reflux. After cooling just below the reflux temperature (79 ° C) is clear filtered through a pressure filter in a second reactor. The pressure filter and hoses are flushed with 16 L isopropyl alcohol via the first reactor. The filtrate in the 2nd reactor is heated to reflux. After cooling to 70 ⁰ C is inoculated with 3.2 g already recrystallized from isopropanol 2,2-Diphenylpropionsäurescopinester methobromide and cooled to 0 ⁰ C within 3.5 hrs. To complete the crystallization is stirred for 3 hrs. At 0 ⁰ C The suspension is centrifuged off and the product is washed with 32 L cold isopropyl alcohol. The 2,2-DiphenylpropionsÄurescopinester-Methobromid recrystallized from isopropanol is dried at 45 ° C in a vacuum dryer, then passed through a 2 mm sieve in Reibschnitzler.

3. recrystallization from water:

10.00 kg (21.8 mol) of 2,2-Diphenylpropionsäurescopinester methobromide are dissolved in 70 L of G-water at 40 ⁰ C. The solution is cooled to 25 ° C and inoculated with 5.0 g of water recrystallized 2,2-Diphenylpropionsäurescopinester methobromide. Within 30 minutes, cooled to 20 ⁰ C and stirred for 2 hrs. At this temperature. Within 1 hr. Is cooled to 0 ° C and stirred for 2.5 hrs. At this temperature. The suspension is centrifuged off and the product is washed with 20 L of ice-cold G water. The recrystallized from water 2,2-Diphenylpropionsäurescopinester-methobromide is dried at 50 ⁰ C in a vacuum oven.

Depending on the degree of purity of the 2,2-Diphenylpropionsäurescopinester-Methobromid- crude product can be recrystallized either only from isopropanol or from isopropanol and then from water.

Claims

claims

1) Process for the preparation of compounds of formula 1

wherein

X ^'is a simply negatively charged anion,

R is hydrogen, hydroxy, methyl, ethyl, -CF 3, CHF 2 or fluorine;

C 1 -C 4 alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2 or halogen

R ⁶ and R ^{6 are} hydrogen or together a single bond; mean,

characterized in that a compound of formula 2

wherein Y ^'is a simply negatively charged anion, and

R ¹ and R ^{2 have} the above meanings,

in one step with a compound of formula 3

wherein

ON-succinimide, ON-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, 2-allyloxy, -S-methyl, -S-ethyl and -S-phenyl, and wherein R, Rβ, Rβ ', R ^, R4 ' _J R ⁶ and R ^{6 have} the meanings given above, is reacted.

2) Process according to claim 1, for the preparation of compounds of the formula Λ_, wherein X ^'is an anion selected from the group consisting of chlorine, bromine, iodine,

Methanesulfonate or trifluoromethanesulfonate R is hydroxy, methyl, CF 3 or fluorine; R1 and R2 are identical or different, methyl or ethyl, R3, R3 ', R4 _and R4' are identical or different and are hydrogen, methyl, methoxy, hydroxyl, -CF3, -CHF2 or halogen and

R ⁶ and R ^{6 are} hydrogen or together a single bond, mean

characterized in that a compound of the formula 2 in which Y ^'may denote chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate, and the radicals R ¹ and R ^{2 may have} one of the meanings given above,

in a step with a compound of formula 3, wherein R ^{5 is} a radical selected from the group consisting of hydroxy, ON succinimide,

ON-Phtalimid, vinyloxy and 2-allyloxy, R ⁶ and R ^{6 is} hydrogen or together a single bond, and the radicals R, R ³ , R ⁴ , R ³ and R ^{4 may have} one of the meanings given above, is reacted.

3) Method according to claim 1 or 2 for the preparation of a compound of

Formula Λ_, in which

X ^'is bromine, methanesulfonate or trifluoromethanesulfonate; R is hydroxy or methyl;

R ¹ and R ^{2 are} identical or different, methyl or ethyl, R ³ , R ³ ', R ⁴ and R ⁴ ' are identical or different, hydrogen, methyl,

Methoxy, hydroxy, -CF 3 and fluorine, and R ⁶ and R ^{6 are} hydrogen or together a single bond,

mean,

characterized in that a compound of formula 2, wherein

Y ^{'may be} bromine, methanesulfonate or trifluoromethanesulfonate, and the radicals R ¹ and R ^{2 may have} one of the meanings given above,

in a step with a compound of formula 3, wherein

R ^{5 is} a radical selected from among hydroxy, ON-succinimide, ON-phthalimide, vinyloxy and 2-allyloxy, preferably vinyloxy and 2-allyloxy,

R ⁶ and R ^{6 are} hydrogen or together a single bond, and the radicals R, R ³ , R ⁴ , R ³ and R ^{4 may have} one of the meanings given above, is reacted.

4) Method according to one of claims 1 to 3 for the preparation of a compound of formula 1, wherein X ^" bromine

R methyl;

R ¹ and R ^{2 are} each methyl R ³ , R ³ ', R ⁴ and R ⁴ ' are each hydrogen and R ⁶ and R ⁶ together are a single bond, characterized in that a compound of formula 2 wherein Y ^'is bromine and

R ¹ and R ^{2 are} each methyl in one step with a compound of formula 3, wherein R ^{5 is} a radical selected from the group consisting of hydroxy, ON

Succinimide, O-N-phthalimide, vinyloxy and 2-allyloxy, preferably vinyloxy and 2-allyloxy,

R methyl and

R ³ , R ⁴ , R ^{3 '} and R ^{4' are} each hydrogen and R ⁶ and R ⁶ together are a single bond, is reacted.

5) Method according to one of claims 1 to 3 for the preparation of a compound of formula 1, wherein X ^" bromine

R methyl;

R1 and R2 are each methyl

R ³ , R ³ ', R ⁴ and R ⁴ ' are each hydrogen and

R ⁶ and R ^{6 are} each hydrogen, characterized in that a compound of formula 2, wherein

Y ^' bromine and

R ¹ and R ^{2 are} each methyl in one step with a compound of formula 3 wherein

R methyl and

R ³ , R ⁴ , R ^{3 '} and R ^{4' are} each hydrogen and

R ⁶ and R ^{6 are} each hydrogen, is reacted.

6) Method according to one of claims 1 to 5, characterized in that the reaction is carried out in an organic solvent selected from the group consisting of acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide and dimethylacetamide.

7) Method according to one of claims 1 to 6, characterized in that in the case of using a compound of formula 3, in which R ⁵ = OH, activating reagents selected from the group carbonyldiimidazole, Carbonyldi-1, 2,4-triazole, dicyclohexylcarbodiimide and ethyl dimethylaminopropylcarbodünnid be used.

8) Method according to one of claims 1 to 7, characterized in that the reaction at a temperature of less than 30 ⁰ C, preferably to a

Temperature between -20 ⁰ C and 20 ° C is performed.

9) Method according to one of claims 1 to 8, characterized in that the reaction is carried out in the presence of an organic or inorganic base.

10) Process according to claim 9, characterized in that the reaction is carried out in the presence of an alkali metal salt of tertiary amylate as a base.

1 1) Process according to claim 10, characterized in that the reaction is carried out in the presence of sodium tertiary amylate as base.

12) Method according to one of claims 1 to 1 1, characterized in that in the case in which in the compounds of formula 1. R is hydroxy, the reaction is carried out in the presence of zeolites as a catalyst.

13) Use of a compound of formula 2

wherein Y ^'is chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate,

as starting material for the preparation of compounds of the formula Λ_

wherein

X ^'is chlorine, bromine, iodine, methanesulfonate or trifluoromethanesulfonate;

R is hydroxy, C 1 -C 4 alkyl, C- | -C4 alkoxy, CF3 or fluorine; R ³ , R ⁴ , R ³ 'and R ⁴ ', same or different, represent hydrogen, -C- | -C 4 alkyl,

C- | C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen, and R ⁶ and R ⁶ together denote a single bond.

14) Use of a compound of formula 2

wherein

^■ X is chlorine, bromine, iodine, methanesulphonate or trifluoromethanesulphonate;

R is hydroxy, C | -C 4 alkyl, C 1 -C 4 alkoxy, CF 3 or fluorine; R ³ , R ⁴ , R ³ 'and R ⁴ ', same or different, represent hydrogen, -C- | -C 4 alkyl,

C 1 -C 4 alkyloxy, hydroxy, -CF 3, -CHF 2, CN, NO 2 or halogen, and

R ⁶ and R ⁶ together denote a single bond, in the presence of an alkali metal salt of tertiary amylate as the base, in particular in the presence of sodium tertiary amylate as the base.