DE102008059772A1 - Production of a special diphenylazetidinone derivative for use, e.g. as a cholesterol-reducing agent, involves acylation of an aminomethylphenyl-azetidinone compound with a long-chain mixed acid anhydride - Google Patents

Abstract

A method for the production of a 1-(p-aminomethylphenyl)-4-(p-methoxyphenyl)-3-[3'-(p-fluorophenyl)-3'-hydroxypropyl]-azetidin-2-one in which the amino group is acylated with a glucosylamidoundecanoyl group, involves reacting the glucosylamidoundecanoic acid with a carboxylic acid chloride and then reacting the resulting mixed acid anhydride with the unacylated amine. A method (M1) for the production of a 1-(p-aminomethylphenyl)-4-(p-methoxyphenyl)-3-[3'-(p-fluorophenyl)-3'-hydroxypropyl]-azetidin-2-one of formula (I), involves (a) reacting the compound of formula HOOC-(CH 2) 10-CONH-CH 2-(CHOH) 4-CH 2OH (II) with a compound of formula R 1-CO-Hal (III) to give a compound of formula R 1-CO-O-CO-(CH 2) 10-CONH-CH 2-(CHOH) 4-CH 2OH (IV) and then (b) reacting (IV) with a compound of formula (V) or its salts. Hal : Br, Cl or I; R 11-18C alkyl, in which one or more CH 2groups may be replaced by -O-, -CO-, -CH=CH-, -Ctriple boundC- or arylene and the alkyl groups may be substituted with one or more F, Cl, Br or I atoms. Independent claims are also included for (1) compounds of formula (IV) as above, and (2) a method (M2) for the production of the compound of formula (CH 3) 2CH-CH 2-OCOOCO-(CH 2) 10-CONH-CH 2-(CHOH) 4-CH 2OH (IVa) by reacting (II) with a compound of formula Hal-COO-isobutyl (IIIa). . [Image].

Description

The The invention relates to an improved method for producing a Diphenylazetidinons.

In WO2004 / 087655 is a Diphenylazetidinon of formula I and syntheses of this compound described.

The Compound of formula I can be used, for example, as a cholesterol-lowering agent be used.

• a) 1-HydroxybenzotriazoL (HOBt) als Reagenz verwendet wird und HOBt als explosionsgefährlicher Stoff bekannt ist.
• b) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimid hydrochlorid (EDC) verwendet wird welches als sensibilisierend und allergieauslösend bekannt ist.
• c) die Kosten der einzelnen Schritte und die Verfügbarkeit der Reagenzien eine wirtschaftliche Herstellung im technischen Maßstab signifikant erschweren würden.

In the WO2004 / 087655 described methods A and B have the disadvantage that

• a) 1-HydroxybenzotriazoL (HOBt) is used as a reagent and HOBt is known as an explosive substance.
• b) N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) is used which is known as a sensitizing and allergenic.
• c) the costs of the individual steps and the availability of the reagents would significantly hinder economic production on an industrial scale.

That too in WO2004 / 087655 described method C has the disadvantage that the alcohol functions of the amino alcohol must first be protected before the compound can be converted into an acid chloride, which is then linked to the amine. These protecting groups must then be split off again, which means additional reaction steps and thus higher environmental impact and higher costs.

The object of the present invention was now to provide an improved process for the preparation of the compound of the formula I, the abovementioned disadvantages of the processes A, B and C from WO2004 / 087655 does not have. In particular, the improved process should also enable a preparation of the compound of the formula I in a large-scale production process. For this purpose, the process to the most economical conditions, ie cost-effective, environmentally friendly and safe to be performed.

worin

• a) die Verbindung der Formel II mit der Verbindung der Formel III, worin R1 ein Alkylrest mit 1 bis 18 C-Atomen ist, worin eine oder mehrere CH₂-Gruppen des Alkylrests durch -O-, -CO-, -CH=CH-, -C≡C- oder Aryl ersetzt sein können und der Alkylrest ein oder mehrfach mit F, Cl, Br oder I substituiert sein kann, zur Verbindung der Formel IV umgesetzt wird und dann weiter
• b) die Verbindung der Formel IV mit einer Verbindung der Formel V oder deren Salze zur Verbindung der Formel I umgesetzt wird.

The object is achieved by production method A)

wherein

• a) the compound of the formula II with the compound of the formula III, wherein R 1 is an alkyl radical having 1 to 18 C atoms, in which one or more CH ₂ groups of the alkyl radical is -O-, -CO-, -CH = CH -, -C≡C- or aryl may be replaced and the alkyl radical may be mono- or polysubstituted with F, Cl, Br or I, is reacted to the compound of formula IV and then further
• b) the compound of the formula IV is reacted with a compound of the formula V or salts thereof to give the compound of the formula I.

preferred Compounds of the formula III are alkyl acid halides and Haloformic acid alkyl ester, is particularly preferred Isobutylchloroformate.

In In another embodiment, R1 is an alkyl radical 1 to 6 carbon atoms. In a further embodiment R1 is a methyl radical, ethyl radical, isopropyl radical, n-butyl radical, isobutyl radical or tert-butyl radical.

In In a further embodiment R1 is an -O-alkyl radical with 1 to 17 carbon atoms. In a further embodiment R1 is an -O-alkyl radical having 1 to 6 C atoms. In another Embodiment R1 is an -O-methyl radical, -O-ethyl radical, -O-iso-propyl, -O-n-butyl, -O-iso-butyl or -O-tert-butyl.

Under an alkyl radical becomes a straight-chain or branched hydrocarbon chain understood with one to eighteen carbons, such as. Methyl, Ethyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, hexyl, heptyl, Octyl.

Under Hal is understood as meaning a halogen radical which has the meaning Br, Cl or I can have. Hal preferably has the meaning Cl.

By an aryl radical is meant a phenyl, naphthyl or biphenyl radical in which one or more Other CH groups can be replaced by O, N or S.

The aryl radicals may be substituted one or more times with suitable groups, such as. B .: F, Cl, Br, I, CF _3, NO _2, CN, COO (C ₁ -C ₆₎ alkyl, CON [(C ₁ -C ₆₎ alkyl] _2, cycloalkyl, (C ₁ -C ₁₀ ) - alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, O- (C ₁ -C ₆ ) -alkyl, O- (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) -alkynyl, O-CO- (C ₁ -C ₆ ) -alkyl, O-CO- (C ₁ -C ₆ ) -aryl, O-CO- (C ₁ -C ₆ ) - Heterocycle, SO ₂ N [(C ₁ -C ₆ ) -alkyl] ₂ , S- (C ₁ -C ₆ ) -alkyl, N ((C ₁ -C ₆ ) -alkyl) ₂ .

In Step a), the compound of formula II in a suitable Solvent at -30 ° C to + 70 ° C, preferably at -10 ° C to + 50 ° C, more preferably dissolved at 20 ° C to 45 ° C and within from 30-150 minutes, preferably 60-120 minutes with a suitable base added, then to a Temperature from -30 ° C to 50 ° C, preferably at -10 ° C to 30 ° C, more preferably cooled at -5 ° C to 10 ° C and within 5-100 minutes, preferably 5-60 Minutes of a compound of formula III added, particularly preferred Isobutylchloroformate.

alternative may also be one at -10 ° C to 30 ° C, preferably -10 ° C cooled to 0 ° C solution of the compound III, preferably isobutyl chloroformate, in one be submitted suitable solvent and then the A compound of formula II and a suitable base in a suitable one Solvent at -30 ° C to + 70 ° C, Preferably at -10 ° C to + 40 ° C, especially preferably at -5 ° C to 0 ° C within from 30-150 minutes, preferably 60-120 minutes be dosed.

at both procedures, the reaction mixture is then at -10 ° C to 40 ° C, preferably at -10 ° C stirred at 10 ° C for 15 to 150 minutes, preferably 30-120 minutes. The reaction mixture can now either be used directly in the subsequent reaction, or the formed Product of formula IV is isolated. The reaction mixture is preferred used directly. To isolate the compound of formula IV is the Solvent evaporated in vacuo. Optionally, the reaction mixture washed with water before evaporation of the solvent.

suitable Bases are exemplified by tertiary amines, such as Triethylamine, ethyldimethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine, N-methylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, preferably triethylamine, N-ethyldiisopropylamine, Tributylamine, N-ethylmorpholine, N-methylmorpholine, more preferred are triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine.

suitable Solvents are exemplary typical aprotic organic solvents such as toluene, chlorobenzene, Dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, Tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, preferably 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone, particularly preferred is N-methylpyrrolidone.

In Step b) is within 5 to 60 minutes, preferably 10-45 Minutes the compound of formula V or salts thereof dissolved in a suitable solvent to a solution of product IV (prepared as described above, either reaction solution used directly or the isolated product dissolved in a suitable solvent) and optionally a suitable one Base in a suitable solvent at -10 ° C until 40 ° C, preferably -5 ° C to 10 ° C added.

suitable Bases are exemplified by tertiary amines such as, for example Triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferred are triethylamine or N-ethylmorpholine.

suitable Solvents are exemplary typical aprotic organic solvents such as toluene, chlorobenzene, Dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, Tetrahydrofuran, 2-methyltertrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone, particularly preferred is N-methylpyrrolidone.

The Reaction mixture is 5 to 150 minutes, preferably 30 to 120 Minutes at -10 ° C to 40 ° C, preferably stirred at -5 ° C to 10 ° C, and then with water or saline and a suitable solvent at 10 ° C-80 ° C, preferably washed out at 10 ° C-30 ° C. The organic phase can then be treated with alkaline and acidic aqueous solutions. After concentrating the organic solution, this becomes to a suitable solvent or solvent mixture metered in the product of formula I is precipitated.

Suitable solvents for extraction are n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, be Particularly preferred are n-butanol and 2-methyltetrahydrofuran.

suitable Solvent for the precipitation of product I are Acetone, diisopropyl ether and water, and mixtures thereof.

The The following examples serve to illustrate of the invention, but without restricting it Experimental Part:

example 1

a) Preparation of the compound of the formula IV

27.5 g (0.07 mol) of the compound of formula II and 9.0 mL (0.07 mol) N-ethylmorpholine in 275 mL of N-methylpyrrolidine by stirring dissolved at room temperature. Cool to -5 to -6 ° C and dosed at this temperature 8.5 mL (0.064 mol) of isobutyl chloroformate within 20 minutes and then stirred for an hour at this Temperature after. This suspension obtained is directly in the step b) further implemented.

b) Preparation of the compound of the formula I

to obtained under step a) suspension is added at -5 to -6 ° C within 40 minutes 30.4 g (0.065 Mol) of the hydrochloride of the compound of formula V and 9.0 mL (0.07 Mol) N-ethylmorpholine in 60 ml of N-methylpyrrolidine. Then stir Continue for another hour at this temperature. The reaction mixture Is added to 2.6 L of ice water, 500 mL of n-butanol and 480 mL of saturated Saline. The organic phase is separated and in succession each with 100 mL 0.5 N hydrochloric acid and saturated Sodium bicarbonate solution extracted. It remains about 200 mL butanol phase. This drops to 2.6 L at 10 ° C dropwise pre-cooled diisopropyl ether. The rainfall is filtered off and stirred again with 0.6 L diisopropyl ether. After aspirating and drying at 20-25 ° C in a vacuum 41.5 g of the compound of the formula I are obtained.

Of the Solid still contains n-butanol and is washed twice with each 880 mL of water stirred at 0 to 5 ° C for one hour and dried after the second suction at 40 ° C in a vacuum. This gives 34.5 g of the compound of formula I.

Example 2

a) Preparation of the compound of the formula IV

19.2 g (0.0488 mol) of the compound of formula II and 6.3 mL (0.0499 mol) N-ethylmorpholine in 225 mL of N-methylpyrrolidine by stirring dissolved at room temperature. Cool to -2 to -3 ° C and dosed at this temperature 6.3 mL (0.0474 mol) of isobutyl chloroformate within 15 minutes and then stirred for 2 hours at this Temperature after. This suspension obtained is directly in the step b) further implemented.

b) Preparation of the compound of the formula I

to obtained under step a) suspension is added at -2 up to -3 ° C within 25 minutes 20.2 g (0.0452 Mole) of the compound of formula V and 5.8 mL (0.0452 mol) of N-ethylmorpholine in 60 ml of N-methylpyrrolidine. Then stir for another hour at this temperature after. The reaction mixture is added to 2.5 L 2% saline and 500 mL n-butanol. The organic Phase is separated and successively with 200 mL 0.5 n Hydrochloric acid and saturated sodium bicarbonate solution extracted. The organic phase will still connect washed four times with 1 L each of 2% saline. After the last extraction, the product starts to oily deposit. After addition of 50 mL n-butanol, the product goes into solution and the organic phase is separated and washed with 95% aqueous n-butanol diluted to 200 mL. The butanol solution thus obtained is pre-cooled within 30 minutes to 2.5 L at 5 to 10 ° C Diisopropyl ether given. The precipitate is sucked off and again washed with 0.6 L diisopropyl ether. After drying at 50 ° C in vacuo, 36 g of the compound of the formula I.

The solid still contains n-butanol and is stirred with 1.4 L of water for one hour at room temperature, filtered off and dried at 60 ° C in a drying oven. This gives 34.3 g of the compound of Formula I.

Example 3

a) Preparation of the compound of the formula IV

3:00 g (7.62 mmol) of the compound of formula II and 0.92 g (8 mmol) of N-ethylmorpholine in 20 mL of N-methylpyrrolidine by stirring at room temperature solved. It is cooled to 2 to 4 ° C and dosed at 0 to 10 ° C within 5 minutes 1.04 g (7.52 mmol) isobutyl chloroformate and stirred then after 25 min at this temperature after. This obtained Suspension is further reacted directly in step b).

b) Preparation of the compound of the formula I

The obtained under step a) suspension is metered at 0 to 10 ° C. within 10 minutes to a solution of 3.24 g (7.24 mmol) of the compound of formula V and 0.92 g (8 mmol) of N-ethylmorpholine in 4 ml of N-methylpyrrolidine. Then it is stirred for another 30 min at this temperature after. The reaction mixture is added to 90 4% saline and 108 mL 2-methyltetrahydrofuran. The aqueous phase is washed twice with 13.5 ml each of 2-methyltetrahydrofuran extracted. The combined organic phases are 30 min with 23.5 ml of 4% saline and 0.6 ml of 33% NaOH solution rested. It is neutralized with 0.6 ml of 30% HCl solution. The organic phase is washed 4 times with 25 ml of 4% saline washed and concentrated to a volume of 32 ml in vacuo. The so obtained solution is at 40 ° C within 10 minutes to a pre-cooled to 0 ° C mixture from 165 ml of diisopropyl ether and 41 ml of acetone. The rainfall is filtered off with suction and washed again with 20 ml of diisopropyl ether. After drying at 40 ° C in vacuo to obtain 4.9 g of the compound of formula I.

Example 4

a) Preparation of the compound of the formula IV

4.18 g (10.4 mmol) of the compound of formula II and 2.54 ml (10.6 mmol) Tributylamine in 22.5 mL of N-methylpyrrolidine by stirring dissolved at room temperature. Cool to 0 to 3 ° C and dosed at 0 to 6 ° C within 5 minutes 1.37 g (10.4 mmol) of isobutyl chloroformate and then stirred for 2 h at this temperature to. This suspension is obtained directly in step b) on implemented.

b) Preparation of the compound of the formula I

The obtained under step a) suspension is metered at 0 to 6 ° C. within 20 minutes to a solution of 4.51 g (10.0 mmol) of the compound of formula V and 0.7 g (3.0 mmol) of tributylamine in 5.5 ml of N-methylpyrrolidine. Then it is stirred for 2 h at this Temperature after. The reaction mixture is added to 150 ml of 4% saline and 40 mL n-butanol. The aqueous phase is washed twice extracted 10 ml of n-butanol. The combined organic phases Take 3 times with 34 ml of 4% saline and 8 times each time with 17 ml of 4% saline extracted. The butanolic Solution will rise to 0 ° C within 20 minutes precooled mixture of 300 ml of diisopropyl ether and 60 ml of acetone. The precipitate is stirred for 1 h, filtered off with suction and washed again with 30 ml of diisopropyl ether. After drying at 40 ° C in vacuo to obtain 7.64 g of the compound of formula I.

Example 5

a) Preparation of the compound of the formula IV

2.9 g (7.4 mmol) of the compound of formula II are dissolved in 20 ml of dimethylformamide dissolved by stirring at 40 ° C. One cools to 0 to 5 ° C and dosed 0.94 ml (7.3 mmol) of N-ethylmorpholine and then 0.95 mL (7.24 mmol) of isobutyl chloroformate and then stirred for 15 minutes at 40 ° C. to. This suspension is obtained directly in step b) on implemented.

b) Preparation of the compound of the formula I

The suspension obtained in step a) is cooled to 0-5 ° C and within 1 minute to a solution of 3.13 g (7.0 mmol) of the compound of formula V and 0.94 mL (7.3 mmol) of N-ethylmorpholine in 20 ml of dimethylformamide added. Then it is stirred for 1 hour at 40 ° C after. The reaction mixture is added to 90 ml of 4% saline and 110 ml of 2-methyl-tetrahydrofuran. The aqueous phase is extracted twice with 7 ml of 2-methyl-tetrahydrofuran. The combined organic phases are washed five times with 20 ml of 4% sodium chloride solution. The organic solution is added over 10 minutes to a pre-cooled to 0 ° C mixture of 150 ml of diisopropyl ether and 38 ml of acetone. The precipitate is stirred for 20 minutes, filtered off with suction and washed again with 30 ml of diisopropyl ether. After drying at 40 ° C. in vacuo, 3.35 g of the compound of the formula I are obtained.

Example 6

a) Preparation of the compound of the formula IV

2.9 g (7.4 mmol) of the compound of formula II are dissolved in 20 ml of dimethylformamide dissolved by stirring at 40 ° C. Man dosed 1.14 ml (7.3 mmol) of N-ethyldiisopropylamine and then 1.05 mL (7.26 mmol) of benzyl chloroformate and then stir for 15 minutes. This obtained Suspension is further reacted directly in step b).

b) Preparation of the compound of the formula I

The obtained under step a) suspension is within 1 minute to a solution of 3.13 g (7.0 mmol) of the compound of Formula V and 1.14 mL (7.4 mmol) of N-ethyldiisopropylamine in 20 mL Dosed dimethylformamide. Then it is stirred for 2.5 hours 40 ° C after. The reaction mixture is added to 90 ml 4% Saline and 110 mL 2-methyl-tetrahydrofuran. The aqueous phase is washed twice with 7 ml of 2-methyl-tetrahydrofuran extracted. The combined organic phases become five times washed with 20 ml of 4% sodium chloride solution. The Organic solution becomes one within 10 minutes Pre-cooled to 0 ° C mixture of 150 ml of diisopropyl ether and 38 ml of acetone. The precipitate is stirred for 20 minutes, filtered off with suction and washed again with 30 ml of diisopropyl ether. After drying at 40 ° C in vacuo to give 2.75 g of the compound of formula I.

Example 7

a) Preparation of the compound of the formula IV

2.9 g (7.4 mmol) of the compound of formula II are dissolved in 20 ml of dimethylformamide dissolved by stirring at 40 ° C. Man dosed 1.04 mL (7.3 mmol) triethylamine and then 0.9 mL (7.26 mmol) of trimethylacetyl chloride and then stirred 15 minutes after. This suspension obtained is directly in the step b) further implemented.

b) Preparation of the compound of the formula I

The obtained under step a) suspension is within 1 minute to a solution of 3.13 g (7.0 mmol) of the compound of Formula V and 1.04 mL (7.4 mmol) of triethylamine in 20 mL of dimethylformamide added. Then it is stirred for 2 hours at 40 ° C after. The reaction mixture is added to 90 ml of 4% saline and 110 mL of 2-methyltetrahydrofuran. The aqueous phase is extracted twice with 7 ml of 2-methyl-tetrahydrofuran. The combined organic phases are five times with 20 each washed with 4% sodium chloride solution. The organic Solution becomes 0 ° C within 10 minutes precooled mixture of 150 ml of diisopropyl ether and 38 ml of acetone. The precipitate is stirred for 20 minutes, filtered off with suction and washed again with 30 ml of diisopropyl ether. After drying at 40 ° C in vacuo to obtain 2.77 g of the compound of formula I.

From Of the compound I obtained was always a comparison means HPLC and / or NMR with an authentic control.

QUOTES INCLUDE IN THE DESCRIPTION

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Cited patent literature

• - WO 2004/087655 [0002, 0004, 0005, 0006]

Claims (26)

Process for the preparation of the compound of the formula I.

characterized in that a) the compound of formula II

with a compound of formula III

in which Hal can have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 C atoms, in which one or more CH ₂ groups of the alkyl radical are substituted by -O-, -CO-, -CH = CH- , -C≡C- or aryl may be replaced and the alkyl radical may be mono- or polysubstituted by F, Cl, Br or I, to the compound of formula IV

is reacted and then in a second step b) the compound of formula IV with a compound of formula V or salts thereof

is converted to the compound of formula I. Process according to claim 1, characterized in that Hal in the compound of the formula III has the meaning C1 owns. A method according to claim 1 or 2, characterized in that R1 is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, methyloxy, ethyloxy, Propyloxy, iso-propyloxy, butyloxy, iso-butyloxy, tert-butyloxy or benzyloxy. A method according to claim 1 or 2, characterized in that R1 has the meaning -O- (C ₁ -C ₆ ) -alkyl. A method according to claim 4, characterized in that R1 denotes -O-methyl, -O-ethyl, -O-iso-propyl, -O-n-butyl, -O-iso-butyl or -O-tert-butyl has. Method according to claim 1, 2, 3, 4 or 5, characterized in that R1 is iso-butyloxy has. Process according to Claim 1 or 2, characterized in that R 1 has the meaning (C ₁ -C ₆ ) -alkyl. A method according to claim 1, 2 or 3, characterized in that R1 is methyl, ethyl, Propyl, iso-propyl, butyl, iso-butyl, tert-butyl has. Method according to claim 1, 2, 3, 4, 5, 6, 7 or 8, characterized in that as solvent toluene, Chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, Diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone is used. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, characterized in that as the solvent 2-methyltetrahydrofuran, dimethylformamide or N-methylpyrrolidone is used. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, characterized in that as the solvent N-methylpyrrolidone is used. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, characterized in that in Step a) as the base triethylamine, ethyldimethylamine, N-ethyldiisopropylamine, Tributylamine, N-ethylmorpholine, N-methylmorpholine, tetramethylethylenediamine, Guanidine or alkylguanidines, is added. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, characterized in that in step a) as base triethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine or N-methylmorpholine is added. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, characterized in step a) as the base triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine is added. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, characterized in that in step b) as base triethylamine, ethyldimethylamine, N-ethyldiisopropylamine, Tributylamine, N-ethylmorpholine, N-methylmorpholine, tetramethylethylenediamine, Guanidine or alkylguanidines, is added. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, characterized in that in step b) as base triethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine or N-methylmorpholine is added. Method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, characterized that in step b) as the base triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine is added. Compound of formula IV

wherein R 1 is an alkyl radical having 1 to 18 C atoms, wherein one or more CH ₂ groups of the alkyl radical may be replaced by -O-, -CO-, -CH = CH-, -C≡C- or aryl and the Alkyl radical may be substituted one or more times with F, Cl, Br or I. A compound of the formula IV according to claim 18, characterized in that R1 has the meaning iso-butyloxy. Process for the preparation of the compound of the formula IVa

characterized in that the compound of the formula II

with a compound of formula IIIa

in which Hal may have the meaning Br, Cl or I, is reacted. A method according to claim 20, characterized characterized in that toluene, chlorobenzene, dichloromethane, Ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N-methylpyrrolidone or Methyl ethyl ketone is used. A method according to claim 20 or 21, characterized in that as solvent 2-methyltetrahydrofuran, Dimethylformamide or N-methylpyrrolidone is used. Method according to claim 20, 21 or 22, characterized in that as the solvent N-methylpyrrolidone is used. Method according to claim 20, 21, 22 or 23, characterized in that in step a) as the base triethylamine, Ethyldimethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine, N-methylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, is added. Method according to claim 20, 21, 22, 23 or 24, characterized in that in step a) as the base triethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine or N-methylmorpholine, is added. Method according to claim 20, 21, 22, 23, 24 or 25, characterized in that in step a) as the base Triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine added becomes.