WO2009112203A1

WO2009112203A1 - Process for preparing a diphenylazetidinone

Info

Publication number: WO2009112203A1
Application number: PCT/EP2009/001598
Authority: WO
Inventors: Theodor Andreas Wollmann; Bernd Junker; Bernhard Otto; Claus-Jürgen MAIER
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2008-03-14
Filing date: 2009-03-06
Publication date: 2009-09-17

Abstract

The invention relates to an improved process for preparing a diphenylazetidinone.

Description

Process for the preparation of a diphenylazetidinone

The invention relates to an improved process for the preparation of a diphenylazetidinone.

WO2004 / 087655 describes a diphenylazetidinone of the formula I and also syntheses of this compound.

I

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

The processes A and B described in WO2004 / 087655 have the disadvantage that

a) 1-hydroxybenzotriazole (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.

The process C likewise described in WO 2004/087655 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 method 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 should be as economic as possible, i. cost-effective, environmentally friendly and safe can be performed.

The object is achieved by production method A)

II III

wherein a) the compound of formula II with the compound of formula III, wherein R 1 is an alkyl radical having 1 to 18 carbon atoms, wherein one or more CH ₂ groups of the alkyl group 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, 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 esters, particularly preferably isobutyl chloroformate.

In a further embodiment, R 1 is an alkyl radical having 1 to 6 C atoms. In a further embodiment, R 1 is a methyl radical, ethyl radical, isopropyl radical, n-butyl radical, isobutyl radical or tert-butyl radical.

In another embodiment, R1 is an -O-alkyl radical having 1 to 17 carbon atoms.

In a further embodiment, R 1 is an -O-alkyl radical having 1 to 6 C atoms.

In a further embodiment, R 1 is -O-methyl, -O-ethyl, -O-isopropyl, -O-n-butyl, -O-iso-butyl or -O-tert-butyl.

By an alkyl radical is meant a straight or branched hydrocarbon chain of one to eighteen carbons, e.g. Methyl, ethyl, iso -propyl, n-butyl, iso-butyl, tert -butyl, hexyl, heptyl, octyl.

Hal is understood to mean a halogen radical which may have the meaning Br, Cl or I. Preferably, HaI has the meaning Cl.

An aryl radical is understood as meaning a phenyl, naphthyl or biphenyl radical in which one or more CH groups can be replaced by O, N or S.

The aryl radicals may be monosubstituted or polysubstituted by suitable groups, such as: F, Cl, Br, I, CF ₃ , NO ₂ , CN, COO (C ₁ -C ₆ ) alkyl, CON [(C ₁ -C ₆ ) alkyl ] _2> cycloalkyl, (Ci-C, ₀₎ alkyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₆₎ -alkynyl, O- (C, -C ₆₎ alkyl, O- ( C ₂ -C ₆₎ -alkenyl, O- (C ₂ -C ₆₎ -alkynyl, O- CO- (C _r _C6) alkyl, 0-CO- _(Ci-C6) - aryl, 0-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 is dissolved in a suitable solvent at -30 ⁰ C to + 70 ° C, preferably at -1O ⁰ C to + 50 ° C, particularly preferably at 20 ⁰ C to 45 ° C and within from 30 to 150 minutes, preferably 60-120 minutes with a suitable base, then to a temperature of -30 ⁰ C to 50 ⁰ C, preferably at -10 ⁰ C to 30 ⁰ C, particularly preferably at -5 ⁰ C bis 1O ⁰ C cooled and within 5 - 100 minutes, preferably added 5-60 minutes of a compound of formula III, particularly preferably isobutyl chloroformate.

Alternatively, a cooled to -10 ° C to 30 ° C, preferably -10 ⁰ C to 0 ° C solution of the compound III, preferably isobutyl chloroformate, are presented in a suitable Lösungsmettel and then the compound of formula II and a suitable base in a suitable solvent at -30 ° C to + 70 ° C, preferably at -10 ⁰ C to + 40 ⁰ C, more preferably at -5 ° C to 0 ° C within 30 to 150 minutes, preferably 60-120 minutes added become. In both procedures, the reaction mixture is then stirred at -10 ⁰ C to 40 ⁰ C, preferably at -10 ⁰ C to 10 ⁰ 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 product of formula IV formed is isolated. Preferably, the reaction mixture is used directly. To isolate the compound of formula IV, the solvent is evaporated in vacuo. Optionally, the reaction mixture is 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 Particularly preferred are triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine.

Suitable solvents are, for example, customary aprotic organic solvents, for example 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), within 5 to 60 minutes, preferably 10 to 45 minutes, the compound of formula V or its salts is dissolved in a suitable solvent to give a solution of product IV (prepared as described above, either using reaction solution directly or the isolated product dissolved in a suitable solvent) and optionally a suitable one Base in a suitable solvent at -10 ° C to 40 ° C, preferably -5 ° C to 10 ° C added.

Suitable bases are, for example, 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, for example, conventional aprotic organic solvents such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltertrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone; N-methylpyrrolidone is particularly preferred.

The reaction mixture is stirred for 5 to 150 minutes, preferably 30 to 120 minutes at -10 ° C to 40 ° C, preferably at -5 ° C to 10 ° C, and then with water or a saline solution and a suitable solvent at 10 ° C. - Washed 80 ° C, preferably at 10 ° C - 30 ° C. The organic phase can then be washed with alkaline and acidic aqueous solutions. After concentrating the organic solution, it is metered into a suitable solvent or solvent mixture, whereby the product of formula I is precipitated.

Suitable solvents for extraction are n-butanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, more preferably n-butanol and 2-methyltetrahydrofuran.

Suitable solvents for the precipitation of product I are acetone, diisopropyl ether and water and mixtures thereof.

The following examples serve to illustrate 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 the formula II and 9.0 ml (0.07 mol) of N-ethylmorpholine are dissolved in 275 ml of N-methylpyrrolidine by stirring at room temperature. It is cooled to -5 to -6 ° C and metered at this temperature within 20 minutes 8.5 mL (0.064 mol) of isobutyl chloroformate to and then stirred for one hour at this temperature. This suspension obtained is further reacted directly in step b).

b) Preparation of the compound of the formula I.

30.4 g (0.065 mol) of the hydrochloride of the compound of the formula V and 9.0 ml (0.07 mol) of N-ethylmorpholine in 60 ml of N-methylpyrrolidine are added to the suspension obtained under step a) at -5 to -6.degree , Then it is stirred 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 brine. The organic

Phase is separated and extracted successively with in each case 100 ml of 0.5 N hydrochloric acid and saturated sodium bicarbonate solution. There remain about 200 mL of butanol phase. This is added dropwise to 2.6 L pre-cooled to 10 ° C diisopropyl ether. The precipitate is filtered off and stirred again with 0.6 L diisopropyl ether. After aspirating and drying at 20-25 ° C in vacuo to obtain 41.5 g of the compound of formula I.

The solid still contains n-butanol and is stirred twice with in each case 880 ml of water 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) of N-ethylmorpholine in 225 mL of N-methylpyrrolidine by stirring at

Room temperature dissolved. It is cooled to -2 to -3 ° C and metered at this temperature within 15 minutes 6.3 mL (0.0474 mol) of isobutyl chloroformate and subsequently stirred for 2 hours at this temperature. This suspension obtained is further reacted directly in step b).

b) Preparation of the compound of the formula I The suspension obtained in step a) is added at -2 to -3 ° C. within 25 minutes

Minutes 20.2 g (0.0452 mol) of the compound of formula V and 5.8 mL (0.0452 mol) of N-ethylmorpholine in 60 ml of N-methylpyrrolidine. Then it is stirred for another hour at this temperature. The reaction mixture is added to 2.5 L of 2% saline solution and 500 mL of n-butanol. The organic phase is separated and washed successively with 200 ml of 0.5 N hydrochloric acid and saturated

Sodium bicarbonate solution extracted. The organic phase is then washed four times with 1 L of 2% saline solution. After the last extraction, the product begins to precipitate oily. After addition of 50 mL n-butanol, the product is dissolved and the organic phase is separated and diluted to 200 mL with 95% aqueous n-butanol. The resulting butanol solution is added over 30 minutes to 2.5 L to 5 to 10 ° C pre-cooled diisopropyl ether. The precipitate is filtered off with suction and washed again with 0.6 L diisopropyl ether. After drying at 50 ° C in vacuo, 36 g of the compound of formula I. The solid still contains n-butanol and is with 1.4 L of water for one hour at

Stirred room temperature, filtered off with suction and dried at 60 ° C in a drying oven. This gives 34.3 g of the compound of the formula I.

Example 3 a) Preparation of the compound of the formula IV

3.00 g (7.62 mmol) of the compound of the formula II and 0.92 g (8 mmol) of N-ethylmorpholine are dissolved in 20 ml of N-methylpyrrolidine by stirring at room temperature. It is cooled to 2 to 4 ° C and metered at 0 to 10 ° C within 5 minutes 1.04 g (7.52 mmol) of isobutyl chloroformate to and then stirred for 25 min at this temperature. This suspension obtained is further reacted directly in step b). b) Preparation of the compound of the formula I.

The suspension obtained in step a) is metered at 0 to 10 ⁰ 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 you still stir

For 30 minutes at this temperature. The reaction mixture is added to 90 ml of 4% saline and 108 ml of 2-methyltetrahydrofuran. The aqueous phase is extracted twice with 13.5 ml each of 2-methyltetrahydrofuran. The combined organic phases are rested for 30 minutes with 23.5 ml of 4% saline solution and 0.6 ml of 33% NaOH solution. It is neutralized with 0.6 ml of 30% HCl solution. The organic

Phase is washed 4 times with 25 ml of 4% saline and concentrated to a volume of 32 ml in vacuo. The resulting solution is added at 40 ° C within 10 minutes to a pre-cooled to 0 ° C mixture of 165 ml of diisopropyl ether and 41 ml of acetone. The precipitate is filtered off with suction and washed again with 20 ml of diisopropyl ether. After drying at 40 ° C. in vacuo, 4.9 g of the compound of the formula I are obtained.

Example 4 a) Preparation of the compound of the formula IV

4.18 g (10.4 mmol) of the compound of the formula II and 2.54 ml (10.6 mmol) of tributylamine are dissolved in 22.5 ml of N-methylpyrrolidine by stirring at room temperature. It is cooled to 0 to 3 ° C and metered 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. This suspension obtained is further reacted directly in step b).

b) Preparation of the compound of the formula I.

The suspension obtained in step a) 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. The reaction mixture is added to 150 ml of 4% saline and 40 mL n-butanol. The aqueous phase is extracted twice with 10 ml of n-butanol. The combined organic phases are extracted three times with 34 ml of 4% saline solution and eight times with 17 ml of 4% saline solution. The butanolic solution is added over 20 minutes to a pre-cooled to 0 ⁰ C 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, 7.64 g of the compound of the formula I are obtained.

Example S a) Preparation of the compound of the formula IV

2.9 g (7.4 mmol) of the compound of the formula II are dissolved in 20 ml of dimethylformamide by stirring at 40.degree. It is cooled to 0 to 5 ° C and metered 0.94 ml (7.3 mmol) of N-ethylmorpholine and then 0.95 mL (7.24 mmol)

Isobutyl chloroformate to and then stirred for 15 minutes at 40 ° C after. This suspension obtained is further reacted directly in step b).

b) Preparation of the compound of 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 1 10 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 to obtain 3.35 g of

Compound of the formula I. Example 6 a) Preparation of the compound of the formula IV

2.9 g (7.4 mmol) of the compound of the formula II are dissolved in 20 ml of dimethylformamide by stirring at 4O ⁰ C. It is metered 1.14 ml (7.3 mmol) of N-ethyldiisopropylamine and then 1.05 mL (7.26 mmol) of benzyl chloroformate and then stirred for 15 minutes. This suspension obtained is further reacted directly in step b).

b) Preparation of the compound of the formula I The suspension obtained in step a) is added over 1 minute to a solution of 3.13 g (7.0 mmol) of the compound of the formula V and 1.14 ml (7.4 mmol) of N-ethyldiisopropylamine in 20 ml of dimethylformamide , Then it is stirred for 2.5 hours at 40 ⁰ C after. The reaction mixture is added to 90 ml of 4% saline and 1 10 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, 2.75 g of the compound of the formula I are obtained.

Example 7 a) Preparation of the compound of Formula IV 2.9 g (7.4 mmol) of the compound of the formula II are dissolved in 20 ml of dimethylformamide by stirring at 40 ⁰ C. It is metered 1.04 mL (7.3 mmol) of triethylamine and then 0.9 mL (7.26 mmol) of trimethylacetyl chloride and then stirred for 15 minutes. This suspension obtained is further reacted directly in step b).

b) Preparation of the compound of the formula I.

The suspension obtained in step a) is added over 1 minute to a solution of 3.13 g (7.0 mmol) of the compound of the formula V and 1.04 ml (7.4 mmol). Triethylamine added in 20 ml of dimethylformamide. 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-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 ⁰ C mixture of diisopropyl ether 150 ml 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, 2.77 g of the compound of the formula I are obtained.

Of the compound I obtained in each case, a comparison was always carried out by means of HPLC and / or NMR with an authentic comparative sample.

Claims

claims:

1. 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

III

.worin Hal may have the meaning Br, Cl or I and in which R1 is an alkyl radical having 1 to 18 carbon atoms, wherein one or more CH ₂ groups of the alkyl may be replaced by -O-, -CO-, - CH = CH-, -C≡C- or aryl and the alkyl radical one or more times with F, Cl, Br or I. may be, to the compound of formula IV

O OH OH

,OH

O OH OH

IV is implemented and then in a second step

b) the compound of the formula IV with a compound of the formula V or salts thereof

H ₃ C

is converted to the compound of formula I.

2. The method according to claim 1, characterized in that HaI in the compound of formula III has the meaning Cl.

3. The method according to claim 1 or 2, characterized in that Rl is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, methyloxy, ethyloxy, propyloxy, iso-propyloxy, butyloxy, iso Butyloxy, tert-butyloxy or benzyloxy has.

4. The method according to claim 1 or 2, characterized in that Rl has the meaning O- (Ci-C ₆ ) alkyl.

5. The method according to claim 4, characterized in that Rl is the meaning -O-methyl radical, -O-ethyl radical, -O-iso-propyl radical, -On-butyl radical, -O-iso-butyl radical or -O-tert-butyl radical has.

6. The method according to claim 1, 2, 3, 4 or 5, characterized in that Rl has the meaning iso-butyloxy.

7. The method according to claim 1 or 2, characterized in that Rl has the meaning- (Ci-C ₆ ) -alkyl.

8. The method according to claim 1, 2 or 3, characterized in that Rl is methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl.

9. The 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.

10. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8 or 9, characterized in that is used as the solvent 2-methyltetrahydrofuran, dimethylformamide or N-methylpyrrolidone.

11. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, characterized in that N-methylpyrrolidone is used as the solvent.

12. The 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.

13. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, characterized in that in step a) as the base triethylamine, N-ethyldiisopropylamine, tributylamine, N-ethylmorpholine or N-methylmorpholine.

14. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, characterized in that in step a) as the base triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine is added.

15. The 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 the base triethylamine, ethyldimethylamine, N-

Ethyldiisopropylamine, tributylamine, N-ethylmorpholine, N-methylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines.

16. The 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 the base triethylamine, N-ethyldiisopropylamine , Tributylamine, N-ethylmorpholine or N-methylmorpholine.

17. The method according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, characterized in that in step b) as the base triethylamine, N Ethyldiisopropylamine or N-ethylmorpholine.

18. 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 may be replaced by -O-, -CO-, - CH = CH-, -C≡C- or aryl and the alkyl radical one or more times with F, Cl, Br or I. can be.

19. A compound of formula IV according to claim 18, characterized in that Rl has the meaning iso-butyloxy.

20. Process for the preparation of the compound of the formula FVa

IVa characterized in that the compound of formula II

with a compound of the formula IIIa

in which Hal can have the meaning Br, Cl or I,

is implemented.

21. The method according to claim 20, characterized in that as solvent toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethylformamide, N-methylpyrrolidone or methyl ethyl ketone is used.

22. The method according to claim 20 or 21, characterized in that 2-methyltetrahydrofuran, dimethylformamide or N-methylpyrrolidone is used as the solvent.

23. The method according to claim 20, 21 or 22, characterized in that N-methylpyrrolidone is used as the solvent.

24. The 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.

25. The 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.

26. The method according to claim 20, 21, 22, 23, 24, 25 or 26, characterized in that in step a) as the base triethylamine, N-ethyldiisopropylamine or N-ethylmorpholine is added.