DE19803408A1 - Alpha, alpha-disubstituted benzyl cyanide preparation in high yield and purity - Google Patents

Abstract

Preparation of an alpha , alpha -disubstituted benzyl cyanide (I) involves reacting an alpha -unsubstituted or alpha -monosubstituted analog (II) with an alkylating agent in presence of a base and a tertiary amine or phosphine. Preparation of an alpha , alpha -disubstituted benzyl cyanide of formula (I) involves reacting an alpha -unsubstituted or alpha -monosubstituted analog of formula (II) (optionally previously dissolved in an organic solvent) with an alkylating agent of formula R1-X (III) or X-CH2CH2-Z-(CH2)n-X (III') in presence of a base and a tertiary amine or phosphine of formula R7-Q(R8)(R9) (IV). R1 = 1-20C alkyl (optionally substituted by 1-3 Q' or phenyl (itself optionally substituted by 1-3 A or Q')) or 2-20C alkenyl (optionally substituted by 1-3 Q' or phenyl (itself optionally substituted by 1-3 A or Q')); R2 = as R1 or phenyl (optionally substituted by 1-3 Q' A); or R1 + R2 = -CH2CH2-Z-(CH2)n-; R3 = phenyl (optionally substituted by 1-3 A or Q'); R4 = H or as R2; A = 1-6C alkyl; Q' = 3-6C cycloalkyl, OH, ACOO, AO, (1-6C) alkoxy-(1-4C) alkoxy, halo, CF3, CN, NO2, COOH, AOCO, OCH2O, NR5R6CO or NR5R6; R5, R6 = H or A; Z = O, S or NR; R = H, A, benzyl or phenyl; n = 1 or 2; X = halo or 1/2 SO4; R7-R9 = 1-30C alkyl or phenyl; Q = N or P.

Description

European patent application EP 0 671 379 describes a method for Methylation of organic compounds in the presence of trialkylamines and dimethyl carbonate. The yield of α, α-dimethylbenzyl cyanide is 29%. Furthermore, the alkylation of benzyl cyanide with alkylating agents such as methyl iodide or methyl chloride in the presence of strong bases such as Sodium hydride, sodium amide or sodium alcoholate (Smith et al., J. Org. Chem. 36 15, pages 2132-2137; Trivedi et al., J. Med. Chem., EN, 36, 22, (1993), pages 3300-3307). The disadvantage of this reaction is increased formation of Ether products, the formation and emission of hydrogen and ammonia together with the alkylating agent. In addition, the strong bases only be manufactured ecologically and economically.

The object of the present invention is to find a method by which Compounds of formula II are alkylated in high yields and purity.

The invention therefore relates to a process for obtaining the compound of the formula I.

where R ¹ for

• 1. (C ₁ -C ₂₀ ) alkyl,
• 2. (C ₁ -C ₂₀ ) alkyl which is mono-, di- or trisubstituted by
  • 2.1. (C ₃ -C ₆ ) cycloalkyl,
  • 2.2. -OH,
  • 2.3. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.4. (C ₁ -C ₆ ) alkyl-O-,
  • 2.5. (C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₄ ) alkyl-O-,
  • 2.6. Halogen,
  • 2.7. -CF ₃ ,
  • 2.8. -CN,
  • 2.9. -NO ₂ ,
  • 2.10. HO-C (O) -,
  • 2.11. (C ₁ -C ₆ ) alkyl-OC (O) -,
  • 2.12. Methylenedioxo,
  • 2.13. R ⁵ - (R ⁶ ) NC (O) -, in which R ⁵ and R ^{6 are} identical or different and represent hydrogen atom or (C ₁ -C ₆ ) - alkyl
  • 2.14. R ⁵ - (R ⁶ ) N-, where R ⁵ and R ^{6 are} identical or different and represent hydrogen atom or (C ₁ -C ₆ ) alkyl, or
  • 2.15. Phenyl which is unsubstituted or substituted once, twice or three times independently of one another by (C ₁ -C ₆ ) -alkyl or as under 2.1. until 2.14. is substituted,
• 3. (C ₂ -C ₂₀ ) alkenyl,
• 4. (C ₂ -C ₂₀ ) alkenyl, which is one, two or three times independently of one another as under 2.1. until 2.15. is substituted,

R ²

the same meaning as R ¹

has or for

• 1. phenyl or
• 2. phenyl which is mono-, di- or trisubstituted by
  • 2.1. (C ₁ -C ₆ ) alkyl, in which the alkyl chain is straight or branched,
  • 2.2. (C ₃ -C ₆ ) cycloalkyl,
  • 2.3. -OH,
  • 2.4. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.5. (C ₁ -C ₆ ) alkyl-O-,
  • 2.6. (C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₄ ) alkyl-O-,
  • 2.7. Halogen,
  • 2.8. -CF ₃ ,
  • 2.9. -CN,
  • 2.10. -NO ₂ ,
  • 2.11. HO-C (O) -,
  • 2.12. (C ₁ -C ₆ ) alkyl-OC (O) -,
  • 2.13. Methylenedioxo,
  • 2.14. R ⁵ - (R ⁶ ) NC (O) -, in which R ⁵ and R ^{6 are} identical or different and represent hydrogen atom or (C ₁ -C ₆ ) - alkyl-, or
  • 2.15. R ⁵ - (R ⁶ ) N-, in which R ⁵ and R ^{6 are} identical or different and represent hydrogen atom or (C ₁ -C ₆ ) alkyl

or R ¹

and R ²

together with the carbon atom to which they are attached form a compound of the formula IV,

where Z is N, O or S atom and n is 1 or 2, or when Z is N or S atom, Z is unsubstituted or substituted by R, where R (C ₁ -C ₆ ) - Means alkyl, benzyl or phenyl,
R ³ for

• 1. phenyl or
• 2. phenyl which is mono-, di- or trisubstituted by
  • 2.1. (C ₁ -C ₆ ) alkyl, in which the alkyl chain is straight or branched,
  • 2.2. (C ₃ -C ₆ ) cycloalkyl,
  • 2.3. -OH,
  • 2.4. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.5. (C ₁ -C ₆ ) alkyl-O-,
  • 2.6. (C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₄ ) alkyl-O-,
  • 2.7. Halogen,
  • 2.8. -CF ₃ ,
  • 2.9. -CN,
  • 2.10. -NO ₂ ,
  • 2.11. HO-C (O) -,
  • 2.12. (C ₁ -C ₆ ) alkyl-OC (O) -,
  • 2.13. Methylenedioxo,
  • 2.14. R ⁵ - (R ⁶ ) NC (O) -, in which R ⁵ and R ^{6 are} identical or different and represent hydrogen atom or (C ₁ -C ₆ ) alkyl-, or
  • 2.15. R ⁵ - (R ⁶ ) N-, in which R ⁵ and R ^{6 are} identical or different and represent hydrogen atom or (C ₁ -C ₆ ) alkyl

which is characterized in that a compound of formula II,

in which
R ^{3 has the} same meaning as in formula I and
R ^{4 represents} hydrogen atom or has the same meaning as R ² in formula I,
optionally first dissolves in an organic solvent or without a solvent with an alkylating agent of the formula III,

R ¹ -X (III)

where R ^{1 has the} same meaning as in formula I and X represents halogen or 2 radicals of R ¹ are bonded to SO ₄ or with an alkylating agent of the formula IIIa,

where Z, X, R and n have the meaning given above,
in the presence of a basic agent and at least one compound of the formula V and / or VI

wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} independently the same or different and are (C ₁ -C ₃₀ ) alkyl or phenyl.

The compounds of the formula I are preferably prepared in which
R ¹ for

• 1. (C ₁ -C ₆ ) alkyl,
• 2. (C ₁ -C ₆ ) alkyl, substituted twice by -O-CH ₃ or
• 3. (C ₁ -C ₆ ) alkyl, simply substituted by R ⁵ - (R ⁶ ) -N-, where R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₃ ) alkyl, stands,

R ²

the same meaning as R ¹

has or represents phenyl or
R ¹

and R ²

together with the carbon atom to which they are attached form a compound of formula IVa

wherein R is (C ₁ -C ₆ ) alkyl, benzyl or phenyl
R ^{3 represents} phenyl, unsubstituted or simply substituted by (C ₁ -C ₃ ) alkyl-O-.

The compounds of the formula I are advantageously prepared in which
R ^{1 is} (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkyl, substituted twice by -O-CH ₃ or -CH (CH ₃ ) -CH ₂ -N- (CH ₃ ) -CH ₃ stands,
R ^{2 has the} same meaning as R ¹ or represents phenyl or
R ¹ and R ² together with the carbon atom to which they are attached form a radical of the formula IVa, in which R denotes -CH ₃ ,
R ^{3 represents} phenyl, unsubstituted or simply substituted by -O-CH ₃ .

Compounds of the formula I are preferably prepared by the process according to the invention, where R ¹ and R ^{2 are} (C ₁ -C ₆ ) -alkyl and R ^{3 is} phenyl.

Dimethylbenzyl cyanide or 1-methyl-4-phenyl is particularly preferred piperidine-4-carbonitrile.

In the preparation of the compound of formula I, the procedure is such that first basic agents and the compound of formulas V and / or VI with stirring are presented and then by adding the compound of formula II, the optionally previously dissolved in an organic solvent, and des Alkylating agent is converted to a compound of formula I.

It is preferred to use 1 mol of the compound of the formula II from 2.1 mol to 2.4 mol, in particular from 2.15 mol to 2.25 mol, of Alkylating agent of formula III and per mol of the compound of formula II is preferably used from 2.5 mol up to 4 mol, in particular from 2.8 mol to 3.2 mol, of the basic agent.

It is preferred to use 100 percent by weight (% by weight) of the compound of the formula II from 0.5% by weight to 5% by weight, in particular 1% by weight to 2% by weight of the Connection of formulas V and / or VI.

The reaction temperature is from 20 ° C to 100 ° C, preferably from 30 ° C to 40 ° C. The reaction time is generally from 2 to 10 hours.

If the alkylating agent is gaseous, as is the case with methyl chloride (chloromethane)  also work with an overpressure of up to 5 bar. In the The alkylation reaction with dialkyl sulfate is the one that forms during the reaction Methyl sulfuric acid by optionally adding further alkali hydroxide bound. After the reaction has ended, the compound of the formula I is isolated. To the mixture is mixed with water and the resulting phases become then separated. The compound of formula I is then from the organic phase. If necessary, the organic Phase of a cleaning process such. B. a distillation under reduced pressure Pressure or crystallization from a solvent.

Preferred basic agents are alkali metal hydroxides, e.g. B. sodium hydroxide, Potassium hydroxide, lithium hydroxide, sodium hydroxide is particularly preferred.

Preferred solvents are, for example:
(C ₅ -C ₇ ) aliphatic and (C ₆ -C ₈ ) cycloaliphatic hydrocarbons such as pentane, 2-methylbutane, hexane, 2,2-dimethylbutane, 2-methylpentane, 3-methylpentane, heptane, cyclohexane, methylcyclohexane, 1 , 2-dimethylcyclohexane, 1,3-dimethylcyclohexane; aromatic hydrocarbons such as toluene, xylenes, ethylbenzene, isopropylbenzoyl; aromatic and aliphatic halogenated hydrocarbons such as chlorobenzene, dichloromethane, dichloropropane, 1,2-dichloroethane; Polyethers such as ethylene glycol dibutyl ether, diethylene glycol ethyl tert-butyl ether, polyethylene glycol dibutyl ether, polypropylene glycol dibutyl ether, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polypropylene glycol diethyl ether, polypropylene glycol methyl ether; heterocyclic hydrocarbons such as N-methylpyrrolidone, pyridine; Ethers such as tetrahydrofuran, dibutyl ether, methyl tert-butyl ether and dimethyl carbonate and dimethyl sulfoxide.

The following compounds of the formula V and / or VI are suitable:

• Trimethylamine, dimethylethylamine, triethylamine, tri-n-propylamine, Triisopropylamine, tributylamine, trioctylamine, tricyclohexylamine, Trihexadecylamine, diphenylmethylamine, dimethylbenzylamine, Dibenzylmethylamine, tribenzylamine, triphenylamine,  
• Trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tributylphosphine, Triisopropylphosphine, trioctylphosphine, triphenylphosphine.

Preferred compounds of the formula V and / or VI are (C ₃ -C ₂₄ ) trioctylamine or (C ₃ -C ₂₄ ) trioctylphosphine. Particularly preferred compounds of the formulas V and / or formula VI are trioctylamine, trioctylphosphine and triethylamine.

Preferred alkylating agents are (C ₁ -C ₆ ) alkyl halides such as alkyl chloride, alkyl bromide, alkyl fluoride or alkyl iodide, in particular methyl chloride, ethyl chloride or propyl chloride; (C ₁ -C ₆ ) dialkyl sulfate such as dimethyl, diethyl, dipropyl, dibutyl, dipentyl or dihexyl sulfate or di- (2-chloroethyl) methylamine.

The term "halogen" means fluorine, chlorine, bromine or iodine. Under the term "alkyl" or "alkenyl" is understood to mean hydrocarbon radicals Carbon chain are straight or branched. Cyclic alkyl radicals are for example 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl. Furthermore, the alkenyl radical can be more than one Double bond, ie also contain 2, 3 or 4 double bonds.

The starting substances for the alkylation reaction according to the invention are after processes known from the literature can be produced, for example by cyanolysis of the corresponding halogen compounds.

The process products are sought compounds for the production of a Variety of secondary products, e.g. B. for the production of anti-allergic Drugs such as 4- [4- [4- (hydroxydiphenyl) -1-piperidinyl] -1-hydroxybutyl] -α, α- dimethylphenylacetic acid (US 4,254,129).

The high yields and the high purity of the products produced are advantageous Products.

example 1 Production of dimethylbenzyl cyanide

1416 g of sodium hydroxide solution, 33% strength and 425 g of caustic soda were placed in a reactor. 6 g of trioctylamine were added to this solution, then 400 g of benzyl cyanide and 380 g of chloromethane were reacted in this mixture at 20 ° C. to 40 ° C. while stirring at elevated pressure. After the internal pressure had dropped below 0.5 bar, the residual pressure was released. Then 2000 ml of water were added, stirred briefly, allowed to settle and then the phases were separated. The organic phase was distilled under reduced pressure. 485.5 g of pure dimethylbenzyl cyanide with a content of more than 99% were obtained (determined by gas chromatography (GC)). This is 98% of theory based on the benzyl cyanide used. The content of monomethylbenzyl cyanide and unreacted benzyl cyanide was in each case less than 0.1%. The content of saponification products such as phenylacetic acid was below the detection limit.

GC:
Separation column: HP1, 25 m long
Injection block temperature: 250 ° C
Start temperature: 50 ° C
Heating rate: 10 ° C / min
Final temperature: 250 ° C
Carrier gas: helium or nitrogen
Split ratio: 1: 100
Detector: FID
Injection quantity: 3 µl (5% solution in toluene)

Retention times:

Benzyl cyanide: approx. 6.9 min
Monomethylbenzyl cyanide: approx. 7.5 min
Dimethylbenzyl cyanide: approx.8.0 min

Example 2 Preparation of 1-methyl-4-phenyl-piperidine-4-carbonitrile (dolantine nitrile)

1160 g of sodium hydroxide solution, 33% strength and 184 g of caustic soda were placed in a reactor. 20 g of trioctylamine were added to this solution. 117 g of benzyl cyanide and a solution of 163.8 g of di- (2-chloroethyl) methylamine in 820 g of toluene were then simultaneously metered in at 60 ° C. to 80 ° C. while stirring well. The mixture was then left to stir for a further 2 to 4 hours. Then 2000 ml of water were added, the mixture was stirred briefly and the phases which formed were separated from one another. The product was separated from the catalyst (trioctylamine) and organic impurities by initially acidic, then alkaline extraction. The toluene was then distilled off from the organic phase under reduced pressure. The distillation residue was then further purified by distillation under high vacuum at a pressure of less than 1 mbar. The distillate obtained 180 g of 1-methyl-4-phenyl-piperidine-4-carbonitrile with a content of more than 99% (determined by gas chromatography (GC)). This corresponds to a yield of 90% of theory based on the benzyl cyanide used.

GC:
Separation column: DB17, 30 m long
Temp. Injection block: 250 ° C
Start temperature: 100 ° C
Heating rate: 10 ° C / min
Final temperature: 250 ° C
Carrier gas: helium
Split ratio: 1: 100
Detector: FID
Injection quantity: 3 µl (5% solution in toluene)

Retention times:

Benzyl cyanide: approx. 9 min
Dolantine nitrile: approx. 18 min

Claims (11)

1. Process for obtaining the compound of formula I.
where R ¹ for

• 1. (C ₁ -C ₂₀ ) alkyl,
• 2. (C ₁ -C ₂₀ ) alkyl which is mono-, di- or trisubstituted by
  • 2.1. (C ₃ -C ₆ ) cycloalkyl,
  • 2.2. -OH,
  • 2.3. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.4. (C ₁ -C ₆ ) alkyl-O-,
  • 2.5. (C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₄ ) alkyl-O-,
  • 2.6. Halogen,
  • 2.7. -CF ₃ ,
  • 2.8. -CN,
  • 2.9. -NO ₂ ,
  • 2.10. HO-C (O) -,
  • 2.11. (C ₁ -C ₆ ) alkyl-OC (O) -,
  • 2.12. Methylenedioxo,
  • 2.13. R ⁵ - (R ⁶ ) NC (O) -, in which R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₆ ) alkyl,
  • 2.14. R ⁵ - (R ⁶ ) N-, in which R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₆ ) alkyl, or
  • 2.15. Phenyl which is unsubstituted or substituted once, twice or three times independently of one another by (C ₁ -C ₆ ) -alkyl or as under 2.1. until 2.14. is substituted,
• 3. (C ₂ -C ₂₀ ) alkenyl or
• 4. (C ₂ -C ₂₀ ) alkenyl, which is one, two or three times independently of one another as under 2.1. until 2.15. is substituted,

R ^{2 has the} same meaning as R ¹ or for

• 1. phenyl or
• 2. Phenyl, mono-, di- or trisubstituted by
  • 2.1. (C ₁ -C ₆ ) alkyl, in which the alkyl chain is straight or branched,
  • 2.2. (C ₃ -C ₆ ) cycloalkyl,
  • 2.3. -OH,
  • 2.4. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.5. (C ₁ -C ₆ ) alkyl-O-,
  • 2.6. (C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₄ ) alkyl-O-,
  • 2.7. Halogen,
  • 2.8. -CF ₃ ,
  • 2.9. -CN,
  • 2.10. -NO ₂ ,
  • 2.11. HO-C (O) -,
  • 2.12. (C ₁ -C ₆ ) alkyl-OC (O) -,
  • 2.13. Methylenedioxo,
  • 2.14. R ⁵ - (R ⁶ ) NC (O) -, in which R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₆ ) alkyl, or
  • 2.15. R ⁵ - (R ⁶ ) N-, in which R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₆ ) alkyl

or R ¹ and R ² together with the carbon atom to which they are attached and the radicals R ³ and -CN form a compound of the formula IV,
where Z is N, O or S atom and n is 1 or 2, or when Z is N or S atom, Z is unsubstituted or substituted by R, where R (C ₁ - C ₆ ) - Means alkyl, benzyl or phenyl,
R ³ for

• 1. phenyl or
• 2. Phenyl, mono-, di- or trisubstituted by
  • 2.1. (C ₁ -C ₆ ) alkyl, in which the alkyl chain is straight or branched,
  • 2.2. (C ₃ -C ₆ ) cycloalkyl,
  • 2.3. -OH,
  • 2.4. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.5. (C ₁ -C ₆ ) alkyl-O-,
  • 2.6. (C ₁ -C ₆ ) alkyl-O- (C ₁ -C ₄ ) alkyl-O-,
  • 2.7. Halogen,
  • 2.8. -CF ₃ ,
  • 2.9. -CN,
  • 2.10. -NO ₂ ,
  • 2.11. HO-C (O) -,
  • 2.12. (C ₁ -C ₆ ) alkyl-OC (O) -,
  • 2.13. Methylenedioxo,
  • 2.14. R ⁵ - (R ⁶ ) NC (O) -, in which R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₆ ) alkyl, or
  • 2.15. R ⁵ - (R ⁶ ) N-, in which R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₆ ) -alkyl,

characterized in that a compound of formula II,
in which
R ^{3 has the} same meaning as in formula I and
R ^{4 represents} hydrogen atom or has the same meaning as R ² in formula I,
optionally first dissolves in an organic solvent or without a solvent with an alkylating agent of the formula III,
R ¹ -X (III)
where R ^{1 has the} same meaning as in formula I and X is halogen or 2 radicals of R ¹ are bonded to the radical SO ₄ or with an alkylating agent of the formula IIIa
wherein Z, X, R and n have the meaning given above, in the presence of a basic agent and at least one compound of the formula V and / or formula VI
wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{12 are} independently the same or different and represent (C ₁ -C ₃₀ ) alkyl or phenyl. 2. The method according to claim 1, characterized in that a compound of formula I is prepared, wherein
R ¹ for

• 1. (C ₁ -C ₆ ) alkyl,
• 2. (C ₁ -C ₆ ) alkyl, substituted twice by -O-CH ₃ or
• 3. (C ₁ -C ₆ ) alkyl, simply substituted by R ⁵ - (R ⁶ ) -N-, where R ⁵ and R ^{6 are} identical or different and denote hydrogen atom or (C ₁ -C ₃ ) alkyl, stands,

R ^{2 has the} same meaning as R ¹ or represents phenyl or
R ¹ and R ² together with the carbon atom to which they are attached and the radicals R ³ and -CN form a compound of the formula IVa,
wherein R is (C ₁ -C ₆ ) alkyl, benzyl or phenyl, and
R ^{3 is} phenyl unsubstituted or simply substituted by (C ₁ -C ₃ ) alkyl-O-. 3. The method according to claim 1, characterized in that the compounds of formula I is prepared, wherein
R ^{1 is} (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkyl, substituted twice by -O-CH ₃ or -CH (CH ₃ ) -CH ₂ -N- (CH ₃ ) -CH ₃ stands,
R ^{2 has the} same meaning as R ¹ or represents phenyl or
R ¹ and R ² together with the carbon atom to which they are attached and the radicals R ³ and -CN form a compound of the formula IVa, and
R ^{3 represents} phenyl, unsubstituted or simply substituted by -O-CH ₃ . 4. The method according to claim 1, characterized in that Dimethylbenzylcyanid or 1-methyl-4-phenyl-piperidine-4-carbonitrile. 5. The method according to one or more of claims 1 to 4, characterized characterized in that a compound of formula V and / or VI Compound from the group trimethylamine, dimethylethylamine, triethylamine, Tri-n-propylamine, triisopropylamine, tributylamine, trioctylamine, Tricyclohexylamine, trihexadecylamine, diphenylmethylamine, Dimethylbenzylamine, dibenzylmethylamine, tribenzylamine, triphenylamine, Trimethylphosphine, triethylphosphine, tri-n-propylphosphine, tributylphosphine, Uses trioctylphosphine, triisopropylphosphine and triphenylphosphine, preferably trioctylamine, trioctylphosphine and triethylamine. 6. The method according to one or more of claims 1 to 5, characterized characterized in that the basic agents are sodium hydroxide, Potassium hydroxide, lithium hydroxide, especially sodium hydroxide. 7. The method according to one or more of claims 1 to 6, characterized in that the alkylating agent (C ₁ -C ₆ ) alkyl halides such as alkyl chloride, alkyl bromide, alkyl fluoride or alkyl iodide, in particular methyl chloride, ethyl chloride or propyl chloride; (C ₁ -C ₆ ) dialkyl sulfate such as dimethyl, diethyl, dipropyl, dibutyl, dipentyl or dihexyl sulfate or di- (2-chloroethyl) methylamine. 8. The method according to one or more of claims 1 to 7, characterized characterized in that 1 mol of the compound of formula II from 2.1 mol to 2.4 mol, in particular from 2.15 mol to 2.25 mol, of Alkylating agent of formula III uses and to 1 mol of the compound of formula II from 2.5 mol to 4 mol, in particular from 2.8 mol to 3.2 mol, of the basic agent. 9. The method according to one or more of claims 1 to 8, characterized characterized in that one per 100 weight percent (wt .-%) of the compound of the formula II from 0.5% by weight to 5% by weight, in particular from 1% by weight to 2% by weight of the compound of the formulas V and / or formula VI. 10. The method according to one or more of claims 1 to 9, characterized characterized in that the alkylation at temperatures from 20 ° C to 100 ° C, preferably from 30 ° C to 40 ° C, is carried out. 11. The method according to one or more of claims 1 to 10, characterized in that the compound of formula II in a solvent from the group (C ₅ -C ₇ ) aliphatic and (C ₆ -C ₈ ) cycloaliphatic hydrocarbons such as pentane , 2-methylbutane, hexane, 2,2-dimethylbutane, 2-methylpentane, 3-methylpentane, heptane, cyclohexane, methylcyclohexane, 1,2-dimethylcyclohexane, 1,3-dimethylcyclohexane; aromatic hydrocarbons such as toluene, xylenes, ethylbenzene, isopropylbenzoyl; aromatic and aliphatic halogenated hydrocarbons such as chlorobenzene, dichloromethane, dichloropropane, 1,2-dichloroethane; Polyethers such as ethylene glycol dibutyl ether, diethylene glycol ethyl tert-butyl ether, polyethylene glycol dibutyl ether, polypropylene glycol dibutyl ether, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, polypropylene glycol diethyl ether, polypropylene glycol methyl ether; heterocyclic hydrocarbons such as N-methylpyrrolidone, pyridine; Ethers such as tetrahydrofuran, dibutyl ether, methyl tert-butyl ether and dimethyl carbonate and dimethyl sulfoxide.