DD155614A1 - PROCESS FOR THE PREPARATION OF DERIVATIVES OF N-PHENYLAETHYLENEDIAMINE - Google Patents

Abstract

Substituted N-phenylethylethylenediamine derivatives can be prepared industrially easily and safely by reacting appropriately substituted aniline, anhydrous aluminum chloride and liquid ethylenimine in the order given and in an approximately equimolar amount in an inert organic solvent such as e.g. Benzene or toluene at temperatures of 30 to 80 degrees C.

Description

M22δ463

Title of the invention

Process for the derivation of derivatives of H-phenylethylenediamine

Field of application of the invention

The invention relates to a process for the preparation of derivatives dea U-Phenyläthylendiamina the general formula

E ¹

-HH-CH ₉ -CHo-BHr

e *

Wherein R, R and R, which may be identical or different and denote hydrogen, fluorine, chlorine, bromine, methyl, methoxy or Hitro, where wenigatena a

12 3 of the Reate R, R and R ^ is no Wasaeratoff that represent valuable intermediates for the Syntheae of drugs ·

n o ππ in cn, on ;,

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Characteristic of the known technical solution

The preparation of U-phenylethylenediamine and its substituted in the phenyl radical derivatives has been described on various Y / egen. Thus, E-phenylethylenediamine is obtained by hydrogenation of anilinoacetonitrile on nickel / kieselguhr in an autoclave (US Pat. No. 2,067,291 / "19337), by hydrogenation of E-phenyl-N *, IT'-dibenzylethylenediamine over palladium in acetic acid (DRP 550 762 / "19307), in addition to bis (2-anilinoethyl) -amine by treating IT- (2-chloroethyl) -aniline with liquid ammonia for two days (Chem. Ber. 7O _-1 979, 986, /" 19377), at Heating of N - / "ß-Oxyäthyl7-H-phenylguanidine hydrochloride with concentrated hydrochloric acid at 180 ⁰ C (DRP 446 547) or by reacting aniline with B-Bronäthylphthalimid and subsequent cleavage of the resulting ^ (2-Anilinoäthyl) -phthaliinids by heating with aqueous hydrochloric acid at 130 ⁰ C (Pourneau, de estrange, Bull Soc Chim · Prance 827 -.. 839).

Substituted in the phenyl radical derivatives of TT-Phenyläthylendiamins can also by reacting 2-Bromoethylamine hydrochloride with twice the molar amount of aniline or * substituted aniline (J.Hed.Chem.Jj. 852-857 / "19667) or by reacting substituted aniline with ß-bromoethyl phthalimide and subsequent cleavage of the thereby resulting lT- (2- (substituted) Anilinoäthyl) -phthalimides by heating with aqueous hydrochloric acid to 130 ⁰ C (Pourneau, de Lestrange) are prepared · H (o-toluyl) ethylenediamine can from o-toluidine and ethanolamine are obtained (J "Pharm.Soc · Japan 75, 1318-1321 /" 195 ^ 7).

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N- (4-chlorophenyl) -ethylenediamine is obtainable by reduction of 4-chloroanilinohydroxanic acid or of 4-chlorophenylaminoacetonitrile with lithium aluminum hydride (Arch. Pharm. (Weinheim), 303-933-938 / 197197). to U- (2-N itro phenyl) - and N- (4-lIitro phenyl) -ätlyendiamin be obtained by reacting 2- or 4-Uitrochlorbenzol with ethylenediamine in the presence of CuCl ₂ (J · Org. Chem · 10 , 283 - 285 £ "19457) ·

Most of the previously known processes for the preparation of phenyl-substituted derivatives of N-phenylethylenediamine in the last or one of the preceding reaction stages are based on the reaction of aniline derivatives with haloalkyl compounds with elimination of hydrohalic acids or hydrogen peroxide. To the requisite reaction conditions include long reaction times, higher reaction temperatures and in some cases an excess of the aniline derivative to intercept vacant acid _e The reaction of ethylenediamine with Hitrochlorbenzolderivaten iat not generally applicable and only allows the preparation of 2- or x 4 flitrophenyläthylendiainin.

It is also known IJ Phenyläthylendiamin by introducing ethyleneimine gas into a mixture of aniline and anhydrous aluminum chloride in tetralin or diphenyl at 180 ⁰ C (Coleman, Callen, J · On · Chem. Soc · 68, £ 2006 "19467) or upon heating ethyleneimine with aniline and aniline hydrochloride (Doklady, Akad. SSSR, 59, 489 Z "19487).

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The process described by Coleman and Callen for the reaction of aliphatic amines or aniline with ethylenimine in the presence of anhydrous AICI3 has not hitherto been extended to the reaction with substituted aromatic amines.

According to the current state of knowledge of the literature are for the implementation of primary amines with Äthylenimin under the elaborated by Coleman and Callen conditions 180 ⁰ C · Furthermore, this method works with an excess of amine and with gaseous Äthylenimin. The high reaction temperature means high expenditure of energy, carries the risk of the formation of decomposition products in itself and leads to low yields · With the use of gaseous Äthylenimin a greater expenditure on equipment, disturbances in the course of the reaction and dangers are connected ·

Also, some of the compounds, eg, nitrophenylethylenediamine derivatives, can not be prepared by this method. It is known that during the heating of Hitrobenzol with anhydrous AlCl 3 to about x 200 ⁰ can be made C explosions (Ber. Dtsch. Ehem. Ges. 25, 3522 ^ "18927, former Ing." Techn. 48 ^ 729 ^ ~ 197§ 7).

Even at temperatures of about 100 ⁰ C in toluene, nitrobenzene reacts with AlCIo to form hydrogen chloride and an aniline derivative (Chem "Ber. _<53 1650 _A ^ ~ 192O7). According to Hach's own observations, even Eitroanilinderivate with AICI3 in toluene at temperatures below 100 ⁰ C to form dark decomposition products to. In addition, the attachment compounds of some aniline derivatives with AlCl ₃ tend to form a tough bottombody at elevated temperatures.

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Object of the invention

The invention makes it possible to prepare substituted U-phenylethylenediamine derivatives by a technically simple, safe and generally applicable process in good yields from the corresponding aniline derivatives, AICI3 and ethyleneimine, it also being possible to prepare nitro-substituted U-phenylethylenediamine derivatives, their preparation was not possible in this way and against whose production on this Y / ege according to the state of the art an already mentioned prejudice existed »

It is also an advantage that in the process according to the invention the reactants can be used in an approximately equimolar amount ratio. This is of particular importance in the interest of a high yield if it is intended to convert difficult to access, expensive aniline derivatives.

Nor could it be foreseen that under these conditions pure reaction products would be obtained in good yield, since Coleman and Callen have used amine and AICI3 in excess of ethyleneimine in order to avoid the formation of larger amounts of difficultly separated polyamines.

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Explanation of the essence of the invention

The invention has for its object to develop a generally applicable, technically simple and safe process for the preparation of H-phenylethylenediamine derivatives of general formula I, which avoids the disadvantages of the previously known methods.

According to the present invention, this is achieved by reacting an appropriately substituted aniline of the general formula

E ¹

R ³

- BH ₂ II

12 3

wherein R, R and R have the abovementioned meaning, with anhydrous aluminum chloride and liquid Äthylenimin in the order given and in about equimolar ratio in an inert organic solvent such. B · benzene or toluene at temperatures of 30 to 80 ⁰ C reacted.

To avoid the risk of an uncontrollable exothermic reaction by excess AICI3, the specified order of addition of the reactants Anilinderivat, AICI3, Äthylenimin must be strictly adhered to the reaction medium. '

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For the work-up of the reaction mixture there are various possibilities according to methods known per se. So you can z. Add the alkali metal hydroxide solution to the reaction mixture after addition of water until the strongly alkaline reaction is complete, remove the organic solvent and separate from this by fractional distillation between unreacted aniline derivative and N-phenylethylenediamine derivative formed.

On the other hand, certain substituted aniline derivatives having weakly basic properties, such as. B · 2,6-dichloroaniline or the nitroaniline derivatives, from the reaction mixture also remove by reacting in highly dilute acid acids, such as. B · 1 η acetic acid, poorly soluble aniline derivative is separated and then isolated in the aqueous solution containing U-phenyläthylendiamin derivative.

Ausfiihrungsbeispiele

Example 1: N- (2,6-dichlorophenyl) ethylenediamine

To a solution of 129.6 g (0.8 mol) of 2.6-Diehloranilin in 400 ml of anhydrous toluene is added with stirring 107 g (0.8 mol) .wasserfreies aluminum chloride, the mixture heated to 80 ⁰ C and added dropwise over 40 minutes 34.4 g (0.8 mol) Athylenimin added. Thereafter, the mixture is allowed to stir at 80 ^° C. for a further 30 minutes. After cooling, 800 ml of V / asser are added dropwise and stirred until the detachment of adhering to the piston edge precipitate. Subsequently, the toluene phase is separated and the aqueous phase extracted with 200 ml of toluene. From the combined toluene solutions obtained after distillative removal of the solvent about 2§ g 2.6-dichloroaniline

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back. 350 ml of concentrated sodium hydroxide solution (about 45 percent) are added to the aqueous solution, and the mixture is extracted with a total of 400 ml of toluene. After distillation of the toluene, the N- (2,6-dichlorophenyl) ethylenediamine is fractionally distilled in vacuo over a 20 cm Fdllkörperkolonne.

Boiling point: Kp _{0 01} 100 to 101 ⁰ C. n ^ ²⁵ 1,5838. Yield; 110 g (67 % of theory).

Example 2: iT- (2,6-dimethylphenyl) ethylenediamine

In a solution of 72.6 g (0.6 mol) of 2,6-dimethylaniline in 400 ml of anhydrous toluene is added slowly with cooling 80.1 g (0.6 Hol) of anhydrous aluminum chloride, the temperature rises to 35 ⁰ C. Then allowed to this mixture within 1 hour while maintaining a temperature of 35 to 40 ⁰ C 25.8 g (0.6 mol) of A'thylenimin added dropwise. The mixture is then stirred for 4 hours at this temperature, allowed to stand overnight at room temperature and heated to 60 ⁰ C for 1 hour. After cooling, 250 ml of water are slowly added to the mixture with stirring and then 250 ml of concentrated sodium hydroxide solution (about 45 percent). The toluene phase is separated off, the aqueous phase is extracted with 300 ml of toluene and the combined toluene solutions are distilled. N- (2 _β 6-dimethylphenyl) -ethylenediamine is by fractional distillation through a 20 cm - purified packed column. Kp ₀ Qr- 86 - 88 ° C # ^ ⁵ 1.5492. Yield: 75.2 g (76.2 % of theory).

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Example 3:

The following compounds were prepared analogously to Examples 1 and 2:

N- (4-methoxyphenyl) -ethylenediamine, ^Kp 0.01 ¹¹ ° - ¹¹⁵ ° ^{c »Pp 59" 62} ° ^c

N- (4-bromophenyl) -ethylenediamine, 0.01 ^{Kp 115-118} ° ^C

N- (3-fluorophenyl) ethylenediamine, ^bp 0.01 ⁷⁵ * ⁷ ° ^C » ¹¹ D ^{5 1} ' ⁵⁶⁰⁶

N- (2-methylphenyl) -ethylenediamine, ^bp 0.05 ^{92-96 0} C, n ²⁵ 1.5705

K- (2-chlorophenyl) ethylenediamine, ^bp 0.05 ⁹² * ⁹⁵ ° ^C » ¹³ D ^{5 1} ' ⁵⁸⁴⁸

K- (4-chlorophenyl) ethylenediamine, ^bp 0.01 ¹¹ ° * ¹¹⁴ ° ^C » ¹¹ D ^{5 1} ' ⁵⁹⁵⁸

N- (3-methylphenyl) ethylenediamine, ^bp 0.05 ¹⁰ ° * ¹⁰⁵ ° ^C

N- (2-bromo-4-methyl) -ethylenediamine,

^Kp 0.01 ¹⁰ ° " ¹⁰² ° ^C » ⁿ D ⁵ 1.5958

N- (2-methyl-3-chloro) -ethylenediamine ^Kp 0.05 ^105-109 ° ^{C 'n} D ^{5 1' 5858}

N- (2,4-dichlorophenyl) ethylenediamine, ^Kp O, O5 ¹⁰⁸ " ¹¹ ° ^C " ¹¹ D ⁵ 1.5983

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N- (2,5-dimethylphenyl) ethylenediamine, ^bp 0.05 ⁹⁰ - ⁹³ ° ^C » ⁿ D ^{5 1} ' ⁵⁶¹⁴

N- (2,4,6-trichlorophenyl) ethylenediamine, ^bp 0.05 ¹⁰⁶ ~ ¹¹ ° ^C » ¹³ D ^{5 1} » 5966

N- (2 .6-dichloro-4-methoxyphenyl) -ethylenediamine, ^bp 0.01 ¹⁰⁷ "" ¹¹² ° ^{C 'n} D ^{5 1' 5763}

Example 4: N- (3-Uitrophenyl) ethylenediamine

To a slurry of 41.4 g (0.3 mol) of 3-hitroaniline in 200 ml of toluene is added with stirring and cooling 40 g (0.3 mol) of anhydrous aluminum chloride, the temperature bia 35 ⁰ C increases. Thereafter, 12.9 g (0.3 mol) Äthyleniinin are added dropwise while maintaining a temperature of 35 bia 40 ⁰ G to the mixture within 30 minutes. Subsequently, stirring is continued for 8 hours at 40 ^° C. Each cooling is carried out successively with cooling 200 The phases are separated and the aqueous phase is extracted twice more with 200 ml of toluene each time. The combined toluene phases are concentrated to dryness in vacuo, the residue is admixed with 400 ml of water and 150 ml of concentrated sodium hydroxide solution (about 45% strength) 1 ml of acetic acid to boiling and allowed to cool the mixture overnight. 16 g of 3-nitroaniline are recovered by suction. From the acetic acid solution, 35.9 g (66.2 % of theory) of N-butyl chloride are obtained by adding 150 ml of concentrated sodium hydroxide solution, extracting twice with 200 ml of toluene and concentrating in vacuo. (3-nitrophenyl) -ethylenediamine ·

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Example 5:

Analogously to Example 4, the following compounds were prepared:

N- (2-Uitrophenyl) -ethylenediamine ^05135-137 ° ^G "" D * ^{1 '6784}

K (4-Uitro phenyl) -äthylendiainin Pp 145-146 ⁰ C.

H- (2α-dichloro-4-nitrophenyl) ethylenediamine Pp 79-83 ⁰ C

Claims (1)

- 12 - 2264b3 claim Process for the preparation of derivatives of H-phenyl ethylenediamine of the general formula E ¹ y HH-CH ₂ -CH ₂ -IiH ₂ , I V? 12 3
in which R, R and R denote hydrogen, fluorine, chlorine, bromine, methyl, methoxy or nitro and wherein 12 3 etens one of the substituents R, R, R is not hydrogen, by reacting ethylene imine with aniline derivatives of the general formula E ¹ -BH ₂ , II R ² ^ f = r> 3 12 3
wherein R, R and R have the same meaning as above, characterized in that substituted aniline, anhydrous aluminum chloride and liquid Äthylenimin in the order given and in approximately equimolar ratio in an inert organic solvent such as benzene or toluene at temperatures from 30 to 80 ⁰ C converts.