DE1083267B - Process for the preparation of di-alkyleneimides - Google Patents

Description

GERMAN

It is already known to produce ethylene minine compounds by reacting phosphorus oxychloride or phosphorus sulfochloride with 1 mole of a saturated primary or secondary amine and 2 moles of ethylene amine (See U.S. Patents 2,606,900 and 2,670,347 and German Patent 854651).

It has now been found that the di-alkylenimides general formula

Ν — Ρ — Ν

CH,

R.

-CIL ₁

in which R _{1 is} a hydrogen atom or a low molecular weight alkyl radical, R _{2 is} an alkenyl, aralkenyl or alkadienyl radical, R _{3 is} a hydrogen atom, an alkyl, cycloalkyl, aralkyl, alkenyl, cycloalkenyl, aralkenyl or an optionally substituted phenyl radical and X denotes an oxygen or sulfur atom is obtained when phosphoric acid or. Thiophosphoric acid amide dihalides of the general formula

R ₃

Shark
Shark

in which R ₂ , R ₃ and X have the meaning given and Hal stands for a halogen atom, treated in a manner known per se with corresponding α, / 9-alkylenimines in the presence of agents which bind hydrogen halides. Examples of phosphoric acid or thiophosphoric acid amide dihalides which can be used as starting material in the process according to the invention are: phosphoric acid allylamide dichloride, phosphoric acid crotylamide dichloride, phosphoric acid cinnamylamide dichloride, phosphoric acid hexadiene (2,4 ) -yl- (l) -amide dichloride, phosphoric acid oleylamide dichloride, phosphoric acid - diallylamide - dichloride, phosphoric acid dicrotylamide - dichloride, phosphoric acid - dicinnamylamide dichloride, phosphoric acid - ethyl - allylamide - dichloride, phosphoric acid - chlorophenyl - dichloride amide phenyl - allylamide - dichloride, phosphoric acid methoxyphenyl - allylamide - dichloride, phosphoric acid tolyl - allylamide - dichloride, phosphoric acid - cyclohexyl method of manufacture
of di-alkylenimides

Applicant:

ίο Farbwerke Hoechst Aktiengesellschaft
formerly Master Lucius & Brüning,
Frankfurt / M., Brüningstr. 45

Dr. Helmut Diery, Frankfurt / M.-Höchst,
Dr. Karl-Heinz Schmidt-Ruppin, Koenigstein,

Dr. Manfred Schorr, Frankfurt / M.-Unterliederbach,

and Dr. Ernst Juergens, Bad Soden (Taunus),

have been named as inventors

allylamide - dichloride, phosphoric acid - benzyl - allylamide dichloride and the corresponding derivatives of thiophosphoric acid. These compounds can be beneficial in a manner known per se by reacting 1 mole of phosphorus oxyhalide or phosphorus sulfohalide with 1 mole of the corresponding amine or its hydrohalic acid salt in the presence or absence of solvents, optionally in the presence of a base.

According to the process, the α, β-alkyleneimine is in particular Ethylenimine used. However, its derivatives alkylated on a carbon atom also come, such as 2-methyl-ethylenimine and 2,2-dimethyl-ethylenimine, in question.

The reaction components are reacted in the presence of agents that bind hydrogen halide, expediently in an organic solvent carried out, preferably such solvents used, in which the end product is soluble, because this allows the separation of the excreted, In organic solvents insoluble hydrohalic acid salt is facilitated. Suitable solvents are for example aromatic hydrocarbons such as benzene, toluene, xylene, ethers, such as Dioxane, or halogenated hydrocarbons, such as methylene chloride, chloroform, tetrachloroethane, trichlorethylene and chlorobenzene.

009 530/526

Recrystallize from diisopropyl ether to bind the released hydrogen halide,

e.g. anhydrous ammonia or tertiary The colorless, very hygroscopic crystals melt

organic bases such as triethylamine, pyridine and dialkyl at 42 to 43 ° C.

aniline. However, you can also use aqueous alkalis, e.g. a -

Use a solution of sodium hydroxide in water. 5 Example 2

In this case, too, the reaction is carried out under the group of phosphoric acid-allylamide-diethylenimide
given conditions carried out; it is advisable

however, by stirring vigorously for good thorough stirring, one drips to a mixture

mixing of the two phases. of 400 g of methylene chloride, 191 g of 48 ° / ₀ sodium hydroxide solution,

The reaction is generally a solution of 174 g at room temperature io 44 g of water and 86 g of ethyleneimine

or at moderately reduced temperatures, preferably phosphoric acid allylamide dichloride in 400 g of methylene

at 5 to 20 ⁰ C carried out. Heating is normal chloride and maintains the temperature by cooling

wisely not necessary, but in some cases it can reach 8 to 12 ° C. The mixture is stirred for another 15 minutes, sucked

it can also be expedient to rapidly remove elevated temperatures from the precipitated common salt, separates in the filtrate

turn around. 15 the methylene chloride layer and dries it over

After the end of the reaction, the sodium sulfate. If the bath temperature does not exceed 60.degree. C., the hydrohalic acid salts are distilled, the solvent is first removed by the bases set off, or the organic phase is filtered off under normal pressure and finally in vacuo. The aqueous alkali is separated off and the residue is distilled off and solidifies on cooling. After recrystallizing the organic solvent, the products of the process are obtained by isolating 95 to 120 g of pure phosphoric acid, the colorless to pale yellow crystals or oils of allylamide diethylenimide with a melting point of 42 to 43 ° C.
represent. The derivatives of phosphoric acid are mostly

water-soluble and partly even hygroscopic, while example 3

the derivatives of thiophosphoric acid in general _, _T ,. ,,. ,, ....

mine does not dissolve in water. The compounds can _a g phosphoric acid crotylamide diethylemmide

be purified by recrystallization or careful distillation in a solution of 13 g of ethyleneimine and 35 g of tri-vacuum. This is partly accompanied by cerium ethylaniine in 150 ecm of benzene and allowed to settle with ice cooling, especially when it is a solution of 28.2 g of phosphoric acid derivatives of primary unsaturated amines, crotylamide dichloride (b.p. ₂ 124 ⁰ C) in 150 ecm benzene The new process products provide valuable 30 drops so that the reaction temperature is 10 to 15 ° C remedies and inhibit the growth of a whole. Then another 2 hours for Zimmer series of experimental tumors. Analog built encryption temperature stirred, hydrophilic compounds triethylamine from which are derived from saturated amines, chloride filtered off and distilling off the benzene at a Badtempesowie other than antitumor agents generally accepted temperature of 6O ⁰ C in vacuo. In the case of the high ethylene imides of phosphoric or thiophosphoric acid, vacuum distillation of the residue is obtained under they are considerably superior in their effect. This is partial decomposition 13 g of phosphoric acid crotylamideindeutig from the accompanying tables indicate in which diäthylenimid from Kp. _{0> above} 131 ° C in the form of a zähdie in various mouse and rat tumors liquid, readily water-soluble oil,
Test results obtained under comparable conditions for the phosphoric acid allylamide diethylenimide of Example 4
corresponding values for the well-known phosphoric acid- ',, ■■, ",,,. ,,. ,, ..,
di-isobutylamide-diethylenimide and for the well-known phosphoric acid-diaUylamid-diethylemmid

Phosphoric acid triethylenimide or thiophosphoric acid 'At a temperature of 10 to 15 ° C is allowed to be compared to triethylenimide. The used solution of 17.4 g of ethyleneimine and 44 g of triethyl cans are in the same proportion to the dos. Toi. 45 amine in 200 ecm of benzene with vigorous stirring, so that the test results can be regarded as a quantitative solution of 42.8 g of phosphoric acid diaylamide dichloride. (Bp. ₉ 102 to 103 ⁰ C) in 200 ecm benzene drop. At-

■ Furthermore, the process products are then stirred for another 2 hours at room temperature Reactivity of valuable intermediate products to the temperature, sucks the triethylamine hydrochloride and Manufacture of plastics represent and can also be distilled the benzene at a 60 ° C not exceeding 50 Textile auxiliaries are used. Bath temperature. The residue is in a high vacuum distilled and rectified. 41.5 g are obtained

Example 1 Phosphoric acid diaUylamide diethylenimide with a boiling point of _{0> 5,132}

■ τ ,,, .. ". .,, ... ,,. . ., up to 133 ° C in the form of a colorless water-soluble oil.

Phosphoric acid-aUylamid-diethylimid -

■ To a solution of 38 g of ethyleneimine and 82 g of tri Example 5

ethylamine in 400 ecm benzene is allowed to drop under __. ,, ",. _n .. _T,. .,

Good stirring a solution of 69.6 g of phosphoric acid-thiophosphoric acid-aUylamid-diethylemmid

allylamide dichloride (bp. _0t6 104 to 106 ⁰ C) in 300 ecm To a solution of 45 g of ethyleneimine and 112 g

Benzene flow in. By cooling, the internal temperature is 60 triethylamine in 500 ecm benzene at a temperature

Tatur kept at 10 to 15 ° C. After completion of the temperature of 10 to 15 ⁰ C with thorough stirring 95 g of thio

added, the reaction mixture is stirred for 3 hours phosphoric acid allylamide dichloride (Kp. ₃ 83 to 85 ° C),

after, then sucks in the precipitated triethylamine dissolved in 300 ecm benzene, dropwise. After 2 hours

hydrochloride, this is washed two to three times with stirring and the triethylamine hydrochloride is filtered off with suction

■ Benzene and concentrates the clear benzene solution first at 65 and the benzene at a bath temperature of 6O ⁰ C im

partial vacuum distilled off at the end under full water jet vacuum. The crude product (101 g) is im

a, wherein the bath temperature ^{does not exceed 6O 0} C high vacuum distilled. At Kp.j. 119 to

target. The liquid residue solidified upon cooling 120 ⁰ C 52 g thiophosphoric acid allylamide-diäthylenimid

crystalline. Obtained in 80 to 90 ⁰ / "yield a colorless form, viscous, water-insoluble

Raw phosphoric acid-allylamide-diethylenimide can by 70 oils over.

Example 6 Thiophosphoric acid diallylamide diethylenimide

In a solution of 22 g of ethylene imine and 55 g triethylamine in 300 cc of benzene is allowed under ice-cooling and stirring at a temperature of 10 to 15 ° C, a solution of 56 g thiophosphoric acid diallylamide dichloride (Kp. _8111-112 ⁰ C) pour into 200 ecm benzene. After the addition has ended, the mixture is stirred for a further 2 hours at room temperature, then the triethylamine hydrochloride is filtered off with suction and distilled in vacuo. ., 138 ⁰ C go at Kp 43 g thiophosphoric acid diallylamide-diäthylenimid in the form of a colorless, water-insoluble oil on.

Example 7
Phosphoric acid-aHyl-ethylamide-diethylenimid

At a temperature of 10 to 15 ° C., a solution of 30.3 g of phosphoric acid-a-ethyl-ethylamide dichloride (bp. _lo 101 ⁰ C) in 150 ecm benzene. The mixture is then stirred for a further 2 hours at room temperature, the precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is distilled in vacuo. At _{b.p. 4} 114 ° C, 31 g of phosphoric acid allyl ethylamide diethylenimide pass over.

Example 8
Phosphoric acid allyl benzylamide diethylenimide

At a temperature of 10 to 15 ° C, a solution of 39.6 g of phosphoric acid-allyl-benzylamide dichloride (boiling point ₅ 148 to 149 ° C) is added to a solution of 13 g of ethyleneimine and 33 g of triethylamine in 150 ecm of benzene. drip into 150 ecm benzene. After 2 hours, the precipitated triethylamine hydrochloride is filtered off with suction, the benzene is distilled off on a water bath and the residue is distilled in a high vacuum. AtKp. _{0> 8} 156 to 158 ° C, 23 g of phosphoric acid-auyl-benzylamide-diethylbnimide pass over in the form of a colorless, viscous oil.

Example 9
Phosphoric acid allyl cinnamylamide diethylenimide

To a solution of 19 g of ethylene imine and 44 g triethylamine in 250 cc of benzene is allowed at a temperature of 10 to 15 ⁰ C under vigorous stirring, a solution of 58 g of phosphoric acid-allyl-cinnamylamiddichlorid (Kp. _Li0 164-165 ° C) in 150 ecm of benzene run in. After 2 hours, the precipitated triethylamine hydrochloride is separated off and the solvent is distilled off in vacuo on a water bath. The residue is distilled in a high vacuum. At b.p. _{0> 08} 184 ° C, 12 to 13 g-phosphoric acid-allyl-cmnamylamiddi-ethyleneimide pass over as a pale yellow colored, viscous oil.

: Example 10

Phosphoric acid N-allylanilide diethylenimide

To a solution of 19 g of ethyleneimine and 44 g of triethylamine in 250 ecm of benzene, a solution of 50 g of phosphoric acid-N-allylanilide dichloride (b.p. ₅ 140 to 142 ° C) in 150 is added at 10 to 15 ° C with thorough stirring ecm benzene drip. After 2 hours, the precipitated triethylamine hydrochloride is filtered off with suction and the benzene is distilled off on a water bath in vacuo. The residue is recrystallized from diisopropyl ether at -2O ⁰ C and dried in a vacuum desiccator over potassium hydroxide. Yield 45 g; M.p. 39 ° C.

The compound easily dissolves in alcohol, propyl glycol and water. . . -.

3 ° - example 11
Phosphoric acid allyl cyclohexylamide diethylenimide

A solution of 12 g Äfhylenimin and 25 g triethylamine in 150 ecm benzene is at a temperature of 5 to 10 ⁰ C with a solution of 25.6 g of phosphoric acid _{allyl-cyclohexylamide dichloride (bp. 3> 5} 145 to 147 ° C) in 50 ecm of benzene added. The reaction mixture is left to stand for 4 hours at room temperature. The precipitated triethylamine hydrochloride is filtered off with suction and then the filtrate in vacuo at a temperature

concentrated from 30 to 4O ⁰ C. 21 g of phosphoric acid-allyl-cyclohexylamide-diethylenimide with a degree of purity of 96 to 97 ° / ₀ remain as residue. The refractive index is n% = 1.5042.

Table I.

link

Transplant

Benzpyrene Sarcoma

mouse

Dose mg / 20 g se.

effect

Transplant

Benzpyrene Sarcoma

rat

dose
mg / 100 g se.

effect

dose
mg / 100 g se.

effect

Phosphoric acid allylamide diethylenimide

Thiophosphoric acid triethylenimide ....

4 x 0.05 4 x 0.025

4 x 0.05 4 x 0.025

0.2
0.1

0.2
0.1

• 0.2

• 0.1

0.2

■ 0.1

Name of the effect:

up to 25%
± 5%
until 50%
up to 75 "/ ₀
up to 100 o _{/ o}
% (Healing in all animals)

Table II

Link Walker Carcinoma
rat

Dose mg / 100 g se. Effect

Transplant

Methylcholanthrene sarcoma

rat

Dose mg / 100 g se.

effect

Phosphoric acid allylamide diethylenimide

Phosphoric acid diisobutylamide diethylenimide.

Phosphoric acid triethylenimide

• 0.2
■ 0.1

• 0.33
• 0.16

0.2
0.1

Name of effect: inhibition of tumor growth compared to controls:
up to 25%

± 5% (20 to 30%) to 50%
up to 75%
up to 100 Y ₀
% (Healing in all animals)

4-0.2 4-0.1

4 x 0.33 4 x 0.16

4-0.2 4-0.1

Claims (1)

Claim: Process for the preparation of di-alkyleneimides the general formula Ν — Ρ — Ν CH, C-CH ₂ 35 in which R _{1 is} a hydrogen atom or a low molecular weight alkyl radical, R _{2 is} an alkenyl, aralkenyl or alkadienyl radical, R _{3 is} a hydrogen atom, an alkyl, cycloalkyl, aralkyl, alkenyl, cycloalkenyl, aralkenyl or an optionally substituted phenyl radical and X denotes an oxygen or sulfur atom, characterized in that phosphoric acid or thiophosphoric acid amide dihalides of the general formula R ₃ in which R ₂ , R ₃ and X have the meaning given and Hal stands for a halogen atom, treated in a manner known per se with corresponding α, / 9-alkylene imines in the presence of agents which bind hydrogen halides. References considered: U.S. Patent No. 2,606,900. ©. 009 530/526 6.60