DE1251770B - Process for the production of aliphatic hydroxydiamines and their acid addition salts - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Inta .: - <C07c

German KL: 12 q-32/01

Number: File number: Registration date: Display day:

1251770 A36805IVb / 12q February 24, 1961 October 12, 1967

The invention relates to the preparation of aliphatic hydroxydiamines of the general formula

R ₂
Ri-N-

where Ri is the group

CH ₂ OH

R ₃ NR ₄

in which R is a low molecular weight alkyl radical, R ₂ and R3 are hydrogen atoms, low molecular weight alkyl or low molecular weight hydroxyalkyl groups, R4 is a low molecular weight alkyl or low molecular weight hydroxyalkyl group, X is an alkylene group optionally substituted with low molecular weight alkyl and having 2 or 3 carbon atoms, at least one of these carbon atoms being a methylene group forms in the chain, mean, as well as their acid addition salts.

These compounds are useful as agents for combating tuberculosis.

The discovery of streptomycin marked a new era in the treatment of tuberculosis initiated. However, streptomycin has a number of important disadvantages such as the fact that it is not consistently well tolerated and that it must be given by injection. Farther resistance to streptomycin can occur so that it loses its therapeutic value. from p-Aminosalicylic acid was also found to be is a weak anti-tuberculosis agent. However, when used with streptomycin, it intensifies it reduces the effects of streptomycin and delays the onset of resistance. Likewise were Nicotinamide and pyrazinamide have been tried, but both compounds are also significant Disadvantage.

The aliphatic hydroxydiamines which can be prepared according to the invention and their acid addition salts have proven to be useful is of great value in the treatment of tubercle bacilli infections. This finding is Surprising because known constitutionally similar compounds such as 2,2 '- (ethylenediimino) -di-l-ethanol and 2,2,2 ', 2' - (ethylenediimino) tetra-1-ethanol have no such therapeutic activity.

Method of manufacture

of aliphatic hydroxydiamines

and their acid addition salts

Applicant:

American Cyanamid Company,

New York, N.Y. (V. St. A.)

Representative:

Dr. I. M. Maas and Dr. W. G. Pfeiffer,

Patent Attorneys, Munich 23, Ungererstr. 25th

Named as inventor:

Raymond George Wilkinson, Montvale, NJ;
Robert Gordon Shepherd, Ridgewood, NJ
(V. St. A.)

Claimed priority:

V. St. v. America of June 2, 1960 (33 399),

dated December 20, 1960

(77 034)
Great Britain 7 February 1961 (4517) - -

The free bases which can be prepared according to the invention are generally white, crystalline solids which Soluble in water and lower alkanols, less soluble and only sparingly in acetone and chloroform are soluble in ether, benzene and petroleum ether. The dihydrochlorides of these bases are generally soluble in water and hot alkanols, but relatively insoluble in non-polar organic solvents.

The inventive method for preparing the new hydroxydiamines of formula I is thereby characterized in that one in a known manner

(a) 2 moles of a compound of the general formula

R — C —A
CH ₂ B

II

wherein A is a halogen atom, an alkyl or Aryl sulfonic ester or a quaternary ammonium group and B denotes a hydroxyl group,

709 677/392

with 1 mole of a compound of the general formula

R ₂

R ₃
ΗΝ —X —NH

(g) 1 mol of a compound of the general formula VI with 1 mol of a compound of general formula

III

implements or

(b) 2 mol of a compound of the general formula R _{3 under reducing conditions}
Halogen - X - N - R ₄

XI

RC = C
CH ₂ B

IV

IO

with 1 mole of a compound of the general formula III or

(c) 2 moles of a compound of the general formula

R-Cn
H ₂ C ^/

:O

20th

with 1 mole of a compound of the general formula III or
(d) 2 moles of a compound of the general formula

HR ₂

■ 1 1

R — C — N — H CH ₂ B

VI

with 1 mole of a compound of the general formula

Halogen - X - Halogen VII

or with 1 mole of a compound of the general formula

O O

■ C -. (X ') "- C - Z

VIII

where Z denotes the hydroxyl group or halogen or a quaternary ammonium group or a hydrogen atom or a low molecular weight alkyl group and η denotes the value O or 1 and X 'denotes a methylene group optionally substituted with a low molecular weight alkyl, and when reacted with a compound of the formula VIII during the reaction or subsequently reduced or 2 moles of a compound of the general formula II with 1 mole of a salt of the general formula

or with 1 mole of a compound of the general formula

OR ₅ R ₃

Il I I

Z - C - (X ') "- CH - N - R ₄ XII

wherein R5 denotes a hydrogen atom or a low molecular weight alkyl group, reacts and in the course of implementation or subsequently reduced

and optionally, when R ₂ , R3 and / or R ₄ is or are hydrogen, alkylated or hydroxyalkylated and optionally converted the free bases obtained into the acid addition salts.

The following examples illustrate the invention.

example 1

N- [N '- (α-methyl- (9-hydroxyethyl) - /? - aminoethyl] - / S-methyl- / S-aminoethanol

A mixture of 37.7 g (0.50 mol) of 2-amino-1-propanol and 12.4 g (0.125 mol) of ethylene dichloride was refluxed for 1 hour. A solution of 30 g (0.55 mol) of sodium methylate in 75 ml of methanol was added to the cooled mixture and the precipitated sodium chloride was separated off by filtration. By distillation 11 g (49% of theory) of a yellow viscous oil, Kp.o, ₂ 150 to 170 ° C. This product crystallized in the template and was obtained from ethanol (6.8 ml / g) to give 2, , 6 g of the meso base as white crystals, mp 137 to 145 ⁰ C, resulted.

Fractional crystallization from the filtrate gave some additional product, mainly as a meso base, while the dl base was not easy to crystallize. Addition of ethanolic HCl to the filtrate, followed by fractional crystallization from methanol resulted in 2.0 g of dl-dihydrochloride in the form weißter crystals, mp 184 to 186.5 ⁰ C.

The meso base was converted into its dihydrochloride, which after recrystallization Methanol weighed 3.5 g, mp 201.5-204.5 ° C.

R ₂ O

OR ₃

55

HN - C - (X ') "- C - NH

IX

reacted and then reduced or 1 mole of a compound of the general Formula II with 1 mole of a compound of

Example2

N- [N '- (a-ethyl- / 3-hydroxyethyl) - / S-aminoethyl] - / 3-ethyl- (3-aminoethanol

general formula
R ₂

R ₃

HN-XNR ₄ CH ₂ B

implements or

To 227 g (2.55 moles) of 2-amino-1-butanol were 100 g (1.0 mol) of ethylene dichloride are added. The mixture was refluxed with im An exothermic reaction occurred over the course of a few minutes. After 10 minutes was another 20 minutes heated. 300 ml of methanol were then added to the hot mixture. For this purpose, 84 g (2.1 mol) sodium hydroxide in 80 ml of water was added. The precipitated sodium chloride was

separated by filtration; the excess 2-amino-1-butanol distilled as a pale yellow oil at 83 to 87 ° C / 13mm. The viscous residue distilled at 165 to 170 ° C / 0.6mm as a light yellow oil, which solidified in the air cooler; yield 108 g (58% of theory).

Recrystallization by dissolving in 80 ml hot ethanol, adding about 150 ml of petroleum ether (bp. 90 to 100 ⁰ C) gave and cooling to 5 ° C overnight 64 g of white crystals, mp 128 to 132.5 ° C. After recrystallization from 100 ml of 95% ethanol, this gave 35 g of white crystals, mp 134.5 to 136 ° C and a second crystallization of 10 g, mp 132.5 to 134 ° C (total yield 45 g, 22% of theory), which consisted of the meso base. The dihydrochloride from it melts at 202 to 203 ° C.

After adding 130 ml, the ethanolic filtrates became about 4 normal ethanolic Hydrochloric acid and 55 g of white crystals obtained after cooling, mp 176.5 to 178 ° C and a second crop from 10 g, m.p. 171.5 to 174.5 ° C. These represent the dihydrochloride of the dl racemate.

Example 3

N- [N '- (a-Isopropyl - /? - hydroxyethyl) - / 3-aminoethyl] - / 3-isopropyl - /? - aminoethanol

A solution of 40 g (0.22 mol) of dl-valine ethyl ester hydrochloride in 100 ml of pyridine was added dropwise with stirring and cooling with a solution of 13.97 g (0.11 mol) of oxalyl chloride in 100 ml of dry ether over a period of time treated by 45 minutes. Sufficient 1N hydrochloric acid was added to bring the pH to 5 and this solution was extracted several times with ether. After concentration, a gummy mass was obtained from the ethereal extract, which crystallized from 50 ml of ethanol after adding 100 ml of water and cooling to 0 ^{° C.} 29 g of oxamide were obtained as a white crystalline solid, mp 44 to 48.degree.

17.2 g (0.05 mol) of the oxamide dissolved in 250 ml of ether was added dropwise to a solution of 10.0 g (0.26 mol) of lithium aluminum hydride in 500 ml of ether, followed by refluxing for 2 hours. Addition of ethyl acetate with subsequent addition of 200 ml of 10N sodium hydroxide resulted in a clear solution. The ether layer was separated and combined with two further ether extracts. In the concentration of the ethereal extracts were, after addition of ethanolic hydrogen chloride and acetone 7.2 g of the dihydrochloride salt in the form of white crystals (47% yield), mp 216-224 ⁰ C. By recrystallization from ethanol and water gave 6.6 g white needles, m.p. 231.5 to 233.5 ° C.

B e i s ρ i el 4

N- [N '- (a-ethyl- / S-hydroxyethyl) - /? - aminoethyl] - /? - ethyl-j9-aminoethanol

It was 2,2 '- (ethylenediimino) -dibutyric acid diethyl ester with lithium aluminum hydride, as in the example 3 described, reduced. The product was obtained by extraction with chloroform and vacuum distillation insulated at 185 ° C (0.8 mm).

Example5

N- [N '- (isopropyl) - / 3-aminoethyl] -j8-ethyl-

/? - aminoethanol

A solution of 48.5 g (0.470 mol) of ß-isopropylaminoethanol in 100 ml of chloroform was cooled and a solution of 59 ml (0.82 mol) of thionyl chloride in 600 ml of chloroform was added dropwise over 40 minutes with vigorous stirring, the Reaction temperature below 10 ⁰ C was kept. After standing at 5 ° C for 1 hour, the mixture was allowed to come to room temperature over 3 hours. Most of the chloroform was distilled off, 50 ml of ethanol were added and the mixture was distilled off, leaving a black, viscous residue which solidified on standing overnight. The residue was dissolved in 200 ml of boiling ethanol and treated with about 5 g of activated charcoal. The red filtrate was concentrated to 80 ml and 180 ml of acetone were added. After cooling to 0 ° C, the resulting crystals were filtered off and dried in a vacuum oven to give a white product weighing 59 g (80% yield), mp 179.5-188 ° C (corrected).
A mixture of 15.8 g (0.1 mol) of β-isopropylaminoethyl chloride hydrochloride and 35.6 g (0.4 mol) of 2-aminobutanol was refluxed for 4 hours. The cooled viscous oil was treated with 100 ml of 10N NaOH and the organic layer was extracted with benzene. Several more benzene extractions followed, whereupon the combined extracts were _{dried over anhydrous Na 2} COe, concentrated and the residue was distilled. The first fraction passed over consisted of 2-aminobutanol, b.p. _15, 80 to 85 ° C. On further distillation, 11 g of product were obtained as a pale yellow oil (63% yield), b.p. 0.000 85 to 86 ° C.

Examples

N-methyl-N-tN'-methyl-N'-ia-ethyl-zS-hydroxyethyl) - (S-aminoethyl] - /? - ethyl / 3-aminoethenol

To 16.5 g (0.36 mol) of 98% formic acid was added 10.0 g (0.048 mol) of N- [N '- (a-ethyl-ß-hydroxyethyl) -ß-aminoethyl] - /? - ethyl- /? - aminoethanol partially added with cooling. 9.0 g (0.105 mol) of 35 to 37% formaldehyde was added and the Mix on the steam bath with considerable effervescence, due to the development of Carbon dioxide, heated for the first hour. The heating was at reflux for an additional 7 hours continued. The solution was cooled, and 15 ml of concentrated HCl and the excess were added of formaldehyde and formic acid removed by evaporation on the steam bath. the remaining gummy mass was treated with 25% NaOH and the organic Layer extracted in benzene. The combined extracts were dried over anhydrous Na2CO3 and concentrated, leaving an oily residue, which after distillation under high vacuum gave the product as a colorless oil, 7.4 g (67%), b.p. 0.01-132-134 ° C.

Example 7

N-ethyl-N- [N '- (isopropyl) - ^ - aminoethyl] - /? - ethyl- / 3-aminoethanol

A mixture of .25 g (0.21 mol) of 2-ethylamino-1-butanol and 11.1 g (0.07 mol) of β-isopropylaminoethyl chloride hydrochloride was heated to 180 ° C. After 20 minutes of heating, there was a violent one Reaction and the solution turned deep red. The mixture was refluxed for an additional 18 hours heated, after which the cooled viscous liquid was treated with about 30 ml of 10N NaOH. That insoluble oil was extracted several times with benzene. The combined extracts were over dry Na2CC> 3 dried. The benzene solution was concentrated and the residue under reduced pressure to remove the excess 2-ethylamino-1-butanol distilled, b.p. 15 75 to 87 ° C. After further distillation, 7 g of the desired was obtained Products' in the form of a pale yellow liquid, b.p. 0.03 82 to 83 ° C.

B e i s ρ i e 1 8

a) N- [1- (Hydroxymethyl) -propyl] -a- [1- (hydroxymethyl) -propylamino] -propionamide

178.2 g (2.0 mol) of 2-amino-1-butanol were dissolved in 100 ml of benzene and placed in a three-necked flask equipped with a dropping funnel, condenser and magnetic stirrer. A solution of 25.0 g (0.2 mol) of ct-chloropropionyl chloride in 50 ml of benzene was added dropwise with cooling and stirring, a white foam developing. The solution was heated for 1 hour with the benzene vented through the air condenser. The viscous yellow oil obtained was treated with a methanolic solution of KOH (0.4 mol). The white product (KCl) that separated was separated by filtration. The filtrate was concentrated to remove the methanol and the residue was distilled under reduced pressure to remove the excess 2-aminobutanol, boiling point 80 to 85.degree. The remaining in the distillation flask residue was dried at b) for the preparation of N- [N '- (a-ethyl- / 3-hydroxyethyl) - β - methyl - β - aminoethyl] - β - ethyl - β - aminoethanol used.

b) N- [N '- (a-ethyl- / S ^: hydroxyethyl) -j8-methyl- (S-aminoethyl] - /? - ethyl / 3-aminoethanol

15.2 g (0.4 mol) of lithium aluminum hydride were added to 700 ml of dry tetrahydrofuran in a three-necked flask equipped with a condenser, mechanical stirrer and dropping funnel, and the suspension was refluxed with stirring for 1 hour. A solution of about 46 g (0.2 mol) of N- [1- (hydroxymethyl) propyl] -a- [1- (hydroxymethyl) propylamino] propionamide in 250 ml of dry tetrahydrofuran was slowly added to the lithium aluminum hydride suspension. After the addition was complete, the mixture was refluxed for an additional 16 hours. The excess lithium aluminum hydride was decomposed by successive additions of 15 ml of water, 11 ml of 20% NaOH and 50 ml of water. The white precipitate was separated by filtration and the filtrate was concentrated by distillation at atmospheric pressure. The residue was distilled under reduced pressure to give 30 g of product, Kp.0,01-0,02 149 ⁰ C.

Example 9

N- [N '- (α-ethyl - /? - hydroxyethyl) -y-aminopropyl] -β-ethyl-; 8-aminoethanol

20.2 g (0.1 mol) of 1,3-dibromopropane were mixed with 44.57 g (0.5 mol) of 2-amino-1-butanol and a violent reaction is initiated by gentle heating. Dense white fumes were developed and the colorless solution turned dark red. The solution was heated for an additional 2 hours and thereafter cooled to give a viscous liquid.

The mixture was neutralized by treatment with excess 10N NaOH and the insoluble base extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous Na2CO3. The extract was concentrated and the residue obtained was distilled in order to remove the excess 2-amino-1-butanol, boiling point 80 to 85 ° C. During the further distillation of the residue, a yellow viscous oil, boiling point 0.8 130 to 170 ° C., passed over. The oil was dissolved in ethanol and ethanolic HCl was added up to a pH of 1. Addition of acetone to the acidic solution caused the precipitation of 9.4 g of a dihydrochloride salt, which after recrystallization from a mixture of ethanol and acetone (1: 4) gave 8.8 g of white crystals, mp 139 to 142 ° C, and probably owns the meso configuration. Concentration of the acidic mother liquor gave a gummy, low-melting dihydrochloride salt which could not be purified. The dihydrochloride salt was converted to the corresponding base by treatment with excess aqueous alkali. 1.7 g of yellow oil were isolated by distillation, Kp.0,3 150 to 170 ⁰ C. This product is probably the dl-racemate.

Example 10

N-ethyl-N- [N'-ethyl-N '- (a-ethylf-hydroxyethyl) -β-aminoethyl-zS-ethyl-jo-aminoethanol

A mixture of 33 g (0.28 mol) of 2-ethylamino-1-butanol and 13.2 g (0.07 mol) of ethylene dibromide was heated to reflux for 2 hours with an initial vigorous reaction. To the cooled mixture, 30 ml of 10N NaOH was added and the resulting oil layer was extracted with benzene. After drying over dry Na2CO ₃ , benzene and excess 2-ethylamino-1-butanol were distilled off, whereupon the residue 12 g was distilled at 90 to 130 ° C / 0.02 mm.

With renewed distillation, the product was obtained at 125 to 140 ° C / 0.07 mm.

B e i s ρ ie I 11 N-Ethyl-N- [N'-ethyl-N '- (a-ethyl - ^ - hydroxyethyl) -

/ I-aminoäthylJ-ß-ethyl-iö-aminoethanol

A different method for the preparation of the product according to Example 10 consists in the treatment of N- [N '- (a-ethyl- _l e-hydroxyethyl) - / 3-aminoethyl] - /? - ethyl- / 3-aminoethanol with excess acetic anhydride to obtain the Ν, Ν ', Ο, Ο'-tetraacetyl derivative. When this intermediate is reduced with lithium aluminum hydride,

speaking of Examples 3 and 8, the desired N, N'-diethyl derivative was obtained while the O-acetyl functions were split off during the reaction.

Example 12

N- [N '- (a-ethyl- / 9-hydroxyethyl) - ^ - aminoethyl] - / S-ethyl- / S-aminoethanol

To 6.0 g (0.03 mol) of 30% aqueous glyoxal were 9.2 g of 2-aminobutanol (with moderate heat development) and 30 ml of absolute ethanol are added. A total of 3.7 g (0.1 mole) of sodium borohydride was partially in the course of 10 minutes added. The reaction mixture became after which the vigorous reaction subsided had heated for 30 minutes. After adding water and extracting with chloroform, the meso isomer, M.p. 132 to 134 ° C, isolated on cooling. The dl isomer was known as the dihydrochloride salt, F. 176 to 178 ° C, obtained when acidifying the filtrate with ethanolic HCl.

B e i s ρ i e 1 13

N- [N '- (a-ethyl- ^ - hydroxyethyl) - / S-aminoethyl] -jS-ethyl- / 3-aminoethanol

A mixture of 25.0 grams (0.068 moles) of ditosyl glycol and 24.24 grams (0.272 moles) of 2-aminobutanol was refluxed for 18 hours to give a viscous red oil. Both the dl isomers (Dihydrochloride, mp 176.5 to 178 ° C) as well as the meso isomer (base, mp 132.5 to 134 ° C) des 2,2 '- (Ethylenediimino) -di-l-butanols were isolated from the cooled reaction mixture after a procedures similar to those previously described.

B e i s ρ i e 1 13 a

N- [N '- (a-ethyl- / S-hydroxyethyl) -ß-aminoethyl] -ß-ethyl-ß-aminoethanol

A. 2,2 '- (Ethylenediimino) -di-1-chlorobutane

A solution of 100 g (0.49 mol) of 2,2 '- (ethylenediimino) di-1-butanol-dl dissolved in 250 ml of chloroform was added dropwise to 260 ml (3.7 mol) of thionyl chloride with cooling and stirring added over 20 minutes. The red-orange solution was refluxed on the steam bath for 3 hours, after which the solution was concentrated under pressure from the aspirator. The gummy mass obtained was treated with benzene, whereupon yellow crystals separated out on concentration. 39 ml of water was added to the filtrate to decompose the excess thionyl chloride and additional product separated out. The mass was dissolved in n-propanol, the solution was cooled to give 147.4 g (96 ° / ₀₎ of crude product. Recrystallization from n-propyl alcohol gave white crystals, mp 235 ° C (decomposition).

B. 1.59 g of sodium methylate (0.03 mol) were added to a solution vori 1.57 g (0.005 mol) of 2,2 '- (ethylenediimino) -di-1-chlorobutane, dissolved in 75 ml of absolute methanol, added and the mixture was refluxed for 15 minutes. The insoluble part was separated by filtration and the filtrate on Diluted 100 ecm and refluxed for a further 20 hours, the desired dl-2,2 '- (ethylenediimino) -di-l-methoxybutane revealed.

Half of the reaction mixture obtained as described above was mixed with 10 ml (0.19 mol) 48% hydrobromic acid refluxed for 20 hours, dl-2,2 '- (ethylenediimino) - di - 1 - butanol (dihydrochloride, mp 176.5 to 178 ° C) ..

Example 14

N- [N '- (a-ethyl-i? -Hydroxyethyl) - ^ - aminoethyl] - /? - ethyl - /? - aminoethanol

A solution of 11.3 g (0.1 mol) of α-chloroacetyl chloride in 50 ml of benzene was added dropwise with cooling and stirring to a solution of 71.2 g (0.8 mol) of 2-aminobutanol in 25 ecm of benzene. The pale yellow solution was heated at reflux for ¹ hour ^ and the viscous oil obtained is neutralized by treatment with KOH. The precipitated KCl was separated off by filtration and the solvent and excess 2-aminobutanol were removed by distillation. The residue, the amino amide, was dissolved in 50 ml of dioxane and reduced at 245 ° C. and 246 kg / sq cm (3500 psi) H ₂ for 3 ¹ ^ hours using 3.3 g of CuO · CuCr2O4 as a catalyst desired 2,2 '- (ethylenediimino) di-l-butanol (meso base, mp 132.5-134 ° C; dl-dihydrochloride, mp 176.5-178 ° C).

Example 15

N- [N '- (a-ethyl-jS-hydroxyethyl) -jS-aminoethyl] - / S-ethyl - /? - aminoethanol

A mixture of 3.3 ml (3.0 g, 0.05 mol) of ethylenediamine and 7.2 g (0.10 mol) of 1,2-butylene oxide with a trace of an acidic ion exchange resin was refluxed for 4 hours, with some white solid formed in the flask. On cooling the mixture solidified and was dissolved in 40 ml of boiling methanol. The resin was removed by filtration and the methanol removed by distillation. To the solid residue were added 35 ml of chloroform and 15 ml (24 g, 0.2 mol) of thionyl chloride, whereby a vigorous reaction was caused. The excess thionyl chloride and chloroform were removed by distillation first at atmospheric pressure and then at 20 mm Hg. The residue gave a white solid from a methanol-n-propanol-acetone mixture. 7.0 ml (0.07 mol) of 10N sodium hydroxide were added to 3.3 g (0.01 mol) of this crude product. The brown oil which separated out was extracted with 10 ml of benzene. The benzene was removed and the residue was dissolved in 30 ml of dioxane. To this solution, 4.0 g (0.024 mol) of p-nitrobenzoic acid was added and the solution was refluxed for 2 hours, after which it was allowed to stand overnight at room temperature. The solution was then refluxed with 3.5 ml (0.035 mol) of 10N sodium hydroxide for 3 hours, during which time a solid was deposited. After the sodium p-nitrobenzoate had been removed, the desired meso isomers (base, melting point 132.5 to 134 ^° C.) and dl isomers (dihydrochloride, melting point 176.5

709 677/392

to 178 ⁰ C) of 2,2 '- (Äthylendiimino) -di-l-butanol, are isolated from the dioxane as previously described.

B e i s ρ i e 1 16

N- [N '- (a-ethyl- / S-hydroxyethyl) - ^ - aminoethyl] - / S-ethyl-j3-aminoethanol

To 4.4 g (0.02 mol) of ethylenediaminedibenzenesulfonic acid salt, dissolved in 15 ml of pyridine, 2.9 g (0.04 mol) of 1,2-butylene oxide were added. The mixture was refluxed for about 4 hours. The pyridine was then removed under reduced pressure, whereupon from the solid residue by neutralization with alkali, extraction with butanol and Chromatography the isomeric products [dl- and meso-2,2 '- (ethylenediimino) -di-l-butanol and dl- and meso-1,1 - (ethylenediimino) -di-2-butanol] could be separated.

On the other hand, the mixture could be treated as above to make it into a mixture to convert the halides by means of thionyl chloride to the bis-butylenimino derivative was cyclized and cleaved, the desired 2,2 '- (ethylenediimino) -di-l-butanol isomers revealed.

Eg 1 17

N- [N'-ia-ethyl - ^ - hydroxyäthylJ - ^ - aminoethyl] -i8-ethyi - /? - aminoethanol

5.0 g (0.09 mol) of sodium methoxide were added to 72 g (1.0 mol of 1,2-butylene oxide in 80 ml of absolute methanol.) The solution was refluxed for 20 hours, during which time the vapor temperature reached 57 rose to 67 ^{° C. After the addition of solid CO 2} , a white precipitate formed and was separated off by filtration. During the distillation of the filtrate, the l-methoxy-2-butanol distilled over at 135 to 139 ° C. as a colorless liquid.

To 63 g (0.603 mol) of this methoxy alcohol in 25 ml of benzene was added 72 ml (1.0 mol) of thionyl chloride with stirring and cooling in an ice bath. The mixture was brought to room temperature over 40 minutes and then refluxed for 1 hour. After the benzene and the excess thionyl chloride had been distilled off, the residue was distilled over under reduced pressure. In the renewed distillation at 1 atm, an average fraction of 17.9 g in the form of a colorless oil at 115 to 128 ^° C. was obtained.

13.9 ml (0.10 mol) of triethylamine were added to 12.3 g (0.10 mol) of this chloromethoxybutane in 20 ml of ethanol and 3.3 ml (0.05 mol) of ethylenediamine were added. When mixing these reagents a reaction took place with the deposition of some solid. The mixture was allowed to complete for 3 hours the reaction heated to reflux.

Part of this reaction mixture was heated with 70% aqueous sulfuric acid for 2 hours, and both the meso isomer (base, melting point 132.5 to 134 ° C.) and the dl isomer were removed from this mixture by means of the isolation process described above (dihydrochloride, mp 176.5 to 178 ⁰ C) of 2,2 '- (Äthylendiimino) -di-l-butanol obtained. ^;

Example 18

N- [N '- (a-ethyl-ß-hydroxyethyl) -ß-aminoethyl] - / I-ethyl-ß-aminoethanol

A. 113 g of chloroacetyl chloride in 50 ml of 1,2-dimethyxyethane were reacted with 13.0 g (10% excess) of trimethylamine gas, which was introduced into the solution. After the release of the heat generation, the reaction mixture was jrwärmt at 50 ⁰ C and 17.8 g of 2-aminobutanol was added. After the initial reaction, the mixture was refluxed for 1 hour and then the volatiles were distilled off to give the amide as a residue. This residue was used directly for reduction to the ethylenediamine, namely 2,2 '- (ethylenediimino) di-l-butanol.

B. This reaction can be carried out using trimethylamine or triethylamine, mainly as an acid acceptor for the reaction of the halide groups, however, goes in each If the reaction is likely in part via the quaternary intermediate.

Example 19 2- [(3-Isopropylamino-n-propyl) -amino] -1-butanol

6.3 g of dimethyl sulfate were added to 9.8 g of S-dimethylaminopropionitrile in 50 ml of 1,2-dimethoxyethane. After half an hour heating at 8O ⁰ C, 17.8 g of 2-aminobutanol was added and increased the .Temperature to the boiling point. After refluxing for 1 hour, the reaction mixture was subjected to catalytic reduction and then 7.9 g of 2-chloropropane were added at the boiling point for one hour. The product was isolated according to the procedure previously described; Bp 0.005 85 to 86 ⁰ C.

Example 20

If the reduction according to Example 11 with hydrogen and copper chromite as set out in Example 14, the same product was obtained.

Example 21

N- [N '- (a-ethyl- / S-hydroxyethyl) - / S-aminoethyl] - /? - ethyl - /? - aminoethanol

The corresponding dioxamide was converted to the specified compound by lithium aluminum hydride, as in example 3, or by hydrogen under pressure with copper chromite, as in example 14, reduced.

Example 22 d-2- (d-sec. Butylaminoethylamino) -1-butanol

21.2 g of lithium aluminum hydride were added to 1200 ml of anhydrous tetrahydrofuran (THF) and the suspension was heated with stirring for one hour. After cooling, a solution of 13.8 g of the aminoamide in 300 ml of THF was added to the suspension and the mixture was heated to reflux with stirring for 24 hours. The excess LiAlH ₄ and complex was decomposed by carefully adding 85 ml of water over the course of one hour. The cooled mixture was filtered and the THF filtrate concentrated in vacuo to a practically colorless oil. The oil was dissolved in ethyl acetate and

dried over anhydrous Na ₂ CO3. Removal of the ethyl acetate and subsequent distillation resulted in a colorless oil, Κρ, ο, οι 90 to 94 ° C., n ² S = 1.4615 after removal of a small forerun.

Example 23

N- [N '- (α-ethyl- / 3-hydroxyethyl) - / 5-aminoethyl] -β-ethyl-jS-aminoethanol

The Ο, Ο'-dibenzyl derivative of the following example was dissolved in ethanol and a palladium-charcoal catalyst treated at 20 ⁰ C with hydrogen under low pressure in the presence of. The theoretical amount of hydrogen was absorbed within a few hours and the product was isolated by distillation in vacuo.

This reaction can also be carried out in an analogous manner with intermediate products with additional reducible products Groups are executed, for example the connections

C ₂ H ₅ CH - NHCO

C ₆ H ₅ CH ₂ O - CH ₂

C ₂ H ₅ CH-NHC-CH ₂ Nh -CHC ₂ H ₅
C ₆ H ₅ CH ₂ OCH ₂ CH ₂ OCH ₂ C ₆ H ₅

lithium aluminum hydride is also used.

B e i s ρ i e 1 24

This substance was also produced in the following manner. To a solution of 1 ^ benzyloxy-2-aminobutane in 3 ml of ethanol, 0.6 g of 30% strength aqueous glyoxal was added and then during 5 minutes 0.37 g sodium borohydride. After heating for half an hour, 5 ml of water was added and the product extracted into benzene and distilled in vacuo.

B e i s ρ i e 1 25

N- [N '- (ct-ethyl-jS-hydroxyethyl) - /? - aminoethyl] - / S-ethyl-ß-aminoethanol

The reduction was carried out at 63 to 95 kg / cm ² at a temperature between 35 and 8O ⁰ C for 2 hours or ¹ Ia at 2.8 kg / cm ² and 20 ⁰ C for 20 hours. When the catalyst was replaced with an equal amount of fresh PtO ₂ and the temperature was increased to HO ⁰ C for 1 ^ ¹ hour, hydrogen uptake increased. By vacuum distillation, a fraction gave, Kp.0,6 about 170 ⁰ C, which was the desired product.

The reduction was also carried out with sodium borohydride or lithium aluminum hydride.

Sodium borohydride was added to the mixture of ethylenediamine and hydroxybutanone in 50 ml of ethanol added in small portions while warming on the steam bath. After a moderately strong reaction at Add the initial fractions and decrease rapidly, followed by heating for 5 hours about 50 ml of 10N NaOH were added and the white solid formed was initially dissolved by adding most of the alcohol was evaporated and then water was added, leaving a clear Solution came up. This was extracted with chloroform and the product was distilled in vacuo.

Example 26

N-methyl-N, N'-bis (o-hydroxymethylpropyl) ethylenediamine

14.1 g of methyl iodide were added to 20.4 g of 2,2 '- (ethylenediimino) di-l-butanol and 20 ml of tert-butanol added and the mixture heated to reflux for 18 hours. The reaction mixture became excess dry hydrochloric acid in acetone-ethanol added so that the white dihydrochloride des N-methylated derivative precipitated.

B e i s ρ i e 1 27

N-methyl-N- [N'-methyl-N '- (a-ethyl-iS-hydroxyethyl) - / S-aminoethyl] -jS-ethyl - /? - aminoethanol

In addition to the route described in the example below, the Ο, Ο'-diacetyl derivative of the above compound can be prepared in various ways. To convert to the above compound, 32 g of the Ο, Ο'-diacetyl derivative were dissolved in 200 ml of boiling 50% ethanol containing 10 g of sodium hydroxide. After lstündigem heating and distilling off most of the solvent the product in benzene was extracted and then distilled (0.02 mm) in vacuum at 140 ⁰ C.

The O-monoacetyl derivative was converted into the specified Compound transferred by the same procedure.

Example 28

N-methyl-N- [N'-methyl-N- (a-ethyl- / S-hydroxyethyl) - / 3-aminoethyl] - / S-ethyl- / S-aminoethanol

The Ο, Ο'-diformyl derivative resulting from the first reaction stage, ie heating with formic acid and formaldehyde, according to Example 6 was converted to the above compound by adding 29 g in 200 ml of boiling 50% ethanol containing 10 g of sodium hydroxide , have been resolved. After lstündigem heating at reflux, the solvents were evaporated and the product taken up in benzene and concentrated in vacuo at 130 ⁰ C distilled (0,0.1 mm).

Claims (1)

Claim: Process for the preparation of aliphatic hydroxydiamines of the general formula R ₂ R ₃ ; R ₁ -NXN-where Ri is the group R ₄ R —C - CH ₂ OH
in which R is a low molecular ■ alkyl radical, R ₂ and R3 are hydrogen atoms, low molecular weight alkyl or low molecular weight hydroxyalkyl groups, R _{4 is} a low molecular weight alkyl or low molecular weight hydroxylalkyl group, X is an alkylene group optionally substituted with low molecular weight alkyl and having 2 or 3 carbon atoms, at least one of these carbon atoms forming a methylene group in the chain , and their acid addition salts, characterized in that in a manner known per se a) 2 moles of a compound of the general formula R-C II CH ₂ B wherein A is a halogen atom, an alkyl or aryl sulfonic ester or a quaternary ammonium group and B represents a hydroxyl group with 1 mole of a compound of the general formula 25th R ₂ R ₃ HN-X-NH III implements or b) 2 mol of a compound of the general formula under reducing conditions 30th R-C = O IV 35 CH ₂ B with 1 mole of a compound of the general formula III or c) 2 moles of a compound of the general formula H R —C \ H ₂ C ⁷ with 1 mole of a compound of the general formula III or
d) 2 moles of a compound of the general formula HR ₂ CN-CH ₂ B VI 55 with 1 mole of a compound of the general formula Halogen - X - Halogen VII or with 1 mole of a compound of the general my formula Z —C - (X ') "—C —Z VIII where Z denotes the hydroxyl group or halogen or a quaternary ammonium group or a hydrogen atom or a low molecular weight alkyl group and η denotes the value 0 or 1 and X 'denotes a methylene group optionally substituted with a low molecular weight alkyl, and when reacted with a compound of the formula VIII during the reaction or subsequently reduced or e) 2 mol of a compound of the general formula II with 1 mol of a salt of the general formula R ₂ O HN (XV OR ₃ NH reacted and then reduced or f) 1 mol of a compound of the general Formula II with 1 mole of a compound of the general formula R ₂ R ₃ HN-XN-: CH ₂ B implements or g) 1 mole of a compound of the general formula VI with 1 mole of a compound of general formula R ₃
Halogen - X - N - R ₄ or with 1 mole of a compound of the general formula OR ₅ R ₃ ZC- (XOn-CH-NR ₄ XII wherein R5 is a hydrogen atom or a low molecular weight Alkyl group means, reacts and reduced in the course of the reaction or subsequently - and optionally, when R ₂ , R3 and / or R4 is / are hydrogen, alkylated or hydroxyalkylated and optionally converted the free bases obtained into the acid addition salts.