HU209469B - Process for producing guanidine derivatives - Google Patents

Abstract

Guanidine derivs. of formula (1) NH=C(NH2)-CH2-CH(OH)-CH2R (where R is guanidinyl-, amino-ethyl-2-amino-, or 1,3-bis(amino-ethyl-2-amino)-propane-2-ol gps.), are prepd. from guanidine coupled with itself, with ethylene-diamine, or 1,3-bis(amino-ethyl-2-amino)-propane-2-ol, in the presence of epichlorohydrin. Methanol is used as solvent and the reaction mixt. is rendered salt free by ion exchange. - Opt. the reaction prods. are used without isolation for the prepn. of ampholites, chromato-focussing gels and eluants.

Description

This invention relates in part to novel guanidine derivatives of formula I wherein R is guanidino, 2-aminoethylamino or 2- [3- (2-aminoethylamino) -2-hydroxypropylamino. ] -ethylamino - by coupling guanidine with itself, ethylenediamine or 1,3-bis (2-aminoethylamino) -propan-2-ol in the presence of epichlorohydrin.

The bases prepared by the process of the invention are useful in the preparation of ampholytes for isoelectric focusing, machines and eluents for a wide range of chromatofocusing (pH 12.5-2.0), and ion exchangers for special purposes.

New compounds of formula I are those wherein R is 2-aminoethylamino or 2- [3- (2-aminoethylamino) -2-hydroxypropylamino] ethylamino. . SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of novel compounds of formula I wherein R is 2-aminoethylamino or 2- [3- (2-aminoethylamino) 2-hydroxypropyl]. amino] ethylamino; and the known 1,3-bis (N'-guanidino-propan-2-ol).

It is known that one of the most important requirements for ampholytes, chromatofocusing gels and eluent fluids for isoelectric focusing is to be able to create a pH gradient over a broad range of pH.

Commercially available chromatofocusing gels and elution buffers contain a basic mixture of tetramethylene tetramine, tetramethylene pentamine and pentaethylene hexamine. Their common feature is that they are no longer functional in the pH range below pH 4 and above pH 10.

The bases of the invention are also suitable for the preparation of gels and eluting fluids having a pH in the range of 2 to 11.5, in particular through their guanidino group. A further advantage is that the epichlorohydrin is incorporated into the molecule as a 2-hydroxypropylene unit, which, on the one hand, provides better accessibility of basic groups by extending the carbon chain and, on the other hand, enables the formation of branched, highly bonded chromatofocusing gels or ion exchangers.

Among the bases of the formula (I) in which R is guanidino, it is otherwise prepared from isothiourea and 1,3-diamino-2-hydroxypropane as an intermediate for use in the manufacture of explosives and rocket propellants. U.S. Pat. It can also be used as a photosensitizer according to European Patent Application 308,750. No. 3,014,073. The main disadvantage of the method disclosed in U.S. Patent No. 4,677,800 is that the starting materials, in particular 1,3-diamino-2-hydroxypropane, are not readily available and can be prepared only in a multi-step reaction.

It has been found that the compounds of formula I can be prepared very simply by coupling the reaction partners with epichlorohydrin. The compounds of formula (I) may thus be prepared by guanidine by itself, ethylenediamine or

1,3-bis (2-aminoethylamino) -propan-2-ol is reacted in the presence of epichlorohydrin.

In a preferred embodiment, the reaction medium is methanol and the reaction is carried out at a temperature corresponding to the boiling point of the reaction mixture.

Among the above reaction parameters, when 1,3-bis (N'-guanidino) propan-2-ol is to be prepared, (R = guanidino), the desired compound is formed almost quantitatively. Compounds containing R = 2-aminoethylamino or 2- [3- (2-aminoethylamino) -2-hydroxypropylamino] ethylamino also have low side reaction rates compared to the main reaction. , 92-96% of the desired target product being formed. In 3-4% side reactions, the coupling of two guanidine molecules results in the compound of formula (I) containing R = guanidino, or two ethylenediamine molecules or two 1,3-bis (2-aminoethylamino) propane-2 The -ol molecule can be linked to one another via a 2-hydroxypropyl group.

If the resulting products are to be used for the purposes described above (ampholytes, eluent liquid, chromatofocusing gels, etc.), the reaction mixture can be used directly after clarification with charcoal and desalting without isolation of the individual components. This mode of application is expedient not only because of the reduction of the process steps, but also because the products of the side reaction, being similar types of bases, increase the muscle number and thus allow for a broader pH gradient.

The desalting of the reaction mixture is most conveniently accomplished using an ion exchange resin in the hydroxycycle and the effluent can be detected by conductivity measurement.

The invention is illustrated by the following examples, without limiting our claims.

Example 1 1,3-bis (N'-guanidino) propan-2-ol

573.18 g (6 mol) of guanidine.HCl are dissolved in 1 L of methanol and refluxed. For the boiling solution in small portions, approx. 277.59 g (3 mol) of epichlorohydrin was added over half an hour. The reaction mixture was refluxed for 8 hours. After standing overnight, evaporate to dryness in vacuo from a water bath at 60 ° C. The residue was dissolved in water (1 L) and the solution was clarified with charcoal (20 g) and filtered.

Subsequently, hydrochloric acid is removed on the basic ion exchange resin. The conductivity of the eluted solution is measured. The conductivity increases from 100 μδ to 220 mS as the base flows. The elution is continued until the conductivity is reduced to the starting value. It eluted

Solution B is concentrated in vacuo and crystallized in a refrigerator.

Yield: 547.51 g 92%

IR (Perkin Elmer 16PC FT-IR): figure

Example 2-

3- (2-Aminoethylamino) -1-guanidino-propan-2-ol

360.6 g (6 mol) of freshly distilled ethylenediamine

Dissolve in 1500 ml of methanol, add 573.18 g (6 mol) of guanidine.HCl and reflux under small portions for ca. Within 3/4 hours, 555.18 g of epichlorohydrin was added. The reaction mixture was refluxed for 8 hours and then filtered the next day. The solution was concentrated in vacuo and the residue was dissolved in water (3 L) and clarified with charcoal (30 g).

The hydrochloric acid formed on the hydroxycyclic anion exchange resin was bound as described in Example 1. The ion-exchanged solution was concentrated in vacuo. Yield: 1062.34 g 92.7%

C ₆ H ₁₇ ON ₅ Molecular Weight: 175,236

N% Calculated: 39.968 Error: 0.23% Found: 38.88

IR spectrum (Perkin Elmer 16PC FT-IR): no. figure

Example 3 1,3-Bis (2-aminoethylamino) -propan-2-ol

Freshly distilled ethylenediamine (360 g, 6 moles) was dissolved in methanol (500 ml) and added dropwise (reflux) in a 3 liter round bottom flask under reflux. 323.85 g of epichlorohydrin over 3/4 hour and reflux for 10 hours. The reaction mixture was diluted with 2 L of water and clarified with 20 g of carbon. The solution was applied to the anion exchange resin in the hydroxycycle and the hydrochloric acid formed was removed as described in Example 1.

The eluate was evaporated in vacuo to give a pale yellow oil consistency.

Yield: 501.6 g 95%

C ₁₇ H ₂₀ ON ₄ Molecular Weight: 176,262

N%: 31.78 Found: 0.97% Found: 31.47

IR spectrum (Perkin Elmer 16PC FT-IR): no. figure

Example 4

3- {2- [3- (2-Aminoethylamino) -2-hydroxypropyl] aminoethylamino} -1-guanidino-propan-2-ol

352 g (2 moles) of 1,3-bis (2 aminoethylamino) propan-2-ol prepared in Example 3 and 191.06 g (2 moles) of guanidine.HCl are dissolved in 1500 ml of methanol and place in a round-bottomed flask fitted with a reflux condenser. 185.06 g (2 moles) of epichlorohydrin are added in small portions and the reaction mixture is heated at reflux for 16 hours.

The resulting solution was evaporated in vacuo, dissolved in 2 L of water, triturated with 20 g of activated carbon and the hydrochloric acid formed on the hydroxycyclic anion exchange resin as described in Example 1.

The eluate was evaporated in vacuo. A pale yellow oil is obtained which has a density of glycerol.

Claims (3)

A process for preparing a guanidine derivative of formula (I): wherein: R is guanidino, 2-aminoethylamino or 2- [3- (2-aminoethylamino) -2-hydroxypropylamino] ethylamino, by coupling guanidine with itself, ethylenediamine or 1,3-bis (aminoethyl-2-amino) -propan-2-ol in the presence of epichlorohydrin, and then desalting the reaction mixture and isolating the target product. Process for the preparation of guanidine derivatives of the formula I according to claim 1, characterized in that the reaction is carried out in an organic solvent, preferably methanol. 3. A process for the preparation of a guanidine derivative of the formula I as claimed in claim 1, characterized in that the reaction mixture is desalted on an ion exchange resin.