This invention relates to the preparation of triazacyclo compounds and, in particular 1,4,7-tritosyl-l,4,7- triazacyclononane.

Triazacyclo compounds and methods for their preparation are described in the literature. For example, Richman and Atkins in J.Am.Chem.Soc 1974, _9_β_, 2268 describes a method for preparing 1,4,7-tritosyl-l,4,7-triazacyclononane, a compound of formula I.

The preparation involves reacting diethylenetriamine- tritosylate disodium salt with ethylene glycol ditosylate in dimethylformamide (DMF) .

A major disadvantage with this route is that it uses DMF as solvent. DMF cannot readily be recycled and therefore, problems exist regarding the disposal of such a material. Furthermore, concern exists that DMF is potentially a harmful substance the use of which, if possible, should be avoided.

Yet a further disadvantage with this known method is that rate of formation of the triazacyclo species is extremely slow.

Thus this method, although suitable for laboratory scale preparation, cannot therefore readily be adopted for commercial production of triazacyclo compounds.

Our copending application S/N 07/906 782, filed 30 June 1992, describes an improved process for obtaining triazacyclononanes which involves forming sulfonamidated diethylenetriamine. This is then reacted with a cyclising unit such as ethylene glycol ditosylate in the presence of an aprotic organic solvent. The sulphonyl groups are removed from the resulting cyclised sulphonamidated triamine compound before it is alkylated.

1, 4, 7-tritosyl-l, 4, 7-triazacyclononane is currently of particular interest in that it be detosylated and subsequently methylated to form 1, 4, 7-trimethyl-l, 4, 7- triazacyclononane. This organic ligand may then reacted with a manganese compound in aqueous medium to form dinuclear manganese complexes for example [Mn ₂ ^IV (μ- 0) ₃ (Me ₄ TACN) ₂ ) (PF ₆ ) ₂ ] as described in copending European

Patent Specifications 458 397 and 458 398 or mononuclear manganese complexes as described in European Patent Specification 549272 and 544519. Such manganese complexes are effective bleach catalysts.

The present invention seeks to provide a simple method for the preparation of triazacyclo compounds which does not require DMF as the solvent and proceeds at a more rapid rate than known methods .

Accordingly, the present invention provides a method for the preparation of triazacyclo compounds which comprises reacting i) diethylenetriamine triarylsulphonate and ii) a cyclising agent selected from diaryl sulphonates, dialkyl sulphonates, ethylene

dibromide, ethylene dichloride and diacetylglycol in alkaline conditions in a reaction medium comprising an organic solvent and water, at a temperature within the range of from 45 to a temperature less than the boiling point temperature of the reaction medium and in the presence of ultrasound.

An advantage of carrying out the aforementioned reaction in the presence of ultrasound is that it is much faster than the corresponding reaction carried out in its absence.

The source of ultrasound may be provided by standard equipment, such as an ultrasound probe operating in the range 20 to 100 KHz.

Preferably the diethylene triamine triarylsulphonate is selected from diethylenetriamine tritosylate and diethylenetriamine tribenzenesulphonate.

Particularly preferred cyclising agents include ethylene glycol ditosylates and ethylene glycol dibenzenesulphonates .

Preferably the reaction is carried out at a temperature within the range 45 to 90°C, most preferably 65 to 85°C.

A water-soluble base is added to the reaction mixture in order to achieve the alkaline conditions. Inorganic basic salts such as sodium hydroxide are preferred. Preferably the pH of the reaction mixture should be within the range 10 to 13, most preferably 11 to 12.

The organic solvent should be chosen such that the cyclising agent is soluble in the solvent. Suitable

organic solvents include toluene, anisole, chlorobenzene and xylene. Most preferred are toluene and xylene because of their low toxicity.

Diethylene triamine tritosylate is preferably used in the form of a dialkli metal salt and, in particular disodium diethylene triamine tritosylate. It may be prepared according to the method described in R W Hay; J Chem Soc Dalton Trans. , 1441-1445 (1979) .

Ethylene glycol ditosylate is prepared according to the method described in G W Kabalka, J Org. Chem., ____, 2386 (1986) .

A cationic phase transfer catalyst (PTC) may be added to the reaction mixture to increase the rate of reaction. A PTC generally is of the structural formula:

(R") ₄ NX wherein R" is selected from aryl, benzyl, phenyl, alkyl; and X is an anion selected from hydroxide iodide, bromide, chloride, bisulphate, sulphate, phosphate optionally with organic moieties attached to the aforementioned anions . A particularly preferred catalyst is Bu ₄ NOH.

The following non-limiting examples further illustrate the invention.

EXAMPLES

Experiments were performed using a Heat Systems Ultrasound probe (Model XL2020; 0.5 inch tip) operating at 20 KHz. The tip was immersed to a depth of about 2 cm in the reaction solution. The reaction vessel was a jacketed Rosett cooling cell (250ml), thermostatted with a Lauda compact thermostat MS3. At timed intervals during the reaction samples were withdrawn from the reaction vessel,

evaporated to dryness, dissolved in CDC1 ₃ and analysed by ^l H nmr, referenced to TMS (δ=0) .

The conversion of ethylene glycol ditosylate (EGT) to 1, 4, 7-tritosyl-l, 4, 7-triazacyclononane (Tos ₃ TACN) was determined from the ratio of the peak areas of the EGT and T0S ₃ TACN CH ₂ signals at 5=4.2 and 3.5 ppm respectively using the formula

conversion^) = 100 x Mint Tos.TACN) / (int EGT))

{3 + (int Tos ₃ TACN)/(int EGT)}

where (int Tos ₃ TACN) and (int EGT) are the integrals of the peak areas for the nmr signals attributable to Tos ₃ TACN and EGT respectively.

Example 1

The reaction vessel was initially thermostated to 65°C.

Thereafter, diethylenetriamine-tritosylate disodium (T0S ₃ DET) (6.00g; O.OlOmol), . ethylene glycol ditosylate (EGT) (3.93g ; O.Olmol), toluene (100ml), NaOH (20ml of 1.16M) and Bu ₄ NOH (1.0 ml of 1.0M) were added to the reaction vessel. The tip of the ultrasound probe was immersed in the reaction vessel. Then the ultrasound probe was switched on and adjusted to maximum power output

(30% for the solvent systems used in the experiments) . The reaction was continued for 5 hours and monitored using the method described above. The results are presented in Table

I below.

Example la

In a comparative set of experiments the reaction was carried out in the absence of a source of ultrasound waves .

Example I was repeated except the reaction vessel was provided with a reflux condenser and a stirring bar. No ultrasound probe was used. The reaction was carried out at the reflux temperature for a toluene/water azeotrope (ie 85°C) . It was continued for 5 hours and monitored by nmr.

The results demonstrate the reaction carried out in the presence of ultrasound is faster than one carried out in the absence of ultrasound.

Example lb

To confirm the increase in reaction rate was due to a sonochemical effect and independent of the method of mixing an experiment was carried out in a baffled reaction vessel with a turbine overhead stirrer operating at various rpm.

To a 1.51 jacketed reaction vessel thermostatted at 65°C with four baffles and equipped with a reflux condenser and

a Heidolph RZR50 overhead stirrer Tos ₃ DET (40.0g; 0.067mol), EGT (26.2g; 0.067mol), NaOH (6.7ml of l.OM) , Bu ₄ NOH and toluene (667ml) was added. The reaction was continued for 5 hours and monitored by nmr.

The results show the reaction rate was independent of the method and speed of mixing.

Example 2 Example 1 was repeated except the power output of the ultrasound probe was reduced to 15%.

These results, when compared with the results of example 1, demonstrate the increase in reaction rate observed is dependent on the power output of the ultrasound source.

Example 3

Example 1 was repeated except toluene was replaced by a range of solvents. The following results were obtained

organic solvent a b c d e

a - toluene; b - anisole; c- chlorobenzene; d - xylene; e - ditertiairybutylether.

With the exception of ditertiarybutylether, the % conversion was independent of the solvent used. The low conversion for ditertiarybutylether can be attributed to the insolubility of EGT in this solvent.

Example 4

Examples 1 and la were repeated over a range of temperatures and the difference in reaction rate (ΔRR) determined, where the difference is % conversion (ultrasound present - ultrasound absence) after a reaction time of 5 hours. The following results were obtained. Temperature/°C ΔRR

35 1.5

45 -0.7

55 6.3

65 21.1 75 16.8

85 14.8

The results demonstrate a temperature of about 65°C gives optimum results.

Example 5 In this example the formation of Tos ₃ TACN in the presence and absence of Bu ₄ NOH was examined. Examples 1 and la were repeated except a temperature of 85°C was used.

The following results were obtained. Conditions

Conditions f - with ultrasound + Bu ₄ NOH g - with ultrasound, no Bu ₄ NOH h - without ultrasound, + Bu ₄ NOH