1 ,2-BIS(4,7-DIMETHYL-1 ,4,7-TRIAZACYCLONON-1-YL)-ETHANE

AND PREPARATION METHOD THEREOF

FIELD OF INVENTION

The present invention concerns the synthesis of an

intermediate useful for the synthesis of 1 , 2-bis ( 1 , 4 , 7- triazacyclonon-l-yl ) -ethane (Me ₄ -DTNE) .

BACKGROUND OF THE INVENTION

Manganese complexes containing the ligands Me ₃ TACN (1,4,7- trimethyl-1 , 4 , 7-triazacyclononane) and Me-j-DTNE (1,2-bis- (4, 7-dimethyl-l, 4 , 7-triazacyclonon-l-yl) -ethane) are of interest for different bleaching of cellulosic and other substrates .

Different methods have been disclosed to synthesise 1,4- ditosyl-1, 4 , 7-triazacyclonone (Ts ₂ TACN) from 1 , 4 , 7-tritosyl- 1 , 4 , 7-triazacyclonone (Ts ₃ TACN) as described below.

Ts ₃ TACN has been treated with a mixture of bromic acid and acetic acid for 20 h at 100°C and subsequently refluxed for 30 h to yield fully detosylated H ₃ TACN as HBr salt, i.e.

H ₃ TACN.HBr; subsequent reaction with 2 equivalents of tosyl chloride afforded Ts ₂ TACN in 60 % yield as disclosed in Inorg. Chem. 1985, 24, 1230.

Ts ₃ TACN has been treated with a mixture of bromic acid, acetic acid and phenol for 36 h at 90°C, to furnish monotosylated TsTACN. Further reaction with 1 equivalent of tosyl chloride to afford Ts2TACN in a higher yield than using method 1 - 76% as disclosed in Inorg. Chem.,1990, 29, 4143.

Ts ₃ TACN has been heated with a mixture of hydrobromic acid and acetic acid under reflux for 3 h to yield a mixture of TsTACN. HBr (68%) and Ts ₂ TAC . HBr ( 30% ) as disclosed in

Synthetic Communication, 2001, 31(20), 3141.

Isolation of protonated 1 , 4-ditosyl-l , 4 , 7-triazacyclonone salt with bromide as counter ion has been described in

synthetic communication 31(20), 3141-3144, 2001; and

US2005/112066.

The reaction of 1 , 4-ditosyl-l , 4 , 7-triazacyclonone with 2 equivalents of ditosyl-ethyleneglycol in DMF to yield Ts ₄ - DTNE is also disclosed in Inorg. Chem. 1985, 24, 1230; Inorg. Chem. 1996, 35, 1974-1979; Inorg. Chem. 1998, 37(5), 3705- 3713; Inorg. Chem. 2005, 44 (2), 401-409; and J. Chem. Soc, Dalton Trans. 1994, 457-464.

Ts ₄ -DTNE has also been obtained using 0, 0' N, N' -tetratosyl- N, N ' -bis ( 2-hydroxyethyl ) ethylenediamine and ethylenediamine (Synthesis 2001, 2381-2383; Inorg. Chem. 2007, 46(1), 238- 250; Green Chem. 2007, 9, 996-1007).

Synthesis of 1, 2-bis (1, 4, -triazacyclonon-l-yl) -ethane (DTNE) from methine-1, 4 , 7-triazacyclononane and dibromoethane or diiodoethane has been disclosed in J. Chem. Soc, Chem Commun 1987, 886; J. Am. Chem. Soc . 1998, 120, 13104-13120; Inorg. Chem. 1993, 32, 4300-4305; Inorg. Chem. 1997, 36, 3125-3132; Chem. Lett. 2000, 416-417; J.Chem.Soc, Dalton Trans. 2000, 3034-3040. Synthesis of Me ₄ -DTNE from DTNE using formaldehyde and formic acid can be found in J. Am. Chem. Soc . 1998, 120, 13104-13120; Inorg. Chem. 1993, 32(20), 4300-4305; Chem. Lett. 2000, 416- 7. SUMMARY OF THE INVENTION

We have found that partial detosylation of 1 , 4 , 7-tritosyl- 1 , 4 , 7-triazacyclonane in a one pot process leads to the formation of 1 , 4-ditosyl-l , 4 , 7-triazacyclonane as its

protonated salt. This is an improvement over the two step process of complete detosylation of 1 , 4 , 7-tritosyl-l , 4 , 7- triazacyclonane followed by ditosylation of the 1,4,7- triazacyclonane adduct . Furthermore, less tosylchloride can be used to make 1, 4-ditosyl-l, 4, 7-triazacyclonane and less tosylate waste compared to the above route has been obtained.

In one aspect the present invention provides a method of producing a compound of formula (A) :

(A) ,

the method comprising the following step:

(a) reacting a compound of formula (B) :

in an acidic medium comprising sulphuric acid, the molar ratio of B to sulphuric acid in the range from 1:0.1 to 1:10, preferably 1:0.5 to 1:10, more preferably 1:0.5 to 1:5, even more preferably from 1:1 to 1:4, wherein P is an

arylsulfonate protecting group and the compound of formula (A) is isolated as a protonated salt in amorphous or

crystalline form. In another aspect the present invention provides a method of producing a compound of formula (A) :

(A) ,

the method comprising the following step:

reacting a compoun of formula

in an acidic medium, wherein P is an arylsulfonate

protecting group, wherein the acidic medium is worked when the conversion of B to A is at least 50 mol % yielding compound (A) .

As disclosed in the background of invention the 1,4-ditosyl- 1 , , 7-triazacyclonane may be used to form TS4-DTNE which can be detosylated and secondary amines of the product

methylated in a similar fashion described in US 5,284,944 for 1, , 7-tritosyl-l, , 7-triazacyclonone (Ts ₃ TACN) . In a similar manner the same applies to the arylsulfonates as a class of protecting groups.

DETAILED DESCRIPTION OF THE INVENTION

The starting material 1 , 4 , 7-tri (arylsulfonate ) -1 , 4 , 7- triazacyclonane is reacted an acid to yield 1,4- di (arylsulfonate) -1,4, 7-triazacyclonane .

A preferred synthetic scheme for obtaining a 1,4-di

arylsulfonate-1 , 4 , 7-triazacyclonone (l,4-ditosyl-l,4,7- triazacyclonone ) is outlined below. propionic acid,

propionic anhydride

Ts ₃ TACN Ts ₂ TACN.TsOH

H2S04(96%), TsOH

The preferred temperature range for monodearylsulfonation of the triarylsulfonate is from 100 to 160 °C, with most preferred from 130 and 150 °C .

The preferred time for the method is from 1 h to 24 h, the most preferred time from 2 to 6 h. Preferably the method is conducted as a one pot reaction.

The preferred acid for monodearylsulfonation of the tri arylsulfonate is sulphuric acid. Other acids, such as methanesulphonic acid and sulfonic acid resins may function to provide the monodetosylation . Preferably, the acidic medium does not contain any hydrogen halides and in this regard, the acidic medium preferably has less than 1 mol% hydrogen halides with respect to B.

Additionally auxiliary anhydrides are preferably present, such as acetic acid anhydride or propionic acid anhydride when excess water is present in the reaction mixture. The amount of acid anhydride required to facilitate the reaction depends upon the amount of water initially present in the reaction .

The acid anhydride serve to maintain the molar ratio of 1 , 4 , 7-tri (arylsulfonate) TACN : water at a level that aids the ideal molar ratio for the reaction, namely 1:1.

The optimum amount of acid anhydride to be added to the reaction mixture is dependent on the amount of 1,4,7- tri (arylsulfonate) TACN and the amount of water in the system (originating from the water present in 1,4,7- tri (arylsulfonate) TACN and sulphuric acid added). If the molar amount of water present in 1,4,7- tri (arylsulfonate) TACN and sulphuric acid is much larger than the molar amount of 1, 4 , 7-tri (arylsulfonate) TACN, the reaction may become less efficient, i.e. more

mono (arylsulfonate) TACN or H ₃ TACN will be formed. It should be noted that one mol of acid anhydride will react with one mol of water to form two moles of acid.

Therefore, the following relation exists (all on molar basis) :

H ₂ 0 (Ts ₃ TACN) + H ₂ 0 (sulphuric acid) - acid anhydride = amount of water available to react with Ts ₃ TACN.

Therefore, H ₂ 0 (Ts ₃ TACN) + H ₂ 0 (sulphuric acid) - Ts ₃ TACN = acid anhydride, which is equal to:

[H ₂ 0 (Ts ₃ TACN) + H ₂ 0 (sulphuric acid) - Ts ₃ TACN] : acid

anhydride = 1. Allowing variables in process conditions, this ratio should be varying between 0.1 and 10, more preferably between 0.3 and 5 and most preferably between 0.8 and 2.

It is preferred that a tosyl group is used as protecting group for the secondary amines of the 1 , , 7-triazacyclonane moiety. The tosyl group (abbreviated Ts or Tos) is CH ₃ C ₆ H ₄ S0 ₂ . This group is usually derived from the compound 4-toluene sulfonyl chloride, CH ₃ C ₆ H ₄ S0 ₂ C1 , which forms esters and amides of toluene sulphonic acid. The para orientation illustrated (p-toluenesulfonyl ) is most common, and by convention tosyl refers to the p-toluenesulfonyl group. Tosylate refers to the anion of p-toluenesulfonic acid (CH ₃ C6H ₄ SC>3~ ) . Whilst the tosyl group is the preferred protecting group other

arylsulfonyl groups (ArS0 ₂ ) will function to provide the advantages of the present invention. Preferably the

arylsulfonyl employed is a benzenesulfonate . Compared to the known procedures to make Ts ₂ TACN, as outlined in the background of the invention, there will be one step less needed to obtain this material in a high yield and purity. Furthermore, less tosylchloride (arylsulphonate) starting materials are needed to form 1, 4-di (arylsulfonate) - 1 , 4 , 7-triazacyclonane (3 instead of 5 molar equivalents) and as a consequence also less tosylate (arylsulphonate) waste will be generated.

In another aspect of the invention the 1,4- di (arylsulfonate) -1, , 7-triazacyclonane can be obtained and isolated as a protonated (HX) salt in which HX is selected from: toluenesulfonic acid; benzenesulfonic acid; sulfuric acid; acetic acid; formic acid; and, propionic acid, most preferably from toluenesulfonic acid, benzenesulfonic acid and sulphuric acid. One skilled in the art will appreciate that some acids will support more than one protonated 1,4- di (arylsulfonate) -1, 4 , 7-triazacyclonane, for example

sulphuric acid. Alternatively, sulphuric acid may support one protonated 1, 4-di (arylsulfonate) -1, 4 , 7-triazacyclonane, as the HS0 ₄ ^" counterion.

From the disclosure it will be evident that conditions and some reagents may be varied to provide the desired 1,4- di (arylsulfonate) -1, , 7-triazacyclonane . With this in mind, one skilled in the art can monitor the progress of the reaction, for example by thin layer chromatography, and determine the extent to which 1, 4-diarylsulfonate-l, , 7- triazacyclonone . When the conversion of B (1,4,7- triarylsulfonate-1, , 7-triazacyclonone) to A (1,4- diarylsulfonate-1, 4 , 7-triazacyclonone) is at least 50 mol % yielding compound (A) the reaction is worked-up, Preferably, the reaction is worked up when the conversion of B to A is at least is at least 50 mol % yielding compound (A) .

The term worked-up is known in the art. In chemistry work-up refers to the series of manipulations required to isolate and purify the product (s) of a chemical reaction.

Typically, these manipulations include:

• quenching a reaction to deactivate any unreacted

reagents

• changing the pH to prevent further reaction

• cooling the reaction mixture or adding an antisolvent to induce precipitation, and collecting or removing the solids by filtration, decantation, or centrifuging

• removal of solvents by evaporation

• separating the reaction mixture into organic and

aqueous layers by liquid-liquid extraction

• purification by chromatography, distillation or

recrystalisation .

The following example illustrates the invention.

The amounts and ratios as given herein apply to the start of the method and will change during the reaction.

EXPERIMENTAL

1. Preparation of Ts ₂ TACN TsOH (Ts ₂ TACN =1 , 4-di (tosyl) - 1 , , 7-triazacyclononane ; TsOH = toluenesulfonic acid)

1, 4, 7-tritosyl-l, , 7-triazacyclononane (Ts ₃ TACN) was been synthesised as disclosed in WO9400439. Ts ₃ TACN (128.3 g, 96.6% containing 3.4% water, 209.5 mmol of Ts ₃ TACN, 242 mmol H ₂ 0) and propionic acid (113 mL) were placed in a 500mL three-necked-flask with thermometer and condenser. While stirring magnetically and warming (bath 160-170 °C) most of the TS ₃ TACN dissolved. Propionic anhydride (12 g, 92 mmol) and sulphuric acid (29.5 mL, 96%, 530 mmol, containing 120 mmol H ₂ O) were then added. (Caution: at the beginning period of adding H ₂ S0 ₄ , exothermic reaction occurred violently) .

Stirring was continued (reaction mixture = 142-143 °C) until the TLC showed the conversion to be complete (about 3hrs) . After partial cooling, the warm (70 ~ 80°C) contents of the flask were poured into 1.5 L ice-water while stirring vigorously. The product was left at room temperature overnight, then filtered over a large frit (φΐθαιη ) and washed with water (6x300 mL) until pH=7, the obtained white solid was dried under vacuum at 60°C with P ₂ 0 ₅ until the weight is constant (at least 2 days) . Yield of Ts ₂ TACN . TsOH : 93 g (74%) with purity: 91.5%. The filtrate was neutralized with aqueous NaOH to pH14, white solid which proved to be Ts ₂ TACN (Ts ₂ TACN =1 , -bis (tosyl ) -1 , , 7-triazacyclononane ) appeared, filtered and washed with water, dried under vacuum to a constant weight. Another 4% product could be obtained with 90% purity. The total yield is about 78%.

¹ H NMR (400 MHz, CDC1 ₃ ):6 2.36 (s, [ArCH ₃ (TsOH), 3H] ) , 2.44 (s, (ArCH ₃ (N-Ts),6H), 3.41 (br.s, [N-CH ₂ , 4H]),3.54 (br. S, [N-CH ₂ , 4H] ) , 3.75 (br . s , [N-CH2 , 4H] ) , 7.20 (d, J = 7.4 Hz , [ArH, 2H] ) , 7.32 (d, J = 7.4 Hz , [ArH, 4H] ) , 7.66 (d, J = 7.4 Hz , [ArH, 4H] ) , 7.90 (d, J = 7.4 Hz , [ArH, 2H] ) .

ESI-MS(ES+): m/z 438 (Ts2TACN + H) ⁺