Title of Invention

METHOD OF SYNTHESIS OF A LIGAND

Abstract

A METhod_fpr the synthesis of a ligand having the structure: wherein: B2,B3 Nandv_B4 each represent a bridging group having zero, one two or three carbon containing nodes for : i substitution, an& B2 Represents a bridging group having at least one carbon containing node for substitution, each said node containing a,C(R), C(R1) (R2) ox ,C(R)2 , each substituent is the same is the same or different from the remaining R substituents and 20 (i) is,selected from the group consisting of alkyl, alkenyi, cyclpalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinatalons thereof, or ii) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit, , said method comprising the steps listed below in the order giver: a) protecting the amino group of an amino acid comprising HOOC-B3-CPR-NH2 and/or HOOC-B4-CPR-NH2, b) activating the carbonyl group of said amino acid, t) reacting the carbonyl-activated amino acid with a diamine H2N-B2-NH2 to I form a diamide diamine, id) deportecting said protected amino groups, and, e) reacting the de-protected diamide diamine with an activated di-carbonyl compound to form a tetra-amine macrocycle.

Full Text

FORM2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10; rule 13) Title of the invention METHOD 00 OF SYNTHESIS OF A LIGAND HINDUSTAN LEVER LIMITED, a company incorporated under the Indian Companies Act, 1913 having its registered office at Hindustan Lever House, 165/166, Backbay Reclamation, Mumbai-400 020, State of Maharashtra, India The following specification particularly describes the nature of this invention and the manner in which it is to be performed GRANTED WO 02/16330 PCT/EP01/09351 - 1 - Field of the Invention 0 A. 5 method The present invention relates to the synthesis and use of macrocyclic metal-ligand exmplexes as bleaching catalysts In particular it relates to a_novel synthetic route -for a group of these ligands and to an improved catalyst 10 containing the ligand. Bacground of the Invention 15 Oxidation catalysts comprising metal-complexes are well known. One class being macrocyclic ligands^ which co¬ordinate with a transition metal ion. Such catalysts have been used in laundry compositions as parts,of a bleaching system. These catalysts activate H202 or other peroxygen 20 sources in water, and are effective at neutral to basic pH.. A catalyst is disclosed in WO 98/03263, filed 21 July 1997, (Collins) , which comprises a macrocyclic (tetra), amido N-v donor. The macrocycle is capable of complexing with a metal 25 ion, for example an iron III or IV. The,, complex also comprises axial ligands, for example as chloride or water, and one or more counter ions, for example tetraphenylphosphonium- and tetraefchylammonium. 30 United States Patent 5,853,428, filed 24 Feb 1997, (Collins) discloses use of similar catalysts in laundry detergent compositions. Field of the Invention The present invention relates to the method of synthesistand useW macrocyclic metal-ligand complexes as bleaching catalysts. In particular it relates to a novel synthetic route for a group of these ligands and to an improved catalyst containing the ligand. Background of the Invention Oxidation catalysts comprising metal-complexes are well known. One class being macrocyclic ligands, which co-ordinate with a transition metal ion. Such catalysts have been used in laundry compositions as parts of a bleaching system. These catalysts activate H202 or other peroxygen sources in water, and are effective at neutral to basic pH. A catalyst is disclosed in WO 98/03263, filed 21 July 1997 (Collins) which comprises a macrocyclic (tetra) amido N-donor. The macrocycle is capable of complexing with a metal ion, for example and iron III or IV. The complex also comprises axial ligands, for example as chloride or water, and one or more counter- ions, for example tetraphenylphosphonium and tetraethylammonium. United States Patent 5,853,428, filed 24 Feb 1997, (Collins) discloses use of similar catalysts in laundry detergent compositions. WO 02/16330 PCT/EPO1/09351 impure material, and is -believed unsuitable for large scale use. An azide based synthetic route to macrocyclic tetra-amido ligands is described in Uffelman, E. S., PhD The-eis (California Institute of Technology, [1992]). This is described in further detail in United States Patent 5,853,428, filed 24 Feb 1997. A further synthetic route is disclosed in US 6127536 (Deline et al., filed May 25th 1999, issued October 3rd 2000). In this synthesis 1,2-phenylenediamine is reacted with 2-bromoisobutyryl bromide to form a precipitating intermediate which is cyclised by reaction with diethyl malonyl 15| dichloride. Sunpaarrv of the Invention 20| WChave determined how an alternative synthetic route can be applied to obtain an improved yield of a ligand, which is believed- to contain low level's of impurities. Furthermore, this yield and purity enables the formation of complexes in which the axial ligand is chlorine or water. in simple terms, this route employs an N-protected amino acid, which is first reacted, at its carbonyl end, in the form of an acid chloride, with a diamine and subsequently deprotected to produce a macro-linker with available amino 30 groups. -This macro-linker is reacted with a di-carbonyl species to form the macrocycle. This differs from the prior route in which the macro-linker is formed by reaction at the WO 02/16330 PCT/EP01/09351 amino group of the-acid and-subsequent ring closuafe occurs across the carbonyl groups of the amino acid residue.. Accordingly, a first aspect of the present invention provides a method for the synthesis of a ligand having the structure: 10 wherein: B2, B3 and B4 each represent a bridging group having zero, one two or three carbon containing nodes for substitution, and B2 represents a bridging group having at least one carbon containing node for substitution, each said node containing a C (R) , C(R2) (R2) or C (R)2 , each R substituent is the same is the same or different from the remaining R substituents and (i) is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, alkynyl, WO 02/16330 PCT/KI'OI/OWSI alkylaryl, halogen, alkoxy, phenoxy and combinations- thereof, or (ii) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit", said method comprising the steps listed below in the order given a) protecting the amino group of an amino aci'd comprising HOOC-B3-CRR-NH2 and/or HOOC-B4-CRR-NB2, b) activating the carbonyl group of said amino acid, c) reacting the carbonyl-activated amino acid with a diamine H2N-B2-NH2 to form a diamide diamine, d) deprotecting said protected amino groups, and, e) reacting the de-protected diamide diamine with an activated di-carbonyl' compound1 to form a tetra-amine macrocycle. It is preferred that HOOC-B3-CRR-NH2 and HOOC-B4-CRR-NH2 in step a) are the same. The aforementioned synthetic method is not restricted to B1 B2, B3 and B4 as defined above. One skilled in the art will appreciate the B1# B2, B3 and B« may represent any suitable spacing group that does not prevent the synthetic method from proceeding. Where required a group that does inhibit the reaction is protected. The particular length B2 B2, B3 WO 02/16330 PCT/EPO1/093 and B4 may effect the reaction because of entropy factors; nevertheless one skilled in the art will appreciate the limits in size of any ring being formed. It is with the scope of the present reaction for a chelating ion to be used to aid cyclization. A further aspect-.of the present invention subsists in those complexes, which, have simple axial ligands (water or halide) and a simple counter-ion (such as lithium). It is believed that these ligands are environmentally and toxicologically more acceptable than ligands such as trifluoroacetate, tetra-phenylphosphonium and tetra-ethylammonium. Accordingly, a further aspect of the present invention provides a bleach activator having the structure: wherein: B1, B3 and B4 each represent a bridging group having zero, one two or three carbon containing nodes for substitution, and B2 represents a bridging group having at WO 02/16330 PCT/EP01/09351 least one carbon containing node for substitution, each 'said node containing a C(R), C(R1)(R2) or C(R)2 , - each R substituent is the same is the same or different from the remaining R substituents, and (i) is selected from the group consisting of alkyl, r alkenyl, cycloalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinations thereof, or (ii) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit; - M is a transition metal ion; - L is an axial ligand selected from the group consisting of water and halide,- and, - Q is an alkali metal counter-ion. It is also within the scope of the present invention to have a bleach activator, wherein M is selected from the group consisting of Fe, ton, Cr, ,Cu, Co, . Ni) Mo,UV/ Zn land W./ The present invention also extends to a packaged composition comprising a bleach activator as defined together with... instructions for its use in a method of laundering fabrics. WO 02/16330 PCT/EPO1/09351 Detailed Description of the Invention Throughout the description and claims generic groups are used, for example alkyl, alkoxy, aryL etc Unless otherwise specified the following are preferred group restrictions that may be applied to generic groups found within compounds disclosed herein Alkyl: linear and branched Cl-C8-alkyl ; alkenyl: C2-C8-alkenyl, cycloalkyl: C3-C8-cycloalkyl; cycloalkenyl: C4-12-cycloalkenyl having a single cyclic ring or multiple condensed rings and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 Cl-C8-alkyl groups; aryl: selected from v homoaromatic compounds having a molecular weight under 300, alkynyl: C2-C12-alkynyl; alkylaryl: Cl-12-alkylaryl, wherein 15 the aryl selected from homoaromatic compounds having a molecular weight under 3 00; halogen: selected from the group consisting of: F; Cl; Br and I; and, alkoxy: Cl-C6-alkoxy. Unless otherwise specified the following are more preferred 20 group restrictions that may be applied to groups found within compounds disclosed herein. Alkyl: linear and branched Cl-C6-alkyl; alkenylv C3-C6-alkenyl: cycloalkyl: C6-C8-cycloalkyl; cycloalkenyl: C4-8-cycloalkenyl having a single cyclic ring or multiple condensed rings and at least >5 one point of internal unsaturation which_can be optionally substituted with- from 1 to. 3 Cl-C8-alkyl groups; aryl: selected from group consisting of: phenyl; biphenyl; naphthalenyl; anthracenyl; and phenanthrenyl; alkynyl: C2-C8-alkynyl, alkylaryl: Cl-6-alkylaryl, wherein the aryl is 3p selected from, selected from group consisting of --: -phenyl; biphenyl; naphthalenyl; anthracenyl; and phenanthrenyl; halogen: selected from the group consisting of: F and Cl; and, alkoxy: C1-C4-alkoxy. WO 02/16330 PCT/EP01/0V351 Preferred compounds of the present invention have R = methyl. B3 and B4 are preferably absent, the two related sides of the ring being derived from a 'cXas»ieal' amino acid in which the amino group is located on the alpha-carbon. A preferred starting amino acid is 2-amino ieo-butyric acid. (H2N-C (CH3) a-COOH) . ,v fn the initial stage of the synthesiSr—fefee—amd-no group of 40 the acid is protected. The choice of protecting groups during synthesis to prevent undesirable reactions will be evident to one skilled in the art. For a discussion of protecting groups in organic synthesis the reader is directed to T. W. Green and P. G. M. Wuts, Protective Groups 1$ In Organic Synthesis 2nd Ed.; J. Wiley and Sons, 1991. Phthalic anhydride has been found to be a suitable protecting agent . Activation of the carbonyl group following protection can be ) achieved by several means. One suitable means is reaction with a thionyl halide.to yield the acyl halide . Reaction with an excess of thionyl chloride is preferred- Following activation of the carbonyl, the protected macro-linker is formed by reaction with a diamine. The preferred diamines are phenylenediamines, preferably the' o-phenylenediamine. These may be optionally substituted as described in the patents of Collins et al., as mentioned above. It is preferred to use the unsubstituTed diamine. 3D The protected amino groups of the macro-linker may be unprotected by any suitable reaction. Where phthalic anhydride has been used as the protecting agent the de- WO 02/16330 PCT/EP01/09351 protection can conveniently be accomplished through treatment with hydrazine hydrate. . Ring closure is conveniently obtained through reaction of the macro-linker with a di-carbonyl species, which has been activated. Preferably, Bl comprises a single substituted carbon atom. It is preferred that the portion of the heterocycle ring comprising Bl is derived from a malonate or oxalate. Bl most preferably is -(Me)2C-. Dimethylraalonyl chloride is a suitable reagent. It is preferable that the ring closure reaction is performed slowly and at high dilution to prevent the formation of side products. The following schematic shows a reaction scheme for the synthesis of a compound according to a preferred ^embodiment of the present invention. The individual reactions are described in more detail below. The amino acid, 2-aminoisobutyric acid, 'A', is reacted with a protecting agent to form a derivative with a protected amino group VB'^ The carbonyl group of the protected amino acid is then activated to form species 'C. Reaction of two moles of XC with a mole.of o-phenylene diamine yields' the derivative lD', which is subsequentlxj^eprotected at 'l' to give the macro-linker 'E' One skilled—is-the art will understand that differing protective groups may be used in the reaction, nevertheless a use of a single type-tSfprotecting group is preferred^Species ' E' is reacted with dimethyl malonyl chloride to close the ring structure and produce the final ligand (not snown). Metallisation of the ligand gives the active catalyst. WO 02/16330 PCT/EPO1/09351 Metallation of the ligand is preferably performed under nitrogen and in a non-aqueous solution such as dry tetrahydrofuran (THP) . The transition metal is„.preferably selected from groups VI, VII, VIII, IX, X and XI of the and- W the g preferred metal. periodic table. More preferably the metal is selected^from the group consisting of _Fj5, Mn,_Cr, Cu, Co, Nl,_ Mo,_3E7—Zn Particularly preferably the metal is selected from the group comprising: Fe, Mn, Cu and Co.Iron/is the most WO 02/16330 PCT/EPO1/09351 Suitable counter ions are K, Li or Na, most preferably (lithium. The,most preferred compound is that in which the ligand is 5,6-benzo-3,8,11,13-tetraoxo-2,2,9,9,12,12-hexamethyl-1,4, 7,J^p-tetraazacyclotridecane as shown below as the Fe form, the axial ligand ' L' is water or preferably chloride. The counter-ion 'Q' is preferably lithium. This can also be described as 3,4,8,9-tetrahydro-3,3,6,6,9,g-hexametHVl-lH-1,4, 8,ll-boiizQteJ;raazocyclotridecane-2, 5,7,10 (6H,11H) tetrone) The present invention also extends to fully formulated products containing the catalysts disclosed herein. Such products will generally contain a detergenta^tive and will typically contain one or more builders together with the typical additive used in detergent compositions. Typical levels of the catalyst of the present invention in fully formulated compositions will range from 0.00005 to 2 wt.% with 0.005 to 1 wt.% being particularly preferred and 0.05 to 0.5 wt.% being most particularly preferred. Typical WO 02/16330 PCT/EP01/09J51 leve'ls of peroxygen source in fully formulated composition will range from 0.05- to 55 wt. % with 1_ to 4 0 wt-% bein9 particularly preferred and 5 to 25 wt. % being most,, particularly preferred. Preferred peroxygen sources include percarbpiiafcje aad- perborate. Examples ' 0 In order that the invention may be further and better understood it will be described in detail with reference to following non-limiting examples. Example 1: Preparation of 2-Methyl 2-phthaiimidopropaiioic lfe acid ,Phtnalic anhydride (1 Kg, 4.84 mol) and 2-aminoisobutyric acid (500 g, 6.75 mol) were pre-mixed and heated to 190 "C with stirring. Once molten, the reaction was held at this temperature until no further water was^expelled, approximately 4 hours. The reaction mixture was poured into large crystallising dishes and, whilst still hot', neutralised with 10 % aqueous sodium bicarbonate solution (12.5 L). The mixture was then filtered to remove any 2$ insolubles. The filtrate was acidified with concentrated hydrochloric acid until a thick white precipitate was observed. The precipitate was filtered and washed with water to remove remaining hydrochloric acid from the precipitate. The precipitate was dried under vacuum to yield tTae title cowpourvd as a. white powder (974 g, 86%) . ^ WO 02/16330 PCT/EP01/09351 15 5H. NMR. (500-MHz, d6 acetone) 7.84 (m, 4H) , 1.83 (s, 6H) ,- 13C NMR (125 MHz) 24.87, 60.87, 123.64, 132.73, 135.19, 168..92, 174.26. Example 2(f"Preparation of 2-Methyl-2-phthalimidopropanoyl chloride Thionyl chloride (750 ml, 10.28 mol) was added to 2-methyl-2-phthalimidopropanoic acid (3 85 g, 1.65 mol) and the mixture refluxed under nitrogen for 3 hours. Excess thionyl chloride was removed under reduced pressure to yield a solid. The solid was washed with diethyl ether (2 x 250 ml) to yield the title compound as a white crystalline solid (408.2 g, 98%). lHNMR (500JMHZ, ds acetone) 7.92 (m,. 4H) ,"1.95 (S, 6H) ; 13C NMR (125 MHz) 24.032, 68.41, 124 .20,.. X3£ .45; 135 .78, 168.48, 175.37. 0 Example 3: Preparation of N,N'-1,2-phenylenebis[2-methyl-2- phthalimidopropanamide] A solution of o-phenylene diamine (34.4 g, 0.32 mol) and triethylamine (75 ml) in THF (1 L) was added drop-wise to a stirred solution of 2-methyl-2-phthalimidopropanoyl chloride (160 g, 0.63 mol) in THF (1.5 L) at a temperature of 0 °C. After addition the reaction was warmed to room temperature and stirred for a further 12 hours and then refluxed for a further 2 hours. The reaction mixture was coollSd in ice, 3|0 filtered and the THF removed under reduced -pises sure. The resultant white solid was dissolved in dichloromethane (1.5 L) and washed with 1 M hydrochloric acid (3 x l L) followed by washing with a 5 % sodium bicarbonate solution. The WO 02/16330 PCT/EPO1/09351 dichloromethane extract was dried (MgS04) , filtered and stripped of solvent under reduced pressure to yield the title compound (149.72 g, 87%). *H^nmr (500 MHz, d* DMSO) 9.41 (s, 2H) , 7.83 (d,d, 4H, 3J = ^.45 Hz, 4J » 3.04 Hz), 7.76 (d,d, 4H, 3J = 5.45 Hz, 4J = 3.04 Hz), 7.51 (m, 2H) , 7.17 (m, 2H) , 1.73 (s, 12H) ; 13C nmr (125 MHz) 24.70, 61.44, 123.21, 124.60, 125.46, 130.85, 132.00, 134..82, 168.66, 171.99. 10 Example 4: Preparation of N,N'-1,2-phenylenebis[2-methyl-2-methylpropanamide] A -slfirred suspension of the protected diamide diamine (N,N'-5( 1,2-phenylenebis [2-methyl-2-phthalimidopropanamide] (141 g, 0.26 mol) in ethanol (3 L) was refluxed and treated with hydrazine (33.7 mL, 0.69 mol). The suspension dissolved after a few minutes and the reaction mixture refluxed for a 15 hours during which a white precipitate was formed. The 2J0 reaction was cooled to room temperature and the ethanol was removed under reduced pressure to yield a solid. The solid was dissolved in 2 M hydrochloric acid* (8'.812 L) and heated at 80 "C for an hour and then cooled to room temperature. The reaction mixture was then filtered and the filtered liquid adjusted to pH 13 with a concentrated sodium hydroxide solution to yield a deep yellow colour solution. The deep yellow colour solution was extracted with dichloromethane (3 x 2 L) , and the combined extracts dried (MgS04) . Removal of solvent under reduced pressure gave an off white solid which was washed with ether (1 L) to yield the title compound as a white solid (69.2 g, 95%). WO 02/16330 PCT/EPO1/09351 2H nmr (500 MHz, d6 DMSO) 7.66 (m, 2H), 7.2 (m, 2H), 4.75 (brs) , 1.36 (s, 12H) ; 13C nmr (125 MHz) 29.03, 55.27, 124.41, 125.15, 131.32, 177.09. j Example 5: Preparation of 3,4,8,9-tetrahydro -3,3,6,6,9,9- hexamethyl-lH-1,4,8,11- benzotetraazocyclotridecane-2, 5,7,10 (6H,11H) tetrone. The following reaction was conducted under nitrogen with vigorous stirring of the reaction mixture. Individual solutions of dimethylmalonyl chloride (18.2 g) in IL THF and a mixture of N,N'-1,2-phenylenebis[2-methyl-2-methylpropanamide] (30g, 0.11 mol) and triethylamine (31mL) 1(5 in THF (IL) were added in a controlled manner over 10 hours to THF (750 mL) whilst maintaining the reaction mixture at 0°C. During the reaction a precipitate was formed and the reaction mixture warmed to room temperature overnight. The reaction mixture was filtered, the precipitate washed with 2|0 water (4 x 500 mL) and dried under reduced pressure to yield the title compound (40.3 g, 100%). XH nmr (500 MHz, ds DMSO) 8.35 (brs, 2H), 7.74 (brs, 2H), 7.47 (m, 2H), 7.16 (m, 2H), 1.47 (s, 12H), 1.45 (s, 6H); "c 5 nmr (125 MHz) 22.70, 25.48, 51.05, 125.12, 125.58, 130.54, 172.45, 173.23. Examples: Metallation of 3,4,8,9-tetrahydro-3,3,6,6,9,9-hexamethyl-1H-1,4,8,11- benzotetraazocyclotridecane-2, 5,7,10 (6H,11H) tetrone. WO 02/16330 PCT/EPO1/09351 A stirred suspension of 3,4,8,9-tetrahydro-3,3,6,6,9,9-hexamethyl-lH-1,4,8,ll-benzotetraazocyclotridecane-2,5,7,10 (6H,11H) tetrone (5 g) in THF (1 L) under a nitrogen atmosphere was heated to 40 °C. The heated suspension was then treated with 31 mL butyl lithium causing the suspension to dissolve; 3 0 minutes after the treatment iron (II) chloride was added. After 36 hours the reaction mixture was cooled and filtered to provide a solid. The solid was dissolved in water (1 L) yielding a solution of pH 12 which lp was stirred and treated with a lithium hydroxide solution (1.5 mL) followed by addition of concentrated hydrochloric acid until the pH of the solution was 5 (colour change from brown to red/orange). The pH of the solution was then adjusted to pH 7 by addition of a lithium hydroxide solution L5 and the solvent removed under reduced pressure to yield a sticky orange solid. The sticky orange solid was washed with methanol to provide a powder. The powder was purified by dissolution in ethanol and elution through a Florisil™ column with acetonitrile to yield the title compound. Wash Examples In the Following wash Examples 7 to 9 a 'base' colour washing powder with approximately the following composition was used (all percentages by weight). This 'base' differs slightly from commercial powders in that it does not contain colour care components. Otherwise, the composition is very similar to that of products available at present in the marketplace. 30( WO 02/16330 PCT/EPO1/09351 Sodium linear alkyl (C12) benzene sulphonate 7.9% C12-14 Nonionic 7EO 5.1% C12-14 Nonionic 3EO 4.0% Soap 0.35% Fatty Acid 0.40% Sodium tripolyphosphate 3 0.0% Sodium silicate 7.9% Sodium sulphate 14.5% Sodium hydrogen carbonate 4.0% Sodium carbonate 8.8% Minors and water to 100% Minors included an antifoam agent, a soil release polymer, protease, lipolase, amylase and perfume. L5 Colour of test samples are expressed in terms of AE. For . further detail of this measurement the reader is directed to "Measuring Colour" by R.W.G. Hunt, Series in Applied Science and Industrial Technology, Ellis Horwood, (1976) and in 2|0 particular page 76 in which the CIELAB colour difference equation is given. The following experiments were performed in what is known as " over the side experiments" ; the components as detailed 2j5 were added separately via the draw of the washing machine to the wash. Example 7: Washing Experiment 3|p The Base colour washing powder (I05g) was placed in the drawer of a Miele Novotronic (RTM) European-type horizontal-axis washing machine and the machine used to wash a 2.566 kg WO 02/16330 PCT/EP01/09351 wash load. The load comprised 125Og non-mercerised white cotton sheeting, 1250g 50:50 white polycotton sheeting, and 5 x 900cm2 green cloth, 'direct green 26' at 5%, unfixed, weighing 66g. The wash was conducted using the machines 4 0°C '5 program and 26 French hard water. After the wash the cloths were tumble dried and examined. Visual examination revealed that both the white cotton and poly-cotton sheeting had both become green due to pick up of 3/0 dye lost from the direct green cloth. Measurement of the CIELAB AE value of the cotton cloth compared to the original white gave a value of 10.5. The experiment was repeated with fresh cloth but in the 15 presence of 0.035g of the catalyst prepared in example 6 and 3.63g of a 35% solution of H202 was added. The CIELAB AE value of the cotton cloth compared to the original white was 2.4. Visual examination showed that the amount of green dye transferred to the white cloths had been significantly reduced. Example 8: Washing Experiment The protocol of example 7 was followed except the wash load 2)5 consisted of 2.566kg of a soiled load (dirty iea towels, pillow cases and towels, all 100% white cotton; 10 400cm2 clean white cotton monitor cloths; 5 900cm2 green cloth, dyed with direct green 26 at 5%, unfixed. !i0 After the washing and drying the white cotton cloths showed transference of the green dye on visual inspection. The WO 02/1633(1 PCT/EP01/09351 CIELAB AE value of the cotton monitor cloth compared to the original white was 7.4 The experiment was repeated with fresh cloth but with the levels of catalyst prepared in example 6 and levels of an aqueous 35% solution of H202 added as shown in Table 1 below. The average CIELAB AE value of the cotton monitor cloths at the various levels of catalyst and peroxide are given in Table 1 below. It can be seen that catalyst has reduced dye transfer when present. Table 1 Added catalyst in grams Added H202 (35%) in grams Measured AE 0 0 7.4 0.035 3.63 4.0 0.035 14.57 4.4 0.070 14.52 3.7 Example 9: Washing Experiment y" The protocol of example 7 was repeated, except the load consisted of 1.5kg of white Terry towelling, ©uOg cotton sheeting, 400g of 1% unfixed Direct Black 22 cotton cloth. When washed without the catalyst being present the white cloth became visibly grey, and the CIELAB AE value of the cotton sheeting was 14.4 compared to the original. When the WO 02/16330 PCT/EPO1/09351 catalyst was added at levels of 0.0035g with 0.36g of a 35% solution of H202, the CIELAB AE value of the cotton sheeting was 6.5 compared to the original. It can again be seen that dye transfer had been considerably reduced in the presence of the catalyst. WO 02/16330 PCT/EP01/09351 WE CLAIMS . A METhod_fpr the synthesis of a ligand having the structure: wherein: B2,B3 Nandv_B4 each represent a bridging group having zero, one two or three carbon containing nodes for : i substitution, an& B2 Represents a bridging group having at least one carbon containing node for substitution, each said node containing a,C(R), C(R1) (R2) ox ,C(R)2 , each substituent is the same is the same or different from the remaining R substituents and 20 (i) is,selected from the group consisting of alkyl, alkenyi, cyclpalkyl, cycloalkenyl, aryl, alkynyl, alkylaryl, halogen, alkoxy, phenoxy and combinatalons thereof, or ii) form a substituted or unsubstituted benzene ring of which two carbons on the ring form nodes in the B-unit, , said method comprising the steps listed below in the order giver: a) protecting the amino group of an amino acid comprising HOOC-B3-CPR-NH2 and/or HOOC-B4-CPR-NH2, b) activating the carbonyl group of said amino acid, t) reacting the carbonyl-activated amino acid with a diamine H2N-B2-NH2 to I form a diamide diamine, id) deportecting said protected amino groups, and, e) reacting the de-protected diamide diamine with an activated di-carbonyl compound to form a tetra-amine macrocycle. 2. A method according to claim 1, wherein R = methyl. 3. A method according to claim 1, wherein B3 and B4 are absent. 4. A method according to claim 1, wherein B3 = B4. Dated this 20th day of February 2003

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