PROCESS FOR PREPARING CROSS-BRIDGED TETRAAZA MACROCYCLES

Abstract: The present invention relates to a process for preparing a cross-bridged tetraaza macrocyclic ligands having formula (I), wherein each R is independently C1-C22 linear alkyl, C1-C22 branched alkyl, C7-C22 alkylenearyl, C8-C22 alkyl substituted alkylenearyl, and mixtures thereof; each index n is independently from 0 to 3, by contacting the a di-quaternary cis tetracycle precursor with as little as one equivalent of a borohydride reducing agent. The present process eliminates the need to use up to a twenty fold excess of reducing agent thereby further eliminating the need for work-up conditions which liberate significant amounts of hydrogen gas and which requires the disposal of large amounts of boron waste products.

Description: PROCESS FOR PREPARING CROSS-BRIDGED TETRAAZA MACROCYCLES FIELD OF THE INVENTION The present invention relates to an improved process for preparing cross-bridged tetraaza macrocycles, said macrocycles suitable as gands for use in preparing transition metal complexes The present invention provides a process which is well suited for use in industrial and other commercial preparations of the herein described crossed-bπdged macrocycles. BACKGROUND OF THE INVENTION Tetraaza macrocyclics, for example, cyclam, have been prepared in numerous ways, however, there is a paucity of information relating to the preparation of cross-bπdged tetraaza macrocyclics inter alia l,5,8,12-tertaaza-bιcyclo[6.6.2]hexadecane. Recently, bis N-substituted tetraaza macrocyclics inter aha 5,12 dialkyl or dialkylenearyl 1,5,8, 12-tetraaza- bιcyclo[6.6.2]hexadecanes have found wide applicability as hgands especially in the area of transition metal catalysts inter aha bleach catalysts. WO 98/39335 Al "Improved Methods of Making Cross-Bridged Macropoly-cycles" discloses a rational procedure for prepaπng cross bridged macropolycyc c hgands which is amenable to high yields necessary for industrial scale-up. However, the reductive ring cleavage step which results in bicyclo bridged-ring formation utilizes a large excess of a borohydπde reducing agent. This excess of reducing agent can place constraints on the formulator. For example, when manufacturing the disclosed hgands on a industrial scale, any excess of reagent beyond the stoichiometπc amount places an increased cost burden on the formulator. In addition, the proper recovery and disposal of boron waste products adds cost to the process. Excess borohydπde requires neutralization which involves the use of acid and the evolution of large quantities of hydrogen gas. Therefore, a need exists for a highly quantitative, stoichiometπc process for preparing cross-bridged macropolycychc hgands. SUMMARY OF THE INVENTION The present invention meets the aforementioned needs m that it has been surprisingly discovered that approximately one mole equivalent of a borohydπde reducing agent is necessary to convert -tetracycles to cross bridged macropolycychc hgands. A first aspect of the present invention relates to a process for prepaπng a cross-bridged tetraaza macrocyclic hgand having the formula. wherein each R is independently Cj-C 2 linear alkyl, C,-C 22 branched alkyl, C 7 -C 22 alkylenearyl, C 8 -C 22 alkyl substituted alkylenearyl, and mixtures thereof; each index n is independently from 0 to 3, said process comprising the steps of. a) reacting one mole equivalent of a tetraaza macrocyclic gand precursor having the formula: wherein X is an anion which provides charge neutrality, with from about 1 mole equivalent to about 3.5 mole equivalents of a reducing agent having the formula MBH 4 wherein M is selected from the group consisting of lithium, sodium, potassium, and mixtures thereof; at a pH of at least about 11 to form a macrocyclic hgand; and b) optionally isolating said macrocyclic gand. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C) unless otherwise specified. All documents cited are m relevant part, incorporated herein by reference. DETAILED DESCRIPTION OF THE INVENTION Until the disclosure of WO 98/39335 Al there was no process for prepaπng cross- bridged tetraaza macrocyclic hgands, especially hgands suitable for use in prepaπng catalysts wter alia manganese (LI) bleach catalysts, which was suitable for industrial application. WO 98/39098 Al "Catalysts and Methods for Catalytic Oxidation" published September 11, 1998 discloses cross-bridged tetraaza macrocyclic hgands and transition metal complexes formed therefrom. These transition metal complexes serve as oxidation catalysts which have a wide range of uses inter aha as bleaching catalysts for use m removing stains from fabric. A preferred catalyst is 5,12-dιmethyl-l,5,8,12-tertaaza-bιcyclo[6.6.2]hexadecane manganese (II) chloride which comprises the cross-bridged hgand 5,12-dιmethyl-l,5,8,12-tertaaza- bιcyclo[6.6.2]hexadecane. WO 98/39335 Al describes the preparation of this hgand wherein 12 moles of NaBH 4 is used to cleave a bιs(quaternary-N-methyl) -tetracycle precursor to 5,12- dιmethyl-l,5,8,12-tertaaza-bιcyclo[6.6.2]hexadecane. The present invention stabilizes the borohydπde by conducting the step (a) at a pH of at least about 11. It has been surprisingly discovered that this transformation and transformations which convert other rø-tetracycles to cross-bridged macrocycles can be conducted in nearly quantitative yield with a near stoichiometπc amount of borohydπde reducing agent. The process of the present invention relates to the reductive cleavage of a cis -tetracycle having the formula: wherein each R is independently Cj-C 22 linear alkyl, C C 2 branched alkyl, C7-C 22 alkylenearyl, C 8 -C 22 alkyl substituted alkylenearyl, and mixtures thereof; X represents an anion which provides electronic neutrality; each index n is independently from 0 to 3. The reductive πng cleavage results m a tetraaza macrocyclic hgand having the formula: wherein R and the index n are the same as defined herein above. X is an anion which serves to provide electronic neutrality to the bis-quaternary cis tetracycle. Those of ordinary skill in the art recognize that the term "electronic neutrality" refers to "a sufficient amount of an anionic species which satisfies the molecular charge balance requirements" and that a mixture of mono-, di-, tπ-, etc. electronic species may be use herein. X preferably has unit negative charge, for example, halogen, tosylate methylsulfate. However, X may have more than one negative charge, for example, sulfate, in which case the formulator requires only half the amount necessary when using a unit negative-charged anion. For the purposes of the present invention the term "linear alkyl" is defined as "any linear alkyl chain" non-hmitmg examples of which include methyl, ethyl, n-propyl. n-decyl, etc. For the purposes of the present invention the term "branched alkyl" is defined herein as "any alkyl chain which has one or more alkyl branches" non-limiting examples of which included, 2- ethylhexyl, 3-methylpentyl, isopropyl, isobutyl, etc. For the purposes of the present invention the term "alkylenearyl" is defined as a unit having the formula: (CH 2 ) X -Ar wherein Ar represents an aromatic moiety having from 6 to 14 carbon atoms and x has the value from 1 to 16 Non-hmitmg examples of Ar units are phenyl and naphthyl. For the purposes of the present invention the term "alkyl substituted alkylenearyl" is defined as "an alkylenearyl unit wherein one or more carbons atoms of the Ar unit has an alkyl unit replacing the hydrogen atom." Non-limiting examples of alkyl substituted alkylenearyl Ar units include 4-methylphenyl (toluyl) and 3,5-dι-tert-butylphenyl. For alkyl substituted alkylenearyl units the index x is from 1 to 15. In its basic form, the process of the present invention comprises a reduction step and an optional isolation and/or purification step. The reduction step is necessary in that the required chemical transformation is performed in this step, however, the isolation and/or purification step is optional. The formulator may find that isolation of the cross-bridged macrocycle is not a necessary step if the next usage of the formed hgand is, for example, formation of a metal complex, and this succeeding step can be successfully performed on the crude, un-isolated product which is still in the reduction step admixture. STEP (a) Reductive Cleavage Step (a) compπses the borohydπde (BH 4 ) reductive cleavage as outlined m the following scheme: wherein the -tetracycle bis quaternary salt is converted to the cross-bridged tetraaza macrocycle. The pH under which Step (a) must be conducted is at least 11, preferably at least 12 Preferably the base which is used to adjust the pH is in the form of an aqueous solution Preferred bases are selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and mixtures thereof. It is satisfactory to use a sufficient amount of 1 M (molar) aqueous base to adjust the pH to the required level A convenient and preferred base is potassium carbonate. Preferably Step (a) is conducted m the presence of a solvent. Non-limiting examples of solvents include benzene, toluene, methanol, ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, and mixtures thereof; prefered solvents are selected from the group consisting of ethanol, n-propanol, isopropanol, and mixtures thereof. When a solvent is present and the base is in the form of an aqueous solution, the ratio of said volume of aqueous base, preferably 1 molar aqueous base, to said solvent is from about 1 :10 to about 1 : 1, preferably the ratio of the volume of aqueous base to solvent is 1:4. It is desirable, but not a requirement, that the aqueous base and solvent form a two phase system. The reducing agent for the process of the present invention is borohydπde, BH 4 " . Non- hmiting examples of reducing agents which are preferred for the process of the present invention include reducing agents having the formula MBH 4 wherein M is selected from the group consisting of lithium, sodium, potassium, and mixtures thereof; preferably M is sodium (sodium borohydπde). Surpπsingly, under the conditions of the present process, only the stoichiometπcally required 1 mole equivalent of sodium borohydπde (corresponding to two moles of H 2 ) is needed to accomplish the desired transformation. However, up to 3.5 mole equivalents can be suitably used, especially in continuous processes wherein the aqueous phase is recycled and the amount of reducing agent which is consumed duπng the chemical πng cleavage is replace pπor to introduction of another batch of starting mateπal. A preferred embodiment, which balances time, reaction temperature, and yield, uses 2 mole equivalents of borohydπde reducing agent. This limitation removes the need for large amounts of acid to destroy the unused borohydnde, thereby eliminating the unnecessary release of excess hydrogen gas duπng work-up and optional isolation. Step (a) may be conducted at any temperature from about 10° C, preferably from about room temperature, more preferably from about 40° C to about 70° C, more preferably to about 50° C. In a preferred embodiment of the process of the present invention, sufficient 1 M base is admixed with ethanol in a suitable reaction vessel to form a two phase system which is mechanically stirred and warmed to about 50° C Concurrently and in a portion-wise manner over equal time intervals, 2 equivalents of sodium borohydπde and a cis tetracycle are added to the reaction vessel maintaining the temperature at about 50° C After addition of the reagents is complete, the reaction is monitored using any convenient means, for the consumption of the cis- tetracycle. Once the starting material is consumed the organic phase is decanted and the product isolated by normal procedures. The following is a non-limiting example of the process of the present invention used to fragment a specific tetracycle. EXAMPLE 1 Preparation of S^-dimethyl-LS. -tertaaza-bicvclofβ.ό. jhexadecane Distilled water (25 mL) and potassium carbonate (13.8 g) are combined in a 250 mL round bottomed flask. Absolute ethanol (75 mL) is added and the resulting two phase solution is stirred and heated to about 60°C. Sodium borohydπde (1.60 g., 42.3 mmol) and the -tetracycle having the formula: wherein X is methylsulfate, (10.0 g, 21.1 mmol) is added to the solution. The reaction is stirred at 60°C for 75 minutes. The reaction mixture is transferred to a separatory funnel and the ethanol layer collected. The ethanol is evaporated under reduced pressure and affords a tan-colored oily solid. The crude material is treated with 5N KOH (5 mL) until dissolved and the aqueous solution extracted with toluene (2 x 50 mL). The toluene is removed in vacuo to afford a crude oil which is subsequently distilled at about 0.2 mm Hg to yield 5.2 g (95%) of 5,12-dιmethyl- 1,5,8, 12-tertaaza-bιcyclo[6.6.2]hexadecane as a colorless oil.

Claims: WHAT IS CLAIMED IS: A process for preparing a tetraaza macrocyclic hgand having the formula wherein each R is independently Cj-C 22 linear alkyl, -C branched alkyl, C7-C 22 alkylenearyl, C 8 -C 22 alkyl substituted alkylenearyl, and mixtures thereof; each index n is independently from 0 to 3, said process comprising the steps of a) reacting one mole equivalent of a tetraaza macrocyclic hgand precursor having the formula: wherem X " is an anion which provides charge neutrality, with from 1 mole equivalent to 3.5 mole equivalents a reducing agent having the formula MBH 4 wherein M is selected from the group consisting of lithium, sodium, potassium, and mixtures thereof; at a pH of at least 11 to form a macrocyclic hgand; and b) optionally isolating said macrocyclic hgand. 2. A process according to Claim 1 wherein R is Cj-C 8 linear alkyl, C 7 -C 10 alkylenearyl, C 8 - Cjo alkyl substituted alkylenearyl, and mixtures thereof. 3. A process according to either of Claims 1 or 2 wherein R is C C 4 linear alkyl, benzyl, and mixtures thereof. A process according to any of Claims 1 - 3 wherein R is methyl. 5 A process according to any of Claims 1 - 4 wherein two of the indices n are equal to 0 and two of the indices n are equal to 1. 6. A process according to any of Claims 1 - 5 wherein said tetraaza macrocyclic hgand formed by said process has the formula: 7. A process according to any of Claims 1 - 6 wherein said reducing agent is NaBH 4 . 8. A process according to any of Claims 1 - 7 wherein said reducing agent is present in the amount of 2 mole equivalents. 9. A process according to any of Claims 1 - 8 wherein said pH of step (a) is at least 12. 10. A process according to any of Claims 1 - 9 wherein step (a) is conducted in the presence of one or more solvents. 1 1. A process according to any of Claims 1 - 10 wherein step (a) is conducted in the presence of water and one or more solvents. 12. A process for prepaπng a tetraaza macrocyclic hgand having the formula: wherein R is Cι-C 22 linear alkyl, C C 22 branched alkyl, C 7 -C 22 alkylenearyl, C 8 -C 22 alkyl substituted alkylenearyl, and mixtures thereof; each index n is independently from 0 to 3, said process compπsmg the steps of: a) combining m a reaction \essel a one molar solution of base and a solvent, wherein the ratio of said base to said solvent is from 1 10 to 1 1 : to form a two phase solution, b) adding to said two phase solution one mole equivalent of a tetraaza macrocyclic hgand precursor having the formula wherein X ' is an anion which provides charge neutrality, and from 1 mole equivalent to 3.5 mole equivalents of a reducing agent having the formula MBH 4 wherein M is selected from the group consisting of lithium, sodium, potassium, and mixtures thereof; at a pH of at least 11 to form a macrocyclic hgand; c) separating the aqueous and non-aqueous phases; and d) optionally isolating said macrocyclic hgand. A process for prepaπng a tetraaza macrocyclic hgand having the formula- wherein R is C|-C 22 linear alkyl, Cj-C 22 branched alkyl, C7-C 22 alkylenearyl, C 8 -C 22 alkyl substituted alkylenearyl, and mixtures thereof; each index n is independently from 0 to 3, said process compnsing the steps of: a) combining m a reaction vessel a one molar solution of base, said base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and mixtures thereof; and a solvent, said solvent selected from the group consisting of benzene, toluene, methanol, ethanol, n-propanol. isopropanol, diethyl ether, tetrahydrofuran, and mixtures thereof; wherein the ratio of said base to said solvent is from 1:10 to 1.1; to form a two phase solution; b) adding to said two phase solution, at a temperature of from 10° C to 70° C. tetraaza macrocyclic hgand precursor having the formula wherein X is an anion which provides charge neutrality, with from 1 mole equivalent to 3 5 mole equivalents a reducing agent having the formula MBH wherein M is selected from the group consisting of lithium, sodium, potassium, and mixtures thereof, at a pH of at least 1 1 to form a macrocyclic hgand, c) separating the aqueous and non-aqueous phases; and d) optionally isolating said macrocyclic hgand from said non-aqueous phase. A process for prepaπng 5,12-dιmethyl-l,5,8,12-tertaaza-bιcyclo[6.6.2]hexadecane having the formula: said process comprising the steps of: a) combining m a reaction vessel a one molar solution of base, said base selected from the group consisting of potassium carbonate, sodium carbonate, and mixtures thereof; and a solvent, said solvent selected from the group consisting of ethanol, n-propanol, isopropanol, and mixtures thereof; wherein the ratio of the volume of said base to said volume of solvent is 1.4; to form a two phase solution compπsing an aqueous phase and a solvent phase; b) adding to said two phase solution, at a temperature of from 50° C, a macrocyclic gand precursor having the formula: wherein X " is an anion which provides charge neutrality, together with 2 mole equivalents of NaBH 4 at a pH of at least 12 to form 4,1 1-dιmethyl-l , 4,8,11 - tetraaza-bιcyclo[6.6.2]hexadecane; c) separating from said two phase system said solvent phase; and d) isolating from said solvent phase 5,12-dιmethyl-l,5.8.12-tertaaza- bιcyclo[6.6.2]hexadecane.

Inventors: HILER GEORGE DOUGLAS II, PERKINS CHRISTOPHER MARK, HILER, GEORGE, DOUGLAS, II, PERKINS, CHRISTOPHER, MARK
Applicants: HILER GEORGE DOUGLAS II, PERKINS CHRISTOPHER MARK, PROCTER & GAMBLE, HILER, GEORGE, DOUGLAS, II, PERKINS, CHRISTOPHER, MARK, THE PROCTER & GAMBLE COMPANY
Application year: 1999
Main classification: C07D487
IPC codes: C07D487