JP2002531457A - Method for producing cross-linked tetraaza macrocycles - Google Patents

Abstract

(57) The present invention relates to contacting a diquaternary cis-tetracycle precursor with hydrogen in an aqueous solution having a pH of at least about 10 at a temperature of about 40 to about 100 ° C in the presence of a palladium catalyst. To form a bridged tetraaza macrocyclic ligand having formula (I) wherein each R is independently C ₁ -C ₈ straight or branched alkyl, — (CH ₂ ) _x CO ₂ M and mixtures thereof; Wherein both R units are not methyl; M is hydrogen or a salt-forming cation; x is 1-6; each index n is independently 0-3). About.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION

The present invention relates to an improved process for making bridged tetraaza macrocycles, which macrocycles are suitable as ligands useful in making transition metal complexes. The present invention provides a process that is well suited for use in the industrial and other commercial manufacture of the crosslinked macrocycles described herein.

[0002]

BACKGROUND OF THE INVENTION

Tetraaza macrocycles, such as cyclam, have been prepared in a number of ways, however, particularly in the field of transition metal catalysts, especially bleach catalysts, crosslinked tetraaza macrocycles have recently found widespread use as ligands. Lack of information on the preparation of macrocycles, especially bis N-substituted tetraaza macrocycles, especially 5,12-dialkyl-1,5,8,12-tetraaza-bicyclo [6.6.2] hexadecanes .

[0003] WO 98/39335 A1 "Improved Process for the Production of Cross-Linked Macropolycycles" produces cross-bridged macropolycyclic ligands which are easy to obtain the high yields required for industrial scale-up. For rational operation. However, the reductive ring cleavage step that results in bicyclo bridged ring formation utilizes a borohydride reducing agent. This type of reducing agent may place restrictions on the trader. For example, the need to decompose the amine / borohydride complex in post-treatment, and proper recovery and disposal of boron waste increases the cost of the process. Moreover, if an excess of borohydride is required, this requires the use of acids and neutralization with the generation of large amounts of hydrogen gas.

[0004] Therefore, a need exists for a highly quantitative, preferably catalytic, process for producing bridged macropolycyclic ligands applicable to continuous flow processes or batch production.

[0005]

[Summary of the Invention]

The present invention fulfills that need in that it has been surprisingly found that selected bis N-substituted tetraaza macrocycles can be converted to bridged macropolycyclic ligands by catalytic hydrogenation.

[0006] A first aspect of the present invention relates to a process for producing a tetraaza macrocyclic ligand having the formula:

Embedded image (Wherein each R is independently C ₁ -C ₈ straight or branched alkyl, — (CH ₂ ) _x CO ₂ M and mixtures thereof, preferably both R units are not methyl M is hydrogen or a salt-forming cation; x is 1-6; each index n is independently 0-3); the process is: a) a tetraaza macrocyclic ligand precursor having the formula: :

Embedded image (Wherein X ⁻ is an anion providing charge neutrality) at a pH of at least 8 with at least about 1 ppm of a transition metal hydrogenation catalyst to form a tetraaza macrocyclic ligand; and b) optionally, isolating the above ligand.

[0007] These and other objects, features and advantages will become apparent to those skilled in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight unless otherwise indicated. All temperatures are in degrees Celsius (° C) unless otherwise noted. All references cited are, in relevant places, incorporated herein by reference.

[0008]

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the catalytic hydrogenation of tetraaza macrocycles having the formula:

Embedded image In the above, the covalent bond between the N-substituted quaternary ring nitrogen and the bridged carbon is broken, and the bridged macrocyclic ligand having the formula:

Embedded image Is obtained.

In the above formula, each R is independently C₁-C₈Linear or branched alkyl,-(CH₂) _x CO₂M and mixtures thereof, preferably both R units are methyl
More preferably one R unit is methyl and the other R unit is ethyl
From the group consisting of, propyl, butyl, pentyl, hexyl and mixtures thereof
Selected; of the methyl / alkyl R unit mixture, preferably one R is methyl
And the other R is ethyl or propyl. The most preferred ligands are
Is a unit in which the R unit is methyl and the other R unit is ethyl. Preferred Riga
Is a macrocycle ring in which each R unit is ethyl. M is hydrogen or salt form
Non-limiting examples are sodium, potassium, calcium, and ammonium.
Nium. R is-(CH₂)_xCO₂When M, the index x is 1 to
It has a value of about 6, and preferably x is 1. Index n is a macrocycle ring
Determine the size of The index n has a value of 0 to about 3. Preferred Mac
In a rocycle ring, as shown in the following general formula, a pair of opposing n indexes is 1 and
, The n index of the other set is 0:

Embedded image In the above formula, R has the same meaning as described above.

A preferred ligand according to the present invention has an R unit pair selected from the group consisting of methyl and ethyl, diethyl, methyl and propyl, ethyl and propyl, methyl and butyl, ethyl and butyl, and mixtures thereof. I have.

The starting material for the process of the present invention is a tetraaza macrocyclic ligand precursor or bisquaternary cis tetracycles having the formula:

Embedded image In the above formula, R and n are as defined above. X is an anion that serves to provide electrical neutrality to the bis-quaternary cis-tetracycle. One skilled in the art will recognize that the term "electroneutral" refers to "sufficient anionic species that meet molecular charge balance requirements",
It is understood that mixtures of a few charged species may also be used here. X preferably has a unit negative charge, for example, halogen, tosylate, methyl sulfate, ethyl sulfate. However, X may be a divalent or more negatively charged, for example sulfate, in which case the trader only needs half the amount required when using unit negatively charged anions. Preferred X is chloride, bromide, iodide, sulfate, ethyl sulfate, methyl sulfate, tosylate, mesylate, triflate and mixtures thereof.

Step (a) Hydrogenation-Reduction Cleavage Step (a) consists of reductive cleavage by catalytic hydrogenation, as shown in the following scheme:

Embedded image In the above, the cis-tetracycle bis quaternary salt is converted to a bridged tetraaza macrocycle.

Step (a) is performed in the presence of a catalyst, preferably a supported catalyst. Non-limiting examples of catalysts include platinum on carbon, palladium on carbon (Pd / C), palladium hydroxide on carbon (Pd (OH) ₂ / C), rhodium on carbon (Rh / C), Raney nickel and mixtures thereof. There is. The preferred catalyst is Pd (OH) ₂ / C.
The supported catalyst contains from about 1 to about 50% by weight of the transition metal, however, a pure metal, ie, palladium, may be used without the need for a “support”, ie, carbon. The "catalytic amount" of the catalyst is sufficient to effect the reduction in step (a). For the purposes of the present invention,
The term catalytic amount is defined as "greater than about 1 ppm at 5 wt% transition metal catalyst". However, traders may use more catalyst than catalyst due to the toxicity of the reaction products to the catalyst surface. The amount of catalyst used in step (a) of the present invention is
Preferably, about 10 ppm or more of a catalyst containing about 5 to 50% by weight of a transition metal,
More preferably at least about 100 ppm, even more preferably at least about 0.1% by weight of the transition metal supported catalyst. A reaction solution containing 0.1% by weight of a transition metal-supported catalyst (for example, the catalyst contains 10% by weight of palladium on carbon) is 0.0% by weight.
1% transition metal or 100 ppm transition metal is present.

The amount of hydrogen gas present in step (a) of the present invention only needs to sufficiently saturate the catalyst surface, preferably the hydrogen pressure is 200 psi, more preferably 400 ps
i, most preferably from 800 psi to about 2000 psi, more preferably 10 psi
Up to 00 psi.

[0015] Step (a) of the process comprises from 20 ° C, preferably about 40 ° C, more preferably from about 60 ° C to about 100 ° C, preferably about 90 ° C, more preferably about 80 ° C,
Most preferably at temperatures up to about 65 ° C.

The pH at which step (a) is to be carried out is at least 8, preferably at least 10
, More preferably at least about 11. Preferably, the base 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. As a non-limiting example, a sufficient amount of 1 to adjust the pH to the required level
If an M (mole) aqueous base is used, that is sufficient. A convenient and preferred base is potassium carbonate.

As a suitable alternative, step (a) may be performed in the presence of a solvent other than water or in the absence of water. A suitable solvent and water mixture is also a suitable means for performing the hydrogenation process of the present invention. In the absence of water, sufficient base must be present to stabilize the reactants and product transition state during hydrogenation. Non-limiting examples of solvents include methanol, ethanol, n-propanol, isopropanol, N, N-dimethylformamide, n-butanol, isobutanol,
There are tert-butanol and mixtures thereof; preferred solvents are ethanol, n
-Propanol, N, N-dimethylformamide and mixtures thereof. When a solvent is present and the base is in the form of an aqueous solution, the ratio of the volume of the aqueous base to the solvent is from about 1:10 to about 1: 1, preferably the ratio of the volume of the aqueous base to the solvent is 1: 4. It is. Preferably, but not necessarily, the aqueous base and solvent form a two-phase system.

In the process of the present invention, an optional but preferred step (b
). Typically, this step involves filtering the reaction to remove the catalyst. In addition, this step may involve a neutralization step, however, the product can be isolated or removed from the reaction matrix as desired by the supplier.

When filtration of the catalyst is the desired step, the reaction containing the bridging ligand is filtered to remove the catalyst and form a crude filtrate. The crude filtrate may be neutralized, or the tetraaza macrocyclic ligand may be isolated, preferably by direct extraction or crystallization from an aqueous solution.

Steps (a), (b) and any other steps, such as a crystallization step, a solvent drying step, a purge step, may be adapted to a batch or continuous process, such as a continuous flow process. As noted above, the process of the present invention may include any other steps deemed necessary and / or desirable by those skilled in the art. These optional steps include, but are not limited to, pre-saturation of the catalyst with hydrogen, vacuuming the system, and recovering the catalyst and solvent.

[0021] Preferably, the ligand formed by the process of the present invention is converted to a manganese-containing transition metal catalyst in a later, but optional, process step. The bleach catalyst consists of a central manganese atom and a bridging ligand formed by the process of the present invention. The final bleach catalyst may contain one or more other compatible ligands, especially chlorine atoms. Preferred catalysts are suitable as bleaches. The following is a non-limiting example of the process of the present invention.

5,12-diethyl-1,5,8,12-tetraaza-bicyclo [6.6.2]
Xadecane production wall thickness glass autoclave sleeve with bis quaternary cis tetracycle having the formula:

Embedded image (3.0 g, 6.8 mmol) and a 1 M aqueous solution of K ₂ CO ₃ (30 ml) are added. The solution was stirred to dissolve the substrate and 20% Pd (OH) ₂ / carbon (0.7 g
, 1.0 mmol). The glass sleeve is placed in a rocking autoclave and hydrogenated at 65 ° C. with 1900 psig hydrogen for 4 hours. The reaction is cooled, the solution is filtered through glass fiber filter paper to remove the catalyst, and the filtrate is concentrated under vacuum to a white solid. The white solid is suspended in refluxing ethanol and undissolved inorganic salts are filtered off. After concentrating the filtrate under vacuum, the resulting oily residue was washed with aqueous 4M KOH
(4 ml), and extracted three times with 25 ml each of toluene. The toluene extracts were combined and concentrated in vacuo to afford a 81% yield of 5,12-diethyl-1,5,8,12-tetraaza-bicyclo [6.6.2] hexadecane as a clear oil (1. 5
6 g) are obtained.

The following are examples of optional but preferred steps of the process of the present invention that convert to a manganese transition metal bleach catalyst. Dichloro 5,12-diethyl-1,5,8,12-tetraaza-bicyclo [6.6
. 2] Preparation of manganese hexadecane In a 100 ml reaction flask, anhydrous acetonitrile (50 ml) and 5,12
-Diethyl-1,5,8,12-tetraaza-bicyclo [6.6.2] hexadecane (1.4 g, 5 mmol). The resulting suspension is degassed under vacuum and then refilled with argon. This process is repeated six times. Manganese (II) chloride (0.5
90 g, 4.7 mmol) are added and the reaction is refluxed for 3 hours. The solution obtained is filtered through a glass fiber filter paper. The obtained filtrate is concentrated at 45 ° C. under reduced pressure to obtain a solid. The solid is suspended in toluene (50 ml) and the resulting dark supernatant is discarded. Repeat the toluene treatment 5 times. The solid obtained is dried under vacuum to give dichloro 5,12-diethyl-1,5,8,12-tetraaza-bicyclo [6.6.2]
Hexadecanemanganese (1.48 g, 73% yield) is obtained.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (71) Application Person ONE PROCTER & GANBLE PLAZA, CINCINNATI, OHIO, UNITED STATES OF AMERICA (72) Inventor Christopher, Mark, Perkins Cincinnati, Ohio, United States of America, Fernbank, Avenue, 7230 F10A FF FF FF GG 001 HH01 4H039 CA42 CB90

Claims (12)

[Claims] 1. A tetraaza macrocyclic ligand having the formula: (Wherein each R is independently C ₁ -C ₈ straight or branched alkyl, — (CH ₂ ) _x CO ₂ M and mixtures thereof, provided that the R units are not both methyl M is hydrogen or a salt-forming cation; x is from 1 to 6; each index n is independently from 0 to 3), wherein: Cyclic ligand precursor: (Wherein X ⁻ is an anion providing charge neutrality) with at least 1 ppm of a transition metal hydrogenation catalyst at a pH of at least 8 to form a tetraaza macrocyclic ligand; and b. Optionally) isolating said ligand; said method comprising the steps of: 2. A transition metal hydrogenation catalyst comprising platinum, palladium, palladium hydroxide, rhodium,
The method of claim 1, wherein the method is selected from the group consisting of Raney nickel and mixtures thereof. 3. The step (a) is carried out at a temperature of from 40 to 100 ° C., at a pH of at least 10 and in the presence of a solvent, the solvent comprising water, N, N-dimethylformamide, methanol, ethanol, isopropanol, n The method according to claim 1 or 2, wherein the method is selected from the group consisting of -butanol, isobutanol, tert-butanol and mixtures thereof. 4. The precursor has the following formula: The method according to any one of claims 1 to 3, wherein R and X have the same meanings as described above. 5. The method according to claim 1, wherein each R is ethyl. 6. The method according to claim 1, wherein one R is methyl and one R is ethyl. 7. A tetraaza macrocyclic ligand having the formula: Wherein one R unit is methyl and the other R unit is selected from the group consisting of ethyl, propyl, butyl, pentyl, hexyl and mixtures thereof, comprising: a) Tetraaza macrocyclic ligand precursor having the formula: (Wherein X ⁻ is an anion providing charge neutrality) at a pH of at least 10.
Hydrogenating with 1 ppm or more of a palladium hydrogenation catalyst to form a tetraaza macrocyclic ligand; and b) optionally isolating the ligand. 8. A tetraaza macrocyclic ligand having the formula: embedded image (Wherein each R is independently C ₁ -C ₈ straight or branched alkyl, — (CH ₂ ) _x CO ₂ M and mixtures thereof, provided that the R units are not both methyl M is hydrogen or a salt-forming cation; x is from 1 to 6; each index n is independently from 0 to 3), wherein: Cyclic ligand precursor: (Wherein X ⁻ is an anion providing charge neutrality) at a temperature of 0 to 100 ° C. in the presence of a solvent (the solvent is water, methanol, ethanol, N, N-dimethylformamide, n-butanol). , Isobutanol, tert-butanol and mixtures thereof), at least at a pH of 8 and at least 1 ppm of a palladium hydrogenation catalyst, wherein the palladium catalyst is supported palladium (0), palladium hydroxide and their mixtures. Selected from the group consisting of mixtures of
Forming a tetraaza macrocyclic ligand; b) filtering off the catalyst to form a crude filtrate; and c) optionally isolating said ligand by crystallization, extraction, distillation or other suitable means. The above-described production method comprising the steps of: 9. The method of claim 8, further comprising treating the ligand with manganese to form a bridged tetraaza macrocyclic transition metal catalyst. 10. A tetraaza macrocyclic ligand having the formula: embedded image (In the above formula, R unit is methyl and ethyl, diethyl, methyl and propyl,
A pair of R units selected from the group consisting of ethyl and propyl, methyl and butyl, ethyl and butyl, and mixtures thereof; M is hydrogen or a salt-forming cation; x is 1-6; Is independently 0 to 3)
Comprising: a) a tetraaza macrocyclic ligand precursor having the formula: (Wherein X ⁻ is an anion providing charge neutrality) with at least 1 ppm of a transition metal hydrogenation catalyst at a pH of at least 8 to form a tetraaza macrocyclic ligand; and b. Optionally) isolating said ligand; said method comprising the steps of: 11. a) A cross-linked ligand having the formula: Wherein each R is independently C ₁ -C ₈ straight or branched alkyl, — (CH ₂ ) _x CO ₂ M and mixtures thereof, provided that both R units are methyl or butyl M is hydrogen or a salt-forming cation; x is 1-6; each index n is independently 0-3); b) manganese; and c) optionally one or more compatibility A transition metal catalyst comprising: a ligand; 12. It has the following formula: A compound according to claim 11.