WO2021001440A1

WO2021001440A1 - Antimicrobial salt for medical gloves

Info

Publication number: WO2021001440A1
Application number: PCT/EP2020/068557
Authority: WO
Inventors: Mark Wilkinson; Paul Wight
Original assignee: Chemical Intelligence Limited
Priority date: 2019-07-01
Filing date: 2020-07-01
Publication date: 2021-01-07
Also published as: CN114341139A; DE112020003192T5

Abstract

A process for the manufacture of phthalocyanine pyridinium salt, wherein the process comprises: (a) reacting a phthalocyanine pyridinium with a methylating agent, and (b) ion exchanging with an anionic counterion.

Description

ANTIMICROBIAL SALT FOR MEDICAL GLOVES

FIELD OF INVENTION

The present invention relates to a process for the manufacture of a phthalocyanine pyridinium salt, a phthalocyanine pyridinium salt obtainable by the process of the present invention, manufacture of an antimicrobial glove comprising the phthalocyanine pyridinium salt, and an antimicrobial glove obtainable by said process.

BACKGROUND OF THE INVENTION

Protective gloves are widely used in hospitals, pharmaceutical plants, food plants, kitchens or even public places. Gloves are generally made of a polymer resin. For example, a so- called vinyl glove is produced by using polyvinyl chloride (PVC) as a main component. Conventionally, the use of a protective glove isolates bacteria from a user's hand so as to reduce the risk of bacterial contamination. Since the bacteria attached to the surface of the glove are not killed, bacteria or other microbes may grow on the glove surface. Therefore, the glove might become a newly contaminating source.

Singlet oxygen generators are known to destroy microorganisms. Singlet oxygen has a greater energy than ground-state, triplet oxygen. The singlet and triplet states of oxygen are distinguished by the singlet state having two electrons of anti-parallel spins and the triplet state having an uncoupled pair of electrons with parallel spins. The singlet oxygen is also distinguished from triplet oxygen because it is a highly reactive species with a lifetime from a few microseconds to several hundred microseconds. During its lifetime singlet oxygen has the potential to react before being deactivated, and therefore has a wide number of applications, including antimicrobial applications such as in medical gloves.

Regardless of the manufacture method, commonly used singlet oxygen generators can still present issues of solubility, aggregation, singlet oxygen generating efficiency, overall unsatisfactory antimicrobial activity and stability. Depending on the antimicrobial agent, its process of manufacture may employ toxic reagents.

There is a need therefore to overcome such problems and optimise ease and safety of synthesis, product shelf life, effective and efficient antimicrobial activity as well as safety for the user. SUMMARY OF THE INVENTION

The present invention provides a process for the manufacture of phthalocyanine pyridinium salt, wherein the process comprises:

(a) reacting a phthalocyanine pyridinium with an alkylating agent, and

(b) ion exchanging with an anionic counterion.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the manufacture of poly-substituted phthalocyanine compounds which can be used to generate singlet oxygen. The phthalocyanine nucleus may be aluminum, titanium or zinc. If aluminium or titanium is used, the aluminum may be further substituted by alkyl, aryl, alkoxy, hydroxy, oxygen or halogen.

Aluminium, and zinc are chosen because they are more efficient in generating singlet oxygen than other metals such as copper or nickel, and they are reasonably small and so can be inserted into the phthalocyanine easily, with the reactions occurring under air, in good yield, as opposed to other metals such as using SiCU, and are easily available in bulk. The central metal atom also influences the position of the absorption maximum of the phthalocyanine, and zinc and aluminium are preferred in the compounds because their absorption is in the visible region of the spectrum especially between 600 - 700nm. The zinc compounds described herein are especially preferred.

For the phthalocyanines of the present invention each of the pendant organic radicals linked via oxygen to the phthalocyanine nucleus is independently selected from N-alkylated pyridinium or pyridinium, such that any one phthalocyanine nucleus may carry two or more different organic radicals. Examples of N-alkylated pyridines are 3 -hydroxy- 1-methylpyridin- 1 -ium, 3 -hydroxy- 1 -ethylpyridin- 1 -ium, 3 -hydroxy- 1 -propylpyridin- 1 -ium.

Further, the phthalocyanines used in the present invention preferably have substituents to the phthalocyanine nucleus in the alpha position, adjacent to the phthalocyanine nucleus (e.g. positions 1,5,12 and 13 in Formula 1). This alpha substitution decreases aggregation of the phthalocyanine. Aggregation is known to reduce singlet oxygen generation efficiency, and therefore this structure prevents aggregation and increases efficiency singlet oxygen generation and hence antimicrobial and other activity. To demonstrate this, phthalocyanine I (see Example 1 below) was compared to an analogue where the oxypyridinium residue was attached to the phthalocyanine core in the beta position (positions 3,6,11 and 14 in Formula 1). 25 mgs of each were dissolved in 1 L water, and the UV / vis absorption compared. It can be seen in the spectra below that the alpha substitution pattern results in much high population of the monomeric phthalocyanine (ca. 675 nm here) compared to the aggregated phthalocyanine (ca. 640 nm here) than is the case for the beta substitution, which favours the aggregate (ca. 635 nm here).

370 400 450 500 550 600 650 700 720 nm

This use of alpha substitution is therefore novel and inventive over the beta substitution pattern..

In addition, after extensive research the present inventors have realised the molecules described herein have other desirable properties. They are more thermally stable, and stable to radical degradation than commercially available analogues such as Tinolux BBS and Tinolux BMC.

The phthalocyanine according to the present invention has a structure with the following formula:

X-(b)

Formula 1

R=R'(a) or R"(b)

R' oxygen linked pyridyl

R" oxygen linked N-alklyated pyridinium wherein:

M is selected from aluminium, titanium or zinc, R” is linked via an oxygen atom to a pyridine group at least 1 of which bears a cationic charge, and the remaining peripheral carbon atoms are an unsubstituted organic radical, a + b = 4

b = 1 to 4

X = Cl , Br , G, methanesulphonate, ethanesulphonate, formate, acetate or other inorganic or organic counter-ion or mixture thereof;

and

wherein alkylation on the pyridine nitrogen is optionally branched C1-C8 alkyl,

The phthalocyanine may also have the formula:

X-(b)

Formula 4

R'(a) or R"(b)

R' 3 -oxygen linked pyridyl

R" 3 -oxygen linked N-alklyated pyridinium

Most preferred is tetrapyridyloxy zinc pthalocyanine with the following formula:

X (2-4)

Formula 5

wherein the mean average total number of alkylated pyridines is 2 to 4, preferably 3 to 4. The preferred counter-ion“X” is iodide due to the solubility and physical properties of this salt. For the phthalocyanines of the present invention, each of the pendant organic radicals linked via oxygen to the phthalocyanine nucleus is independently selected from N-alkylated pyridinium or pyridinium, such that any one phthalocyanine nucleus may carry two or more different organic radicals. Examples of N-alkylated pyridines are 3 -hydroxy- 1-methylpyridin- 1 -ium, 3 -hydroxy- 1 -ethylpyridin- 1 -ium, 3 -hydroxy- 1 -propylpyridin- 1 -ium. In the preferred group of such phthalocyanines, the total number of cationic substituents is 2 to 4, and more preferably 3 to 4. The compounds described herein may have a charge of at least +1, and up to +4, preferably +2 to + 4 and most preferably +3 to +4. Suitable counter-ions for the N-alkylated pyridines include, but are not limited to, iodide, chloride, bromide, methanesulphonate, toluenesulphonate, acetate and hexafluorophosphide. The antimicrobial agent used in the present invention may be activated by light and offers a sustained release of singlet oxygen from the glove. It is known that singlet oxygen is a strong antimicrobial agent to kill most bacteria. The advantage of singlet oxygen generating dyes is that they are catalytic and not exhausted over time, and the singlet oxygen they release is not persistent, due it its very short half-life of typically a few microseconds. This has major advantages in toxicity and potential for development of resistant organisms.

The phthalocyanines of Formula 1 can be prepared by reacting:

(1) a substituted 1,2-dicyanobenzene of Formula 2:

Y=F,Cl,BrI,N0₂

Formula 2 wherein Z is selected from chloro, bromo and iodo or nitro and is in the 3 position (alpha) to one of the CN groups, with

(2) a compound pyridine-OH whereby the group Z, is replaced by pyridine-0 groups to form a compound of Formula (3):

Formula 3 This can then be followed by reaction of one or more 1,2-dicyanobenzene compounds of Formula 3, or a combination of one or more compounds of Formula 3 and 1,2-dicyanobenzene, with an appropriate metal or metal salt optionally in an inert liquid at an elevated temperature to form a phthalocyanine of Formula 1.

Such reactions are fully described in GB 1489394, GB 2200650 and DE 2455675.

In the manufacturing process, the alkylation of the pyridine groups is done last. If the process is not done to completion, some of the pyridyl substituents can remain unalkylated and uncharged. The process can be modified by temperature and stoichiometry to give higher or lower degrees of final alkylation.

However, such alkylation steps may employ toxic reagents. Dimethyl sulfate is a human carcinogen and is on the ECHA (European Chemicals Agency) list of“Substances of Very High Concern” in respect to its toxicity. Additionally dimethyl sulfate would not return the required halide, such as iodide, counter-ion. Methyl iodide would give the correct counter ion, but has toxicity concerns as an IARC (International Agency for Research on Cancer, part of the WHO) class 2 carcinogen. In addition methyl iodide is highly volatile, requiring expensive engineering controls for its industrial handling and containment.

The present invention therefore also provides alternative methods of manufacture which avoid the use of such toxic reagents where the alkylation is carried out with an alkylating agent such as sulfonates or carbonates, preferably methylating agents, most preferably methyl p- toluenesulfonate. This reagent has no reported carcinogenicity risks, and having a low vapour pressure may be charged industrially as an easily handled liquid. The phthalocyanine pyridinium tosylate first formed gives an unacceptable physical form as a sticky gum. In the case of phthalocyanine pyridinium iodide for example, the present invention realises that counter ion exchange may be achieved by quenching the reaction with a solution of an iodide salt or iodine.

The utilisation of a halide, such as iodide, solution is an advantage of the present invention. For such counter ion exchanges the use of an ion exchange resin would be most typical. However, this has the disadvantage of the requirement to form a dilute solution of the poorly soluble product, and the use of the expensive resin which is not readily commercially available in the iodide form. The requirement to use a dilute solution with the resin would therefore be very inefficient in commercial manufacturing.

In addition, in the process of the present invention where intermediate pyridyl phthalocyanine may be advanced into the alkylation reaction with sulfonate or carbonate, preferably methyl p- toluenesulfonate, without a separate drying step. Pyridyl phthalocyanine is formed from the cyclisation of pyridyl phthalonitrile in a conventional fashion well understood by those skilled in the art. After cyclisation, pyridyl phthalocyanine is precipitated with an antisolvent. Such an antisolvent may be water, a ketone, ester or aromatic solvent, or preferably an alcohol solvent such as methanol, ethanol, or a propanol isomer. Drying of the“wet cake” of pyridyl phthalocyanine can be lengthy, significantly impacting manufacturing cycle times. The present invention has further realised that the“wet cake” can be charged directly to the alkylation reaction medium without drying. The present invention has also found that the alkylation reaction can proceed successfully especially if that excess antisolvent is removed by distillation first. The methylating agent such as sulfonate or carbonate, preferably methyl p- toluenesulfonate, may then be charged and the alkylation reaction proceeds to give a phthalocyanine pyridinium compound, such as an iodide, without impact. This invention reduces manufacturing cycle time and significantly reduces cost.

The antimicrobial agent manufactured by the process of the present invention can be used to coat medical gloves which can provide effective and continuous antimicrobial protection. In addition, the physical properties of the glove are not significantly reduced.

While the invention has been described in terms of what is presently considered to be the most practical and preferred embodiments, it is to be understood that the invention needs not be limited to the disclosed embodiments. On the contrary, it is intended to cover various modifications and similar arrangements included within scope of the appended claims which are to be accorded with the broadest interpretation so as to encompass all such modifications and similar structures.

The present invention will now be illustrated, but in no way limited, by reference to the following examples. EXAMPLES

Example 1 - Preparation of phthalocyanine pyridinium iodide I from pyridyl phthalocyanine II using methyl p-toluenesulfonate and lithium iodide

To NMP (360 g) is added pyridyl zinc phthalocyanine II (140 g, 1 eq, 0.147 mol) and methyl p-tolueneslufonate (120 g, 0.644 mol, 4.4 eq). The reaction is stirred and heated to 107 to 111 °C (internal vessel temperature) for 20 hours, then cooled to 50 to 60 °C (internal vessel temperature). Meanwhile, to a second vessel is added iso-propanol (14 vols, 2000 mL) and lithium iodide trihydrate (125 g = 0.668 mol = 4.54 eq). The reaction mixture is transferred to the second vessel to precipitate the crude product, which is isolated by filtration and washed with further iso-propanol. The wet cake of the crude product is recharged to a vessel with iso propanol (8 vols, 1100 mL) and lithium iodide trihydrate (35 g, 0.187 mol, 1.27 eq). The slurry is heated to 80 to 83 °C (internal vessel temperature), then cooled to room temperature. The final product is isolated by filtration and washed with further iso-propanol, before being dried in an oven.

Example 2 - Preparation of phthalocyanine pyridinium iodide I from pyridyl phthalonitrile III without drying of the intermediate

To 2-ethylhexanol (242 g) is added 3-(oxypyridyl) phthalonitrile (145 g, 0.656 moles, 1 eq), and the vessel purged with inert gas. Zinc chloride is charged (21 g, 0.154 moles, 94% of theoretical charge) followed by DBU (51 g, 0.335 moles, 0.51 eq). The reaction is heated to ca. 107 °C (internal vessel temperature) for at least 16 hours. The reaction is cooled and isopropyl alcohol (1600 mL) charged to the reaction mixture. After cooling to room temperature, the pyridyl zinc phthalocyanine II is isolated by filtration and washed with further iso-propanol. The crude, wet cake pyridyl zinc phthalocyanine II is charged to NMP (360 g) and heated to 80 °C. The solvent carried in with the wet cake was removed by distillation under reduced pressure. Next methyl p-tolueneslufonate (120 g = 0.644 mol = 4.4 eq) is charged. The reaction is stirred and heated to 107 to 111 °C (internal vessel temperature) for 20 hours, then cooled to 50 to 60 °C (internal vessel temperature). Meanwhile, to a second vessel is charged iso-propanol (14 vols, 2000 mL) and lithium iodide trihydrate (125 g = 0.668 mol = 4.54 eq). The reaction mixture is transferred to the second vessel to precipitate the crude product which is isolated by filtration and washed with further iso-propanol. The wet cake of the crude product is recharged to a vessel with iso-propanol (8 vols, 1100 mL) and lithium iodide trihydrate (35 g, 0.187 mol, 1.27 eq). The slurry is heated to 80 to 83 °C (internal vessel temperature), then cooled to room temperature. The final product is isolated by filtration and washed with further iso-propanol, before being dried in an oven.

Example 3 -preparation of phthalocyanine pyridinium, with the p-toluenesulfonate counter ion

To NMP (18.10 g) is added pyridyl zinc phthalocyanine II (7.25 g, 1 eq, 0.0076 mol) and methyl p-toluenesulfonate (6.22 g, 0.0334 mol, 4.4 eq). The reaction is stirred and heated to 107 to 111 °C (internal vessel temperature) for 20 h, then cooled to 50 to 60 °C (internal vessel temperature). Meanwhile, to a second vessel is charged iso-propanol (14 vols, 102 mL). The reaction mixture is transferred to the second vessel to precipitate the crude product. The product precipitates as a sticky mass. When the standard isolation by filtration is attempted, not all of the sticky mass pours out of the reaction flask, remaining adhered to the internal surfaces. Thus the p-toluenesulfonate (“tosylate”) counter-ion does not give the product with appropriate physical properties for manufacturing.

Claims

1. A process for the manufacture of a phthalocyanine pyridinium salt, wherein the process comprises:

(a) reacting a phthalocyanine pyridinium with an alkylating agent in which the displaced “leaving group” on the alkylating agent is not an iodide, and

(b) subsequently ion exchanging with an anionic halide counterion.

2. A process for the manufacture of a phthalocyanine pyridinium salt, wherein the process comprises:

(a) reacting a phthalocyanine pyridinium with methyl p-toluenesulfonate, and

(b) subsequently ion exchanging with an anionic halide counterion to give the final product as an iodide salt.

3. The process according to claim 1 or 2, wherein the alkylating agent is a methylating agent, preferably a sulfonate or a carbonate, most preferably methyl p-toluenesulfonate.

4. The process according to any preceding claim, wherein the final anionic counterion is an iodide.

5. The process according to any preceding claim, wherein ion exchange is without an ion exchange resin.

6. The process according to any preceding claim, wherein an intermediate pyridyl phthalocyanine is isolated from an anti-solvent by filtration.

7. The process according to claim 6, wherein the intermediate pyridyl phthalocyanine isolate is used in the alkylation as a wet cake without a separate drying step.

8. The process according to claim 7 wherein the wet cake has an anti-solvent content of 0 -300 % wt/wt, preferably 0 - 100 % wt/wt, most preferably between 20 - 60 % wt/wt.

9. The process according to any of claims 6 to 8, wherein the anti-solvent is selected from an organic solvent or water.

10. The process according to any of claims 6 to 9, wherein the anti-solvent is a ketone, ester or alcohol, preferably wherein an isomer of propanol.

11. The process according to any of claims 6 to 10, further comprising a solvent for alkylation, and wherein the anti-solvent is removed by distillation.

12. The process according to claim 11, wherein the solvent is an organic solvent or water.

13. The process according to claim 11 or 12, wherein the solvent is a polar solvent, preferably an ester, amide, alcohol or aromatic, more preferably a dipolar aprotic solvent - for example (but not limited to) DMF, NMP or DMSO.

14. The salt prepared by a process according to any preceding claim, having any of the following formula, and wherein the degree of N alkylation is either 3 or 4, including mixtures of the two: