EP4258868A1 - Lactam composition and use - Google Patents

Lactam composition and use

Info

Publication number
EP4258868A1
EP4258868A1 EP21802747.2A EP21802747A EP4258868A1 EP 4258868 A1 EP4258868 A1 EP 4258868A1 EP 21802747 A EP21802747 A EP 21802747A EP 4258868 A1 EP4258868 A1 EP 4258868A1
Authority
EP
European Patent Office
Prior art keywords
lactam
composition
lactate
solvent
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21802747.2A
Other languages
German (de)
French (fr)
Inventor
Nicholas Joseph BROWNBILL
Joanne Clare O'keeffe
Neil James Parry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Unilever Global IP Ltd
Unilever IP Holdings BV
Original Assignee
Unilever Global IP Ltd
Unilever IP Holdings BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Unilever Global IP Ltd, Unilever IP Holdings BV filed Critical Unilever Global IP Ltd
Publication of EP4258868A1 publication Critical patent/EP4258868A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof

Definitions

  • the invention relates to an improvement in the field of hygiene, in particular to a composition comprising a lactam which displays improved solubility and stability of the lactam.
  • Hygiene in particular inhibition of bacterial species, is important to consumers.
  • Lactams are known as inhibitors of bacterial species. They may be applied to surfaces to inhibit bacterial species.
  • the invention relates in a first aspect to a composition
  • a composition comprising:-
  • composition has a pH of from 4 to 6.50, preferably pH 4 to 6.25, more preferably 4.50 to 6.00; wherein the lactam is selected from:
  • the pH is from 4 to 5.40, more preferably from 4.50 to 5.40.
  • lactam is selected from:
  • lactam is:
  • the lactam is delivered from an aqueous based composition, preferably comprising from 0.1 to 98 wt.%, preferably from 0.5 to 80 wt.%, more preferably from 1 to 75 wt.% water.
  • the solvent is selected from the group: alcohol; levulinate derivatives; lactate derivatives; and solvents with a dielectric constant of 15 of higher, preferably the solvent is selected from the group: alcohol, levulinate derivatives; and lactate derivatives; more preferably the solvent is selected from the group: levulinate derivatives and lactate derivatives.
  • solvents are: of alcohols, preferably a C1-C4 alcohol, more preferably ethanol; of lactate derivatives, preferably ethyl lactate and/or butyl lactate; of levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate, and/or ethyl levulinate glycerol ketal (LGK); and of solvents with a dielectric constant of 15 of higher, preferably dimethyl sulfoxide (DMSO).
  • alcohols preferably a C1-C4 alcohol, more preferably ethanol
  • lactate derivatives preferably ethyl lactate and/or butyl lactate
  • levulinate derivatives preferably 2-methyltetrahydrofuran, ethyl levulinate, and/or ethyl levulinate glycerol ketal (LGK)
  • LGK ethyl levulinate glycerol ketal
  • the solvent is selected from the group: ethanol; ethyl lactate, butyl lactate; 2- methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
  • the solvent is selected from the group: levulinate derivatives; and lactate derivatives.
  • the solvent is selected from the group: ethyl lactate, butyl lactate; 2- methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
  • the solvent is present at a level of from 0.5 to 95 wt.%, preferably from 0.5 to 90 wt.%, more preferably from 0.5 to 80 wt.%.
  • the solvent may be present at a lowest level of from 0.5 wt.%, 0.75 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, 2.5 wt.% or even 5 wt.%.
  • the solvent may be present at a highest level of from 95 wt.%, 90 wt.%, 85 wt.%, 80 wt.%, 70 wt.%, 60 wt.%, 50 wt.%, 40 wt.%, 30 wt.%, 25 wt.%, 20 wt.% or even 10 wt.%. Any higher level of solvent is meant to be combinable with any lower level of solvent.
  • the composition comprises one or more surfactants.
  • the surfactant may be present at a level of from 0.25 to 25 wt.%, preferably from 0.25 to 20 wt.%, more preferably from 0.25 to 15 wt.%, even more preferably from 0.25 to 10 wt.%, or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.
  • the surfactant may be present at a level of from 0.25 to 25 wt.%, preferably from 0.25 to 20 wt.%, more preferably from 0.25 to 15 wt.%, even more preferably from 0.25 to 10 wt.%, or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.
  • the surfactant is preferably selected from anionic, nonionic, cationic and/or amphoteric surfactants.
  • Preferred surfactants are nonionic surfactants.
  • the composition preferably comprises a buffer.
  • the invention relates in a second aspect to a method of treatment of a surface, to improve resistance of said surface to bacterial fouling, by treatment with a composition according to the first aspect of the invention.
  • the surface to be treated is selected from plastic, metal, wood, polymer, paper, textile, and/or wipes.
  • the lactam is selected from:
  • the invention further relates in a third aspect to the use in a lactam composition, of a combination of a solvent and application of pH at from 4 to 6.5, preferably 4 to 6.25, more preferably 4.50 to 6.00 to said composition, to improve the solubility and stability of said lactam in the composition.
  • the lactam is selected from:
  • Figure 1 is a photograph showing the solubility of the lactam 488 at pH 5, pH 7 and pH 8
  • Figure 2 demonstrates the pH effect on the solubility and stability of the lactam 488. Lactam initial solubility (Left hand axis and circular data points) and stability (right hand axis and square data points) vs buffer pH, with lactam delivered in ethanol, to a total of 2% solvent and 100 ppm lactam in solution
  • a lactam is a cyclic amide.
  • the lactam is a lactam selected from:
  • lactam is selected from: Most preferably the lactam is:
  • the lactam is cationic in nature
  • the cation can be used or with a suitable counterion (e.g. iodide).
  • the lactam is present at a level of from 0.0001 to 2.5 wt.%, preferably from 0.0001 to 1 wt.%.
  • the lactam may be suitably present at levels of 0.001 to 1 wt.%, or even 0.01 to 1 wt.%, or even 0.01 to 0.5 wt.%.
  • the lactam is delivered from an aqueous based composition, preferably comprising from 0.1 to 98 wt.%, preferably from 0.5 to 80 wt.%, more preferably from 1 to 75 wt.% water.
  • the composition may comprise any amount of water ranging from lower amounts of 0.1 , 0.5, 1, 1.5, 2 or even 5 wt.% water up to 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or even 99 wt.% water.
  • the composition comprises a solvent.
  • Preferred solvents are selected from the group: alcohol; levulinate derivatives; lactate derivatives; and, solvents with a dielectric constant of 15 of higher.
  • Preferred examples of solvents are: of alcohols, preferably a C1-C4 alcohol, more preferably ethanol; of lactate derivatives, preferably ethyl lactate and/or butyl lactate; of levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate, and/or ethyl levulinate glycerol ketal (LGK); and of solvents with a dielectric constant of 15 of higher, preferably dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the solvent is selected from the group: ethanol; ethyl lactate, butyl lactate; 2- methyltetrahydrofuran (2Me-THF), ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
  • the solvent is selected from the group: levulinate derivatives; and lactate derivatives.
  • the solvent is selected from the group: ethyl lactate, butyl lactate; 2- methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
  • 2Me-THF, ethyl levulinate and LGK can be classed as levulinic acid derivatives (or levulinate derivatives).
  • Levulinic acid may be derived from lignocellulosic biomass (i.e. corn husks, sugar cane waste etc), and can be converted in to 2Me-THF in a cyclisation reaction, ethyl levulinate in one step esterification, and LGK in 2 steps (esterification and ketal synthesis).
  • Ethyl lactate and butyl lactate are lactic acid (lactate) derivatives. Lactic acid is a byproduct of fermentation which is then reacted with ethanol or butanol to generate ethyl and butyl lactate.
  • the solvent is present at a level of from 0.5 to 95 wt.%, preferably from 0.5 to 90 wt.%, more preferably from 0.5 to 80 wt.%.
  • the solvent may be present at a lowest level of from 0.5 wt.%, 0.75 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, 2.5 wt.% or even 5 wt.%.
  • the solvent may be present at a highest level of from 95 wt.%, 90 wt.%, 85 wt.%, 80 wt.%, 70 wt.%, 60 wt.%, 50 wt.%, 40 wt.%, 30 wt.%, 25 wt.%, 20 wt.% or even 10 wt.%. Any higher level of solvent is meant to be combinable with any lower level of solvent.
  • the solvent may be present at a level of from 1 to 80 wt.%, preferably from 1 to 50 wt.%, more preferably from 1 to 40 wt.%.
  • the solvent level may also be from 1 to 30 wt.%, 1 to 20 wt.%, or even 1 to 15 wt.% or 1 to 10 wt.%.
  • the composition comprises one or more surfactants.
  • the surfactant may be present at a level of from 0.25 to 25 wt.%, preferably from 0.25 to 20 wt.%, more preferably from 0.25 to 15 wt.%, even more preferably from 0.25 to 10 wt.%, or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.
  • the surfactant is preferably selected from anionic, nonionic, cationic and/or amphoteric surfactants.
  • Preferred surfactants are nonionic surfactants.
  • the composition may preferably comprise a buffer to assist in maintaining any resulting composition within a specified pH range.
  • Buffering systems may be any usual buffering system known in the art. These may for example include citrate, acetate, phosphate, and or carbonate buffers, or mixtures thereof.
  • composition may comprise further ingredients such as surfactants, chelating agents, thickeners, pH modifiers, and perfumes.
  • 1-(4-Chlorophenyl)propan-2-one (40.00 g, 34.75 mL, 237.2 mmol), glyoxylic acid monohydrate (32.75 g, 355.8 mmol) and phosphoric acid (69.74 g, 711.7 mmol) were combined at room temperature before heating to 85 °C overnight. After cooling to room temperature, the mixture was poured into a mixture of water (500 mL) and ethyl acetate (500 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (500 mL).
  • aqueous layer was extracted with dichloromethane (100 mL), and the combined organic layers washed with a 1 :1 mixture of water and saturated aqueous sodium hydrogen carbonate solution (100 mL), dried (MgSC and filtered. Silica was added to the filtrate and the mixture stirred for 10 minutes before filtering through a plug of silica, washing through with dichloromethane followed by a 3:1 mixture of dichloromethane:diethyl ether. Fractions containing the desired product were combined and concentrated under reduced pressure.
  • lactam used was lactam 488.
  • This example shows the effect of the pH on the solubility of the lactam in an aqueous based composition with a solvent included.
  • a targeted 10,000 ppm stock of lactam 488 in EtOH was prepared and left on the bottle rollers for 24 hrs, before filtration through a syringe filter to yield a saturated solution (likely around 8000 ppm in EtOH).
  • This stock solution was mixed in a 1 :2 ratio with 0.1 M acetate buffer at pH 5.2, or with 0.1M phosphate buffer at pH 7 or 8, agitated in vial and observed visually for any precipitate formed, indicating insolubility.
  • Figure 1 glass picture
  • the lactam was mostly solubilised to an acceptable level at 5, while at pH 7 and 8, the solubility was greatly reduced.
  • Example 3 This example demonstrates the lack of stability of the lactam composition at pH below pH 4 and above pH 6.5.
  • Lactam 488 was dissolved to maximum concentration ( ⁇ 10 mg/mL) in d6-DMSO, and mixed in a 2:1 ratio with a range of pH buffers (pH 7.4 0.2M phosphate buffer, pH 6 0.1 M citrate buffer, pH 5.2 0.1M acetate buffer, 4, 2) and water. These samples were then filtered and studied by water suppression 1 H NMR a weekly time points for 4 weeks. Relative %lactam remaining was quantified using the integration of the buffer peak compared to the lactam resonance at 5.22 ppm.
  • the lactam is only initially solubilised and displays long term stability (4 weeks) for compositions where the pH is from 4 to 6.5. Above this pH, the composition does not solubilise well enough and is also not stable, and below pH 4, the composition is not stable.

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

The invention relates to a composition comprising: (a) from 0.0001 to 5 wt.% of a lactam; and, (b) 1 to 80 wt.%, of a solvent; wherein the composition has a pH of from 4 to 6.50; wherein the lactam is selected from the formulae. The invention also relates to a method of treatment of a surface, to improve resistance of said surface to bacterial fouling; and also to the use in a lactam composition, of a combination of a solvent and application of pH at from 4 to 6.50 to said composition, to improve the solubility and stability of said lactam in the composition.

Description

LACTAM COMPOSITION AND USE
Field of Invention
The invention relates to an improvement in the field of hygiene, in particular to a composition comprising a lactam which displays improved solubility and stability of the lactam.
Background of the Invention
Hygiene, in particular inhibition of bacterial species, is important to consumers.
Lactams are known as inhibitors of bacterial species. They may be applied to surfaces to inhibit bacterial species.
There is a wish to improve the availability of the lactam and provide a formulation that displays improved solubility and stability of the lactam.
Summary of the Invention
We have found that by formulating a composition comprising a lactam in combination with a solvent at pH 4 to 6.50, the resulting formulation displays improved solubility and stability of the lactam.
The invention relates in a first aspect to a composition comprising:-
(a) from 0.0001 to 5 wt.%, preferably from 0.0001 to 2.5 wt.%, more preferably from 0.0001 to 1 wt.%, more preferably from 0.001 to 1 wt.% of a lactam; and,
(b) from 0.5 to 95 wt.%, preferably from 0.5 to 90 wt.%, more preferably from 0.5 to 80 wt.% of a solvent; wherein the composition has a pH of from 4 to 6.50, preferably pH 4 to 6.25, more preferably 4.50 to 6.00; wherein the lactam is selected from:
Preferably the pH is from 4 to 5.40, more preferably from 4.50 to 5.40.
More preferably the lactam is selected from:
Most preferably the lactam is:
4-(4-chlorophenyl)-5-methylene-pyrrol-2-one
Preferably the lactam is delivered from an aqueous based composition, preferably comprising from 0.1 to 98 wt.%, preferably from 0.5 to 80 wt.%, more preferably from 1 to 75 wt.% water.
The solvent is selected from the group: alcohol; levulinate derivatives; lactate derivatives; and solvents with a dielectric constant of 15 of higher, preferably the solvent is selected from the group: alcohol, levulinate derivatives; and lactate derivatives; more preferably the solvent is selected from the group: levulinate derivatives and lactate derivatives.
Preferred examples of solvents are: of alcohols, preferably a C1-C4 alcohol, more preferably ethanol; of lactate derivatives, preferably ethyl lactate and/or butyl lactate; of levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate, and/or ethyl levulinate glycerol ketal (LGK); and of solvents with a dielectric constant of 15 of higher, preferably dimethyl sulfoxide (DMSO).
Preferably the solvent is selected from the group: ethanol; ethyl lactate, butyl lactate; 2- methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
Preferably the solvent is selected from the group: levulinate derivatives; and lactate derivatives.
Most preferably the solvent is selected from the group: ethyl lactate, butyl lactate; 2- methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
The solvent is present at a level of from 0.5 to 95 wt.%, preferably from 0.5 to 90 wt.%, more preferably from 0.5 to 80 wt.%. The solvent may be present at a lowest level of from 0.5 wt.%, 0.75 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, 2.5 wt.% or even 5 wt.%. The solvent may be present at a highest level of from 95 wt.%, 90 wt.%, 85 wt.%, 80 wt.%, 70 wt.%, 60 wt.%, 50 wt.%, 40 wt.%, 30 wt.%, 25 wt.%, 20 wt.% or even 10 wt.%. Any higher level of solvent is meant to be combinable with any lower level of solvent.
Preferably the composition comprises one or more surfactants. The surfactant may be present at a level of from 0.25 to 25 wt.%, preferably from 0.25 to 20 wt.%, more preferably from 0.25 to 15 wt.%, even more preferably from 0.25 to 10 wt.%, or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.
The surfactant may be present at a level of from 0.25 to 25 wt.%, preferably from 0.25 to 20 wt.%, more preferably from 0.25 to 15 wt.%, even more preferably from 0.25 to 10 wt.%, or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%.
The surfactant is preferably selected from anionic, nonionic, cationic and/or amphoteric surfactants. Preferred surfactants are nonionic surfactants.
The composition preferably comprises a buffer. The invention relates in a second aspect to a method of treatment of a surface, to improve resistance of said surface to bacterial fouling, by treatment with a composition according to the first aspect of the invention.
Preferably the surface to be treated is selected from plastic, metal, wood, polymer, paper, textile, and/or wipes.
Preferably in the method, the lactam is selected from:
The invention further relates in a third aspect to the use in a lactam composition, of a combination of a solvent and application of pH at from 4 to 6.5, preferably 4 to 6.25, more preferably 4.50 to 6.00 to said composition, to improve the solubility and stability of said lactam in the composition.
Preferably in the use, the lactam is selected from:
Brief Description of the Figures
Figure 1 Figure 1 is a photograph showing the solubility of the lactam 488 at pH 5, pH 7 and pH 8
Figure 2 Figure 2 demonstrates the pH effect on the solubility and stability of the lactam 488. Lactam initial solubility (Left hand axis and circular data points) and stability (right hand axis and square data points) vs buffer pH, with lactam delivered in ethanol, to a total of 2% solvent and 100 ppm lactam in solution
Detailed Description of the Invention The indefinite article "a" or "an" and its corresponding definite article "the" as used herein means at least one, or one or more, unless specified otherwise.
It will be appreciated that, except where expressly provided otherwise, all preferences are combinable.
Lactam
A lactam is a cyclic amide. The lactam is a lactam selected from:
More preferably the lactam is selected from: Most preferably the lactam is:
4-(4-chlorophenyl)-5-methylene-pyrrol-2-one.
Where the lactam is cationic in nature, the cation can be used or with a suitable counterion (e.g. iodide).
Levels of lactam
Preferably the lactam is present at a level of from 0.0001 to 2.5 wt.%, preferably from 0.0001 to 1 wt.%. For example, the lactam may be suitably present at levels of 0.001 to 1 wt.%, or even 0.01 to 1 wt.%, or even 0.01 to 0.5 wt.%.
Compositions
Preferably the lactam is delivered from an aqueous based composition, preferably comprising from 0.1 to 98 wt.%, preferably from 0.5 to 80 wt.%, more preferably from 1 to 75 wt.% water. The composition may comprise any amount of water ranging from lower amounts of 0.1 , 0.5, 1, 1.5, 2 or even 5 wt.% water up to 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or even 99 wt.% water.
Solvents
The composition comprises a solvent.
Preferred solvents are selected from the group: alcohol; levulinate derivatives; lactate derivatives; and, solvents with a dielectric constant of 15 of higher. Preferred examples of solvents are: of alcohols, preferably a C1-C4 alcohol, more preferably ethanol; of lactate derivatives, preferably ethyl lactate and/or butyl lactate; of levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate, and/or ethyl levulinate glycerol ketal (LGK); and of solvents with a dielectric constant of 15 of higher, preferably dimethyl sulfoxide (DMSO). Preferably the solvent is selected from the group: ethanol; ethyl lactate, butyl lactate; 2- methyltetrahydrofuran (2Me-THF), ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
Preferably the solvent is selected from the group: levulinate derivatives; and lactate derivatives.
Most preferably the solvent is selected from the group: ethyl lactate, butyl lactate; 2- methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof.
2Me-THF, ethyl levulinate and LGK can be classed as levulinic acid derivatives (or levulinate derivatives). Levulinic acid may be derived from lignocellulosic biomass (i.e. corn husks, sugar cane waste etc), and can be converted in to 2Me-THF in a cyclisation reaction, ethyl levulinate in one step esterification, and LGK in 2 steps (esterification and ketal synthesis). Ethyl lactate and butyl lactate are lactic acid (lactate) derivatives. Lactic acid is a byproduct of fermentation which is then reacted with ethanol or butanol to generate ethyl and butyl lactate.
The solvent is present at a level of from 0.5 to 95 wt.%, preferably from 0.5 to 90 wt.%, more preferably from 0.5 to 80 wt.%. The solvent may be present at a lowest level of from 0.5 wt.%, 0.75 wt.%, 1 wt.%, 1.5 wt.%, 2 wt.%, 2.5 wt.% or even 5 wt.%. The solvent may be present at a highest level of from 95 wt.%, 90 wt.%, 85 wt.%, 80 wt.%, 70 wt.%, 60 wt.%, 50 wt.%, 40 wt.%, 30 wt.%, 25 wt.%, 20 wt.% or even 10 wt.%. Any higher level of solvent is meant to be combinable with any lower level of solvent.
The solvent may be present at a level of from 1 to 80 wt.%, preferably from 1 to 50 wt.%, more preferably from 1 to 40 wt.%. The solvent level may also be from 1 to 30 wt.%, 1 to 20 wt.%, or even 1 to 15 wt.% or 1 to 10 wt.%.
Preferably the composition comprises one or more surfactants. The surfactant may be present at a level of from 0.25 to 25 wt.%, preferably from 0.25 to 20 wt.%, more preferably from 0.25 to 15 wt.%, even more preferably from 0.25 to 10 wt.%, or even 0.5 to 10 wt.% or even 0.5 to 5 wt.%. The surfactant is preferably selected from anionic, nonionic, cationic and/or amphoteric surfactants. Preferred surfactants are nonionic surfactants.
The composition may preferably comprise a buffer to assist in maintaining any resulting composition within a specified pH range. Buffering systems may be any usual buffering system known in the art. These may for example include citrate, acetate, phosphate, and or carbonate buffers, or mixtures thereof.
Further Ingredients
The composition may comprise further ingredients such as surfactants, chelating agents, thickeners, pH modifiers, and perfumes.
The invention will be further described with the following non-limiting examples.
Examples
Example 1 - Preparation of examples of preferred lactams
Preparation of 4-(4-chlorophenyl)-5-hvdroxy-5-methylfuran-2(5H)-one
1-(4-Chlorophenyl)propan-2-one (40.00 g, 34.75 mL, 237.2 mmol), glyoxylic acid monohydrate (32.75 g, 355.8 mmol) and phosphoric acid (69.74 g, 711.7 mmol) were combined at room temperature before heating to 85 °C overnight. After cooling to room temperature, the mixture was poured into a mixture of water (500 mL) and ethyl acetate (500 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (500 mL). The combined organic layers were washed with a 1:1 mixture of water and brine (2 x 500 mL), dried (MgSO4) and concentrated under reduced pressure to yield 4-(4- chlorophenyl)-5-hydroxy-5-methylfuran-2(5H)-one (66.00 g, >100% yield) as a brown oil. The material was used in the next step without further purification. Preparation of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-1 H-pyrrol-2(5H)-one
4-(4-Chlorophenyl)-5-hydroxy-5-methylfuran-2(5H)-one (66.00 g, 293.8 mmol) was dissolved in thionyl chloride (196.8 g, 120.0 mL, 1654 mmol) and heated at 40 °C for 1 hour, then 80 °C for 2 hours. The mixture was concentrated under reduced pressure and azeotroped with 2-methyltetrahydrofuran (200 mL). The residue was diluted with 2-methyltetrahydrofuran (160 mL) and this solution added to a cooled stirring mixture of 28% ammonia in water (180 mL) in 2-methyltetrahydrofuran (20 mL) at 0 °C. The mixture was warmed to room temperature and stirred overnight. Water (100 mL) and ethyl acetate (200 mL) were added and the layers separated. The aqueous phase was extracted with ethyl acetate (200 mL), and the combined organic extracts dried (MgSC ) and concentrated under reduced pressure. Purification by dry flash column chromatography (5-60% ethyl acetate in heptane) yielded 4-(4-chlorophenyl)-5-hydroxy-5-methyl-1H-pyrrol-2(5H)-one (23.18 g, 35% yield) as a cream coloured solid.
1H NMR (400 MHz, d6-DMSO) 8.55 (brs, 1 H), 7.88-7.83 (m, 2H), 7.51-7.46 (m, 2H), 6.37 (d, 1 H), 6.32 (s, 1H), 1.45 (s, 3H)
UPLC (Basic) 1.51/5.00 min, 100% purity, M+H+ 224 MP 177 °C
Preparation of 4-(4-chlorophenyl)-5-methylene-1 H-pyrrol-2(5H)-one
To a cooled solution of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-1H-pyrrol-2(5H)-one (10.00 g, 44.51 mmol) in dry dichloromethane (100 mL) at 0 °C was added a solution of boron trifluoride diethyl etherate (8.213 g, 7.142 mL, 57.87 mmol) in dry dichloromethane (45 mL) over 15 minutes. The mixture was stirred at 0 °C, before slowly warming to room temperature and stirring for 2 hours. The reaction was quenched with ice-water (100 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (100 mL), and the combined organic layers washed with a 1 :1 mixture of water and saturated aqueous sodium hydrogen carbonate solution (100 mL), dried (MgSC and filtered. Silica was added to the filtrate and the mixture stirred for 10 minutes before filtering through a plug of silica, washing through with dichloromethane followed by a 3:1 mixture of dichloromethane:diethyl ether. Fractions containing the desired product were combined and concentrated under reduced pressure. Upon concentration a precipitate formed, which was collected by filtration, washing with diethyl ether, to yield 4-(4-chlorophenyl)-5-methylene-1 H-pyrrol-2(5H)-one (5.25 g, 57% yield) as a cream coloured solid.
1H NMR (400 MHz, d6-DMSO) 10.10 (s, 1H), 7.54-7.47 (m, 4H), 6.36 (s, 1H), 5.04 (t, 1H), 4.85 (s, 1 H)
UPLC (Basic) 1.87/5.00 min, 100% purity, M+H+ 206 MP 182 °C
Preparation of 5-hydroxy-5-methyl-4-(p-tolyl)furan-2(5H)-one
1-(p-Tolyl)propan-2-one (25.00 g, 24.00 mL, 168.7 mmol), glyoxylic acid monohydrate (23.29 g, 253.0 mmol) and phosphoric acid (49.60 g, 506.1 mmol) were combined at room temperature before heating at 90 °C overnight. After cooling to room temperature, the mixture was poured into a stirring mixture of ice-water (400 mL) and ethyl acetate (400 mL). The layers were separated and the organic phase washed with water (100 mL), dried (MgSC ) and concentrated under reduced pressure. The mixture was azeotroped with 2- methyltetrahydrofuran (50 mL) to yield 5-hydroxy-5-methyl-4-(p-tolyl)furan-2(5H)-one (16.50 g, 48% yield) as a brown solid.
1H NMR (400 MHz, de-DMSO) 7.86 (s, 1 H), 7.75 (d, 2H), 7.28 (d, 2H), 6.59 (s, 1 H), 2.32 (s, 3H), 1.61 (s, 3H)
Preparation of 5-hydroxy-5-methyl-4-(p-tolyl)-1 H-pyrrol-2(5H)-one 50 - 80 C 5-Hydroxy-5-methyl-4-(p-tolyl)furan-2(5H)-one (16.50 g, 80.80 mmol) was dissolved in thionyl chloride (48.06 g, 29.47 mL, 404.0 mmol) and heated at 50 °C for 1 hour, before heating at reflux for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure and azeotroped with 2-methyltetra-hydrofuran (2 x 50 mL). The residue was diluted with 2-methyltetrahydrofuran (60 mL) and this solution added to a cooled stirring mixture of 28% ammonia in water (55 mL, 808.0 mol) in 2-methyltetrahydrofuran (10 mL) at 0 °C. The mixture was warmed to room temperature and stirred overnight. 2- Methyltetrahydrofuran was removed under reduced pressure, and the residue diluted with water (200 mL) and diethyl ether (100 mL) and the mixture stirred for 20 minutes at room temperature. The solids were collected by filtration and stirred in water (100 mL) and diethyl ether (50 mL) at room temperature for 10 minutes. The solids were collected by filtration and washed with water, diethyl ether and dried under vacuum at 50 °C to yield 5-hydroxy-5- methyl-4-(p-tolyl)-1H-pyrrol-2(5H)-one (10.49 g, 31% yield) as a light beige solid.
1H NMR (400 MHz, d6-DMSO) 8.44 (brs, 1H), 7.73 (d, 2H), 7.21 (d, 2H), 6.24 (s, 2H), 2.29 (s, 3H), 1.45 (s, 3H)
13C NMR (400 MHz, d6-DMSO) 170.4 (s, 1C), 161.1 (s, 1C), 139.8 (s, 1C), 129.7 (s, 2C), 128.9 (s, 1C), 128.2 (s, 2C), 119.1 (s, 1C), 87.8 (s, 1C), 26.7 (s, 1C), 21.5 (s, 1C) UPLC (Basic) 1.41/5.00 min, 100% purity, M+H+ 204 MP 178 °C Decomposition
Preparation of 5-methylene-4-(p-tolyl)-1H-pyrrol-2(5H)-one
To a cooled solution of 5-hydroxy-5-methyl-4-(p-tolyl)-1H-pyrrol-2(5H)-one (8.68 g, 42.7 mmol) in dry dichloromethane (87 mL) at 0 °C was added a solution of boron trifluoride diethyl etherate (6.85 g, 5.96 mL, 55.5 mmol) in dry dichloromethane (40 mL) over 15 minutes. After 1 hour the mixture was allowed to slowly warm to room temperature. After a further 3 hours, the reaction was diluted with dichloromethane (50 mL) and ice-water (100 mL) and stirred for 10 minutes. The layers were separated and the organic layer washed with water (100 mL), a 1:1 mixture of water and saturated aqueous sodium hydrogen carbonate solution (100 mL) and brine (100 mL) and the organic layer filtered through Celite, washing with dichloromethane. Any excess water was removed by pipette before drying the filtrate (MgSCU) and concentrating under reduced pressure to a brown solid. The solids were stirred in hot dichloromethane (120 mL) for 15 minutes before slowly cooling to room temperature and then 0 °C. The solids were collected by filtration to yield 5-methylene-4-(p- tolyl)-1H-pyrrol-2(5H)-one (3.87 g, 49% yield) as a yellow solid. Silica was added to the filtrate and the mixture stirred for 10 minutes before filtering through a plug of silica, washing through with dichloromethane and then a 4:1 mixture of dichloromethane:diethyl ether. The filtrate was concentrated under reduced pressure to yield 5-methylene-4-(p-tolyl)-1H-pyrrol- 2(5H)-one (0.58 g, 7%) as a yellow solid. Total yield of 5-methylene-4-(p-tolyl)-1H-pyrrol- 2(5H)-one (4.45 g, 56% yield).
1H NMR (400 MHz, d6-DMSO) 10.11 (brs, 1 H), 7.35 (d, 2H), 7.25 (d, 2H), 6.25 (s, 1 H), 5.01 (s, 1 H), 4.85 (s, 1 H), 2.31 (s, 3H)
UPLC (Basic) 1.83/5.00 min, 100% purity, M+H+ 186
MP 200 °C Decomposition
Materials Used
In the following examples, the lactam used was lactam 488.
This is 4-(4-chlorophenyl)-5-methylene-pyrrol-2-one and the structure is shown below:-
Example 2
This example shows the effect of the pH on the solubility of the lactam in an aqueous based composition with a solvent included. A targeted 10,000 ppm stock of lactam 488 in EtOH was prepared and left on the bottle rollers for 24 hrs, before filtration through a syringe filter to yield a saturated solution (likely around 8000 ppm in EtOH). This stock solution was mixed in a 1 :2 ratio with 0.1 M acetate buffer at pH 5.2, or with 0.1M phosphate buffer at pH 7 or 8, agitated in vial and observed visually for any precipitate formed, indicating insolubility. As can be seen from Figure 1 (glass picture), the lactam was mostly solubilised to an acceptable level at 5, while at pH 7 and 8, the solubility was greatly reduced.
Example 3 This example demonstrates the lack of stability of the lactam composition at pH below pH 4 and above pH 6.5.
Initial lactam solubility (3 hrs) was measured by preparing a 5 mg/ml solution of lactam 488 in ethanol. A 0.1M Phosphate/Citrate/Carbonate mixed buffer was prepared and adjusted to a pH range between 2-10 (exact values are in Figure 2 and Table 1), then the lactam 488/EtOH stock was added to a total of 2%, corresponding to a theoretical 100 ppm lactam concentration in solution.
The solutions were left to equilibrate for 3 hrs, then 7 repeats of 200pl of each was dispensed into a 96 well microtitre plates (Greiner, UV-Star), with an 8th well as a non-lactam containing background. On a Varioskan Lux UV/Vis plate reader, a UV absorbance spectra were recorded at a range of 200-450nm in order to quantify the intensity of the lactam peak (Amax = 280 nm), and against a calibration of known EtOH/Lactam solutions the signal was converted to ppm lactam in solution.
Long term lactam stability was measured using solution-state 1H NMR. Lactam 488 was dissolved to maximum concentration (~10 mg/mL) in d6-DMSO, and mixed in a 2:1 ratio with a range of pH buffers (pH 7.4 0.2M phosphate buffer, pH 6 0.1 M citrate buffer, pH 5.2 0.1M acetate buffer, 4, 2) and water. These samples were then filtered and studied by water suppression 1H NMR a weekly time points for 4 weeks. Relative %lactam remaining was quantified using the integration of the buffer peak compared to the lactam resonance at 5.22 ppm.
The results for the lactam stability and solubility are shown for the UV/Vis and 1H NMR data in Figure 2. The values in figure 2 are also shown in table 1 .
Table 1 Initial concentration calculated using UVA/is spectroscopy, decay measured by NMR spectroscopy - values with * were not measured, but estimated by extrapolation from the graph
The lactam is only initially solubilised and displays long term stability (4 weeks) for compositions where the pH is from 4 to 6.5. Above this pH, the composition does not solubilise well enough and is also not stable, and below pH 4, the composition is not stable.

Claims

1. A composition comprising:
(a) from 0.0001 to 5 wt.%, preferably from 0.0001 to 2.5 wt.%, more preferably from 0.0001 to 1 wt.%, more preferably from 0.001 to 1 wt.% of a lactam; and,
(b) from 1 to 80 wt.%, preferably from 1 to 50 wt.%, more preferably from 1 to 40 wt.% of a solvent; wherein the composition has a pH of from 4 to 6.50, preferably pH 4 to 6.25, more preferably 4.50 to 6.00; wherein the lactam is selected from:
2. A composition according to claim 1 , wherein the pH is from 4 to 5.40, preferably 4.50 to 5.40.
3. A composition according to claim 1 or claim 2, wherein the lactam is selected from: A composition according to any preceding claim, wherein the lactam is: chlorophenyl)-5-methylene-pyrrol-2-one. A composition according to any preceding claim, wherein the composition is an aqueous based composition, preferably comprising from 0.1 to 98 wt.%, preferably from 0.5 to 80 wt.%, more preferably from 1 to 75 wt.% water. A composition according to any preceding claim, wherein the solvent is selected from the group: alcohol; levulinate derivatives; lactate derivatives; and solvents with a dielectric constant of 15 of higher; preferably the solvents are: alcohols, preferably a C1-C4 alcohol, more preferably ethanol; lactate derivatives, preferably ethyl lactate and/or butyl lactate; levulinate derivatives, preferably 2-methyltetrahydrofuran, ethyl levulinate, and/or ethyl levulinate glycerol ketal (LGK); and solvents with a dielectric constant of 15 of higher, preferably dimethyl sulfoxide (DMSO). A composition according to any preceding claim, wherein the solvent is selected from the group: ethanol; ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof; preferably ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof. A composition according to any preceding claim, wherein the solvent is selected from the group: ethyl lactate, butyl lactate; 2-methyltetrahydrofuran, ethyl levulinate, and ethyl levulinate glycerol ketal (LGK), or mixtures thereof. A composition according to any preceding claim, wherein the composition comprises a buffering system. A method of treatment of a surface, to improve resistance of said surface to bacterial fouling, by treatment with a composition according to any one of claims 1 to 9. 17
11. A method according to claim 10, wherein the surface to be treated is selected from plastic, metal, wood, polymer, paper, textile, and/or wipes.
12. A method according to claim 10 or claim 11 , wherein the lactam is selected from:
13. Use in a lactam composition, of a combination of a solvent and application of pH at from 4 to 6.50, preferably from pH 4 to 6, more preferably 4.50 to 5.50, to said composition, to improve the solubility and stability of said lactam in the composition.
14. Use according to claim 14, wherein the lactam is selected from:
EP21802747.2A 2020-12-09 2021-11-05 Lactam composition and use Pending EP4258868A1 (en)

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