Cyclic carbamates and uses thereof

Abstract

The present disclosure concerns cyclic carbamates, the methods of synthesis and uses thereof. The cyclic carbamates are synthesized from alcoholamine and dialkylcarbonate.

Description

[0001] Cyclic Carbamates and Uses Thereof

[0002] Technical Field

[0003] The present disclosure relates, in general terms, to cyclic carbamates, the methods of synthesis and uses thereof.

[0004] Background

[0005] Organic solvents are commonly used in academia and industry for dissolution, reaction media, separation and purification of chemical compounds, and equipment cleaning. Over the past decades, there is increasing emphasis on the development of solvent-free or water-based reactions by following the principles of green chemistry. However, many important and useful pharmaceutical compounds such as nitrofurantoin, trimethoprim, and griseofulvin are insoluble in water and require polar aprotic solvents (acetonitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP)) for dissolution.

[0006] Dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP), derived from dimethylamine / carbon monoxide and butanediol / methylamine respectively, have been used extensively as polar aprotic solvent in chemical & petrochemical, agrochemical, pharmaceutical, and electronics industries. However, DMF / NMP are flammable, and toxic to both human and environment.

[0007] Therefore, there is strong need to develop a sustainable and safer polar aprotic solvent with similar performance to DMF / NMP, in effort to improve the sustainability in various chemical processes. Other alternative green solvents such as Cyrene™, ionic liquid, and deep eutectic liquid have high viscosity and high boiling point, which are not ideal in many applications. Carbonate-based solvents (dimethyl carbonate, propylene carbonate) are considered as the greenest solvent by GlaxoSmithKline. However, it is unstable under basic / acidic conditions and non-compatible with amine-based reactions.

[0008] It would be desirable to overcome or ameliorate at least one of the above-described problems.

[0009] Summary

[0010] The present disclosure provides a method of synthesising a cyclic carbamate of Formula (I), or a salt, stereoisomer or derivative thereof, comprising reacting an alcoholamine of Formula (II) and a dialkylcarbonate of Formula (III):

[0011] o

[0012] R3R4

[0013] ' N-Ri

[0014] X2N

[0015] nU A-j rx-| R3-2'X.’ R2R2

[0016] (II) (I)

[0017]

[0018] wherein

[0019] Ri is selected from H, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted sulfonyl;

[0020] Xi and X2are independently C or N;

[0021] R2is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted cycloalkyl, and optionally substituted aryl;

[0022] R3is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted cycloalkyl, and optionally substituted aryl;

[0023] R4is selected from H, and optionally substituted alkyl; and

[0024] R5and R6are independently selected from optionally substituted alkyl.

[0025] In some embodiments, Ri is selected from H, optionally substituted C1-C5 alkyl, optionally substituted C3-C8cycloalkyl, and optionally substituted arylsulfonyl.

[0026] In some embodiments, Xi is C.

[0027] In some embodiments, X2is C.In some embodiments, R2is selected from H, and optionally substituted C1-C5 alkyl.

[0028] In some embodiments, R3is selected from H, and optionally substituted C1-C5 alkyl.

[0029] In some embodiments, R4, Rs and Re are independently selected from H, and optionally substituted C1-C5 alkyl.

[0030] In some embodiments, the cyclic carbamate of Formula (I) is selected from:

[0031]

[0032] In some embodiments, the alcoholamine of Formula (II) is selected from:

[0033]

[0034] In some embodiments, the dialkylcarbonate of Formula (III) is selected from:

[0035] o o

[0036]

[0037] In some embodiments, the reaction is conducted in the presence of an amine base.

[0038] In some embodiments, the amine base is selected from triethylamine (TEA), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylethylenediamine (TMEDA), l,5,7-triazabicyclo[4.4.0]dec-5-enetriazabicyclodecene (TBD), pyridine, 4-dimethylaminopyridine, imidazole, diisopropylethylamine, or a combination thereof.

[0039] In some embodiments, the amine base is provided at a concentration of about 0.1 mole % to about 20 mole %, or preferably about 0.9 mole % to about 1.5 mole %.

[0040] In some embodiments, a mole ratio of alcoholamine of Formula (II) to amine base is about 1:0.01 to about 1:0.2.

[0041] In some embodiments, a mole ratio of alcoholamine of Formula (II) to dialkylcarbonate of Formula (III) is about 1:0.5 to about 1:20.

[0042] In some embodiments, the reaction is performed in the absence of an aminebase.

[0043] In some embodiments, the reaction is conducted at a temperature of about 0 °C to about 150 °C.

[0044] In some embodiments, the reaction is conducted at ambient pressure. In some embodiments, the reaction is conducted at 1 atm.

[0045] In some embodiments, the reaction is conducted for a duration of 0.5 h to about 24 h.

[0046] In some embodiments, when Ri is H, the method further comprises a step of modifying the cyclic carbamate of Formula (I) by:

[0047] i) reacting the cyclic carbamate of Formula (I) with another dialkylcarbonate of Formula (III);

[0048] ii) reacting the cyclic carbamate of Formula (I) with halo donor;

[0049] iii) reacting the cyclic carbamate of Formula (I) with a compound having an alkenylene moiety at a α,β position relative to an electron withdrawing group (EWG) in order to form an alkylamino moiety;

[0050] iv) reacting the cyclic carbamate of Formula (I) with an epoxy compound in order to form an alkylamino moiety; or

[0051] v) reacting the cyclic carbamate of Formula (I) with a sulfonyl compound.

[0052] In some embodiments, the cyclic carbamate of Formula (I) is characterized by a pH of about 6 to about 8.

[0053] The present disclosure concerns a cyclic carbamate of Formula (I) as disclosed herein, or a salt, stereoisomer or derivative thereof;

[0054] wherein the cyclic carbamate of Formula (I) is characterized by a pH of about 6 to about 8.

[0055] The present disclosure concerns a use of a cyclic carbamate of Formula (I) as disclosed herein, or a salt, stereoisomer or derivative thereof as a polar protic solvent.In some embodiments, the use is selected from amide reaction, peptide synthesis, nuclei acid synthesis, polymer dispersion, paint removal, compound synthesis, solvent-based carbon fiber-reinforced plastics recycling, membrane fabrication, lithium-ion battery manufacturing or recycling, semiconductor integrated circuit chips and wafers cleaning, cosmetic formulation, solventsolvent extraction, extractive distillation, perovskite solar cell manufacturing, enzymatic reaction, and graphene / carbon nanotubes dispersion.

[0056] In some embodiments, the cyclic carbamate of Formula (I) is used in combination with a further solvent.

[0057] In some embodiments, the solvent is characterized by a pH of about 6 to about 8.

[0058] Brief description of the drawings

[0059] Embodiments of the present invention will now be described, by way of nonlimiting example, with reference to the drawings in which:

[0060] Figure 1. The cradle-to-gate synthesis route to cyclic carbamates.

[0061] Figure 2. Overall synthetic scheme of cyclic carbamates.

[0062] Figure 3. Application of 3-methyloxazolidin-2-one as solvent for the synthesis of amide from carboxylic acid and aniline with HATU as coupling agent.1H NMR was used to determine the conversion percentage of benzoic acid to product.

[0063] Figure 4. Application of 3-methyloxazolidin-2-one and 3-ethyloxazolidin-2-one as solvents for the solid phase peptide synthesis of Fmoc-Phe-NH2.

[0064] Figure 5. Application of cyclic carbamates as solvent for the recycling of cathode from spent lithium-ion battery.

[0065] Figure 6. Global warming potential (kg CO2eq per kg of solvent production) for NMP, DMF, 3-methyloxazolidin-2-one (commercial source) and 3-methyloxazolidin-2-one_(from this work).

[0066] Figure 7. Toxicity profile (LD50, oral, rat) for NMP, DMF, and 3-methyloxazolidin-2-one.Figure 8. (A) 3-Methyloxazolidin-2-one from this work exhibits a pH of 6, significantly lower than the commercial source, which has a pH of 10. (B) The cyclic carbamate from this work shows better thermal stability after heating at 200 °C for 6 hours compared to commercial source.

[0067] Detailed description

[0068] The present disclosure is predicated on the understanding that cyclic carbamates when used as a solvent, are less toxic and may be tunable to suit the needs of different industrial applications. For example, 3-methyloxazolidin-2-one may be used in amide and solution phase peptide synthesis with high conversion yield (83 - 91%); and in solid phase peptide synthesis with 97% yield of target peptide.

[0069] Cyclic carbamates may be used as alternative greener polar protic solvent, substituting toxic dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP) in various chemical processes such as coupling reactions. For example, the substitution may be a full "drop in" replacement, or partial replacement, or both. Cyclic carbamate-based solvent has 2.75 times lower toxicity (based on LD50, oral) than DMF.

[0070] The cyclic carbamates may be derived from renewable and / or green sources such as glucose, cellulose or glycerol (Figure 1). The cyclic carbamates may be derived from renewable glycerol. Cyclic carbamates may also be synthesised from less toxic alkanolamines (dotted box, Figure 1). For example, CO2 derived non-toxic dimethyl carbonate may be used. In this regard, cyclic carbamates may be synthesised via an efficient (single-step, high yield, less waste generated) and safe (benign chemicals) process (see Scheme 1). An organic base may be used. This contrasts with conventional synthesis of cyclic carbamates that used toxic carbon monoxide or thionyl chloride.

[0071] The presently disclosed method may be modified to synthesize other important and high-value cyclic carbamate or cyclic carbonates (such as monomers for polyurethanes, or carbamate-based active molecules for pharmaceuticals). Forexample, cyclic carbamates may be chemically functionalized at the nitrogen and / or carbon atom of the cyclic ring to realize solvent power tunability.

[0072] Conventional synthesis for cyclic carbamates such as 3-methyloxazolidin-2-one has high global warming potential as it requires high pressure, high heat and extensive purification. In comparison, the presently disclosed method has 96x lesser in global warming potential. The present method also has a lower carbon footprint with low E-factor of 0.06 (less waste production), and easily recyclable side product (methanol) in comparison to the conventional route. The synthesis of cyclic carbamates with isolated yield of up to 99% at ambient pressure without nitrogen protection, with E-factor of 0.06 and lower carbon footprint (93 times less GWP) as compared to carbon monoxide-based route. The cyclic carbamate of the present disclosure may thus be produced with a better purity.

[0073] Accordingly, the present disclosure concerns a use of a cyclic carbamate of Formula (I), or a salt, stereoisomer or derivative thereof as a solvent:

[0074]

[0075] R2(i)

[0076] wherein

[0077] Ri is selected from H, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted sulfonyl;

[0078] Xi and X2are independently C or N;

[0079] R2is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted cycloalkyl, and optionally substituted aryl; and

[0080] R.3 is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted cycloalkyl, and optionally substituted aryl.

[0081] The use of cyclic carbamate may be as a polar protic solvent." Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.

[0082] " Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0083] " Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (eg. phenyl) or multiple condensed rings (eg. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like.

[0084] " Heteroaryl" refers to a monovalent aromatic heterocyclic group which fulfils the Huckel criteria for aromaticity (ie. contains 4n + 2 n electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen). Such heteroaryl groups can have a single ring (eg. pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (eg. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).

[0085] Examples of heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine and the like.

[0086] " Acyl" refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein." Amino" refers to the group -NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

[0087] " Cycloalkyl" refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 11 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, indanyl, 1, 2,3,4-tetrahydronapthalenyl and the like.

[0088] " Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. It will be understood that where, for instance, R2 or R' is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.

[0089] " Sulfonyl" refers to groups H-S(O)2-, alkyl-S(O)2-, cycloalkyl-S(O)2-, aryl-S(O)2-, heteroaryl-S(O)2-, and heterocyclyl-S(O)2-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

[0090] In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy,difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and dialkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the like, and may also include a bond to a solid support material, (for example, substituted onto a polymer resin). For instance, an "optionally substituted amino" group may include amino acid and peptide residues.

[0091] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. " Optically-enriched," as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).A polar aprotic solvent is a solvent that lacks an acidic proton and is polar. For example, such solvents may lack hydroxyl and amine groups. In contrast to protic solvents, these solvents do not serve as proton donors in hydrogen bonding, although they can be proton acceptors.

[0092] The cyclic carbamate may be used in organic synthesis, for example amide reactions, solution phase peptide synthesis and solid phase peptide synthesis. The cyclic carbamate may further be used as solvent for nuclei acid or DNA / RNA synthesis, polyurethane dispersion for making synthetic leather, paint or coating removal / stripper, compound synthesis such as pharmaceutical reaction / drug synthesis and agrochemical (pesticides, insecticides) synthesis, solvent-based carbon fiber-reinforced plastics recycling, membrane (reverse osmosis, nanofiltration etc) fabrication, lithium-ion battery manufacturing / remanufacturing / direct recycling, solvents for IC cleaning in semiconductor, formulation for cosmetic industry, solvent-solvent extraction, extractive distillation, polymer manufacturing or recycling, perovskite solar cells manufacturing, enzymatic reactions, and dispersion of graphene / carbon nanotubes for composites, coatings, and electronics

[0093] In particular, the cyclic carbamate may be used as a solvent in solid phase peptide synthesis, amidation, battery recycling, extractive distillation (cyclic carbamates is added to modify the relative volatilities of close-boiling organic mixtures, facilitating improved separation), liquid-liquid extraction (cyclic carbamates is used as polar organic phase to extract compound of interest from nonpolar organic phase), Nucleophilic Aromatic Substitution (SNAr), membrane fabrication (cyclic carbamates is used as solvent to dissolve Matrimid (Polyimide) or Polysulfone (Psf) for membrane fabrication), dissolution of PVDF for battery manufacturing, and dissolution of polycarbonate for recycling.

[0094] The use of the cyclic carbamates of the present disclosure as a solvent is different from its use as an electrolyte in battery manufacturing. The function of a solvent is to dissolve or dilute other substances or materials. In contrast, an electrolyte functions to transfers ions back and forth between the battery'stwo electrodes, causing the battery to charge and discharge, and is not involved dissolving the PVDF binder in the electrode coating. The electrolyte is also not used to recycle lithium cathode materials.

[0095] In some embodiments, Ri is selected from H, halo, optionally substituted alkyl and optionally substituted cycloalkyl. In some embodiments, Ri is selected from H, optionally substituted alkyl, and optionally substituted cycloalkyl. In some embodiments, Ri is selected from H, and optionally substituted C1-C5 alkyl and optionally substituted C3-C8cycloalkyl. In some embodiments, Ri is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, and secbutyl.

[0096] In some embodiments, Xi is C. The cyclic carbamate may be represented by Formula (Ia):

[0097] x / N-R’

[0098] ^2~<

[0099]

[0100] R2 (la).

[0101] In some embodiments, X2is C. The cyclic carbamate may be represented by Formula (lb):

[0102] O

[0103]

[0104] In some embodiments, the cyclic carbamate is represented by Formula (Ic):

[0105] O

[0106]

[0107] In some embodiments, when Xi is N, R2is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, and optionally substituted aryl.In some embodiments, R2is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted aryl. In some embodiments, R2is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl. In some embodiments, R2is selected from H, halo, optionally substituted alkyl, optionally substituted aryl. In some embodiments, R2is selected from H, halo, and optionally substituted alkyl. In some embodiments, R2is selected from H, and optionally substituted alkyl. In some embodiments, R2is selected from H, and optionally substituted C1-C5 alkyl.

[0108] In some embodiments, when X2is N, R3is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, and optionally substituted aryl.

[0109] In some embodiments, R3is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted aryl. In some embodiments, R3is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl. In some embodiments, R3is selected from H, halo, optionally substituted alkyl, optionally substituted aryl. In some embodiments, R3is selected from H, halo, and optionally substituted alkyl. In some embodiments, R3is selected from H, and optionally substituted alkyl. In some embodiments, R3is selected from H, and optionally substituted C1-C5 alkyl.

[0110] In some embodiments, the cyclic carbamate of Formula (I) is selected from:

[0111]

[0112] In some embodiments, the cyclic carbamate of Formula (I) is selected from:

[0113]

[0114] In some embodiments, the cyclic carbamate of Formula (I) is selected from:

[0115]

[0116] The cyclic carbamate may be used alone, or in combination with other solvents. The solvent may be an aqueous medium, which refers to a water based solvent or solvent system, and which comprises of mainly water. The solvent may be an organic solvent, which refers to a carbon-based medium. Such solvents can be either polar or non-polar, and / or either protic or aprotic. Solvent systems refer to combinations of solvents which resulting in a final single phase. Both 'solvents' and 'solvent systems' can include, and is not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, dioxane, chloroform, diethylether, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, nitromethane, propylene carbonate, formic acid, butanol, isopropanol, propanol, ethanol, methanol, acetic acid, ethylene glycol, diethylene glycol or water.

[0117] In some embodiments, the solvent comprises cyclic carbamate and a further solvent. In other embodiments, a weight of the cyclic carbamate relative to the solvent is about 30 %w / w to about 99 % w / w. In other embodiments, the weight is about 40 %w / w to about 99 % w / w, about 50 %w / w to about 99 % w / w, about 60 %w / w to about 99 % w / w, about 70 %w / w to about 99 % w / w, about 80 %w / w to about 99 % w / w, or about 90 %w / w to about 99 % w / w.In some embodiments, the solvent is characterized by a pH of about 6 to about 8, about 6 to about 7, or about 6. For example, the cyclic carbamate produced by the present method may be synthesised at a pH of about 6 to about 8, about 6 to about 7, or about 6. It was found that at this pH, the solvent has better thermal stability when heated at 200 °C for 6 h compared to when at pH 10 (commercial cyclic carbamate).

[0118] The present disclosure also concerns a cyclic carbamate of Formula (I), or a salt, stereoisomer or derivative thereof:

[0119] O

[0120] R2

[0121]

[0122] (I)

[0123] wherein

[0124] R1, R2, R3, X1and X2are as disclosed herein.

[0125] In some embodiment, the cyclic carbamate of Formula (I) is characterized by a pH of about 6 to about 8, about 6 to about 7, or about 6. In some embodiment, the cyclic carbamate of Formula (I) is characterized by a thermal stability of at least 10 h at 200 °C.

[0126] In some embodiments, Xi and X2are both C.

[0127] In some embodiments, Ri is selected from H, and optionally substituted C1-C5 alkyl and optionally substituted C3-C8cycloalkyl.

[0128] In some embodiments, R2is selected from H, and optionally substituted C1-C5 alkyl. In some embodiments, R2is H.

[0129] In some embodiments, R3is selected from H, and optionally substituted C1-C5 alkyl.The present disclosure also concerns a method of synthesising a cyclic carbamate of Formula (I), or a salt, stereoisomer or derivative thereof, comprising reacting an alcoholamine of Formula (II) and a dialkylcarbonate of Formula (III):

[0130] O

[0131] R3R4

[0132] 1 N-Ri

[0133] X2N

[0134] nU A-j rx-| R3-2'XJ R2R2

[0135]

[0136] (II) (I) wherein

[0137] R4is selected from H, and optionally substituted alkyl; and

[0138] R5and R6are independently selected from optionally substituted alkyl.

[0139] In some embodiments, R4, Rs and Re are independently selected from H, and optionally substituted C1-C5 alkyl. In some embodiments, R4is H. In some embodiments, R5and R6are independently optionally substituted C1-C5 alkyl. In some embodiments, Rs and Re are independently methyl, ethyl or propyl.

[0140] In some embodiments, the alcoholamine of Formula (II) is an alkanolamine. In some embodiments, the alcoholamine of Formula (II) is selected from:

[0141]

[0142]

[0143] In some embodiments, the dialkylcarbonate of Formula (III) is selected from:

[0144]

[0145] In some embodiments, the reaction is conducted in the presence of a base. The base may be an organic base, in particular an amine base. For example, the base may be a weak base, having a pKbof about 13 to about 30. The organic bases may be selected from triethylamine (TEA), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylethylenediamine (TMEDA), l,5,7-triazabicyclo[4.4.0]dec-5-enetriazabicyclodecene (TBD), pyridine, 4-dimethylaminopyridine, imidazole, diisopropylethylamine, or a combination thereof. In some embodiments, amine base is selected from triethylamine (TEA), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylethylenediamine (TMEDA), l,5,7-triazabicyclo[4.4.0]dec-5-enetriazabicyclodecene (TBD), ora combination thereof. In some embodiments, amine base is l,5,7-triazabicyclo[4.4.0]dec-5-enetriazabicyclodecene (TBD).

[0146] Basicity strength of some traditional bases.

[0147] Product NameMeCNpKBH+2,6-Lutidine (2,6-Dimethylpyridine) 13.92 Collidine 14.77 Tributlyamine 18.09

[0148] 1,4-Diazabicyclo[2.2.2]octan (TED) 18.29 Triethylamine 18.46 Pempidine (PMP) 18.62 2,2,6,6-Tetramethylpiperidine (TMP) 18.64 Quinuclidine 19.51 1,1,3,3-Tetramethylguanidine (TMG) 23.3

[0149] l,5-Diazabicyclo[4.3.0]non-5-ene (DBN) 23.89 l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) 24.33

[0150] 7-Methyl-l,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD) 25.44

[0151] l,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD) 25.98

[0152]

[0153] In some embodiments, the amine base is provided at a concentration of about 0.1 mole % to about 20 mole %. In some embodiments, the amine base is provided at a concentration of about 0.1 mole % to about 18 mole %, about 0.1 mole % to about 16 mole %, about 0.1 mole % to about 15 mole %, about 0.1mole % to about 14 mole %, about 0.1 mole % to about 12 mole %, about 0.1 mole % to about 10 mole %, about 0.1 mole % to about 8 mole %, about 0.1 mole % to about 6 mole %, about 0.1 mole % to about 5 mole %, or about 0.3 mole % to about 5 mole %. In some embodiments, the amine base is provided at a concentration of about 0.5 mole % to about 2 mole %, about 0.6 mole % to about 2 mole %, about 0.7 mole % to about 2 mole %, about 0.8 mole % to about 2 mole %, about 0.9 mole % to about 2 mole %, about 0.9 mole % to about 1.8 mole %, or about 0.9 mole % to about 1.6 mole %. In some embodiments, the amine base is provided at a concentration of about 0.9 mole % to about 1.5 mole %.

[0154] In some embodiments, a mole ratio of alcoholamine of Formula (II) to amine base is about 1:0.01 to about 1:0.2. In some embodiments, a mole ratio of alcoholamine of Formula (II) to amine base is about 1:0.01 to about 1:0.18, about 1:0.01 to about 1:0.16, about 1:0.01 to about 1:0.14, about 1:0.01 to about 1:0.12, about 1:0.01 to about 1:0.1, about 1:0.01 to about 1:0.09, about 1:0.01 to about 1:0.08, about 1:0.01 to about 1:0.07, about 1:0.01 to about 1:0.06, about 1:0.01 to about 1:0.05, about 1:0.01 to about 1:0.04, about 1:0.01 to about 1:0.03, about 1:0.01 to about 1:0.02, or about 1:0.01 to about 1:0.01.

[0155] In some embodiments, a mole ratio of alcoholamine of Formula (II) to dialkylcarbonate of Formula (III) is about 1:0.5 to about 1:20, about 1:0.8 to about 1:20, about 1:1 to about 1:20, about 1:1 to about 1:15, or about 1:1 to about 1:12. In some embodiments, a mole ratio of alcoholamine of Formula (II) to dialkylcarbonate of Formula (III) is about 1:1 to about 1:10. In some embodiments, a mole ratio of alcoholamine of Formula (II) to dialkylcarbonate of Formula (III) is about 1:1 to about 1:9, about 1:1 to about 1:8, about 1:1 to about 1:7, about 1:1 to about 1:6, about 1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, or about 1:1 to about 1:2. In some embodiments, a mole ratio of alcoholamine of Formula (II) to dialkylcarbonate of Formula (III) is about 1:1 to about 1:1.8, about 1:1 to about 1:1.6, about 1:1 to about 1:1.4, about 1:1 to about 1:1.2, or about 1:1 to about 1:1.1.In some embodiments, the reaction is performed in the absence of an amine base.

[0156] In some embodiments, the reaction is conducted at a temperature of about 0 °C to about 150 °C, about 2 °C to about 150 °C, about 5 °C to about 150 °C, about 10 °C to about 150 °C, about 15 °C to about 150 °C, about 20 °C to about 150 °C, about 20 °C to about 130 °C, or about 20 °C to about 120 °C. In some embodiments, the reaction is conducted at a temperature of about 25 °C to about 100 °C. In some embodiments, the reaction is conducted at a temperature of about 25 °C to about 90 °C, about 40 °C to about 90 °C, about 50 °C to about 90°C, or about 60 °C to about 90 °C.

[0157] In some embodiments, the reaction is conducted at ambient pressure. In some embodiments, the reaction is conducted at a pressure of about 1 atm. In some embodiments, the reaction is conducted at a pressure of about 0.7 atm to about 1.5 atm, about 0.8 atm to about 1.4 atm, or about 0.8 atm to about 1.2 atm.

[0158] In some embodiments, the reaction is conducted for a duration of 0.5 h to about 24 h. In some embodiments, the reaction is conducted for a duration of at least 1 h, 2 h, 4 h, 6 h, or 10 h.

[0159] In some embodiments, the method further comprises a step of modifying the cyclic carbamate of Formula (I).

[0160] In some embodiments, when Ri is H, the method further comprises a step of reacting the cyclic carbamate of Formula (I) with another reagent to form a cyclic carbamate of Formula (I'):

[0161]

[0162] (I) (I')wherein R7is selected from halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted sulfonyl.

[0163] The cyclic carbamate may thus be derivatized.

[0164] In some embodiments, when Ri is H, the method further comprises a step of reacting the cyclic carbamate of Formula (I) with a further dialkylcarbonate to form a cyclic carbamate of Formula (I'):

[0165] o o oX o"\

[0166] O+' N-R7

[0167] A2 X1

[0168] R2R2

[0169]

[0170] For example, cyclic carbamate of Formula (I) may be methylated. For example:

[0171] Dimethyl carbonate

[0172] base

[0173]

[0174] In some embodiments, the reaction is conducted in the presence of a base. The base may be an organic base, in particular an amine base. The organic bases may be selected from triethylamine (TEA), tetramethylethylenediamine (TMEDA), or a combination thereof.

[0175] Thus, if the mole ratio of alcoholamine of Formula (II) to dialkylcarbonate of Formula (III) is such that dialkylcarbonate of Formula (III) is in excess, the cyclic carbamate of Formula (T) may be obtained in a single step.

[0176] In some embodiments, a mole ratio of alcoholamine of Formula (II) to a further dialkylcarbonate is about 1:2 to about 1:20. In some embodiments, a mole ratio of alcoholamine of Formula (II) to the further dialkylcarbonate is about 1:2 to about 1:19, about 1:2 to about 1:18, about 1:2 to about 1:17, about 1:2 to about 1:16, about 1:2 to about 1:15, about 1:2 to about 1:14, about 1:2 toabout 1:13, about 1:2 to about 1:12, about 1:2 to about 1:11, about 1:2 to about 1:10, about 1:2 to about 1:9, about 1:2 to about 1:8, about 1:2 to about 1:7, about 1:2 to about 1:6, or about 1:2 to about 1:5.

[0177] In some embodiments, when Ri is H, the method further comprises a step of reacting the cyclic carbamate of Formula (I) with halo donor. For example, the halo donor may be Selectfluor™:

[0178] O O

[0179] Selectfluor

[0180] I NH - ► l N-F

[0181]

[0182] R'7'''''7R""^7

[0183] l-(Chloromethyl)-4-fluoro-l,4-diazabicyclo[2.2.2]octane-l,4-diiumditetrafluoroborate (Selectfluor™), is a reagent in chemistry that is used as a fluorine donor. This compound is a derivative of the nucleophillic base DABCO.

[0184] ,. CI

[0185] BF;

[0186]

[0187] F BF'

[0188] Alternatively, trichloroisocyanuric acid may be used for chlorination.

[0189] In some embodiments, when Ri is H, the method further comprises a step of reacting the cyclic carbamate of Formula (I) with a compound having an alkenylene moiety at a u,0 position relative to an electron withdrawing group (EWG) in order to form an alkylamino moiety. The method may be an aza Michael addition. The compound may be a a, 0- unsaturated carbonyl derivatives, or may be an acrylate compound. For example:

[0190] R

[0191] o Y ° Acrylate

[0192] NH o YX° N O

[0193] base R

[0194]

[0195] R

[0196] In some embodiments, the acrylate is selected from alkyl, aryl, alkoxy and / or alkyl acrylates.In some embodiments, when Ri is H, the method further comprises a step of reacting the cyclic carbamate of Formula (I) with an epoxy compound in order to form an alkylamino moiety. The method may be a nucleophilic ring-opening reaction. For example:

[0197] O HO

[0198] Epoxy

[0199] base

[0200]

[0201] In some embodiments, when Ri is H, the method further comprises a step of reacting the cyclic carbamate of Formula (I) with a sulfonyl compound having a labile moiety such as a sulfonimide or sulfonyl chloride compound. For example:

[0202] N-Fluorobenzenesulfonimide (NFSI)

[0203]

[0204]

[0205] n-Butyllithium

[0206]

[0207] 0 °C

[0208] In some embodiments, a mole ratio of the cyclic carbamate of Formula (I) to the further reagent is 1:1, 1:1.1, 1:1.2, or 1:1.5.

[0209] Thus, the cyclic carbamate of the present disclosure may be modified depending on the specific application requirement. This allows the introduction of various functionalities to modulate the polarity and other physicochemical properties of the solvent.

[0210] In some embodiment, the cyclic carbamate of Formula (I) is characterized by a pH of about 6 to about 8, about 6 to about 7, or about 6. In some embodiment, the cyclic carbamate of Formula (I) is characterized by a thermal stability of at least 10 h at 200 °C.

[0211] Examples

[0212]

[0213] ic carbamateEtnry

[0214] N

[0215] H base, heat

[0216]

[0217] Scheme 1. Slhli / Acooamneeqynthesis of 3-methyloxazolidin-2-one

[0218] 3-Methyloxazolidin-2-one was synthesised from the carbonylation of 2- ihl Dtmey

[0219] (methylamino)ethanol by using dimethyl carbonate in the presence of a base b / t caronaeeq

[0220] catalyst (Scheme 1). The reaction was carried out at elevated temperature for hours. The reaction conditions are shown in Table 1. The chemical structure of 3-methyloxazolidin-2-one was coni b Amneasefirmed byXH and13C NMR analysis.

[0221] Table 1. Reaction conditions for synthesis of 3-methyloxazolidin-2-one

[0222] i b / Amneaseeq

[0223] i / h Tmer

[0224] (°C) Temp

[0225] 1 0.5 1 Nil Nil 6 90 20

[0226] ild (%) Ye

[0227] 2 0.5 6 TBD 0.1 6 90 89

[0228] 3 0.5 1 DBU 0.1 6 90 75

[0229] 4 0.5 1 DBU 0.01 2 90 60

[0230] 5 0.5 1 DBN 0.1 6 90 70

[0231] 6 0.5 1 DBN 0.01 2 90 60

[0232] 7 5 1 TBD 0.01 6 90 93

[0233] 8 0.5 1 DBU 0.01 6 90 62

[0234] 9 0.5 2 TBD 0.01 6 50 95

[0235] 10 0.5 1 TEA 0.01 2 90 25

[0236] 11 0.5 1 TBD 0.01 2 50 86

[0237] 12 0.5 1 TBD 0.01 2 r.t. 35

[0238]

[0239] The optimized reaction condition was demonstrated by Entry 9, where 2 equivalent of dimethyl carbonate and 0.01 equivalent of TBD were used, resulting in isolated yield of 95%. The reaction was completed at 90 °C for 2hr Etnrys at ambient air and pressure. The reaction can be done easily on various alcoholamines (Scheme 2) to obtain 3-ethyloxazolidin-2-one and 3-isopropyloxazolidin-2-one in good yields.

[0240] o

[0241] lhli / Acooamneeq

[0242]

[0243] Scheme 2. Synthesis of 3-ethyloxazolidin-2-one and 3-isopropyloxazolidin-2-one

[0244] ihl Dtmey

[0245] Table 2. Reaction conditions for synthesis b / t caronaeeq of 3-ethyloxazolidin-2-one and 3-isopropyloxazolidin-2-one i b Amnease

[0246] i b / Amneaseeq

[0247] i / h Tmer

[0248] (C) T°temperaure

[0249] 3-ethyloxazolidin-2-one 0.6 (Et) 1 TBD 0.1 6 90 9ild (%) Ye1 3-ethyloxazolidin-2-one 6 (Et) 2 TBD 0.1 6 90 99 3-ethyloxazolidin-2-one 0.6 (Et) 2 DBU 0.1 6 90 89 3-isopropyloxazolidin-2-one 0.2 (Pr) 2 DBN 0.1 10 90 84 3-isopropyloxazolidin-2-one 0.2 (Pr) 2 DBU 0.1 10 90 72 3-isopropyloxazolidin-2-one 0.2 (Pr) 2 TBD 0.1 6 85 92

[0250]

[0251] Et: Ethanolamine; Pr: Propanolamine

[0252] O O O O

[0253] H2N -0 0* JI0 0JI

[0254]

[0255] TEA, heat LyNHTMEDA, heat LyNScheme 3. 2-step synthesis towards 3-methyloxazolidin-2-one from ethanolamineEtnry

[0256] Alkanolamine with primary amine (ethanolamine) was able to form 2-oxazolidinone via this method in the presence of triethylamine (TEA). Following this, the 3-methyloxazolidin-2-one was obtained by reacting the 2-oxazolidinone with the dimethyl carbonate in the presence of tetramethylethylenediamine (TMEDA) (Table 3). The chemical structures were confirmed b

[0257]

[0258] y NMR analysis.

[0259] lhli / Acooamneeq

[0260] Table 3. Reaction condition for the synthesis of 3-methyloxazolidin-2-one from ethanolamine.

[0261] ihl Dtmey

[0262] b / t caronaeeq

[0263] i b Amnease

[0264] 2-Oxazolidinone 0.5 (Et) 2 TEA 0i b / Amneaseeq.1 6 80 85 i / h Tmer

[0265] (C) Tt°emperaure

[0266] ild (%) Ye 3-Methyloxazolidin-2-one 0.1 20 TMEDA 0.1 18 95 60

[0267]

[0268] Purity of cyclic carbamatesThe method was tracked using GC-MS. As an example, 3-methyloxazolidin-2-one was used (Table 4). N-methylaminoethanol was reacted with dimethyl carbonate. After 10 mins of reaction, the desired cyclic carbamate (3-methyloxazolidin-2-one) was formed. The uncyclized intermediate N-methyl-N-(2-hydroxyethyl)carbamic acid, methyl ester was also present. After 180 min, 3-methyloxazolidin-2-one as the main product is obtained. 3-methyloxazolidin-2-one may be further purified using distillation, such that a high purity of at least 98% may be achieved. The pH is about 6 to less than 10 (or about pH 6 to 9) due to trace amounts of the amine base. No other impurities were found.

[0269] Figure 8 shows the pH of 3-methyloxazolidin-2-one from the present disclosure (about pH 6) compared to a commercial source (about pH 10) using pH paper. When measured using a pH meter, 3-methyloxazolidin-2-one of the present disclosure has a pH of about 8 and the commercial source has a pH of about 11.5.

[0270] Table 4. Reaction to form 3-methyloxazolidin-2-one

[0271] Component Concentration (After 10 Concentration (After mins reaction) (M) 180 mins reaction) (M) 3-methyloxazolidin-2- 2.5 5.9

[0272] one

[0273] N-methyl-N-(2- 4.4 0.4 hydroxyethyl)carbamic

[0274] acid, methyl ester

[0275] N-methylaminoethanol 1.22 0.005

[0276] Dimethyl carbonate 1.82 0.26

[0277] Methanol 8.64 11.6

[0278]

[0279] The application of cyclic carbamates as solvent in amide / peptide synthesis

[0280] The application of 3-methyloxazolidin-2-one, 3-ethylloxazolidin-2-one, 3-isopropyloxazolidin-2-one, and 3-butyloxazolidin-2-one as solvent in amide synthesis with l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate (HATU) as coupling agent wasexplored. HATU is considered as the gold standard reagent for amide formation and difficult peptide synthesis. However, HATU is not soluble in water and therefore requires DMF for dissolution. Cyclic carbamate was used to dissolve the 3,4-dimethylbenzoic acid, aniline and HATU to form a homogenous solution (Figure 3). The conversion of starting materials into the product was determined to be 91% after 1 hr at room temperature byXH NMR analysis (disappearance of peak a). On the other hand, DMF showed conversion of 90% under same reaction condition. The high conversion (83%) of amino acids into target peptide (Scheme 4) was also demonstrated by using cyclic carbamate as solvent in solution phase peptide synthesis.

[0281] HATU, DIPEA

[0282] r.t., 1 hr

[0283] HATU, DIPEA

[0284] Conversion: 80 - 91%

[0285]

[0286] 25 °C, 1hr Scheme 4. Synthesis of peptide from Boc-Ala-OH and L-Proline methyl ester hydrochloride (Pro-OMe HCI) with HATU as coupling agent. 3-Methyloxazolidin-2-one, 3-ethylloxazolidin-2-one, 3-isopropyloxazolidin-2-one, and 3-butyloxazolidin-2-one were used as solvent and the reaction was carried out at room temperature for 1 hr.

[0287] of cvclic carbamate as solvent in solid

[0288]

[0289]

[0290] Next, the solid phase peptide synthesis (Figure 4) was explored by using 3-methyloxazolidin-2-one or 3-ethyloxazolidin-2-one as solvent for resin swelling and washing. To note, the solvent should assist in good swelling of resin for efficient peptide synthesis later. The swellings of PAL-NovaSyn TG resin weregood for both 3-methyloxazolidin-2-one and 3-ethyloxazolidin-2-one that were comparable to DMF. The yield of isolated peptide was found to be high (97%, Table 5) after synthesis when 3-methyloxazolidin-2-one_was used, and the peptide structure was confirmed by mass spectrometry analysis ([M + l]+= 387 m / z).

[0291] Table 5. Solid phase peptide synthesis and yields of Fmoc-Phe-NH2by using different solvents. 100 mg of resin was used which contains 0.25 mmol of NH2. The theoretical mass of product after reaction is 9.65 mg.

[0292] Solvent Isolated Yield Remark peptide

[0293] (mg)

[0294] DMF 8.92 mg 92% Good Resin Swelling 3-methyloxazolidin-2-one 9.32 mg 97% Good Resin Swelling, target peptide was identified by LC-MS 3-ethyloxazolidin-2-one 7.80 mg 81% Good Resin Swelling

[0295]

[0296] Application of cyclic carbamate in spent lithium-ion battery recycling The recovery of cathode materials (LiCoO2, LiMn2O4, LiFePCU, or LiNiMnCoO2) from spent lithium-ion battery by using conventional methods such as pyrometallurgical (>700 °C), hydrometallurgy (strong acids for lithium ion leaching and recovery later) results in high carbon footprints, release of HF (thermal decomposition of PVDF binder), and extra retreatment processes (precipitation & thermal treatment for new battery manufacturing). One of the challenges is the effective separation of active lithium-ion compounds from the aluminum foil in the cathode system. The solvent assisted separation of lithium compounds from aluminum foil by dissolving the PVDF binder is considered as low-cost and efficient method. The use of cyclic carbamates to separate the active lithium-ion compounds from the aluminum foil was explored (Figure 5). It was found that the separation of lithium compounds was achieved by stirring the cathode in cyclic carbamates at 80 - 100 °C in less than 60 seconds. Following this, the lithium-ion compounds and aluminum foil were separately recovered by simple filtration.Environmental impact of cyclic carbamate

[0297] In effort to study the environmental impact of the cyclic carbamate synthesis, life cycle analysis was carried out to understand the global warming potential (GWP) of 3-methyloxazolidin-2-one. To note, the estimation on 3-methyloxazolidin-2-one is based on gate-to-gate scenario owing to the insufficient inventory data of starting materials. A full cradle-to-gate life cycle analysis of the 3-methyloxazolidin-2-one synthesis is also performed. The method showed the potential reduction in GWP (96x lower) as compared to conventional CO route to 3-methyloxazolidin-2-one (Figure 6). It is promising to achieve 3-methyloxazolidin-2-one with lower GWP than DMF or NMP by utilizing renewable sources (glucose, cellulose) and efficient conversion of the intermediate molecules into 3-methyloxazolidin-2-one.

[0298] The toxicity of 3-methyloxazolidin-2-one was estimated based on the lethal dose (LD50, oral, rat) as shown in Figure 7. It was found that the 3-methyloxazolidin- 2-one has 2.7x higher LD50 as compared to that of DMF. This showed that the 3-methyloxazolidin-2-one could be potential alternative solvent to DMF, while retaining the desired polarity for intended application.

[0299] Thermal Stability of Cyclic Carbamate

[0300] The cyclic carbamate of the present disclosure was tested against commercial cyclic carbamate (Figure 8). The cyclic carbamate of the present disclosure has a pH of 6 and is stable when heated at 200 °C for 6 h. GCMS analysis showed no change in the chemical structure of the cyclic carbamate following the thermal stability test. In contrast, the commercial cyclic carbamate has a pH of 10 and degraded when heated at 200 °C.

[0301] Experimental Procedures

[0302] Materials

[0303] All reagents and solvents were purchased from commercial sources and used without further purification. Dimethyl carbonate (98 %), N, N, N', N'-tetramethylethylenediamine (TMEDA, 98 %), triethylamine (99 %), diisopropylethylamine (DIPEA, 99 %), trifluoroacetic acid (99 %) werepurchased from Tokyo Chemical Industry. 2-(methylamino)ethan-l-ol (98 %), l,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD, 98 %), 2-(ethylamino)ethan-l-ol (98 %), 2-(isopropylamino)ethan-l-ol (98 %), amino-2-propanol (94%), ethanolamine (98 %), 3,4-dimethylbenzoic acid (99 %), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate (HATU, 97 %), aniline (99.5 %), PAL-NovaSyn TG resin were purchased from Sigma Aldrich. N-Boc-L-alanine (Boc-Ala-OH), L-Proline methyl ester hydrochloride (Pro-OMe HCI), Fmoc-L-alanine (Fmoc-Ala-OH) were purchased from Creosalus. All solvents used were analytical grade and without further purification.

[0304] Characterization methods

[0305] 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400 Autosampler (400 MHz) using CDCl3as the solvent. The chemical shifts were reported in parts per million (ppm) and the following abbreviations were used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. NMR spectra were referenced to the residual solvent peaks (CDCl3: 7.26 ppm for1H, 77.16 ppm for13C). Gas Chromatography Mass spectrometry (GC-MS) spectra were recorded on a Agilent GC7890B / MS5977B / UNITY.

[0306] Synthesis of Cyclic Carbamates Derivatives

[0307] Example 1:

[0308]

[0309] TEA, heat

[0310] A solution of ethanolamine (0.5 g, 8.18 mmol) and TEA (0.08 g, 0.8 mmol) in dimethyl carbonate (1.47 g, 16.3 mmol) was heated at 85 °C for overnight. After the reaction, the excess dimethyl carbonate was removed under reduced pressure. The crude product was precipitated in diethyl ether to obtain the white powder as 2-oxazolidinone (0.6 g, yield 85%).1H NMR (400 MHz, CDCl3) δ 4.41 (dd, 2H), 3.64 (dd, 2H). GC-MS: m / z = 87.08Example 2:

[0311]

[0312] TMEDA, heat

[0313] A solution of 2-oxazolidinone (0.1 g, 1.15 mmol) and TMEDA (0.013 g, 0.11 mmol) in dimethyl carbonate (2 ml_) was heated at 90 °C for overnight. After the reaction, the excess dimethyl carbonate was removed under reduced pressure to obtain the 3-methyloxazolidin-2-one (0.07 g, yield 60%).1H NMR (400 MHz, CDCl3) δ 4.31 (dd, 2H), 3.55 (dd, 2H), 2.87 (s, 3H). GC-MS: m / z = 101.11

[0314] Example 3:

[0315]

[0316] base, heat

[0317] A solution of 2-(methylamino)ethan-l-ol (0.5 g, 6.65 mmol), dimethyl carbonate (0.6 g, 6.66 mmol) and amine base (1 mol%) was heated for 2 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a pale yellow oil (0.65 g, yield 96%).1H NMR (400 MHz, CDCl3): δ 4.34 - 4.25 (m, 2H), 3.59 - 3.51 (m, 2H), 2.88 (s, 3H).

[0318] 13C NMR (100 MHz, CDCl3) δ: 158.9, 61.60, 46.9, 31.2. GC-MS: m / z = 101.11

[0319] Example 4:

[0320]

[0321] base, r.t A solution of 2-(methylamino)ethan-l-ol (0.5 g, 6.65 mmol), dimethyl carbonate (0.6 g, 6.66 mmol) and amine base (1 mol%) was stirred at room temperature up to 24 hr.Example 5:

[0322] . OH

[0323] N

[0324]

[0325] H base, r.t

[0326] A solution of 2-(ethylamino)ethan-l-ol (6 g, 67.3 mmol), dimethyl carbonate (12 g, 13.3 mmol) and amine base (1 mol%) was heated at 90 °C for 6 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a pale yellow oil (7.65 g, yield 99%).1H NMR (400 MHz, CDCl3) δ: 4.31 - 4.09 (m, 2H), 3.59 - 3.36 (m, 2H), 3.22 (q, J = 7.3 Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, CDCl3d) δ: 158.4, 61.8, 44.1, 39.0, 12.7. GC-MS: m / z = 115.03

[0327] Example 6:

[0328]

[0329] base, heat A solution of 2-(ethylamino)ethan-l-ol (6 g, 67.3 mmol), dimethyl carbonate (12 g, 13.3 mmol) and amine base (1 mol%) was stirred at room temperature up to 48 hr. The reaction mixture was monitored by using GC-MS. The product peak at 7.83 min showed 98% conversion after 48 hr.

[0330] Example 7:

[0331]

[0332] H

[0333] base, heat

[0334] A solution of 2-(isopropylamino)ethan-l-ol (0.2 g, 1.94 mmol), dimethyl carbonate (0.35 g, 3.88 mmol) and amine base (1 mol%) was heated for 6 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a pale yellow oil (0.35 g, yield 93 %).1H NMR (400 MHz, CDCl3) δ 4.30 (t, 2H), 4.10 (m, 1H), 3.49 (t, 2H), 1.18 (s, 3H), 1.16 (s, 3H). GC-MS: m / z = 129.08

[0335] Example 8:

[0336] OH

[0337]

[0338] base, heat

[0339] A solution of 2-(isopropylamino)ethan-l-ol (0.2 g, 1.94 mmol), dimethyl carbonate (0.35 g, 3.88 mmol) and amine base (lmol%) was stirred at room temperature for 18 hours. The reaction mixture was monitored by using GC-MS. The product peak at 8.39 min showed 95% conversion after 18 hr.

[0340] Example 9:

[0341]

[0342] base, 6hr

[0343] A solution of ethanolamine (20 g, 0.33 mol), dimethyl carbonate (30 g, 0.33 mmol) and amine base (1 mol%) was heated for 6 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a white solid (22 g, yield 95 %).1H NMR (400 MHz, CDCl3) δ 4.41 (dd, 2H), 3.64 (dd, 2H).13C NMR (101 MHz, CDCl3d) δ: 161.03, 65.13, 40.80. GC-MS: m / z = 87.08

[0344] Example 10:

[0345]

[0346] OH base, 6hr

[0347] A solution of l-Aminopropan-2-ol (10 g, 133 mmol), dimethyl carbonate (12 g, 133 mmol) and amine base (1 mol%) was heated at for 6 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug toafford the colorless liquid (10.8 g, yield 80 %).1H NMR (400 MHz, CDCl3) δ 4.80 (m, 1H), 3.71 (t, 1H), 3.21 (t, 1H), 1.46 (d, 3H). GC-MS: m / z = 101.11

[0348] Example 11:

[0349]

[0350] A solution of 2-(methylamino)ethan-l-ol (0.5 g, 6.65 mmol) and dimethyl carbonate (0.6 g, 6.66 mmol) was heated at 90 °C for 2 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a pale yellow oil (0.034 g, yield 5%).1H NMR (400 MHz, CDCl3): δ 4.34 - 4.25 (m, 2H), 3.59 - 3.51 (m, 2H), 2.88 (s, 3H).13C NMR (100 MHz, CDCl3) δ: 158.9, 61.60, 46.9, 31.2. GC-MS: m / z = 101.11

[0351] Example 12:

[0352] DBU

[0353] 90 °C A solution of 2-(methylamino)ethan-l-ol (0.5 g, 6.65 mmol), dimethyl carbonate (0.6 g, 6.66 mmol) and DBU (0.01 g, 0.066 mmol) was heated at 90 °C for 2 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a pale-yellow oil (0.41 g, yield 60%).1H NMR (400 MHz, CDCl3): δ 4.34 - 4.25 (m, 2H), 3.59 - 3.51 (m, 2H), 2.88 (s, 3H).13C NMR (100 MHz, CDCl3) δ: 158.9, 61.60, 46.9, 31.2. GC-MS: m / z = 101.11

[0354] Example 13:

[0355] DBN

[0356]

[0357] 90 °CA solution of 2-(methylamino)ethan-l-ol (0.5 g, 6.65 mmol), dimethyl carbonate (0.6 g, 6.66 mmol) and DBU (0.008 g, 0.066 mmol) was heated at 90 °C for 2 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a pale yellow oil (0.34 g, yield 60%).1H NMR (400 MHz, CDCl3): δ 4.34 - 4.25 (m, 2H), 3.59 - 3.51 (m, 2H), 2.88 (s, 3H).13C NMR (100 MHz, CDCl3) δ: 158.9, 61.60, 46.9, 31.2. GC-MS: m / z = 101.11

[0358] Example 14:

[0359] Base

[0360]

[0361] 90 °C To a solution of 2-(fluoroamino)ethan-l-ol (3.8 mmol) and dimethyl carbonate (3.8 mmol) was added amine base (5.5 mol%) at room temperature. After stirred the mixture for 6 h at 90°C, the reaction mixture was concentrated under reduced pressure to obtain a brown liquid (yield 23%). GC-MS: m / z = 106.03

[0362] Example 15:

[0363]

[0364] A solution of 2-amino-2-methyl-l-propanol (0.5 g, 5.6 mmol), dimethyl carbonate (0.51 g, 5.6 mmol) and amine base (10 mol%) was heated for 2 hours. The reaction mixture was concentrated and purified by flushing over a short silica plug to afford the product as a pale yellow oil (0.45 g, yield 70%). GC-MS: m / z = 115.10

[0365] Example 16:

[0366]

[0367] ACN, r.t.

[0368] To a solution of l,3-oxazolidin-2-one (1.0 mmol) and methyl acrylate (1.5 mmol) in MeCN (0.5 ml) was added DBU (0.5 mmol) at room temperature. After stirred the mixture for 6 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (50% petroleum ether / diethyl ether), and the pure azaMichael adduct was isolated in 85% yield.1H NMR (400 MHz, CDCl3) δ 4.33 - 4.25 (m, 2H), 3.70 (s, 3H), 3.67 - 3.59 (m, 2H), 3.56 (td, J = 6.6, 0.6 Hz, 2H), 2.62 (t, J = 6.6 Hz, 2H).13C NMR (101 MHz, CDCl3) δ 172.06, 158.37, 61.92, 51.95, 45.33, 40.19, 32.66. [M + 1]+= 174.2

[0369] Example 17:

[0370]

[0371] To a solution of l,3-oxazolidin-2-one (1.0 mmol) and propylene oxide (4 mmol) was added DBU (0.5 mmol) at room temperature. After stirred the mixture for 6 h, the reaction mixture was concentrated under reduced pressure to afford the product. GC-MS: m / z = 145.10

[0372] Example 18:

[0373] O

[0374]

[0375] 130 °C

[0376] To a solution of 2-(Phenylamino) ethanol (137. lmg, 1.0 mmol) in diethyl carbonate (DEC) (5 mmol, 590 mg) was added l-Butyl-3-methylimidazolium acetate (BmimOAC) (5%, 0.05 mmol, 20 mg). The resultant mixture was heated at 130 °C for 3 h. The pure products were obtained by chromatography on silicagel (50% petroleum ether / diethyl ether). The compound has been characterized by1H and13C NMR spectroscopy and mass spectrometry.1H NMR (400 MHz, CDCl3) δ 7.54 (dt, J = 7.9, 1.1 Hz, 2H), 7.37 (dd, J = 8.7, 7.4 Hz, 2H), 7.20 -7.09 (m, 1H), 4.49 - 4.42 (m, 2H), 4.07 - 4.01 (m, 2H).13C NMR (101 MHz, CDCl3) δ 155.38, 138.36, 129.16*2, 124.17, 118.33*2, 61.39, 45.28. [M + 1] + = 164.2

[0377] Example 19:

[0378] Base

[0379]

[0380] 90 °C

[0381] To a solution of glycolamide (4 mmol) and dimethyl carbonate (4 mmol) was added with amine base (35 mol%) at room temperature. After stirred the mixture for 6 h at 90°C, the reaction mixture was concentrated under reduced pressure to obtain a white solid (yield 10%).XH NMR (400 MHz, DMSO-d6) 6 4.78

[0382] Example 20:

[0383] Base

[0384]

[0385] r.t. to 90 °C

[0386] To a 10-mL flask was added 2-amino-l-phenylethanol (137.2 mg, 1 mmol), dimethyl carbonate (450.5 mg, 0.42 mL, 5 mmol), and amine base (20mol%). The mixture was heated at 90 °C for 3 hours. The resultant mixture was then cooled to room temperature and dissolved in CH2CI2 (20 mL), and the mixture was washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, and concentrated. The residual was purified by flash chromatography (hexane / EtOAc, 1 / 1) to obtain (white solid, 138.2 mg, 85 %).1H NMR (400 MHz, CDCI3) 6 7.52 - 7.31 (m, 5H), 5.96 (bs, 1H), 5.63 (t, J = 8.2 Hz, 1H), 3.99 (tq, J = 8.7, 0.7 Hz, 1H), 3.55 (ddt, J = 8.7, 7.6, 0.9 Hz, 1H).13C NMR (101 MHz,CDCl3) δ 159.95, 138.50, 129.08, 129.06*2, 125.81*2, 78.04, 48.45. [M + 1] + = 164.2

[0387] Example 21:

[0388]

[0389] To a 10-mL flask was added 2-amino-2-phenylethanol (137.2 mg, 1 mmol), dimethyl carbonate (450.5 mg, 0.42 mL, 5 mmol), and amine base (20 mol%). The mixture was heated at 90 °C for 3 hours. The resultant mixture was then cooled to room temperature and dissolved in CH2CI2 (20 mL), and the mixture was washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, and concentrated. The residual was purified by flash chromatography (hexane / EtOAc, 1 / 1) to obtain (white solid, 125.4 mg, 77 %).1H NMR (400 MHz, CDCl3) δ 7.47 - 7.31 (m, 5H), 5.66 (s, 1H), 5.05 - 4.89 (m, 1H), 4.74 (t, J = 8.7 Hz, 1H), 4.20 (dd, J = 8.6, 7.0 Hz, 1H).13C NMR (101 MHz, CDCl3) δ 159.64, 139.49, 129.38*2, 129.05, 126.21*2, 72.70, 56.51. [M + 1]+ = 164.2

[0390] Example 22:

[0391] N-Fluorobenzenesulfonimide (NFSI)

[0392]

[0393] n-Butyllithium

[0394]

[0395] 0 °C

[0396] To a round-bottom flask with a stir bar was added l,3-oxazolidin-2-one (1.0 mmol) (87.0 mg, 1 mmol, 1 equiv) under Ar. Anhydrous THF (5 mL, 0.2 M) was added and the solution stirred until all solid dissolved. The solution was cooled to 0 °C on an ice bath for 10 minutes. n-Butyllithium (0.48 mL of 2.5 M in hexanes solution, 1.2 mmol, 1.2 equiv) was added dropwise, and the reaction stirred at 0 °C for 1 hour. / V-Fluorobenzenesulfonimide (NFSI) (470 mg, 1.5 mmol, 1.5 equiv) in THF (0.4 mL, 0.6 M) was added dropwise via syringe pump over 1 hour at 0 °C. The reaction stirred for 14 h, slowly warming to room temperature. The resulting residue was purified by silica gel columnchromatography (50% petroleum ether / diethyl ether), and the white solid product was isolated in 112 mg (49% yield).1H NMR (400 MHz, CDCl3) δ 8.12 - 8.00 (m, 2H), 7.75 - 7.65 (m, 1H), 7.63 - 7.52 (m, 2H), 4.37 (dd, J = 8.6, 6.9 Hz, 2H), 4.06 (dd, J = 8.6, 6.9 Hz, 2H).13C NMR (101 MHz, CDCl3) δ 152.08, 136.94, 134.71, 129.47, 128.41, 62.44, 44.75.

[0397] Synthesis of Amide by using cyclic carbamate as solvent

[0398] HATU, DIPEA

[0399]

[0400] A solution of 3,4-dimethylbenzoic acid (0.04 g, 0.27 mmol) and HATU (0.114 g, 0.3 mmol) in 3-methyloxazolidin-2-one, 3-ethylloxazolidin-2-one, 3-isopropyloxazolidin-2-one, or 3-butyloxazolidin-2-one (1.2 g) was added with DIPEA (0.1 g, 0.77 mmol). The reaction mixture was stirred for 10 minutes at room temperature, followed by addition of aniline (0.025 g, 0.27 mmol) into the reaction mixture. The reaction mixture was stirred for 1 hr at room temperature. The conversion of starting materials into product was calculated based on1H NMR integration.

[0401] Synthesis of Peptide by using cyclic carbamate as solvent

[0402] HATU, DIPEA

[0403]

[0404] 25 °C, 1hr A solution of Boc-Ala-OH (47 mg, 0.25 mmol) and HATU (236 mg, 0.62 mmol) in 3-methyloxazolidin-2-one, 3-ethylloxazolidin-2-one, 3-isopropyloxazolidin-2-one, or 3-butyloxazolidin-2-one (1.25 g) was added with DIPEA (130 pL, 0.75 mmol). The reaction mixture was stirred for 10 minutes at room temperature, followed by addition of Pro-OMe HCI (45 mg, 0.27 mmol) into the reaction mixture. The reaction mixture was stirred for 1 hr at room temperature. Theconversion of starting materials into product was calculated based on

[0405]

[0406] NMR integration.

[0407] Solid Phase Peptide Synthesis using 3-methyloxazolidin-2-one and 3- ethyloxazolidin-2-one

[0408] PAL-NovaSyn TG resin (100 mg, 0.025 mmol NH2) was added with 1 mL of the solvent (DMF, 3-methyloxazolidin-2-one_or 3-ethyloxazolidin-2-one) at room temperature. The swelling of resin was carried out for 3 hrs. In a separated vial, the reaction cocktail was prepared by dissolving Fmoc-Ala-OH (77.5 mg, 0.2 mmol), HATU (76 mg, 0.2 mmol), and DIPEA (34 pL, 0.2 mmol) in the respective solvents. After draining the solvent from the resin, the reaction cocktail (0.5 mL) was added at room temperature. The reaction mixture was agitated for 30 mins at room temperature. After the reaction, the reaction cocktail was drained away, and the resin was washed with respective solvent (0.5 mL) and DCM (3 x 1 mL). The target peptide was cleaved from resin by using trifluoroacetic acid (0.95 mL), which was subsequently diluted with water (0.025 mL) and followed by freeze drying for 24 hrs.

[0409] E-factor calculation for 3-methyloxazolidin-2-one

[0410] 1 Base

[0411]

[0412] Total Amount of Reactants; 0.5 g + 0.6 g + 0.009 g = 1.109 g

[0413] Total Amount of Products: 0.646 g + 0.4 g = 1.046 g

[0414] Amount of waste: 1.109 – 1.046 = 0.063 g

[0415] E-factor: Amount of waste / Amount of product = 0.06

[0416] Enzymatic Oxygenation of Ionone in Cyclic Carbamates

[0417]

[0418] In a 1.5 ml_ microcentrifuge tube, 20 pL of 50 |jM DcaUPO (unspecific peroxygenase from Daldinia caldariorum) in 50 mM pH = 7 potassium phosphate buffer was added (final cone. 5 pM). A master mix containing 160 pL 50 mM potassium phosphate buffer, 10 pL of 100 mM 0-ionone dissolved in acetone (final cone. 5 mM, acetone 5% v / v), 10 pL of 150 mM H2O2(final cone.

[0419] 7.5 mM) per reaction was prepared and added to the DcaUPO. A blank reaction was also set up, using 20 pL of 50 mM potassium phosphate buffer instead of DcaUPO. The above procedure was repeated using 3-methyloxazolidin-2-one solvent to replace acetone. The reaction mixtures were allowed to shake overnight, 400 rpm, 25 °C. Reaction was quenched by added 200 pL of 0.5 mM of Methyl 3.4.5-trimethoxybenzoate (internal standard) in methanol and extracted with ethyl acetate and sent for GC-MS analysis. Methyl 3.4.5-trimethoxybenzoate used as internal standard with MW = 226. The results of GC-MS analysis were summarized in the table below.

[0420] Retention Time Compound Acetone 3- (min) (relative area) methyloxazolidin- 2-one (relative area) 13.7 SM 225 270

[0421] 14.0 Product [M + 14] 2 2

[0422] 15.1 Product [M + 16] 16 15

[0423] 16.3 Product [M + 16] 27 23

[0424] 16.6 Product [M + 16] 1 1

[0425] 17.1 IS 100 100

[0426]

[0427] In conclusion, enzymatic oxygenation of Ionone can be carried out in 3-methyloxazolidin-2-one_without any adverse effects on the enzyme.

[0428] Enzymatic Oxygenation of Naphthalene in Cyclic Carbamates

[0429] H2O2H2O2OH

[0430] Aromatic >

[0431]

[0432] Oxygenation

[0433] Naphthalene 1 -Naphthol

[0434] UPO catalyzed Absorption at 324 nm

[0435] reaction

[0436] In a 1.5 ml_ microcentrifuge tube, 20 pL of 50 |jM enzyme unspecific peroxygenase (UPO) in 50 mM pH = 7 potassium phosphate buffer was added (final cone. 5 pM). A master mix containing 160 pL 50 mM potassium phosphate buffer, 10 pL of 100 mM 1-naphthalene dissolved in acetonitrile (final cone. 5 mM, acetonitrile 5% v / v), 10 pL of 150 mM H2O2(final cone. 7.5 mM) per reaction was prepared and added to the UPO. A blank reaction was also set up, using 20 pL of 50 mM potassium phosphate buffer instead of UPO. The above procedure was repeated using 3-methyloxazolidin-2-one solvent to replace acetonitrile. The reaction mixtures were allowed to shake, 400 rpm, 25 °C. The conversion was analysed by the absorption on a micro-plate reader.

[0437] Conversion

[0438] Averag Std.

[0439] Testi Test2 Test3 e Dev No co-solvent 3.1% -2.5% 2.2% -0.1% 0.033 3-Methyloxazolidin-2- 12.1 11.5 11.8

[0440] one % % % 11.6% 0.003

[0441] 11.0 11.1

[0442] Acetonitrile 4.3% % % 8.8% 3.182

[0443]

[0444] In conclusion, enzymatic oxygenation of Naphthalene can be carried out in 3-methyloxazolidin-2-one_without any adverse effects on the enzyme.

[0445] It will be appreciated that many further modifications and permutations of various aspects of the described embodiments are possible. Accordingly, thedescribed aspects are intended to embrace all such alterations, modifications, and variations that fall within the spirit and scope of the appended claims.

[0446] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0447] Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase "consisting essentially of", and variations such as "consists essentially of" will be understood to indicate that the recited element(s) is / are essential i.e. necessary elements of the invention. The phrase allows for the presence of other non-recited elements which do not materially affect the characteristics of the invention but excludes additional unspecified elements which would affect the basic and novel characteristics of the method defined.

[0448] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

Claims1. A method of synthesising a cyclic carbamate of Formula (I), or a salt, stereoisomer or derivative thereof, comprising reacting an alcoholamine of Formula (II) and a dialkylcarbonate of Formula (III):oR3R4oI N-R!HO'*2X;N'RI R3-2'X.’R2R2whereinRi is selected from H, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted sulfonyl;Xi and X2are independently C or N;R.2 is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted cycloalkyl, and optionally substituted aryl;R.3 is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, optionally substituted cycloalkyl, and optionally substituted aryl;R.4 is selected from H, and optionally substituted alkyl; andRs and R6are independently selected from optionally substituted alkyl.

2. The method according to claim 1, wherein Ri is selected from H, optionally substituted C1-C5 alkyl, optionally substituted C3-C8cycloalkyl, and optionally substituted arylsulfonyl.

3. The method according to claim 1 or 2, wherein Xi is C and / or X2is C.

4. The method according to any one of claims 1 to 3, wherein R2is selected from H, and optionally substituted C1-C5 alkyl.

5. The method according to any one of claims 1 to 4, wherein R3is selected from H, and optionally substituted C1-C5 alkyl.

6. The method according to any one of claims 1 to 5, wherein R4, Rs and Re are independently selected from H, and optionally substituted C1-C5 alkyl.

7. The method according to any one of claims 1 to 6, wherein the cyclic carbamate of Formula (I) is selected from:alcoholamine of Formula (II) is selected from:

9. The method according to any one of claims 1 to 8, wherein the dialkylcarbonate of Formula (III) is selected from:

10. The method according to any one of claims 1 to 9, wherein the reaction is conducted in the presence of an amine base.

11. The method according to claim 10, wherein the amine bases is selected from triethylamine (TEA), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetramethylethylenediamine (TMEDA), l,5,7-triazabicyclo[4.4.0]dec-5-enetriazabicyclodecene (TBD), pyridine, 4-dimethylaminopyridine, imidazole, diisopropylethylamine, or a combination thereof.

12. The method according to claim 10 or 11, wherein the amine base is provided at a concentration of about 0.1 mole % to about 20 mole %.

13. The method according to any one of claims 10 to 12, wherein a mole ratio of alcoholamine of Formula (II) to amine base is about 1:0.01 to about 1:0.2.

14. The method according to any one of claims 1 to 13, wherein a mole ratio of alcoholamine of Formula (II) to dialkylcarbonate of Formula (III) is about 1:0.5 to about 1:20.

15. The method according to any one of claims 1 to 11, wherein the reaction is performed in the absence of an amine base.

16. The method according to any one of claims 1 to 15, wherein the reaction is conducted at a temperature of about 0 °C to about 150 °C, and / or at ambient pressure.

17. The method according to any one of claims 1 to 16, wherein the reaction is conducted for a duration of 0.5 h to about 24 h.

18. The method according to any one of claims 1 to 17, wherein when Ri is H, the method further comprises a step of modifying the cyclic carbamate of Formula (I), wherein the step is one of the following:a) reacting the cyclic carbamate of Formula (I) with another dialkylcarbonate of Formula (III);b) reacting the cyclic carbamate of Formula (I) with halo donor;c) reacting the cyclic carbamate of Formula (I) with a compound having an alkenylene moiety at a α,β position relative to an electron withdrawing group (EWG);d) reacting the cyclic carbamate of Formula (I) with an epoxy compound; ande) reacting the cyclic carbamate of Formula (I) with a sulfonyl compound.

19. The method according to any one of claims 1 to 18, wherein the cyclic carbamate of Formula (I) is characterized by a pH of about 6 to about 8.

20. A cyclic carbamate of Formula (I), or a salt, stereoisomer or derivative thereof:OO^xORS"2X,R2(I)whereinRi is selected from H, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted sulfonyl;Xi and X2are independently C or N;R.2 is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, and optionally substituted aryl; andR.3 is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, and optionally substituted aryl; wherein the cyclic carbamate of Formula (I) is characterized by a pH of about 6 to about 8.

21. A use of a cyclic carbamate of Formula (I), or a salt, stereoisomer or derivative thereof as a polar protic solvent:OO^x' N-RiR3'2 X.'R2 (I)whereinRi is selected from H, halo, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted sulfonyl;Xi and X2are independently C or N;R2is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, and optionally substituted aryl; andR3is selected from H, halo, optionally substituted alkyl, optionally substituted acyl, optionally substituted amino, and optionally substituted aryl.

22. The use according to claim 21, wherein the use is selected from amide reaction, peptide synthesis, nuclei acid synthesis, polymer dispersion, paint removal, compound synthesis, solvent-based carbon fiber-reinforced plastics recycling, membrane fabrication, lithium-ion battery manufacturing or recycling, semiconductor cleaning, cosmetic formulation, solvent-solvent extraction, extractive distillation, perovskite solar cell manufacturing, enzymatic reaction, and graphene / carbon nanotubes dispersion.

23. The use according to claim 21 or 22, wherein the cyclic carbamate of Formula (I) is used in combination with a further solvent.

24. The use according to any one of claims 21 to 23, wherein the solvent is characterized by a pH of about 6 to about 8.

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