FIELD OF THE INVENTION

The present invention relates to a P2S5 2C5H5N formulation. More particularly, the invention relates to a formulation comprising P2S52C5H5 in particular a formulation in the form of a liquid solution of P2S5'2C5H5 in a sulfolane-containing solvent phase.

BACKGROUND OF THE INVENTION

The compound P2S52C5H5N, formed from reaction of pyridine and P2Ss (or the dimer P4S10), is a useful reagent in thionation reactions of C=O functionality in organic molecules, thus providing an interesting alternative to the widely used Lawesson’s reagent. The crystalline form of the compound, its preparation and its use were described in the international application No. PCT/EP2012/051864, published as WO 2012/104415 A1. In said application, improved thionation reactions were also described, comprising preparing the crystalline material in pyridine, separating it from the pyridine wherein it was prepared and using the crystalline material as a thionating agent, by allowing the crystalline material to react with a compound to be thionated in a reaction performed in a solvent medium for the crystalline material and said compound. However, it has been found that the crystalline material is sensitive to oxygen and water, forming for example, the oxidation product P2S4O2C5H5N. This sensitivity is an impediment to convenient production, storage, shipping and handling of the material. There therefore is a need for providing P2S52C5H5N with improved storage stability and more convenient handling.

The scaling up of the process for preparing P2S5 2C5H5N also has encountered some problems, in that P4S10 tends to coagulate in pyridine to form stone-like lumps. On a laboratory scale, the lumps may easily be mechanically broken, but in large scale production, the lump formation may be more problematic and lead to increased energy consumption in production of P2S52C5H5N.

SUMMARY OF THE INVENTION

The present invention is based on the discovery that when present in sulfolane as a solvent medium, P2S52C5H5N remains stable over a prolonged period of time, i.e. the compound does not give rise to any significant amounts of decomposition products, even after a prolonged period of storage.

Consequently, a method and formulation allowing to increase the long-term storage stability of P2S5 2C5H5N is provided herein. A first aspect thus is a storage stable formulation of P2S5 2C5H5N, comprising a solution of P2S5 2C5H5N in sulfolane. Such a formulation, allowing for convenient storage P2S52C5H5N, may also be referred to as a “stock formulation”. The storage stable P2S52C5H5N formulation (stock formulation) comprises a solution of P2S5 2C5H5N in sulfolane, wherein the sulfolane acts as a solvent or carrier phase for P2S5 2C5H5N.

A further aspect is a P2S52C5H5N formulation (P2S5 2C5H5N stock formulation) as defined herein, in a sealed container.

A further aspect is a sealed container containing a P2S5 2C5H5N formulation (P2S52C5H5N stock formulation) as defined herein.

An advantageous feature of the present stock formulation is its stability against chemical degradation, which is such that under appropriate conditions of storage (free from moisture) at least 80 % of the initial amount of P2S5 2C5H5N in the formulation, generally at least 90 %, will remain after a period of time of at least 6 months from preparation of the formulation.

A further aspect is a process for preparing a formulation containing P2S5 2C5H5N wherein P2S5 2C5H5N has an increased storage stability.

A further aspect is a simplified process for preparing P2S52C5H5N, by allowing P4S and pyridine to react with each other in sulfolane as a reaction medium.

A further aspect is a method for improving the stability of P2S52C5H5N against chemical degradation, said method comprising preparing a solution of P2S52C5H5N in sulfolane.

A further aspect is a process for providing storage stable P2S5 2C5H5N, by preparing a solution of P2S52C5H5N in sulfolane.

A still further aspect is a process for transforming a group >C=O (I) in a compound into a group >C=S (II) or into a tautomeric form of group (II) in said compound, by allowing pyridine to react with P4S10 in sulfolane as a reaction medium to obtain a solution of P2S5 2C5H5N in sulfolane, followed by admixing the obtained solution with said compound and allowing the P2S5 2C5H5N in the solution to react with said compound. A still further aspect is a process for transforming a group >C=O (I) in a compound into a group >C=S (II) or into a tautomeric form of group (II) in said compound, comprising admixing a solution of P2S5 2C5H5N in sulfolane and said compound, with a solvent medium for the reaction, e.g. an aprotic organic solvent selected from pyridine, a C1-C3 alkylnitrile, a cyclic sulfone and a C1-C3 dialkylsulfone or a mixture of one or more thereof, and allowing the P2S52C5H5N in the solution to react with said compound.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 is a ³¹ P NMR spectrum of a solution obtained by dissolving crystalline P2S5 2C5H5N in sulfolane, recorded at the day of preparing the solution.

FIGURE 2 is a ³¹ P NMR spectrum of a solution obtained by dissolving crystalline P2S5 2C5H5N in pyridine, recorded at the day of preparing the solution.

FIGURE 3 is a ³¹ P NMR spectrum of a solution obtained by dissolving crystalline P2S5 2C5H5N in sulfolane, recorded 72 hours after preparing the solution.

FIGURE 4 is a ³¹ P NMR spectrum of a solution obtained by dissolving crystalline P2S5 2C5H5N in pyridine, recorded 72 hours after preparing the solution.

FIGURE 5 is a ³¹ P NMR spectrum of a solution obtained by reacting P4S10 and pyridine in sulfolane, as described in EXAMPLE 4.

FIGURE 6 is a ³¹ P NMR spectrum of a solution obtained by reacting P4S10 and pyridine in sulfolane, as described in EXAMPLE 5.

FIGURE 7 is a ³¹ P NMR spectrum of a solution obtained by reacting P4S10 and pyridine in sulfolane, as described in EXAMPLE 6.

FIGURE 8 shows an LC-MS chromatogram of the product solution obtained by reaction of acridone (20 minutes at 100 °C) with a 2-month sample of the solution of EXAMPLE 5.

DETAILED DESCRIPTION OF THE INVENTION

The formulation (stock formulation) disclosed herein comprises P2S5 2C5H5N in sulfolane, wherein the sulfolane is a solvent or carrier medium for the P2S52C5H5N.

The structural formula of the zwitterionic P2S52C5H5N is:

As mentioned herein above, preparation, properties and uses of the compound P2S52C5H5N are described in WO 2012/104415 A1 , the content of which is incorporated herein by reference.

Sulfolane (IIIPAC name: thiolane 1 ,1-dioxide) is a cyclic sulfone, having the empirical formula C4H8O2S and the structural formula:

Sulfolane is widely used as an industrial solvent and as a solvent in various chemical reactions. At normal pressure (760 mm Hg), sulfolane has a melting point of about 27.6 °C and a boiling point of about 285.0 °C.

While sulfolane is hygroscopic and miscible with water, the formulation of the present invention preferably has a low water content, e.g. lower than 1 %, preferably lower than 0.5 %, more preferably lower than 0.25 % (w/w). Therefore, in some embodiments, the formulation includes molecular sieves, such as 3A or 4A molecular sieves. Furthermore, the sulfolane used according to the present invention should be as free from moisture as possible. For example, a suitably low water content may be achieved by treating the sulfolane with molecular sieves before use, or by any other means of drying, e.g. by treating the sulfolane with a drying agent, such as calcium chloride (CaCh), calcium sulfate (CaSC ), potassium permanganate (KMnC ) or potassium hydroxide (KOH), and/or by use of azeotrope distillation using anhydrous benzene.

The word “formulation” may be used herein synonymously with the word “composition” and refers to a mixture of two different substances, for instance a formulation as provided herein comprising sulfolane and P2S52C5H5N. In some embodiments, the formulation comprises P2S5 2C5H5N as a solute in sulfolane as a solvent.

In some embodiments, the formulation of the invention may be referred to as a stock formulation. By “stock formulation of P2S52C5H5N” or “P2S5 2C5H5N stock formulation”, or similar expression, as used herein, is meant a formulation allowing for storage of P2S52C5H5N for a period of time, such as several days (e.g. 1 , 2, 3, 4, 5, 6 or 7 days), weeks (e.g. 1 , 2, 3 or 4 weeks), months (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months), or even several years, e.g.

1 to 3 years, or more.

By “storage stable”, is meant the capability of a chemical material of having a stability over time such as that a portion of the material of at least 80 %, preferably 90 %, more preferably at least 95 %, even more preferably at least 97 %, at least 98 %, at least 99 %, or at least 99.5 % remains in the formulation after a period of time (e.g. from preparation of the formulation). Such period of time preferably should be at least several days, (e.g. 1 , 2, 3, 4, 5, 6 or 7 days), weeks (e.g. 1 , 2, 3 or 4 weeks), months (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months), or even several years, e.g. 1 to 3 years, or more.

In a formulation of P2S52C5H5N allowing for storage for a period of time, P2S52C5H5N should remain essentially storage stable (e.g. against chemical decomposition) during the period of time. Thus, preferably a portion of at least 80% of the initial amount, or at least 90% of the initial amount of the P2S5 2C5H5N in the formulation should remain in the formulation, more preferably at least 95% of initial amount of P2S5 2C5H5N, even more preferably at least 97%, even more preferably at least 98%, or even at least 99% of the initial amount of P2S5 2C5H5N, e.g. at least 99.5% of the initial amount of P2S52C5H5N.

For example, in some embodiments, a formulation of P2S52C5H5N is provided, wherein at least 80 % of the initial amount of P2S5 2C5H5N in the formulation remains after a period of time of at least one week, more preferably, at least one month, even more preferably at least

2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or even at least one year.

In some further embodiments, a formulation of P2S5 2C5H5N is provided, wherein at least 90 % of the initial amount of P2S52C5H5N in the formulation remains after a period of time of at least one week, more preferably, at least one month, even more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or even at least one year.

In some further embodiments, a formulation of P2S5 2C5H5N is provided, wherein at least 95 % of the initial amount of P2S52C5H5N in the formulation remains after a period of time of at least one week, more preferably, at least one month, even more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or even at least one year.

In some embodiments, a formulation of P2S5 2C5H5N is provided, wherein at least 97 % of the initial amount of P2S5 2C5H5N in the formulation remains after a period of time of at least one week, more preferably, at least one month, even more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or even at least one year.

In some embodiments, a formulation of P2S5 2C5H5N is provided, wherein at least 98 % of the initial amount of P2S5 2C5H5N in the formulation remains after a period of time of at least one week, more preferably, at least one month, even more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or even at least one year.

In some embodiments, a formulation of P2S5 2C5H5N is provided, wherein at least 99 % of the initial amount of P2S5 2C5H5N in the formulation remains after a period of time of at least one week, more preferably, at least one month, even more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or even at least one year.

In some embodiments, a formulation of P2S5 2C5H5N is provided, wherein at least 99.5 % of the initial amount of P2S5 2C5H5N in the formulation remains after a period of time of at least one week, more preferably, at least one month, even more preferably at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or even at least one year.

The formulation may suitably be stored at ambient temperature or at lower temperature, e.g. at a temperature of from 1 °C ( in a refrigerator) to 35 °C, or at a temperature in the range of from 5 °C to 35 °C, or from of from 15 °C to 35 °C, or from 15 °C to 30 °C, or from 15 °C to 25 °C, or at room temperature (about 20 to 25 °C).

It is noted that in order for a suitable stability to be achievable, the formulation should be essentially free from water (e.g. have a molar ratio of water to P2S52C5H5N of less than 1 :50, less than 1 :100, less than 1 :500, or even less than 1 :1000) and also essentially free from compounds containing a group susceptible of reacting with P2S52C5H5N, such as ketones, amides, esters or any other compound containing an oxo group. To further increase stability, the formulation may also suitably be preserved from surrounding air, e.g. by use of an inert gas blanket in the formulation storage vessel or container.

Depending on factors such as the surrounding temperature and the weight (or molar) ratio of P2S5 2C5H5N to sulfolane in the formulation, the formulation may be solid (at a temperature below the melting point of sulfolane), or partly solid, e.g. containing both dissolved and nondissolved (e.g. crystalline) P2S5 2C5H5N in sulfolane as a liquid carrier, or entirely liquid, i.e. a formulation containing P2S5 2C5H5N as a solute, in sulfolane as a liquid solvent medium.

In some embodiments, the formulation comprises P2S5 2C5H5N as a solute, in sulfolane as a liquid carrier, optionally in the presence of solid P2S5 2C5H5N, e.g. in the form of a particle dispersion or as a precipitate in the sulfolane.

It is contemplated that the inventive formulation will be useful as a stock formulation in, for example, chemical industry, such as pharmaceutical chemical industry, in material sciences, chemical battery industry, cosmetics industry, agrochemical industry, as well as in research, just to mention a few areas of application. Suitably, the formulation may be provided in a wide range of concentrations of P2S52C5H5N in sulfolane, adapted to the particular circumstances of use. Likewise, the formulation provided herein may be provided in containers or bottles having a high volume, e.g. several litres, to only small bottles, e.g. several millilitres, e.g. from 10 mL, up to volumes as large as 1000 L or even larger, e.g. 20 mL to 500 L, or 50 mL to 100 L, or 100 mL to 50L.

In one aspect the P2S52C5H5N formulation of the invention is provided in a sealed (optionally re-sealable) container, such as a vial, flask, bottle, can, canister, barrel, drum, tank etc.

In some embodiments, the P2S5 2C5H5N formulation of the invention is provided in a sealed (optionally re-sealable) container containing an inert atmosphere (i.e. an “inert atmosphere blanket”). In some embodiments, the P2S52C5H5N formulation of the invention is provided in a sealed container containing a drying agent, e.g. a molecular sieve.

In some embodiments, therefore, a sealed container as mentioned herein is provided, containing a P2S5 2C5H5N formulation of the invention, said container optionally also containing a drying agent, such as a molecular sieve, and said container optionally also containing an inert gas (e.g. N2) atmosphere. In some embodiments, the formulation of the invention is provided in a container such as a bottle, vial, can, flask etc. of a size suitable for laboratory work, e.g. a volume of a few millilitres to a few litres, e.g. 10 mL to 10 L, or 10 mL to 5 L, or 10 mL to 1 L, or 10 mL to 500 mL, or 10 mL to 100 mL.

In some embodiments, the formulation of the invention is provided in large volume containers, e.g. barrels, drums, tanks, canisters or cans, having an internal volume of up to 50 L or 100 L, 200 L, 500 L, 1000 L (i.e. 1 m ³ ), or even larger volumes, for large scale industrial use.

In some embodiments, the container has an outlet suitable for being connected to an inlet of a chemical reactor.

Thus, in some embodiments the formulation of the invention is provided in a tank, drum, barrel or similar container capable of containing large volumes, which container may have an outlet suitable for connecting to an inlet of a chemical reactor, so as to allow for mass transfer of the inventive formulation to the chemical reactor. Such means for transferring the formulation of the invention as a reactant may allow for higher security in the handling of the reactant, and by suitable dosage means, e.g. a valve or flow regulator, may allow for providing proper dosing of the reactant.

The reactor may comprise further inlets for reactants and reaction medium, as well an outlet for the reaction medium containing the reaction product.

The formulation of the invention may contain P2S52C5H5N in sulfolane at a high concentration or at lower concentrations, and even very low concentrations. For reasons of reduced consumption of sulfolane, shipping costs, storage costs etc. a high concentration formulation may be preferred. However, in some instances, e.g. when only small amounts are to be used, such as in experimental use in the laboratory, a lower concentration formulation may be preferable, for easier dispensing of the proper amount.

In some embodiments a formulation is provided, containing about, 10 % by weight of P2S5 2C5H5N, about 9.5 % by weight of P2S52C5H5N, about 9.4 % by weight of P2S52C5H5N, about 9.3 % by weight of P2S52C5H5N, about 9.2 % by weight of P2S5 2C5H5N, about 9.1 % by weight of P2S52C5H5N, about 9.0 % by weight of P2S5 2C5H5N, about 8.5 % by weight of P2S5 2C5H5N, about 8.0 % by weight of P2S52C5H5N, about 7.5 % by weight of P2S52C5H5N, about 7.0 % by weight of P2S52C5H5N, about 6.5 % by weight of P2S5 2C5H5N, about 6.0 % by weight of P2S52C5H5N, about 5.5 % by weight of P2S5 2C5H5N, about 5.0 % by weight of P2S5 2C5H5N, about 4.5 % by weight of P2S52C5H5N, about 4.0 % by weight of P2S52C5H5N, about 3.5 % by weight of P2S52C5H5N, about 3.0 % by weight of P2S5 2C5H5N, about 2.5 % by weight of P2S52C5H5N, about 2.0 % by weight of P2S5 2C5H5N, about 1.5 % by weight of P2S5 2C5H5N, or about 1 .0 % by weight of P2S5 2C5H5N, by total weight of the formulation.

In some embodiments, a formulation is provided containing P2S5 2C5H5N in an amount in the range of 0.01 % by weight to 10 % by weight, 0.01 % by weight to 9.9 % by weight, 0.01 % by weight to 9.8 % by weight, 0.01 % by weight to 9.7 % by weight, 0.01 % by weight to 9.6 % by weight, 0.01 % by weight to 9.5 % by weight, 0.01 % by weight to 9.4 % by weight, 0.01 % by weight to 9.3 % by weight, 0.01 % by weight to 9.2 % by weight, 0.01 % by weight to 9.1 % by weight, 0.01 % by weight to 9.0 % by weight, 0.01 % by weight to 8.5 % by weight, 0.01 % by weight to 8.0 % by weight, 0.01 % by weight to 7.5 % by weight, 0.01 % by weight to 7.0 % by weight, 0.01 % by weight to 6.5 % by weight, 0.01 % by weight to 6.0 % by weight, 0.01 % by weight to 5.5 % by weight, 0.01 % by weight to 5.0 % by weight, 0.01 % by weight to 4.5 % by weight, 0.01 % by weight to 4.0 % by weight, 0.01 % by weight to 3.5 % by weight, 0.01 % by weight to 3.0 % by weight, 0.01 % by weight to 2.5 % by weight, 0.01 % by weight to 2 % by weight, 0.01 % by weight to 1 .5 % by weight, 0.01 % by weight to 1 .0 % by weight, 0.01 % by weight to 0.5 % by weight, 0.01 % by weight to 0.1 % by weight, or 0.01 % by weight to 0.05 % by weight, by total weight of the formulation.

In some of the above embodiments, the formulation contains P2S52C5H5N in an amount of at least 0.02 % by weight, at least 0.03 % by weight, at least 0.04 % by weight, at least 0.05 % by weight, at least 0.07 % by weight, at least 0.1 % by weight, at least 0.2 % by weight, at least 0.3 % by weight, at least 0.4 % by weight, at least 0.5 % by weight, at least 0.6 % by weight, at least 0.7 % by weight, at least 0.8 % by weight, at least 0.9 % by weight, or at least 1 .0 % by weight, by total weight of the formulation.

In some embodiments, a formulation is provided containing P2S5 2C5H5N in an amount ranging from 0.01 % by weight to 10 % by weight, from 0.05 % by weight to 10 % by weight, from 0.1 % by weight to 10 % by weight, from 0.5 % by weight to 10 % by weight, from 1 % by weight to 10 % by weight, from 2 % by weight to 10 % by weight, from 3 % by weight to 10 % by weight, from 4 % by weight to 10 % by weight, from 5 % by weight to 10 % by weight, from 5.5 % by weight to 10 % by weight, from 6 % by weight to 10 % by weight, from 6.5 % by weight to 10 % by weight, from 7 % by weight to 10 % by weight, from 7.5 % by weight to 10 % by weight, from 8 % by weight to 10 % by weight, from 8.5 % by weight to 10 % by weight, or from 9.0 % by weight to 10 % by weight, by total weight of the formulation. In some of these embodiments, the formulation contains P2S5 2C5H5N in an amount of at most 9.9 % by weight, at most 9.8 % by weight, at most 9.7 % by weight, at most 9.6 % by weight, at most 9.5 % by weight, at most 9.4 % by weight, at most 9.3 % by weight, at most 9.2 % by weight, at most 9.1 % by weight, or at most 9.0 % by weight, by total weight of the formulation.

Preferably, P2S52C5H5N and sulfolane together constitute at least 80.0 % by weight of the formulation, at least 80.5 % by weight of the formulation, at least 90.0 % by weight of the formulation, at least 95.0 % by weight of the formulation, at least 96.0 % by weight of the formulation, at least 97.0 % by weight of the formulation, at least 98.0 % by weight of the formulation, at least 98.5 % by weight of the formulation, at least 98.6 % by weight of the formulation, at least 98.7 % by weight of the formulation, at least 98.8 % by weight of the formulation, at least 98.9 % by weight of the formulation, at least 99.0 % by weight of the formulation, at least 99.5 % by weight of the formulation, at least 99.6 % by weight of the formulation, at least 99.7 % by weight of the formulation, at least 99.8 % by weight of the formulation, or at least 99.9 % by weight of the formulation, e.g. essentially 100 % by weight of the formulation.

In some embodiments, the formulation contains at least 0.1 % by weight of P2S52C5H5N, at least 0.5 % by weight of P2S5 2C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S5 2C5H5N, at least 3 % by weight of P2S5 2C5H5N, at least 4 % by weight of P2S5 2C5H5N, at least 5 % by weight of P2S52C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S52C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S52C5H5N; and P2S52C5H5N and sulfolane together constitute at least 80 % by weight of the formulation.

In some embodiments, the formulation contains at least 0.1 % by weight of P2S52C5H5N, at least 0.5 % by weight of P2S5 2C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S5 2C5H5N, at least 3 % by weight of P2S5 2C5H5N, at least 4 % by weight of P2S5 2C5H5N, at least 5 % by weight of P2S52C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S52C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S52C5H5N; and P2S52C5H5N and sulfolane together constitute at least 85 % by weight of the formulation.

In some embodiments, the formulation contains at least 0.1 % by weight of P2S52C5H5N, at least 0.5 % by weight of P2S5 2C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S5 2C5H5N, at least 3 % by weight of P2S5 2C5H5N, at least 4 % by weight of P2S5 2C5H5N, at least 5 % by weight of P2S52C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S52C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S52C5H5N; and P2S52C5H5N and sulfolane together constitute at least 90 % by weight of the formulation.

In some further embodiments, the formulation contains at least 0.1 % by weight of P2S5 2C5H5N, at least 0.5 % by weight of P2S52C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S52C5H5N, at least 3 % by weight of P2S52C5H5N, at least 4 % by weight of P2S52C5H5N, at least 5 % by weight of P2S5 2C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S5 2C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S5 2C5H5N; and P2S52C5H5N and sulfolane together constitute at least 95 % by weight of the formulation.

In some further embodiments, the formulation contains at least 0.1 % by weight of P2S5 2C5H5N, at least 0.5 % by weight of P2S52C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S52C5H5N, at least 3 % by weight of P2S52C5H5N, at least 4 % by weight of P2S52C5H5N, at least 5 % by weight of P2S5 2C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S5 2C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S5 2C5H5N; and P2S52C5H5N and sulfolane together constitute at least 97 % by weight of the formulation.

In some further embodiments, the formulation contains at least 0.1 % by weight of P2S5 2C5H5N, at least 0.5 % by weight of P2S52C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S52C5H5N, at least 3 % by weight of P2S52C5H5N, at least 4 % by weight of P2S52C5H5N, at least 5 % by weight of P2S5 2C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S5 2C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S5 2C5H5N; and P2S52C5H5N and sulfolane together constitute at least 98 % by weight of the formulation.

In some further embodiments, the formulation contains at least 0.1 % by weight of P2S5 2C5H5N, at least 0.5 % by weight of P2S52C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S52C5H5N, at least 3 % by weight of P2S52C5H5N, at least 4 % by weight of P2S52C5H5N, at least 5 % by weight of P2S5 2C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S5 2C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S5 2C5H5N; and P2S52C5H5N and sulfolane together constitute at least 99 % by weight of the formulation. In some further embodiments, the formulation contains at least 0.1 % by weight of P2S5 2C5H5N, at least 0.5 % by weight of P2S52C5H5N, at least 1 % by weight of P2S5 2C5H5N, at least 2 % by weight of P2S52C5H5N, at least 3 % by weight of P2S52C5H5N, at least 4 % by weight of P2S52C5H5N, at least 5 % by weight of P2S5 2C5H5N, at least 6 % by weight of P2S52C5H5N, at least 7 % by weight of P2S5 2C5H5N, at least 8 % by weight of P2S5 2C5H5N, or at least at least 9 % by weight of P2S5 2C5H5N, and P2S52C5H5N and sulfolane together constitute at least 99.5 % by weight of the formulation.

Additional components of the formulation may comprise, for example, P4S10 and/or pyridine, and/or P2S52C5H5N decomposition products, and/or a further aprotic solvent, or any further compound not susceptible of reacting with P2S5 2C5H5N or sulfolane. Since P2S52C5H5N is susceptible to reacting with any oxo group present in the formulation, the formulation will essentially not contain any oxo group-containing compound, such as an ester, ketone, amide etc.

For example, in some embodiments, a formulation of the invention may comprise minor amounts of, for example, P2S4O.2C5H5N, having a ³¹ P-NMR peak at 98,5 ppm, and minor amounts of other unknown impurities, as illustrated by ³¹ P-NMR spectra herein.

In some embodiments, a formulation of the invention may contain pyridine in an amount of up to 10 % by weight of the total weight of the formulation, more preferably less than 9%, less than 8 %, less than 7 %, less than 6 %, less than 5 %, less than 4 %, less than 3 %, less than 2 %, less than 1 %, or less than 0.5 % by weight of the formulation.

In some embodiments, a formulation of the invention contains components other than P2S5 2C5H5N and sulfolane in an amount of up to 20 % by weight, preferably at most 15 % by weight, at most 10 % by weight, more preferably at most 9%, at most 8 %, at most 7 %, at most 6 %, at most 5 %, at most 4 %, at most 3 %, at most 2 %, at most 1 %, or at most 0.5 % by weight of the formulation.

The molar ratio of P2S5 2C5H5N to sulfolane in the formulation may vary within broad ranges. In some embodiments, the molar ratio of P2S5 2C5H5N to sulfolane in the formulation (mol P2S5 2C5H5N : mol sulfolane) is within the range of from 1 :2500 to 1 :25, e.g. within the range of from 1 :250 to 1 :25, from 1 :100 to 1 :25, from 1 :75 to 1 :25, from 1 :70 to 1 :25, from 1 :65 to 1 :25, from 1 :60 to 1 :25, from 1 :55 to 1 :25, from 1 :50 to 1 :25, from 1 :45 to 1 :25, from 1 :40 to 1 :25, or from 1 :35 to 1 :25, from 1 :32 to 1 :25, from 1 :31 to 1 :25, or from 1 :30 to 1 :25. In some embodiments, the molar ratio of P2S5 2C5H5N to sulfolane in the formulation is within the range of from 1 :2500 to 1 :26, from 1 :250 to 1 :26, e.g. within the range of from 1 :100 to 1 :26, from 1 :75 to 1 :26, from 1 :70 to 1 :26, from 1 :65 to 1 :26, from 1 :60 to 1 :26, from 1 :55 to 1 :26, from 1 :50 to 1 :26, from 1 :45 to 1 :26, from 1 :40 to 1 :26, or from 1 :35 to 1 :26, from 1 :32 to 1 :26, from 1 :31 to 1 :26, or from 1 :30 to 1 :26.

In some embodiments, the molar ratio of P2S5 2C5H5N to sulfolane in the formulation is within the range of from 1 :2500 to 1 :27, e.g. within the range of from 1 :250 to 1 :27, from 1 :100 to 1 :27, from 1 :75 to 1 :27, from 1 :70 to 1 :27, from 1 :65 to 1 :27, from 1 :60 to 1 :27, from 1 :55 to 1 :27, from 1 :50 to 1 :27, from 1 :45 to 1 :27, from 1 :40 to 1 :27, or from 1 :35 to 1 :27, from 1 :32 to 1 :27, from 1 :31 to 1 :27, or from 1 :30 to 1 :27.

In some embodiments, the molar ratio of P2S5 2C5H5N to sulfolane in the formulation is within the range of from 1 :2500 to 1 :28, e.g. within the range of from 1 :250 to 1 :28, from 1 :100 to 1 :28, from 1 :75 to 1 :28, from 1 :70 to 1 :28, from 1 :65 to 1 :28, from 1 :60 to 1 :28, from 1 :55 to 1 :28, from 1 :50 to 1 :28, from 1 :45 to 1 :28, from 1 :40 to 1 :28, or from 1 :35 to 1 :28, from 1 :32 to 1 :28, from 1 :31 to 1 :28, or from 1 :30 to 1 :28.

In some embodiments, the molar ratio of P2S5 2C5H5N to sulfolane in the formulation is within the range of from 1 :2500 to 1 :29, e.g. within the range of from 1 :250 to 1 :29, from 1 :100 to 1 :29, from 1 :75 to 1 :29, from 1 :70 to 1 :29, from 1 :65 to 1 :29, from 1 :60 to 1 :29, from 1 :55 to 1 :29, from 1 :50 to 1 :29, from 1 :45 to 1 :29, from 1 :40 to 1 :29, or from 1 :35 to 1 :29, from 1 :32 to 1 :29, from 1 :31 to 1 :29, or from 1 :30 to 1 :29.

In some embodiments, the molar ratio of P2S5 2C5H5N to sulfolane in the formulation is within the range of from 1 :2500 to 1 :30, e.g. within the range of from 1 :250 to 1 :30, from 1 :100 to 1 :30, from 1 :75 to 1 :30, from 1 :70 to 1 :30, from 1 :65 to 1 :30, from 1 :60 to 1 :30, from 1 :55 to 1 :30, from 1 :50 to 1 :30, from 1 :45 to 1 :30, from 1 :40 to 1 :30, or from 1 :35 to 1 :30, from 1 :32 to 1 :30, or from 1 :31 to 1 :30.

In some embodiments, the molar ratio of P2S5 2C5H5N to sulfolane in the formulation is within the range of from 1 :2500 to 1 :31 , e.g. within the range of from 1 :250 to 1 :31 , from 1 :100 to 1 :31 , from 1 :75 to 1 :31 , from 1 :70 to 1 :31 , from 1 :65 to 1 :31 , from 1 :60 to 1 :31 , from 1 :55 to 1 :31 , from 1 :50 to 1 :31 , from 1 :45 to 1 :31 , from 1 :40 to 1 :31 , or from 1 :35 to 1 :31 , or from 1 :32 to 1 :31. The formulation (composition) disclosed herein may be provided in a sealed container, e.g. a sealed container also including a desiccant, such as 3A or 4A molecular sieves.

In some embodiments, the formulation of the invention is provided in a sealed container, e.g. a sealed container equipped with a septum allowing for repeated withdrawal of portions of the formulation (e.g. by use of syringe), such as a Sure/Seal™ bottle (e.g. Sure/Seal™ glass bottles as sold by Sigma Aldrich), having a crimp-top system, to ensure that the required state of dryness of the formulation is maintained throughout long-term storage and use.

In some embodiments, before filling the container with the formulation of the invention, the container is treated to remove moisture from its inside, e.g. by oven drying, and the formulation is then fed into the container or prepared directly in the container, for example under an inert atmosphere of dry nitrogen or any other inert gas, such as argon. The container is then sealed, e.g. with a Sure/Seal™ liner and crown cap.

Thus, a further aspect is a container, such as a large volume container or tank, or a flask, bottle, or vial of smaller volume, containing the formulation of the invention and optionally a desiccant, such as 3A or 4A molecular sieves.

The container may be for one-time use or allow for multiple withdrawals of portions of the formulation. In some embodiments, the container is a sealed container equipped with a septum allowing for repeated withdrawal of portions of the formulation.

In some embodiments, a container containing the inventive formulation is provided, wherein the container has a metal (e.g. aluminium) crimp seal and a septum crimp top.

The container material may be, for example, glass, such as amber glass, a plastic material, e.g. thermoplastic material, an inert polymeric material such as polytetrafluoroethylene (PTFE), or a metal, such as aluminium, whereby the metal container may optionally be lined on the inside with an inert material such as PTFE.

It should be realized that if the formulation (e.g. in its container) is kept at a low temperature, e.g. in a refrigerator, solidification of the formulation may occur. In such case, in order to liquefy the formulation, it may be sufficient simply to keep the formulation for some time at room temperature. As an alternative, the formulation may be heated in a water bath at a temperature higher than the melting point of the sulfolane, e.g. a temperature of 30-40 °C. A further aspect of the invention is a process for preparing the inventive formulation of P2S5 2C5H5N in sulfolane. In some embodiments, crystalline P2S52C5H5N is prepared, such as by the process described in WO 2012/104415 A1 (cf. Example 1 in said WO pamphlet) and then admixed with sulfolane to provide a stock formulation as defined herein. Before admixing with sulfolane, the crystalline material may be washed, e.g. with an aprotic nonsolvent, such as tert-butyl methyl ether, and dried.

In some further embodiments, dry (anhydrous) pyridine and P4S10 are admixed in sulfolane and allowed to react with each other in the sulfolane as a reaction medium for the reaction, in a reaction according to the following general reaction scheme:

2 pyridine + 1 P ₄ S ₁₀ - ► P2S5.2C5H5N sulfolane

In some such embodiments, P4S10 is allowed to react with pyridine in sulfolane at a temperature of from room temperature to e.g. 80 °C, for a time period of e.g. 5 minutes to 1 hour, or until no solid material is visible in the reaction mixture. The formulation may then be transferred to a suitable container, e.g. a Sure/Seal™ bottle, allowing for long-term storage of the formulation.

Thus, in some embodiments, a process for preparing a formulation containing P2S5 2C5H5N in sulfolane is provided, wherein P4S10 and pyridine are admixed in sulfolane and allowed to react with each other at a temperature in a range of from room temperature to e.g. 80 °C, e.g. a temperature at least 20 °C, at least 25 °C, at least 27 °C, at least 27.5 °C, at least 27.6 °C, at least 28 °C, at least 30 °C, at least 35 °C, at least 40 °C, or at least 50 °C, for a time period of e.g. 5 minutes to 1 hour, or until no solid material is visible in the reaction mixture.

In some embodiments, pyridine and P4S10 are admixed in sulfolane in a molar ratio of pyridine to P4Sio (moles of pyridine:moles of P4S10) in the range of 1 :10 to 10:1 , 1 :8 to 8:1 , 1 :6 to 6:1 , 1 :5 to 5:1, 1 :4 to 4:1 , 1 :3 to 3:1 , or 1 :2 to 2:1.

In connection to this, it is noted that a molar ratio of 1 :1 of pyridine to P4S10 is equivalent to a molar ratio of 1 :2 of pyridine to P2S5.

In some of these embodiments, the molar ratio of pyridine to P4S10 is at most 8:1 , at most 7:1 , at most 6:1 , or at most 5:1. In some embodiments, the molar ratio of pyridine to P4S10 is at least 1 :5, at least 1 :4, at least 1 :3, at least 1 :2, at least 1 :2, at least 1 :1 , at least 2:1 , at least 3:1 , or at least 4:1. In some embodiments, pyridine and P4S10 are admixed in a molar ratio of pyridine to P4S10 of from 1 :1 to 10:1 , from 1 :1 to 8:1 , from 1 :1 to 6:1 , from 1 :1 to 5:1 , from 1 :1 to 4:1 , from 1 :1 to 3:1 , or from 1 :1 to 2:1. In some embodiments, pyridine and P4S10 are admixed in a molar ratio of pyridine to P4S10 of from 2:1 to 10:1 , from 2:1 to 8:1 , from 2:1 to 6:1 , from 2:1 to 5:1 , from 2:1 to 4:1 , or from 2:1 to 3:1. In some embodiments, pyridine and P4S are admixed in a molar ratio of pyridine to P4Sio of from 3:1 to 10:1 , from 3:1 to 8:1 , from 3:1 to 6:1 , from 3:1 to 5:1 , or from 3:1 to 4:1. In some embodiments, pyridine and P4S10 are admixed in a molar ratio of pyridine to P4S10 of from 4:1 to 10:1 , from 4:1 to 8:1 , from 4:1 to 6:1 , or from 4:1 to 5:1.

A further aspect of the invention is the use of the inventive stock formulation in a thionation reaction, as a thionating agent. In some embodiments, in such use, the inventive formulation is admixed with a suitable reaction medium for the thionation reaction, which may comprise an aprotic solvent selected from, for example, pyridine, a C1-C3 alkylnitrile (such as acetonitrile), a cyclic sulfone (such as sulfolane), a C1-C3 dialkylsulfone (such as dimethylsulfone) or a mixture of one or more aprotic solvents. In some embodiments, the reaction medium with which the formulation is admixed is different from sulfolane.

The compound to be thionated may be present in the reaction medium at the time of admixing the latter with the formulation of the invention, and/or may be admixed with the reaction medium containing the inventive formulation.

In some embodiments, the compound to be thionated may be admixed directly with the stock formulation of the invention. In other embodiments, a suitable amount of the stock formulation is admixed with the compound to be thionated, or with a solution of the compound to be thionated.

It should be noted that the inventive formulation allows for a very convenient thionating agent, having a very high storage stability in combination with an excellent thionating power, which in many cases allows the thionation to be performed even at as low a temperature as room temperature. Very advantageously, it is generally not considered necessary to separate the P2S52C5H5N (the thionating agent) from the sulfolane (its vehicle or solvent phase) before the thionating reaction.

One aspect is method for improving the stability of P2S5 2C5H5N against chemical degradation, said method comprising preparing a solution of P2S52C5H5N in sulfolane. The solution preferably is a stock formulation as described herein. Very advantageously, the method allows to provide P2S52C5H5N having a storage stability such that the amount of P2S5 2C5H5N decreases (e.g. by chemical decomposition or chemical reaction) by no more than 20 % by weight, more preferably no more than 10 % by weight, even more preferably no more than 5 % by weight, no more than 3 % by weight, no more than 2 % by weight, no more than 1 % by weight of P2S5 2C5H5N, or no more than 0.5 % by weight over a time period of at least several (e.g. 1-7) days, more preferably several (e.g. 1-4) weeks, even more preferably several (e.g. 1-12) months and most preferably even several (e.g. 1-3) years, e.g. a time period of at least one week, at least one month, at least 3 months, at least 6 months, or at least 1 year.

A further aspect is a process for transforming a group >C=O (I) (an oxo group) in a compound into a group >C=S (II) or into a tautomeric form of group (II), by bringing the compound into contact with the formulation of the invention, optionally in the presence of an aprotic solvent medium, e.g. an aprotic solvent medium comprising a solvent selected from pyridine, a C1-C3 alkylnitrile (such as acetonitrile), a cyclic sulfone (such as sulfolane), a C1- C3 dialkylsulfone (such as dimethylsulfone) or a mixture of one or more solvents. In some embodiments, if the aprotic solvent medium includes sulfolane, then it also includes at least one further aprotic solvent.

Thus, in some embodiments, a process is provided for transforming a group >C=O (I) in a compound into a group >C=S (II) or into a tautomeric form of group (II) in the compound, by bringing the formulation of the invention into contact with the compound containing the group >C=O (I), optionally dissolved in an aprotic solvent medium, as mentioned herein above, and allowing a thionation reaction to occur.

In some very advantageous embodiments of the invention, the inventive formulation, e.g. a formulation as described herein above, obtained by admixing pyridine and P4S10 in sulfolane, may allow for a thionation reaction of an oxo group containing compound to occur essentially without heating, e.g. at a temperature of about room temperature, or slightly higher temperature, such as a temperature in the range of from 20 to 60 °C, from 25 to 60 °C, from 26 to 60 °C, from 27 to 60 °C, from 27.5 to 60 °C, from 28 to 60 °C, from 29 to 60 °C, from 30 to 60 °C, e.g. a temperature of less than 55 °C, less than to 50 °C, less than 45 °C, less than 40 °C, less than 35 °C, or less than 30 °C.

Also provided herein is a process for transforming a group >C=O (I) in a compound into a group >C=S (II) or into a tautomeric form of group (II) in the compound wherein the thionation agent is prepared in situ, i.e. a process comprising admixing pyridine and P4S with sulfolane, and allowing the pyridine and the P4S10 to react with each other in the sulfolane as a reaction medium, to obtain a solution of P2S5 2C5H5N in sulfolane (e.g. a solution as described herein above), followed by bringing the sulfolane solution of P2S5 2C5H5N into contact with the compound containing the group >C=O (I), optionally dissolved in an aprotic solvent medium, as mentioned herein above, and allowing the thionation reaction to occur.

EXAMPLES

The invention will be illustrated by the following non-limiting EXAMPLES, wherein the materials used are indicated in TABLE 1.

TABLE 1

In the Examples, samples taken were analyzed by NMR using triphenylphosphate (SigmaAldrich TraceCert MW 326.28) as standard. Product singlet at 103 ppm; standard singlet at -16ppm. ³¹ P NMR Spectra were recorded on a Jeol 400 MHz instrument at 161 MHz frequency. Chemical shift was set as zero for the external standard (85% H3PO4 in H2O) during the device installation. The device remembers the exact frequency for this sample and references every sample to it. Chemical shift might be slightly different to the one with D- solvent but usually the difference is observed only from the third decimal place and is negligible for ³¹ P. Lock was not used during the measurements. By default, the gradient shim of the fid itself was used.

Analytical HPLC-MS was performed using an Agilent 1100 series Liquid Chromatograph/Mass Selective Detector (MSD) (Single Quadrupole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed using an ACE 3 C8 (3.0 x 50 mm) column with a gradient of acetonitrile in 0.1 % aqueous TFA over 3 min and a flow of 1 mL/min. ¹ H-NMR spectra (not shown) were recorded on a Bruker 400

MHz instrument at 25 °C.

EXAMPLE 1

Step 1 : Anhydrous pyridine (50mL) was degassed by sparging with nitrogen gas at room temperature for 2 hours. P4S10 (2.3g) was added at room temperature and the vessel was inerted by flushing with nitrogen. The mixture was stirred and heated with a hot-air gun up to reflux temperature for 10 minutes until the solids had completely dissolved giving a clear, orange solution. Within 10 minutes of stopping heating, a light-yellow powder had begun to precipitate. The mixture was cooled in a water bath for 20 minutes bringing it to room temperature. The solids were then collected quickly by vacuum filtration under a blanket of nitrogen.

Step 2: A portion of the wet solids (some mother-liquor was still present) was dissolved in anhydrous sulfolane and a sample of the obtained solution was analysed by ³¹ P NMR. The obtained spectrum is shown in FIGURE 1.

REFERENCE EXAMPLE 1

A portion of the wet solids obtained in Step 1 of EXAMPLE 1 was dissolved in anhydrous pyridine and a sample of the obtained solution was analysed by ³¹ P NMR. The obtained spectrum is shown in FIGURE 2.

EXAMPLE 2

A sample of the solution obtained in Step 2 of EXAMPLE 1 was stored for 72 hours at room temperature and was then analysed by ³¹ P NMR. The spectrum is shown in FIGURE 3.

REFERENCE EXAMPLE 2

A sample of the solution obtained in REFERENCE EXAMPLE 1 was stored for 72 hours at room temperature and was then analysed by ³¹ P NMR. The obtained spectrum is shown in FIGURE 4.

A comparison of FIGURE 1 and FIGURE 2 shows that at the day of preparation, the pyridine solution of P2S52C5H5N and the sulfolane solution of P2S52C5H5N gave essentially equivalent spectra, containing a large peak at 104 ppm corresponding to P2S52C5H5N. On the other hand, the ³¹ P NMR spectra obtained for samples of the two solutions after storage at room temperature for 3 days (72 hours) differ greatly. Thus, whereas the ³¹ P NMR spectrum (FIGURE 3) representative of the sulfolane solution after three days remained essentially the same as that obtained at day 0, the ³¹ P NMR spectrum corresponding to the 3-day old pyridine solution was greatly affected (FIGURE 4).

EXAMPLE 3

A portion (50 ml) of the formulation prepared in Example 1 is transferred into a dry 50-ml amber glass bottle under an inert (N2) atmosphere and the bottle is fitted with Sure Seal™ liner and crown cap.

EXAMPLE 4

A 250-mL Duran® bottle fitted with butyl-rubber closure was charged with P4S10 (15.1 g, 34 mmol) followed by sulfolane (200 ml). The vessel was inerted by applying vacuum for 5 minutes then introducing nitrogen gas. Anhydrous pyridine (13.5mL, 168 mmol, 5 mol. eq.) was then charged via syringe. Inerting with vacuum then nitrogen was repeated and stirring of the mixture started at room temperature. Most of the solids had dissolved within 4 hours giving a clear, yellow solution phase, although some solid particles remained. These dissolved overnight (18 hours after charging pyridine) to give a clear, yellow solution. The solution was stored at room temperature under nitrogen.

A sample was taken for ³¹ P NMR analysis of the obtained product. The obtained ³¹ P NMR spectrum is shown in FIGURE 5.

The theoretical concentration of P2S52C5H5N in the sulfolane solution was 9.2 % w/w (corresponding to about 0.3 M). The concentration based on the ³¹ P NMR assay was 8.0 % w/w.

EXAMPLE 5

The procedure of EXAMPLE 4 was repeated, using 7.77 g (17.5 mmol) of P4S10, 7 mL (86.7 mmol, 4.95 eq.) of pyridine, and 200 ml of sulfolane. The obtained ³¹ P NMR spectrum is shown in FIGURE 6. The theoretical concentration of P2S52C5H5N in the sulfolane solution was 5 % w/w. The concentration based on the ³¹ P NMR assay was 4.1 % w/w.

EXAMPLE 6

The procedure of EXAMPLE 4 was repeated, using 7.85 g (17.7 mmol) of P4S10, 7 mL (86.7 mmol, 4.95 eq.) of pyridine, and 200 ml of sulfolane. The obtained ³¹ P NMR spectrum is shown in FIGURE 7. The theoretical concentration of P2S52C5H5N in the sulfolane solution was 5 % w/w. The concentration based on the ³¹ P NMR assay was 4.1 % w/w. The solutions obtained in EXAMPLES 4-6 were stored at room temperature under nitrogen for up to 6 months. Samples of solutions obtained in EXAMPLE 5 were taken monthly and tested by ³¹ P NMR assay, while samples of solutions obtained in EXAMPLES 4 and 6 were taken at the end of the 6-month test period for the same assay.

Determination of P2S5 2C5H5N concentrations by ³¹ P NMR assay

The assays were performed by weighing in the standard (triphenylphosphate TraceCert standard) into a 4-mL vial which was then closed with a screw cap bearing a PTFE septum and inerted by applying vacuum then filling with nitrogen gas. Approximately 1ml of the obtained product solution (only solution phase in case of some solids being present) was then charged and the vessel weighed. The mixture was gently shaken and warmed slightly (heat-gun set to 50 °C) until a clear solution was obtained with no visible solids present. ³¹ P NMR was performed with a lengthened relaxation time. TABLE 2 shows the calculated concentration (% w/w) of P2S52C5H5N in sulfolane solution after the indicated storage period.

TABLE 2

Data in TABLE 2 are from one sample assay per reagent solution in months 0-2; two sample assays per solution from and in months 3-4; and three sample assays per solution in months 4-6. These indicate that the obtained solutions have a high stability over time in terms of P2S5 2C5H5N concentration.

EXAMPLE 7

Samples taken from the solutions obtained in EXAMPLES 4-6 (monthly for 6 months for EXAMPLE 5, and at 0 and 6 months for EXAMPLES 4 and 6) were reacted with acridone to give thioacridone (acridine-9(10H)-thione), according to the following reaction scheme: acridone thioacridone Approximately 200 mg of acridone were weighed into 4-ml vials fitted with magnetic stirrers. The vials were sealed with septa and inerted with nitrogen. Samples of the example solutions were then charged into the vials, in an amount sufficient to provide a molar ratio of P2S52C5H5N to acridone of 1:3, and the samples were stirred whilst heating to 100 °C (except in the first monthly test where the samples were heated to 60 °C). As the reactions proceeded, the solids dissolved, giving rise to blood-red solutions. Samples were analysed by LC-MS for conversion using and ACE3 C8 50x3 mm HPLC column, gradient of 10-90 % MeCN in 1.5 minutes, flow rate 1ml/min. In all cases, the conversion of acridone to thioacridone was > 98 % within about 20 minutes at 100 °C. FIGURE 8 is an example of an LC-MS chromatogram of a product solution obtained after 20 minutes of reaction at 100 °C

EXAMPLE 8

Acridone (224 mg) was dissolved in a 2-month sample (3.53 g) of the solution obtained in EXAMPLE 5 (0.35 eq. P2S52C5H5N) at room temperature and the solution was kept under magnetic stirring at room temperature. Conversion to thioacridone reached 5 % within 1 hour, 33 % within 1 day, 50 % within 2 days, 66 % within 3 days, 77 % within 4 days, and 95 % within 5 days. Addition of water (2 ml) to the mixture resulted in a slurry which was filtered, and the filter cake was washed with 2-methyltetrahydrofuran until the washings were colourless. Air-drying at room temperature for 1 week resulted in 194 mg of thioacridone (80 % yield) as a red-orange powder.

EXAMPLE 9

A 250 ml DURAN bottle fitted with butyl-rubber closure was charged with P4S10 (9.5 g, 21.4 mmol) followed by sulfolane (200 ml). The vessel was inerted by applying vacuum for 5 minutes then introducing nitrogen. Anhydrous pyridine (9.78 g, 124 mmol, 5.79 eq) was charged via syringe. Inerting was repeated and stirring started at room temperature. All solids dissolved within 3.5 hours giving a clear, yellow solution. The solution was assayed using ³¹ P NMR with triphenylphosphate (SigmaAldrich TraceCert MW 326.28) as standard. The product singlet appeared at 103ppm; the standard singlet at -16ppm. The P2S52C5H5N concentration (according to duplicate NMR assay) was 4.6 % w/w.

EXAMPLE 10

P4S10 (17.3 g) was charged to a dried 500 mL round-bottomed-flask fitted with a magnetic stirrer and the vessel was inerted. Anhydrous pyridine (90 ml) was charged via syringe with stirring. The mixture was stirred for 3 hours then was filtered using nitrogen pressure to push the mother liquor out. The filter cake was rinsed with MTBE (50 ml), again using N2 pressure to squeeze out the mother liquor. The solids were transferred to a 250 ml round-bottomed flask and dried under reduced pressure at room temperature overnight. Dry weight = 21.78g, light-yellow powder. A 250 ml DURAN bottle fitted with butyl-rubber closure was charged with the P2S52C5H5N (16.6 g) prepared above. Sulfolane (200 ml) was then charged. The vessel was inerted by applying vacuum for 5 minutes then introducing nitrogen. The mixture was stirred at room temperature for 1 hour during which all the solids dissolved giving a clear, yellow solution. The solution was assayed using ³¹ P NMR with triphenylphosphate (SigmaAldrich TraceCert MW 326.28) as standard. Product singlet at 103 ppm; standard singlet at -16ppm. The obtained P2S52C5H5N concentration (according to duplicate NMR assay) was 3.5 % w/w.

EXAMPLE 11

Six glass vials (4 ml) with magnetic stirrer bars were charged with acridone (204-208 mg). To 3 of the vials (A-C), samples (2.8 g) of the formulation obtained in EXAMPLE 9 were added, corresponding to 0.37 equivalent of P2S52C5H5N relative to acridone. To the 3 other vials (D- F), samples (3.5 g) of the formulation obtained in EXAMPLE 10 were added, corresponding to 0.35 equivalent of P2S52C5H5N relative to acridone. Pyridine (0.53 g) was added to vials B and E, corresponding to 6.4 equivalents relative to acridone, and to vials C and F, (1.13 g) corresponding to 13.6 equivalents relative to acridone. The vials were heated and the mixtures stirred using multi-vial heating block held at 62 °C. The solids dissolved within 5 minutes giving clear yellow solutions in all vials. Samples were taken at 25, 70, 125 and 210 minutes of reaction and were diluted in acetonitrile and analysed by LC-MS. The degree of conversion of acridone to thioacridone in the samples was calculated by area % thioacridone/ (area% acridone + area % thioacridone) at 215-395 nm. The results are shown in TABLE 3.

TABLE 3 The results shown in TABLE 3, indicate that all reactions went to “full” conversion with approximately 1/3 equivalent of P2S5 2C5H5N, but the addition of pyridine slowed down the reactions. The formulation prepared by dissolving solid P2S5 2C5H5N in sulfolane (EXAMPLE 10) gave a faster conversion than the formulation prepared by reacting pyridine and P4S10 in sulfolane (EXAMPLE 9). The formulation of EXAMPLE 9 had a higher concentration of P2S5 2C5H5N than that of EXAMPLE 10 (4.6 % w/w vs. 3.5 % w/w), but also contained nonreacted pyridine.

EXAMPLE 12

The acridone thionation reaction was repeated essentially as described in EXAMPLE 11 , using the formulations of EXAMPLES 9 and 10, respectively, but adding pyridine to the reaction solution containing the formulation of EXAMPLE 10 in an amount corresponding to 1 .9 eq., relative to acridone. The percent conversion of acridone to thioacridone was followed over time for the two formulations. The results are presented in TABLE 4.

TABLE 4

From the data presented in TABLES 3 and 4, it appears that the presence of pyridine in the reaction medium has the effect of slowing down the thionation reaction.

EXAMPLE 13

A 100 ml round-bottomed flask was charged with P4S10 (3.14 g, 7.1 mmol) followed by sulfolane (70 ml). The vessel was inerted by applying vacuum for 5 minutes then introducing nitrogen. Anhydrous pyridine (2.41 g, 4.3 eq.) was charged via syringe. Inerting was repeated and stirring started at room temperature. Most of the solids had dissolved within 70 minutes but some remained even after 3 hours and the mixture was stirred overnight (20 hours total time), all solids then having dissolved giving a clear, yellow solution. The solution was assayed using ³¹ P NMR with triphenylphosphate (SigmaAldrich TraceCert MW 326.28) as standard. Product singlet at 103 ppm; standard singlet at -16ppm. The obtained P2S5 2C5H5N concentration (according to duplicate NMR assay) was 3.5 % w/w. EXAMPLE 14

The acridone thionation reaction was repeated essentially as described in EXAMPLE 11 , using the formulations of EXAMPLES 9, 10, and 13 respectively. The results are presented in TABLE 5.

TABLE 5

As may be seen, the conversion rate obtained in vial B is faster than that obtained in vial A. One contributing factor to this faster conversion may be the higher amount of solvent (sulfolane) present in the thionation reaction using the formulation of EXAMPLE 10. Indeed, this formulation contained only 3.5 % w/w of P2S52C5H5N versus 4.6 % w/w of P2S52C5H5N in the formulation of EXAMPLE 9, which means that a higher volume of the formulation of EXAMPLE 10 had to be used to achieve the indicated amount of P2S52C5H5N. Since the reaction is initially a slurry, gradually becoming a solution as thionation progresses, the additional solvent may also have the effect of accelerating the thionation reaction by contributing to the dissolution of the acridone. If such effect does exist, the reaction could be accelerated by overall dilution.

When comparing the conversion rate obtained in vials B and C, respectively, it is noted that again the conversion rate is higher in vial B, while the sulfolane volume is essentially equal in both vials (both the formulation of EXAMPLE 10 and of EXAMPLE 13 contained 3.5 % w/w of P2S5 2C5H5N). The difference in reaction rate may be due to the higher amount of thionating agent present in vial B (0.39 eq.) compared to vial C (0.34 eq.).

Finally, a comparison of the conversion rate obtained using vials A and C shows that a formulation containing P2S5 2C5H5N prepared using only a slight excess of pyridine versus P4S (4.3 eq. in EXAMPLE 13, versus 5.79 eq. in EXAMPLE 9) performs well as a thionating agent.

EXAMPLE 15

Formulations of the invention were used to thionate benzanilide according to the following reaction scheme: benzanilide thiobenzanilide

Seven 4 ml glass vials with magnetic stirrer bars were charged with benzanilide (200-206 mg), followed by the formulations of EXAMPLES 9 and 10 and different amounts of pyridine, as shown in the below TABLE 6. The vials were heated, and the mixtures stirred using a multi-vial heating-block at 62 °C. The solids dissolved within 5 minutes giving clear, yellow solutions in all the vials. Samples were taken, diluted in acetonitrile and analysed by HPLC- MS at 1 h, 4h, 6h, 24h and 47h. The heating-block temperature was increased to 100 °C and a further sample taken from one of the vials after a further 2 hours.

Conversion was calculated by area% thiobenzanilide I (area% benzanilide + area% benzanilide) at 215-395 nm. Results are presented in TABLE 6.

TABLE 6 n.d = not determined, * relative to benzanilide, ** relative to P2S5 2C5H5N

Upon cooling to room temperature, the reaction solutions were combined, and water (60 ml) was charged with stirring at room temperature. A dark, red oil precipitated from solution. The mixture was extracted with MTBE (2 x 30mL) then the combined MTBE phases were washed with water (2 x 30 ml). The organic phase was washed with 3M HCI (30 ml) to remove residual pyridine and the clear, orange solution was concentrated to dryness under reduced pressure at 40°C. A brown solid was obtained (1.56 g). 1

The results presented in TABLE 6 shown that all reactions went to “full” conversion with approximately 1/3 ^rd equivalent of the thionating agent (P2S52C5H5N). The reaction rate was lower in the presence of pyridine. The reaction was the fastest in Vial D, containing the formulation of EXAMPLE 10 without any pyridine, while addition of even a small amount of pyridine resulted in a significant slowing down of the thionation reaction, cf. Vial G.

EXAMPLE 16

A further benzanilide thionation reaction was performed as described in EXAMPLE 15, using the conditions and reactant corresponding to Vial A, but at a reaction temperature of 100°C.

At this temperature, the conversion reached 96 % within 30 minutes and >98% conversion within 60 minutes.