Patent Application
20240025865
The present invention relates to the field of organic synthesis, specifically to an improved method for the preparation of prothioconazole and its intermediates 2-(1-chloro-cycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxy-propyl-1-hydrazine and 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazolidine-3-thione.
Prothioconazole, 2-[(2RS)-2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2H-1,2,4-triazole-3(4H)-thione, is a fungicide used to treat infected crops, first described in U.S. Pat. No. 5,789,430. The structure is reproduced below:
Key intermediates in the preparation of prothioconazole are 2-(1-chlorocycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxypropyl-1-hydrazine and 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazolidine-3-thione. Their preparation still presents many challenges as it can be deduced from the problems of the different strategies disclosed in the prior art.
DE4030039A1 teaches the preparation of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)propan-2-ol starting from 2-(1-chlorocyclopropyl)-2-(2-chlorobenzyl) oxirane using a two stage process. For the first stage, the oxirane is reacted with hydrazine in the presence of a solvent and, optionally, a phase transfer catalyst to provide 2-(1-chlorocycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxypropyl-1-hydrazine. The solvents used by DE4030039A1 for this reaction are alcohols and ethers, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, diethyl ether, dioxane and tetrahydrofuran. For the second stage, DE4030039A1 teaches the same solvents. The hydrazine derivative is reacted with formamidine acetate in the presence of a phase transfer catalyst to provide 2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-(1,2,4-triazol-1-yl)propan-2-ol. The subsequent transformation of this intermediate into prothioconazole is achieved by reactions that involve the use of sulfur and, optionally butyllithium.
A similar teaching is found in WO 2021/074739. According to the description, the solvent used to obtain the 2-(1-chlorocycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxypropyl-1-hydrazine can be C1-C4 alcohols selected from methanol, ethanol, isopropanol and t-butanol; cyclohexanol, toluene, acetonitrile (ACN), N, N-dimethyl formamide (DMF) and sulfolane. In the example shown on page 11 n-butanol is however used, which is partially soluble in water (about 73 g/L at 25° C.).
In order to solve the above and other problems to reach 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazolidine-3-thione, US 2001/0011138 discloses its preparation directly from 2-(1-chlorocycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxypropyl-1-hydrazine by reacting the latter with a thiocyanate in toluene (paragraph [0089]). For the preparation of the hydrazine derivative used as starting material, US 2001/0011138 relies on the teachings of DE4030039A1.
An important problem of the two prior methods is the instability of 2-(1-chlorocycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxypropyl-1-hydrazine. U.S. Pat. No. 6,559,317 seeks to solve this problem by generating its hydrochloric salt, a far more stable compound. U.S. Pat. No. 6,559,317 teaches the preparation of the hydrochloric salt of the hydrazine derivative by first reacting 2-(1-chlorocyclopropyl)-2-(2-chlorobenzyl)oxirane with hydrazine in a mixture of toluene and acrylonitrile and then passing hydrochloric gas through the mixture.
WO 2019/123368 further improves the conditions disclosed in U.S. Pat. No. 6,559,317 and teaches against the use of toluene for the formation of 2-(1-chlorocycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxypropyl-1-hydrazine. According to WO 2019/123368, 1-chloro-2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)propan-2-ol is a more advantageous starting material than 2-(1-chlorocyclopropyl)-2-(2-chlorobenzyl)oxirane.
In the search for a more efficient process the inventors have designed a strategy that is surprisingly more efficient than those of the prior art, and provides 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazolidine-3-thione in good yield and purity.
The first aspect disclosed herein is therefore a process for the preparation of a mixture comprising the neutral form of a hydrazine derivative of Formula (I) and a first solvent or mixture of solvents, the process comprising (i) a two-phase reaction between an oxirane of Formula (II) and hydrazine in the presence of water and the first solvent or mixture of solvents, wherein said first solvent or mixture of solvents consist of one or more water-insoluble solvents;
A second aspect is a process for the preparation of a thiono derivative of Formula (III) comprising
Therefore, by using only solvents that have low solubility in water (referred to as the “first solvent or mixture of solvents”) in step (i) achieved a one-pot process starting from the oxirane derivative of Formula (II) all the way to the thiono derivative of Formula (III), that is 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2,4-triazolidine-3-thione, without the need of isolating the intermediate hydrazine derivative of Formula (I), that is 2-(1-chloro-cycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxy-propyl-1-hydrazine.
It is not only that the hydrazine derivative of Formula (I) can be used without isolation, there is not even the need to evaporate the solvent, and the mixture can be used as it is directly for the next step, or after simple conditioning steps (e.g. washing or filtrating). This notably simplifies the industrial process.
Other processes in the prior art use solvents that are partially soluble in water, such as methanol. These solvents drag some of the product into the water phase and therefore have to be evaporated, a procedure that in the presence of hydrazine causes many safety concerns that limit or even prevents industrial application. Such evaporation is also necessary to recycle the hydrazine.
Therefore, a further aspect is a mixture comprising a first solvent or mixture of solvents and between 1% w/w and 99% w/w of the hydrazine derivative of Formula (I), wherein the first solvent or mixture of solvents consist of one or more water-insoluble solvents.
A further aspect is the use to prepare prothioconazole of a mixture comprising between 1% w/w and 99% w/w of a hydrazine derivative of Formula (I) in a first solvent or mixture of solvents, wherein said first solvent or mixture of solvents consist of one or more water-insoluble solvents.
The processes described herein provide the thiono derivative of Formula (III) in high yield and purity. This result is surprising given the instability of the hydrazine derivative of Formula (I). To solve this problem the prior art has suggested different solvent systems for the reactions or the preparation of the corresponding hydrochloric salt, even at the expense of introducing additional steps. The processes disclosed herein solve the stability problem by preparing a mixture wherein the hydrazine derivative of Formula (I) is sufficiently stable, while allowing to directly proceed to the next stage with the crude product. The use of water-insoluble solvents also avoids other solvents recommended in the prior art, such as methanol, which create safety issues during evaporation.
Therefore, contrary to DE4030039A1, the processes disclosed herein use water-insoluble solvents (e.g. toluene) as a solvent in step (i), allowing the preparation of a crude solution of 2-(1-chlorocycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxypropyl-1-hydrazine (the hydrazine derivative of Formula (I)) typically in toluene that can be used directly in the next step.
Neither does US 2001/0011138 teach the use of water-insoluble solvents, such as toluene, for obtaining the hydrazine derivative of Formula (I). In fact, US 2001/0011138 teaches that the preferred starting material for obtaining this intermediate is not the oxirane derivative of Formula (II), but the hydroxy-chloride derivative 1-chloro-2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)propan-2-ol. Example 2 teaches a one-pot process starting from this hydroxy-chloride, not from the oxirane derivative of Formula (II), to prepare the thiono derivative of Formula (III). The first step of the process uses no solvent, and the second step of the process takes place in methyl tert-butyl ether, not toluene, providing an overall poor yield (47% from the hydroxy-chloride). The yields of the process disclosed herein are higher (almost 75%). Therefore, US 2001/0011138 fails to teach the use of toluene in the production of the hydrazine derivative of Formula (I) or the possibility of improving the yields using a one-pot process starting from the oxirane derivative of Formula (II) and using a water-insoluble solvent all the way to the thiono derivative of Formula (III).
The process disclosed herein by the inventors also avoids the use of the hydrochloric salt of the hydrazine derivative of Formula (I), as taught in U.S. Pat. No. 6,559,317 or WO 2019/123368, notably simplifying the process. Although preparing the more stable salt may seem attractive, it requires two additional steps: the formation of the salt itself, which uses gaseous hydrochloric acid, and the subsequent neutralization with a base.
Thus, a further aspect is a process for the preparation of prothioconazole comprising
The starting material used in the processes disclosed herein is the oxirane derivative of Formula (II), which can be obtained by methods already taught in the art, for example in DE4030039A1 or in U.S. Pat. No. 5,097,047. See for example columns 10 and 11 of U.S. Pat. No. 5,097,047. For example, the oxirane derivative of Formula (II) can be obtained by intracyclization of the corresponding hydroxy-chloride in the presence of an acid binder, as disclosed in paragraphs [0078]-[0081] of US 2001/0011138. Alternatively, the intramolecular cyclization can be performed using a base as taught in example 1.b) of DE4030039A1. The one or more water-insoluble solvents used in the process of the invention allow the two-phase reaction to proceed efficiently and in good yield. Further, the separation of the water phase and the organic phase once the reaction has finished is simple and effective. The aqueous phase retains unreacted hydrazine and other impurities, and the organic phase is a mixture comprising the hydrazine derivative of Formula (I) in neutral form and the first solvent or mixture of solvents that are water-insoluble. This organic phase is sufficiently pure to directly proceed to the next step of the process, and does not require any evaporation steps in the presence of hydrazine. Some conditioning processes, such as filtration or washing (e.g. with a neutral of basic aqueous solution) are optional. Any solvent that is insoluble in water is suitable for the process of the invention. It is preferred that the one or more water-insoluble solvents comprise one or more solvents selected from the group consisting of a C7-C20 alcohol, a C6-C20 aromatic hydrocarbon and mixtures thereof, preferably a C7-C12-aromatic hydrocarbon selected from the group consisting of toluene, xylene and mixtures thereof.
Thus, the process of the invention preferably comprises (i) a two-phase reaction between an oxirane of Formula (II) and hydrazine, in the presence of water and the first solvent or mixture of solvents, wherein said first solvent or mixture of solvents consist of one or more water-insoluble solvents selected from the group consisting of a C7-C20 alcohol, a C6-C20 aromatic hydrocarbon and mixtures thereof.
Typically, the process comprises (i) a two-phase reaction between an oxirane of Formula (II) and hydrazine, in the presence of water and the first solvent or mixture of solvents, wherein said first solvent or mixture of solvents consist of one or more water-insoluble solvents comprising a C6-C20 or C7-C20 aromatic hydrocarbon.
The water-insoluble solvent typically comprises toluene and can be the only water-insoluble solvent used.
The process preferably takes place in the presence of one, that is, a single, water-insoluble solvent. Therefore, the process of the invention typically comprises (i) a two-phase reaction between an oxirane of Formula (II) and hydrazine, in the presence of water and the first solvent, wherein said first solvent consists of one water-insoluble solvent, preferably wherein the water-insoluble solvent consists of toluene.
Water is not necessarily added as such, but typically comes with the reagents, mainly with the hydrazine.
The preparation of the hydrazine derivative of Formula (I) may therefore proceed by contacting the oxirane derivative of Formula (II) with hydrazine using toluene as the only water-insoluble solvent.
Hydrazine can be used in any suitable form, typically hydrazine hydrate. Hydrazine is typically fed into the reaction mixture as an aqueous solution, for example, a 20 to 65% w/w aqueous solution, for example, it can be added as hydrazine hydrate 100% (i.e. 65% w/w hydrazine). It can be added alone or together with a phase transfer catalyst. The hydrazine is typically used in molar excess with respect to the oxirane derivative of Formula (II). The inventors have found that the process disclosed herein requires a lower excess of hydrazine, especially when using a phase transfer catalyst, which is another advantage of the process. Thus, the proportion between the hydrazine and the oxirane of Formula (II) is typically comprised between 1:1 and 20:1, for example, between 3:1 and 20:1, or between 15:1 and 10:1, preferably, between 8:1 to 7:1. Said excess of hydrazine can be recycled into the reaction. If no recycling is desired, the process can function even at lower excesses of hydrazine, for example, the proportion between the hydrazine and the oxirane of Formula (II) can be comprised between 1:1 and 5:1, or between 1.05:1 and 3:1.
The process may use a phase transfer catalyst, such as ammonium or phosphonium compounds. Phase transfer catalysts can be selected from the group consisting of tetraalkyl ammonium salts, trialkyl aralkylammonium salts or tetraalkyl-phosphonium salts such as tetrabutylammonium bromide or chloride, methyl trioctylammonium bromide, methyl tributylammonium chloride, triethyl benzyl ammonium bromide or chloride, and benzyl dodecyl dimethyl ammonium chloride (known as Zephirol®). Numerous brands exist such as the Aliquat® series. The phase-transfer catalysts are generally used in aqueous or alcoholic solutions. The phase transfer catalyst can be a single species such as methyl tributylammonium chloride (Aliquat® 175) or a mixture such as Aliquat® 336 (Stark's catalyst), which is quaternary ammonium salt that contains a mixture of octyl and decyl chains.
The reaction can proceed in the presence of a wide range of phase transfer catalyst proportions. Preferably, the molar percentage of phase transfer catalyst with respect to the oxirane is between 0.1 and 50 mol %, preferably between 0.5 and 40 mol %. It has been found that the use of a solid PTC is surprisingly efficient and can reduce by more than half the total amount of PTC used. Thus, when using solid PTC its amount used with respect to the oxirane is between 0.1 and 50 mol %, preferably between 1 and 40 mol %, or even between 1 and 20 mol %.
The reaction typically proceeds at atmospheric pressure, but other pressures can be used. Temperature is typically required to proceed in a reasonable time and the reaction is usually maintained at reflux, typically at a temperature comprised between 20° C. and 150° C., for example between 40° C. and 150° C., for example between 20° C. and 100° C., for example between 50° C. and 95° C.
Therefore, the process is typically a two-phase system. Once the reaction is complete, the process can comprise an additional step (ia) wherein the two phases of the two-phase reaction mixture are separated to create a first current and a second current, wherein the first current comprises aqueous unreacted hydrazine (and, optionally, also the phase transfer catalyst), and the second current comprises the first solvent or mixture of solvents (e.g toluene) and the hydrazine derivative of Formula (I). This separation can be done at a temperature comprised between 20° C. and 80° C., preferably between 40° C. and 70° C. The first current comprising unreacted hydrazine (and, optionally, also the phase transfer catalyst) can be directly recycled for subsequent reactions, especially when a large excess is used, optionally after being mixed with fresh hydrazine. For example, the process can use a proportion between the hydrazine and the oxirane of Formula (II) comprised between 3:1 and 20:1 or between 4:1 and 20:1, wherein the excess of hydrazine is recycled for subsequent reactions.
The reaction can take place at a gentle reflux. The material distilled can be recovered in a separate current or condensed back into the reaction. Thus, the evaporation of water and hydrazine from the reaction mixture can start before the reaction is complete without interfering in the final yield or conversion.
The second current comprising toluene and the hydrazine derivative of Formula (I) can be optionally washed, for example, at least one time with a neutral or basic solution, and then be used directly in the next step to obtain the thiono derivative of Formula (III). This hydrazine derivative of Formula (I) is sufficiently stable in the first solvent or mixture of solvents to be used in subsequent steps without any change of solvent (no evaporation is necessary), which is a very efficient strategy. This solution can be obtained at different concentrations, typically between 1% w/w and 99% w/w of the hydrazine derivative of Formula (I) and toluene, for example between 5% w/w and 95% w/w, preferably between 10% w/w and 80% w/w, preferably between 12% w/w and 60% w/w, more preferably between 15% w/w and 50% w/w, preferably between 15% w/w and 40% w/w, even more preferably between 20% w/w and 30% w/w of the hydrazine derivative of Formula (I) in toluene.
As mentioned above, a further aspect is a comprising
The solution comprising the neutral form of the hydrazine derivative of Formula (I) and the first solvent or mixture of solvents resulting from step (i) is fed into step (ii) without isolation as a mixture comprising between 1% w/w and 99% w/w of the hydrazine derivative of Formula (I), with respect to the total weight of the solution.
Optionally, the mixture of hydrazine derivative of Formula (I) in the water-insoluble solvent resulting from step (i) is washed with an aqueous solution before use. Thus, the process for the preparation of a thiono derivative of Formula (III) may comprise
Step (i) of this process proceeds as described above in the previous section. Step (ii) may also use a second solvent or mixture of solvents that is water-insoluble, and requires formaldehyde and a thiocyanate for completion, and optionally an acid, typically an inorganic acid, such as phosphoric acid, HCl, sulfuric, or organic acids, such as formic acid or acetic acid.
It is preferred that the solvent used in step (ii) is the same as in step (i), that is, it is preferred that the first solvent or mixture of solvents is the same as the second solvent or mixture of solvents. Step (ii) typically proceeds at atmospheric pressure, but other pressures can be used. Temperature is typically required to proceed in a reasonable time and the reaction is usually maintained at a temperature comprised between 20° C. and 100° C., for example between 30° C. and 80° C.
Again, there is no need to add water as such, which usually comes together with the reagents, formaldehyde, the thiocyanate and the acid.
The formaldehyde can be employed as paraformaldehyde, as gaseous formaldehyde or as Formalin solution (aqueous formaldehyde solution). Preference is given to using Formalin solution. The preferred thiocyanate is sodium thiocyanate. Both, formaldehyde and the thiocyanate are typically used in excess, for example from 1 to 2 equivalents of formaldehyde and/or from 1 to 2 equivalents of thiocyanate for every mol of hydrazine derivative of Formula (I). Typically, up to 1.5 equivalents of formaldehyde are used, preferably, between 1 and 1.4 or between 1 and 1.2.
The thiono derivative of Formula (III) obtained can be purified through the usual processes, such as chromatographic purification or recrystallization, for example, in the same water-insoluble solvent, e.g. toluene. The order of addition of formaldehyde, thiocyanate and acid is irrelevant.
In order to provide prothioconazole, the thiono derivative of Formula (III) must be oxidxidized or aromatized. This can be done by following processes already disclosed in the prior art, such as for example, WO 2019/123368 A1 (see pages 9 through 13). Exemplary methods to perform the oxidation involve the aromatization in the presence of an oxidizing agent in a suitable solvent or mixture of solvents. Alternatively, aromatization can be acid catalyzed in the presence of an oxidizing agent in a suitable solvent or mixture of solvents. Acids can be selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, benzoic acid, substituted benzoic acid, trifluoroacetic acid, and formic acid. Acids can also be Lewis acids such as, aluminium chloride, stannous chloride, stannic chloride, titanium tetrachloride, boron trifluoride diethyl etherate, boron THF complex, or zinc chloride. Oxidizing agents can be selected from the group consisting of hydrogen peroxide, m-chloro perbenzoic acid (ra-CPBA), oxone, tert-butyl hydrogen peroxide (TBHP), copper sulphate, sodium nitrite, t-butyl nitrite, Ferric Chloride (III) and tert-butyl nitrite.
An 8 liter reactor was vented with nitrogen, and then fed with toluene (2700 gr), 2-(1-chloro-cycloprop-1-yl)-2-(2′-chloro-benzyl)-oxirane (1200 gr in 77.7% w/w purity), Aliquat® 175 (10 gr of a 75% w/w methyltributylammonium chloride in water). The reactor was heated to 60° C. and 1205 gr of hydrazine hydrate and additional 300 gr of Aliquat® 175 (75% w/w) were added. The temperature was raised to 90° C. and the reaction mixture stirred for 5 hours. When more than 98.5% of the oxirane was consumed, the reaction was consider finished. The mixture was cooled to 60° C. and the organic and aqueous phases separated. The aqueous phase containing unreacted hydrazine and Aliquat® 175 was recycled for the next batch (this reduced in subsequent batches the addition of fresh hydrazine to 291 gr and of fresh Aliquat® to 10 gr). The organic phase was washed with 2500 gr of an aqueous solution of sodium carbonate (10% w/w). The organic phase was separated to provide a 24% w/w toluene solution of the hydrazine derivative of Formula (I) (2-(1-chloro-cycloprop-1-yl)-3-(2-chloro-phenyl)-2-hydroxy-propyl-1-hydrazine), which was used directly in the next step (90% yield). This notably increases the yield disclosed in example 2 of US 2001/0011138 (47%), which in the case of the present invention is 70% from the oxirane derivative of formula (II).
An 10 liter reactor was vented with nitrogen, and then fed with toluene (3120 gr), 2-(1-chloro-cycloprop-1-yl)-2-(2′-chloro-benzyl)-oxirane (1310 gr), solid Aliquat® 175 (207.76 gr of a 98% w/w methyltributylammonium chloride). The reactor was heated to 95° C. and 411.6 gr of hydrazine hydrate were added. the reaction mixture stirred for 5 hours. When more than 98.5% of the oxirane was consumed, the reaction was consider finished. The mixture was cooled to 60° C. and washed with 1200 gr water twice and phases separated. The 24% w/w toluene solution of the hydrazine derivative of Formula (I) (2-(1-chloro-cycloprop-1-yl)-3-(2-chloro-phenyl)-2-hydroxy-propyl-1-hydrazine), was used directly in the next step (88% yield).
The use of the PTC in solid form allowed the reduction of the proportion needed with respect to the oxirane starting material. In Example 1 it was about 26 mol %, while in this example it was about 16 mol %. Also, the amount of hydrazine hydrate could be significantly reduced.
A 250 liter reactor was vented with nitrogen, and then fed with toluene (70 Kg) and 2-(1-chloro-cycloprop-1-yl)-2-(2′-chloro-benzyl)-oxirane (25 Kg in 77.7% w/w purity). The reactor was heated to 80° C. and 60 Kg of hydrazine hydrate were added. The temperature was raised to 95° C. and after 4 hours water evaporated for 1.5 hours. When more than 98.5% of the oxirane was consumed, the reaction was consider finished. The mixture was cooled to 60° C. and the organic and the aqueous phases separated. The aqueous phase containing unreacted hydrazine was recycled for the next batch. The organic phase was washed twice with 40 Kg of water. The organic phase was separated to provide a 20% w/w toluene solution of the hydrazine derivative of Formula (I) (2-(1-chloro-cycloprop-1-yl)-3-(2-chloro-phenyl)-2-hydroxy-propyl-1-hydrazine), which was used directly in the next step (90% yield).
A 250 liter reactor was nitrogen vented and charged at room temperature with 100 Kg of the toluene solution from the previous step containing the (2-(1-chloro-cycloprop-1-yl)-3-(2-chloro-phenyl)-2-hydroxy-propyl-1-hydrazine). The reactor was heated to 50° C. and fed with 16 Kg of a 50% w/w water solution of sodium thiocyanate over a period of 10 minutes and stirred for additional 15 minutes at 50° C. 6 Kg of formalin and 8 Kg of H3PO4 were added over a period of 4 hours at 50° C. with vigorous stirring. The temperature was raised to 75° C. and stirred for 1 hour to yield 132 Kg of crude solution of the thiono derivative of Formula (III). The reaction mixture was cooled, filtrated and dried. 21 Kg of the thiono derivative of Formula (III) were obtained in 98% purity.
The reactor was nitrogen vented and charged at room temperature with 3950 Kg of the toluene solution from the previous step comprising (2-(1-chloro-cycloprop-1-yl)-3-(2-chloro-phenyl)-2-hydroxy-propyl-1-hydrazine). The reactor was heated to 50° C. and fed with 758.4 Kg of a 50% w/w water solution of sodium thiocyanate over a period of 10 minutes and stirred for additional 15 minutes at 50° C. 324 Kg of formalin and 398 Kg of H3PO4 were added over a period of 4 hours at 50° C. with vigorous stirring. The temperature was raised to 60° C. and stirred for 1 hour to yield 5430 Kg of crude solution of the thiono derivative of Formula (III). The reaction mixture was cooled and filtrated, and the thiono derivative of Formula (III) was recrystallized from toluene.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2021/051375 | 11/18/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63115631 | Nov 2020 | US |
