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Title:
DIOXANE SOLVATE OF PROTHIOCONAZOLE AND PROCESS FOR PREPARATION THEREOF
Document Type and Number:
WIPO Patent Application WO/2020/174432
Kind Code:
A1
Abstract:
The present invention relates to a stable crystalline dioxane solvate of Prothioconazole formula (I) and process for preparation thereof. The present invention also relates to crystalline 1,4-dioxane solvate of prothioconazole (II) and process for preparation thereof.

Inventors:
NAMBIAR SUDHIR (IN)
GHOSH SANTOSH KUMAR (IN)
DOKE SURESH (IN)
RAO LAKONDA NAGAPRASADA (IN)
MITTAPALLI SUDHIR (IN)
LAMBATE VINAYAK SHIRISHKUMAR (IN)
NIPUNGE DNYANESHWAR SAMBHAJIRAO (IN)
Application Number:
PCT/IB2020/051674
Publication Date:
September 03, 2020
Filing Date:
February 27, 2020
Export Citation:
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Assignee:
HIKAL LTD (IN)
International Classes:
A01N43/653; A01N43/64; C07D249/02
Foreign References:
CN108546251A2018-09-18
Attorney, Agent or Firm:
SHARMA, Sweety (IN)
Download PDF:
Claims:
We Claim:

1. Crystalline dioxane solvate of Prothioconazole formula (I)

2. Crystalline 1,4-dioxane solvate of prothioconazole formula (II)

3. Crystalline 1,4 dioxane solvate of prothioconazole formula (II) as claimed in claim 2 characterized by at least one of the following parameters:

a) at least one characteristic 2-theta value (±0.2) at 6.7, 9.2, 11.7, 13.4, 13.6, 16.0, 16.8, 16.9, 19.3, 20.2, 21.5, 23.9, 25.7, 26.4, 27.0, 27.1, 30.3 and 34.0; b) DSC desolvation peak 89 to 91 °C;

c) TGA weight loss is 6.0 to 11.0%;

d) peak maxima in the FTIR spectrum at with wave numbers in cm-1 1548, 1485, 1457, 1407, 1390, 1345, 1323, 1292, 1259, 1138, 1101, 1079, 1101, 1052, 959, 910, 851, 754, 637 and 619;

e) a unit cell having the following dimensions a = 7.1231(3) A, b = 10.0503(4)A, c = 13.5445(5) A, a = 82.646(2)°, b = 76.939(2)°, g = 72.4430(10)°,

V= 898.69(6) A3;

f) a melting point of 140.46° C.

4. Crystalline 1,4 dioxane solvate of prothioconazole formula (II) of claim-2 comprises a particle density of 1.435 g/cm3.

5. A process for preparation of crystalline dioxane solvate of prothioconazole (I) comprises the steps:

a) dissolving prothioconazole of formula (III) in first solvent at 50°C to 70°C; b) adding an anti- solvent; c) with or without maintaining at 50°C to 70°C;

d) cooling at 0°C to 30°C;

e) filtering to obtain crystalline dioxane solvate of prothioconazole of formula

(I); and

f) with or without washing crystalline dioxane solvate of prothioconazole formula (I) with second solvent after filtration.

6. A process for preparation of crystalline 1,4-dioxane solvate of prothioconazole (II) comprises the steps:

a) dissolving prothioconazole of formula (III) in 1, 4-dioxane at 50°C to 70°C; b) adding an anti- solvent;

c) with or without maintaining at 50°C to 70°C;

d) cooling at 0°C to 30°C;

e) filtering to obtain crystalline 1, 4-dioxane solvate of prothioconazole formula

(II); and

f) with or without washing crystalline 1, 4-dioxane solvate of prothioconazole formula (II) with second solvent after filtration.

7. The process as claimed in claim 5, wherein first solvent is selected from group consisting of 1,2-dioxane, 1,3-dioxane and 1,4-dioxane.

8. The process as claimed in claim 5 and claim 6, wherein an anti-solvent and second solvent is selected from group consisting of water, toluene, anisole and hexane.

9. Crystalline dioxane solvate of prothioconazole obtained by a process as claimed in claim 5 and claim 6 is solvate or hemisolvate.

10. Crystalline 1,4 dioxane solvate of prothioconazole obtained by a process as claimed in claim 6 have higher solubility as compared to prothioconazole DMSO solvate, prothioconazole crystal form I and form II.

Description:
DIOXANE SOLVATE OF PROTHIOCONAZOLE AND PROCESS FOR

PREPARATION THEREOF

RELATED APPLICATION

This application claims the benefit to Indian Provisional Application No. 201921007950, filed on February 28, 2019, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a crystalline dioxane solvate of prothioconazole formula (I), composition, use and process for preparation thereof. The present invention further relates to a crystalline 1,4-dioxane solvate of prothioconazole formula (II), composition, use and process for preparation thereof.

BACKGROUND OF THE INVENTION

Prothioconazole is a broad spectrum anti-fungal agent of triazolinthione family and is used as a fungicide to treat infected crops especially in cereals. The IUPAC systematic name of prothioconazole is 2-[2-(l-Chlorocyclopropyl) -3-(2-chlorophenyl) -2-hydroxypropyl] -2, 4- dihydro-3H-l, 2, 4-triazole-3-thione. The structure of prothioconazole (III) with a molecular formula of C14H15CI2N3OS and a molecular weight of 344.26 is shown below. Prothioconazole was first disclosed in US Patent 5,789,430 and corresponding patent publications, as a triazolyl derivative.

The US Patent 7,176,226 (henceforth ‘226) discloses the crystal form I and II of prothioconazole, a process for preparation of form II using form I and the composition of form II. The US patent‘226, further discloses that the prothioconazole crystal form I is metastable and crystal form II is thermodynamically stable at room temperature. The US Patent 9,290,461 discloses the crystalline dimethyl sulfoxide (DMSO) solvate of prothioconazole, amorphous prothioconazole, microbicidal compositions comprising them and uses thereof.

The Chinese Patent application 108546251 A discloses the crystalline toluene solvate of prothioconazole and process for the preparation thereof.

The different polymorphic forms of biologically active molecules, including amorphous form and crystalline solvates, often possess different physical properties, which may be useful in different contexts. The differences in stability, solubility, hygroscopicity, melting point, particle density and flow ability may exert a strong influence on the quality and the effectiveness of crop treatment agents. Among these solubility in aqueous solutions is one of the most important physical properties of biologically active compounds. The different polymorphs of the same compound can reportedly do have different aqueous solubilities.

Since prothioconazole is an agricultural fungicide, it is highly desirable to obtain new forms for having improved solubility and/or dissolution rate. Such new forms of prothioconazole may require lower dosage, reduce application rate, as compared to less soluble forms. The discovery of new forms such as solvated form used in agriculturally, veterinary or medicinally useful compounds which may provide an opportunity to improve the performance characteristics of a product. Thus, it will be advantageous to have new solvated crystalline forms of prothioconazole, and efficient methods for their preparation.

Hence, the instant inventors are motivated to explore the research for the synthesis of new solvate form of prothioconazole and the process for preparation thereof. Therefore, the present invention relates to a crystalline dioxane solvate of prothioconazole of formula (I) and process for preparation thereof. Particularly, the present invention relates to a crystalline 1,4-dioxane solvate of prothioconazole of formula (II) and process for preparation thereof.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide a crystalline dioxane solvate of prothioconazole formula (I) and process for preparation thereof.

The another objective of the present invention is to provide a stable crystalline 1,4-dioxane solvate prothioconazole (II) and process for preparation thereof in a simple, economical, user- friendly and commercially viable manner.

Another objective of the present invention is to provide a process for the preparation of compound of formula (I), (II) with a greater yield and higher chemical purity, which would be easy to implement on commercial scale and makes the present invention eco-friendly as well.

Another objective of the present invention is to provide a composition of crystalline dioxane solvate of prothioconazole formula (I) with acceptable excipients.

Another objective of the present invention is the use of a crystalline dioxane solvate of prothioconazole formula (I) and composition thereof with acceptable excipients.

Another objective of the present invention is to provide a composition of compound formula (II) with acceptable excipients.

Yet another objective of the present invention is the use of compound formula (II) and composition thereof with acceptable excipients.

SUMMARY OF THE INVENTION

The present invention relates to a crystalline dioxane solvate of prothioconazole formula (I). The present invention is directed to a crystalline 1,4-dioxane solvate of prothioconazole formula (II).

The present invention is further directed to a process for the preparation of the crystalline dioxane solvate of prothioconazole formula (I), which comprising the step of:

a) dissolving prothioconazole of formula (III) in a suitable first solvent at a suitable temperature;

b) adding an anti- solvent;

c) optionally maintaining the reaction mixture at a suitable temperature;

d) cooling the reaction mixture at a suitable temperature;

e) filtering the precipitate to get crystalline dioxane solvate of prothioconazole of formula (I); and

f) with or without washing the crystalline dioxane solvate of prothioconazole of formula (I) with second solvent after filtration.

The above process is illustrated in the following general synthetic scheme;

BRIEF DESCRIPTION OFTHE FIGURES

FIG. 1 illustrates a representative PXRD pattern for crystalline 1,4-dioxane solvate of prothioconazole formula (II).

FIG. 2 illustrates a representative DSC scan for crystalline 1,4-dioxane solvate of prothioconazole formula (II).

FIG. 3 illustrates a representative TGA scan for crystalline 1,4-dioxane solvate of prothioconazole formula (II).

FIG. 4 illustrates a representative FTIR pattern for crystalline 1,4-dioxane solvate of prothioconazole formula (II). FIG. 5: illustrates a representative 1 H-NMR Spectra for crystalline 1,4-dioxane solvate of prothioconazole formula (II).

FIG. 6: illustrates a representative 13 C-NMR Spectra of crystalline 1,4-dioxane solvate of prothioconazole formula (II).

FIG. 7: illustrates the ORTEP (Oak Ridge Thermal Ellipsoid Plot) diagram for 1,4-dioxane solvate of prothioconazole of formula (II).

FIG. 8: illustrates the Packing diagram for 1,4-dioxane solvate of prothioconazole of formula (II).

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms“a”,“an”,“the”, include plural referents unless the context clearly indicates otherwise.

In accordance with the objectives, wherein the present invention provides crystalline dioxane solvate of prothioconazole formula (I), crystalline 1,4-dioxane solvate of prothioconazole formula (II) and process for preparation of thereof.

In another embodiment of the present invention, wherein the prothioconazole of formula (III) of step (a) having chemical purity at least 90%.

In another embodiment of the present invention, wherein the suitable first solvent of step (a) may be selected from the dioxane solvent such as 1,2-dioxane, 1,3-dioxane and 1,4-dioxane and the like.

In another embodiment of the present invention, wherein the said suitable temperature of step

(a) between 50°C to 70°C.

In another embodiment of the present invention, where in the said an anti-solvent used in step

(b) is one or more selected from water, toluene, anisole, hexane. In another embodiment of the present invention, wherein the said reaction mixture of step (c) may be maintained at a suitable temperature between 50°C to 70°C.

In another embodiment of the present invention, wherein the said reaction mixture of step (d) may be cooled to a temperature between 0°C to 30°C with stirring.

In another embodiment of the present invention, wherein the said crystalline dioxane solvate of prothioconazole of formula (I) of step (e) isolated by filtration or other isolation technique with or without purification.

In another embodiment of the present invention, wherein the said second solvent in step (f) for washing of crystalline dioxane solvate of prothioconazole formula (I) is one or more selected from water, toluene, anisole, hexane.

In another embodiment of the present invention, wherein the crystalline dioxane solvate of prothioconazole obtained by a process is hemisolvate.

In another embodiment of the present invention, the compounds (I), (II) are in substantially pure form. As used herein, the term“substantially pure', when used in reference to a solvate of prothioconazole, refers to a dioxane solvate of prothioconazole which is having purity at least 99% by HPLC.

In another embodiment of the present invention, the crystalline 1,4-dioxane solvate prothioconazole formula (II) shows higher solubility than DMSO solvate, crystalline prothioconazole form I and form II. According to another embodiment of the invention, wherein the solubility of crystalline 1,4-dioxane solvate of prothioconazole formula (II) is higher than Crystalline prothioconazole Form I, Form II, and prothioconazole DMSO solvate; In this embodiment the solubility was performed in pH 7 water solution at 20°C and the compared in table- 1.

Table 1: The crystalline 1,4-dioxane solvate of prothioconazole formula (II) was characterized by its powder X-ray diffraction pattern and recorded on Bruker D8 advance diffractometer (Bruker- AXS, Karlsruhe, Germany) using Cu-Ka X-radiation (l = 1.5406 A) at 40 kV and 40 mA powers. X-ray diffraction patterns were collected over the 20 range 2° to 40° with time per step 0.5(s).

In another embodiment of the present invention, wherein the crystalline 1,4-dioxane solvate of Prothioconazole formula (II) characterized by its PXRD pattern with at least one characteristic 2-theta value (±0.2) at 6.7, 9.2, 11.7, 13.4, 13.6, 16.0, 16.8,16.9, 19.3, 20.2, 21.5, 23.9, 25.7, 26.4, 27.0, 27.1, 30.3 and 34.0 as shown in Table 2.

In another embodiment of the present invention, wherein the crystalline 1,4-dioxane solvate of prothioconazole formula (II) is stable at room temperature. The stability studies were carried-out in different intervals and found that there are no significant changes in 2 Q values.

Table 2:

The crystalline 1,4-dioxane solvate of prothioconazole formula (II) was further characterized using Differential Scanning Calorimetry (DSC 3+), measured using a Differential Scanning calorimeter from Mettler Toledo, measuring from 25°C to 400°C at 10°C/min and samples of 2-10 mg each were purged by a stream of nitrogen flowing at 60 mL/min. The Aluminium standard crucibles of 40pL with pin were used. The evaluation of the results was performed using STAR 6 software from Mettler-Toledo.

In another embodiment the compound (II) is characterized by DSC desolvation peak in between temperature 80°C to 100°C.

In another embodiment the crystalline 1,4-dioxane solvate of prothioconazole formula (II) was further characterized using The rmogravimetric analysis (TGA 2), on Mettler Toledo measuring from 25°C to 400°C at 10°C/min and samples of 4-10 mg each were purged by a stream of nitrogen flowing at 60 mL/min. The Aluminium standard crucibles of 40pL with pin were used. The evaluation of the results was performed using STAR 6 software from Mettler-Toledo. According to a more specific embodiment of the present invention, wherein the crystalline 1,4-dioxane solvate of prothioconazole (II) exhibits a TGA weight loss of about 6.0-11.0% when heated up to about 140°C. In another embodiment of the present invention, wherein the crystalline 1,4-dioxane solvate of prothioconazole formula (II) was further characterized using Fourier-transform infrared spectroscopy (FTIR), on Nicolet 6700 FT-IR spectrometer with a FTIR Module and the samples dispersed in KBr pellets having one or more additional FTIR absorption bands and characteristic values (expressed as cm 1 ) 1548, 1485, 1457, 1407, 1390, 1345, 1323, 1292, 1259, 1138, 1101, 1079, 1101, 1052, 959, 910, 851, 754, 637, and 619.

In another embodiment of the present invention, wherein the crystalline 1,4-dioxane solvate of prothioconazole formula (II) was further characterized using Proton Nuclear magnetic resonance spectroscopy ( ' H-NMR).

In another embodiment of the present invention, wherein the crystalline 1,4-dioxane solvate of prothioconazole formula (II) was further characterized using Carbon- 13 Nuclear magnetic resonance spectroscopy ( 13 C-NMR).

In yet another embodiment of the present invention, wherein the crystalline 1,4-dioxane solvate of prothioconazole formula (II) was crystallized from methanol and 1,4 dioxane solvent mixture. The crystal structure of dioxane solvate of prothioconazole was confirmed by single crystal X-Ray diffractogram, where the solvate is crystallized in P-1 space group under triclinic crystal system (a=7.1231 (3)A, b = 10.0503(4) A, c= 13.5445(5) A, a = 82.646(2)°, b= 76.939(2)°, g= 72.443(10)°, v = 898.69(6) A 3 ).

In yet another embodiment of the present invention, wherein the crystallographic information of single crystal structure, bond lengths, bond angles of the crystalline 1,4-dioxane solvate of prothioconazole formula (II) are shown in Table 3, 4, 5 respectively.

Table 3:

Table 4:

Table 5:

The following non-limiting examples are given by way of illustration of the present invention and therefore should not be construed as limitation of the invention scope.

Example l:Preparation of crystalline 1,4-dioxane solvate of prothioconazole

The prothioconazole of formula (III) (2.0 g, 0.0058 moles, purity of >99%) was dissolved in to 1,4-dioxane (2mL, 0.022 moles) under stirring at 60°C. The resulting reaction mixture was maintained at same temperature for about 1 h. Then water (2.5mL) was added to the mixture and the reaction mixture was cooled to 25°C to 30°C. After reaching the temperature between 25°C to 30°C, the reaction mixture was further cooled to 0°C and stirred for about 2 to 3 h at same temperature. The reaction mixture was filtered to yield white crystalline 1,4-dioxane solvate of prothioconazole (II) (1.4g, 62%) with HPLC purity of 99.6%. The final product was characterized and confirmed by PXRD, DSC, TGA, 1 H-NMR, 13 C-NMR, FT-IR and finally by single crystal XRD.

Example 2: Preparation of crystalline 1,4-dioxane solvate of prothioconazole (II)

The prothioconazole of formula (III) (10.0 g, 0.029 moles, purity of >99%) was dissolved in to 1,4-dioxane (lOmL, 0.113 moles) under stirring at 60°C. The resulting mixture was maintained at same temperature for about 2 to 3h. The water (lOmL) was added to the mixture at the same temperature (60°C) and the reaction mixture was maintained for about 10 to 15min. Then the reaction mixture was cooled to 25°C to 30°C. After reaching the temperature between 25°C to 30°C, the reaction mixture was further cooled to 0°C and stirred for about 4 to 5h at same temperature. The reaction mixture was filtered, washed with water (50mL) to yield white crystalline 1,4-dioxane solvate of prothioconazole (II) (10.9 g, 96.6%) with HPLC purity 99.6%. The final product was characterized and confirmed by PXRD, DSC, TGA and FTIR. Abbreviations