Crystalline 2-fluoro-3-nitrotoluene and preparation method thereof

Abstract

The present invention relates to a crystalline 2-fluoro-3-nitrotoluene compound of formula (I), and a method for preparing the same. In addition, the present invention relates to a method for synthesizing a compound of formula (II) or a salt thereof by using the crystalline 2-fluoro-3-nitrotoluene.

Description

Technical Field

[0001] The present invention relates to crystalline 2-fluoro-3-nitrotoluene (abbreviated FNT) compounds having the formula (I):

[0002]

[0003] And a method for preparing the same. In addition, the present invention relates to a method for synthesizing a compound having formula (II):

[0004]

[0005] or a salt thereof and use of crystalline 2-fluoro-3-nitrotoluene in synthesizing the compound of formula (II) or a salt thereof. Background Art

[0006] Methods for preparing the compound 2-fluoro-3-nitrotoluene in a liquid physical state are known in the art, and such liquid products are commercially available. Typically, such liquid compounds are purified by distillation.

[0007] In particular, EP 2 172 198 A1 (corresponding to international patent application WO 2009014100 A1) discloses a method for preparing FNT starting from 2-chloro-3-nitrotoluene and cesium fluoride in dimethyl sulfoxide. The final FNT product is obtained as a yellow oil and purified by distillation under reduced pressure (boiling point: 118° C. to 122° C. / 0.0197 atm).

[0008] WO 2007091736 A1 discloses a method for preparing FNT using cesium chloride in dimethyl sulfoxide, the final product being obtained as a yellow oil which is purified by distillation under reduced pressure (boiling point: 118° C. to 122° C. / 0.0197 atm).

[0009] Julius, V. et al., Berichte der Deutschen Chemichen Gesellschaft [Abteilung] B [Reports of the German Chemical Society [Division] B]: Abhandlungen [Collection of Papers], Volume: 64B, pp. 2465-73, (1931), discloses a method for obtaining 2-fluoro-3-nitrotoluene (20%-23% yield) from 2-nitro compounds and amyl nitrite via 3-nitro-diazonium fluoroborate and sand.

[0010] However, handling of the liquid product and purification of the substance in liquid form, usually by distillation, is considered to be complicated and potentially hazardous due to the nitrotoluene nature of the substance concerned. Summary of the invention

[0011] The problem solved by the present invention was therefore to provide a crystalline form of 2-fluoro-3-nitrotoluene (FNT) which can be easily purified and handled, wherein this crystalline form is also obtained in high yield.

[0012] This problem is solved by a crystalline form of 2-fluoro-3-nitrotoluene and a process for its preparation by a specific purification process.

[0013] Further features and advantages of the crystalline form according to the invention and of the corresponding preparation process will become apparent from the description of the preferred embodiments reported below, given by way of non-limiting examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown is the XPRD diffraction pattern of a crystalline solid form of 2-fluoro-3-nitrotoluene (FNT).

[0015] Figure 2 is an optical micrograph (4x) of the crystalline solid form of 2-fluoro-3-nitrotoluene (FNT).

[0016] Figure 3 , 4A , 4B, 5A and 5B show the DSC of samples A1800449 (analysis B), A1800450 (analysis A and B) and A1800451 (analysis A and B), respectively. DETAILED DESCRIPTION

[0017] According to a first aspect, the present invention relates to crystalline 2-fluoro-3-nitrotoluene having formula (I):

[0018]

[0019] It has a DSC peak starting point at a value between 25.0°C and 26.0°C or has a DSC peak maximum point at a value between 26.0°C and 27.5°C or has a characteristic X-ray powder diffraction pattern, wherein a characteristic peak expressed as a 2-θ value (2θ) is at 14.3±0.2.

[0020] Advantageously, the Applicant has surprisingly found that the 2-fluoro-3-nitrotoluene is obtained as a crystalline solid by a purification process by crystallization, the complexity of its preparation is significantly reduced, and the handling of the crystalline form itself is also significantly improved. In addition, this new crystalline form is obtained in high yield (i.e., greater than 90%). In fact, since this method provides a product with higher purity, it shows a much higher melting point, thus making the product easier to handle.

[0021] As a further advantage, the compound of formula (I) prepared according to the process of the present invention has a reduced amount of the isomeric impurity 2-fluoro-4-nitrotoluene having the formula:

[0022]

[0023] It is an impurity that is particularly difficult to remove by distillation, since it has a similar boiling point to FNT and since it reacts similarly to FNT, it produces isomeric impurities in products prepared starting from FNT. In particular, the process of the invention reduces the amount of said impurity, as illustrated in Example 4. For said purpose, a volume ratio of methanol / H2O 1:1 or methanol / water 2:1 is preferred.

[0024] According to a preferred embodiment, the crystalline 2-fluoro-3-nitrotoluene has a DSC peak starting point at a value between 25.0°C and 26.0°C and / or a DSC peak maximum point at a value between 26.0°C and 27.5°C and has a characteristic X-ray powder diffraction pattern, wherein the characteristic peak expressed as a 2-θ value (2θ) is at 14.3±0.2.

[0025] According to another preferred embodiment, the crystalline 2-fluoro-3-nitrotoluene has a DSC peak starting point at a value between 25.0°C and 26.0°C and a DSC peak maximum point at a value between 26.0°C and 27.5°C and has a characteristic X-ray powder diffraction pattern, wherein the characteristic peak expressed as a 2-θ value (2θ) is at 14.3±0.2.

[0026] According to another preferred embodiment, the crystalline 2-fluoro-3-nitrotoluene has a DSC peak onset at a value between 25.0°C and 26.0°C and a characteristic X-ray powder diffraction pattern, wherein a characteristic peak expressed as a 2-theta value (2θ) is at 14.3±0.2.

[0027] Preferably, the crystalline 2-fluoro-3-nitrotoluene has a DSC peak maximum at a value between 26.0°C and 27.5°C and a characteristic X-ray powder diffraction pattern wherein a characteristic peak expressed as a 2-theta value (2θ) is at 14.3±0.2.

[0028] Preferably, the crystalline 2-fluoro-3-nitrotoluene has a DSC peak onset at a value between 25.0°C and 26.0°C and a DSC peak maximum at a value between 26.0°C and 27.5°C.

[0029] In addition, the crystalline 2-fluoro-3-nitrotoluene may have an additional peak at 11.3±0.2 expressed as a 2-θ value (2θ) at a characteristic X-ray powder diffraction pattern.

[0030] According to another preferred embodiment of the present invention, the crystalline 2-fluoro-3-nitrotoluene has a DSC peak onset at a value between 25.0°C and 25.5°C.

[0031] Preferably, the crystalline 2-fluoro-3-nitrotoluene has a DSC peak maximum at a value between 26.5°C and 27.2°C.

[0032] As for the meaning of the term DSC peak starting point, as generally known to the technician, the extrapolation starting temperature (according to DIN EN ISO 11357-1:2010-03) is the designed intersection of the extrapolated baseline and the inflection tangent line at the beginning of the melting or crystallization peak. The baseline and the inflection tangent line are determined from the temperature-dependent heat flow signal. In the case of pure and homogeneous materials, the starting temperature can be expressed as the melting temperature. Compared with the peak temperature, the starting temperature is less dependent on the heating rate and the sample quality. In addition, the starting temperature is usually used for the temperature calibration of DSC.

[0033] According to a further aspect, the present invention relates to a method for preparing crystalline 2-fluoro-3-nitrotoluene of formula (I) as defined above:

[0034]

[0035] A method of preparing a 2-fluoro-3-nitrotoluene product comprising crystallizing 2-fluoro-3-nitrotoluene of formula (I) from a mixture of water and a solvent selected from a C1-C3 alcohol.

[0036] As intended herein, the expression C1-C3 alcohol means methanol, ethanol, isopropanol, n-propanol, respectively.

[0037] According to a preferred embodiment, the method further comprises a stirring step. Advantageously, involving a stirring step makes it possible to obtain crystals with a larger particle size, which allows for faster filtration of the suspension containing the product of formula (I).

[0038] Preferably, the mixture of water and solvent (preferably C1-C3 alcohol, more preferably methanol or ethanol, even more preferably methanol) is stirred for a period of more than 10 min, more preferably more than 30 min. Preferably, the mixture of water and solvent is stirred for a period of from 30 min to 4 hours, more preferably from 1 hour to 3 hours, even more preferably about 2 hours. Preferably, the stirring is carried out at a temperature of from 0°C to 30°C, preferably from 5°C to 25°C, even more preferably from 10°C to 20°C.

[0039] According to another preferred embodiment, a mixture of water and a solvent (preferably a C1-C3 alcohol, more preferably methanol or ethanol, even more preferably methanol) is stirred at a temperature from 0°C to 30°C, preferably from 5°C to 25°C, more preferably from 10°C to 20°C, for a period of from 30 min to 4 hours, preferably from 1 hour to 3 hours, more preferably about 2 hours.

[0040] According to another preferred embodiment, the mixture is a mixture of water and methanol, stirred at a temperature from 5 to 25°C, preferably from 10 to 20°C, for a period of time from 1 hour to 3 hours.

[0041] As will be apparent to the skilled person, the preparation and handling of the crystalline form of the present invention is advantageously easier than one of the other physical forms, such as a compound in liquid form (e.g., oil, liquid with oily consistency). Furthermore, since the purification process of the present invention is represented by the crystallization itself, complex purification steps, such as distillation, for example, can be avoided.

[0042] According to a preferred embodiment of the present invention, the method is carried out by dissolving 2-fluoro-3-nitrotoluene in a solvent selected from C1-C3 alcohols, preferably methanol and ethanol, even more preferably methanol, and then adding water as an anti-solvent.

[0043] Regarding the volume ratio between the solvent and water, a ratio of from 3: 1 to 1: 3 may be provided. Preferably, the volume ratio between the solvent and water is 1: 1 or 2: 1, with 1: 1 being more preferred.

[0044] According to another particularly preferred embodiment, the C1-C3 alcohol is methanol or ethanol, preferably methanol, and the volume ratio between the solvent and water is 1:1.

[0045] As intended herein, the term volume means the volume of solvent per unit of product, thus, for example, 1 volume is 1 liter / 1 kilogram, or 1 mL (for 1 gram), or 1 microliter / 1 milligram. Thus, 10 volumes means, for example, 10 liters / 1 kilogram of material, in which case the solvent and water used as a mixture of solvent and water are used to prepare crystalline 2-fluoro-3-nitrotoluene of formula (I).

[0046] As for the volume of each solvent and water used in the mixture of solvent and water (for preparing crystalline 2-fluoro-3-nitrotoluene having formula (I)), preferably from 1 to 10 volumes, more preferably from 1 to 5 volumes, even more preferably 2 volumes can be used.

[0047] According to an alternative embodiment of the present invention, the crystalline 2-fluoro-3-nitrotoluene having formula (I) as defined above:

[0048]

[0049] It can be prepared according to the following method, which comprises the following steps:

[0050] - adding the compound of formula (I) as a liquid to a mixture of water and a solvent C1-C3 alcohol as defined above;

[0051] - heating the mixture until complete homogeneity is achieved;

[0052] - Cooling the resulting solution. After the cooling step, a further step of stirring and filtering the suspension of the compound of formula (I) may be carried out.

[0053] According to a further aspect, the present invention relates to a method for synthesizing a compound having formula (II):

[0054]

[0055] or a salt thereof,

[0056] The method comprises the following steps:

[0057] - preparing crystalline 2-fluoro-3-nitrotoluene of formula (I) as defined above according to the process as defined above:

[0058]

[0059] - converting the crystalline 2-fluoro-3-nitrotoluene into the compound of formula (II).

[0060] The conversion step from crystalline 2-fluoro-3-nitrotoluene to the compound of formula (II) can be carried out according to the teaching from pages 15 to 18 and from pages 21 to 28 of WO 2014 / 152270.

[0061] According to a further aspect, the crystalline 2-fluoro-3-nitrotoluene of formula (I) as defined above may be used to synthesize a compound of formula (II):

[0062]

[0063] or a salt thereof.

[0064] Experimental Section

[0065] All starting materials are commercially available, for example, through Sigma-Aldrich.

[0066] For the synthesis of 2-fluoro-3-nitrotoluene to be crystallized by the method of the present invention, any method known in the art can be used. For example, it can be prepared according to the procedures disclosed in CN 101177400 A, WO2009014100 (paragraph 657).

[0067] Example 1 - Purification by crystallization

[0068] Into a 4-neck round bottom flask was charged 150 g of 2-fluoro-3-nitrotoluene (FNT) having the following formula:

[0069]

[0070] The 2-fluoro-3-nitrotoluene is obtained by the method disclosed in WO 2009014100 and dissolved in 300 ml (2 V) of methanol at a temperature of 30°C. The homogeneous solution is cooled to 17°C / 18°C. 300 ml (2 V) of water is added at 17°C-19°C within 2 h. The solution is stirred at 15°C for 2 hours to obtain a suspension of the product, which is filtered at 15°C (rapid filtration and clarification of the mother liquor) and then washed (MeOH / H2O (0.5 V / 0.5 V) and dried in vacuo to provide a crystalline solid compound (I) with a yield of 90%, wherein the XPRD diffraction pattern of the solid form is Figure 1 The corresponding data are also reported in Table 1 below.

[0071] Table 1

[0072]

[0073]

[0074] The solid crystals of 2-fluoro-3-nitrotoluene (FNT) obtained were Figure 2 Shown in , where optical microscopy pictures (4x) are reported.

[0075] Example 2 - Purification by crystallization

[0076] Example 1 was repeated by using the same total volume of solvent and water and having a volume ratio of 2:1 and 1:2 between methanol and water, obtaining yields of 80% and 88%, respectively.

[0077] Example 3 - Purification by crystallization

[0078] Example 1 was repeated by using ethanol instead of methanol and a yield of 88% was obtained.

[0079] Example 4 - Correlation between purification and solvent / water volume ratio

[0080] Experimental tests were carried out in order to evaluate the purity of the product obtained in correspondence with the purification and the solvent / water volume ratio used. Table 2 below shows the results obtained.

[0081] Table 2

[0082]

[0083]

[0084] Example 5 - DSC Analysis

[0085] Samples of 2-fluoro-3-nitrotoluene (A1800449, A1800450 and A1800451) were stored at 4°C before DSC analysis. The solids were gently ground at 4°C to obtain a homogeneous powder suitable for DSC analysis. DSC sample preparation was then performed in a temperature-controlled cold room at 17.0°C ± 0.5°C to avoid any possible sample melting. DSC analyses were recorded with a Mettler Toledo DSC2. The NF-Tol samples were weighed into a 40 μL aluminum crucible with a pinhole cover at approximately 17°C and heated from 5°C to 40°C at 10K / min under nitrogen (50mL / min). For each batch, duplicate analyses (A and B) were performed. The samples were also analyzed at 5K / min from 5°C to 40°C under nitrogen (50mL / min) to examine the possible influence of the heating rate, but similar DSC curves were obtained. The results of these analyses are summarized in Table 3 below. The DSC performed at Figure 3 , 4A , 4B, 5A and 5B.

[0086] Table 3

[0087]

[0088] Example 6 - XPRD Method

[0089] For the XPRD method, the instrument used, instrument parameters and other parameters are reported in Table 4 below. The XPRD diffraction pattern of FNT obtained is Figure 1 Report in.

[0090] Table 4

[0091]

[0092]

Claims

1. A crystalline 2-fluoro-3-nitrotoluene having the formula (I): It has a DSC peak onset at a value between 25.0°C and 26.0°C and / or has a DSC peak maximum at a value between 26.0°C and 27.5°C; and The compound has a characteristic X-ray powder diffraction pattern, wherein characteristic peaks represented by 2-θ values ​​(2θ) are at 11.3±0.2 and 14.3±0.

2.

2. The crystalline 2-fluoro-3-nitrotoluene according to claim 1, having a DSC peak onset at a value between 25.0° C. and 26.0° C. and having a characteristic X-ray powder diffraction pattern, wherein characteristic peaks expressed in 2-θ values ​​(2θ) are at 11.3±0.2 and 14.3±0.

2.

3. The crystalline 2-fluoro-3-nitrotoluene according to claim 1 or 2, which has a DSC peak onset at a value between 25.0°C and 25.5°C.

4. The crystalline 2-fluoro-3-nitrotoluene according to claim 1 or 2, which has a DSC peak maximum at a value between 26.5°C and 27.2°C.

5. A method for preparing a crystalline 2-fluoro-3-nitrotoluene of formula (I) as defined in any one of claims 1 to 4 method, in which The process comprises crystallizing 2-fluoro-3-nitrotoluene having formula (I) from a mixture of water and a solvent selected from methanol and ethanol.

6. The method according to claim 5, wherein: The method is performed by dissolving 2-fluoro-3-nitrotoluene in a solvent selected from methanol and ethanol, and then adding water as an anti-solvent.

7. The method according to claim 5 or 6, wherein: The volume ratio between the solvent and water was 1:

1.

8. The method according to claim 5 or 6, further comprising a stirring step.

9. The method according to claim 8, wherein: The stirring step is carried out at a temperature from 0°C to 30°C.

10. A method for synthesizing a compound of formula (II): or a salt thereof, The method comprises the following steps: - Preparation of crystalline 2-fluoro-3-nitrotoluene of formula (I) as defined in any one of claims 1 to 4 according to a process as defined in any one of claims 5 to 9: - converting the crystalline 2-fluoro-3-nitrotoluene into the compound of formula (II).

11. Use of crystalline 2-fluoro-3-nitrotoluene of formula (I) as defined in any one of claims 1 to 4 for the synthesis of a compound of formula (II): or the use of its salts.

Images