Crystal form of 2-methyl-3-trifluoromethylaniline and synthesis method

Abstract

The invention discloses a crystal form of 2-methyl-3-trifluoromethylaniline and a synthesis method, the crystallization process is simple, the generated waste liquid is less, the environment is protected, and the prepared crystal form I of 2-methyl-3-trifluoromethylaniline is not easy to absorb moisture, has good stability, and has no change after being placed at 25 + / -1 DEG C for 60 days.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a crystal form and a synthesis method of 2-methyl-3-trifluoromethylaniline. Background Art

[0002] 2-Methyl-3-trifluoromethylaniline is a pharmaceutical intermediate, and its downstream product, flunixin meglumine, is a veterinary anti-inflammatory analgesic. It has antipyretic, anti-inflammatory and analgesic effects. When used alone or in combination with antibiotics, it can significantly improve some clinical symptoms and enhance the activity of antibiotics. In veterinary clinics, this drug can relieve pain and anti-inflammation caused by visceral colic, muscle and bone disorders when used on horses; it can control acute inflammation caused by various infections, such as laminitis and arthritis when used on cattle; it can assist in the treatment of sows with mastitis, metritis, agalactia syndrome and other diseases when used on sows. It is one of the few approved veterinary non-steroidal drugs developed by Schering-Plough in the United States in the 1990s. It mainly exerts antipyretic, anti-inflammatory and analgesic effects by inhibiting cyclooxygenase and reducing the production of inflammatory mediators such as prostaglandins. The drug was first used to relieve inflammation, musculoskeletal disorders, colic and other related pain in horses. It was subsequently approved for use in acute inflammation caused by infectious diseases in cattle, auxiliary treatment of agalactia syndrome in sows, and endotoxemia in dogs. It is now widely used in many countries.

[0003] 2-Methyl-3-trifluoromethylaniline is a colorless to light-colored crystalline solid. Currently, there is no research on the crystal form of 2-methyl-3-trifluoromethylaniline. For drugs and drug intermediates, different crystal forms can have different physical and chemical properties, and these physical and chemical properties will affect or even directly determine the effect of the drug.

[0004] In terms of crystallization process, the invention with patent publication number CN117843494A discloses a method for preparing 2-methyl-3-trifluoromethylaniline, that is, the fraction obtained after vacuum distillation of the obtained crude 2-methyl-3-trifluoromethylaniline is dissolved in ethanol, and then water is added for crystallization.

[0005] CN 117843497A adds n-heptane to the concentrate for pulping, and then filters and dries to obtain a white solid, but the crystal form is not studied and the stability is not tested.

[0006] Therefore, there is an urgent need in the art to conduct research on the crystalline form of 2-methyl-3-trifluoromethylaniline in order to find an advantageous crystalline form with high stability, low moisture absorption rate and the ability to be stably produced in industrial quantities. Summary of the invention

[0007] To this end, it is necessary to provide a crystalline form I of 2-methyl-3-trifluoromethylaniline and a synthesis method, the preparation process of the crystalline form is simple, the industrial production is stable, and the obtained crystalline form has high stability and low moisture absorption rate.

[0008] To achieve the above object, the present invention provides a crystalline form I of 2-methyl-3-trifluoromethylaniline, wherein the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ values ​​of 14.20°±0.2°, 16.30°±0.2°, 17.31°±0.2°, 19.31°±0.2°, 20.52°±0.2°, 23.40°±0.2°, 24.30°±0.2°, 24.82°±0.2°, 27.03°±0.2°, and 33.79°±0.2°.

[0009] Preferably, it has the same Figure 1 Essentially identical XRPD patterns.

[0010] Preferably, it is white needle-shaped crystals.

[0011] The present invention also provides a method for preparing the crystalline form I of 2-methyl-3-trifluoromethylaniline, the preparation method comprising the following steps:

[0012] (1) Adding crude 2-methyl-3-trifluoromethylaniline, a crystallization solvent and activated carbon into a reaction bottle;

[0013] (2) While stirring, the temperature is raised to 60-70°C at a uniform rate, and after the material is dissolved, the temperature is kept and stirred for 0.5-1h;

[0014] (3) After the insulation is completed, filter and remove the activated carbon while it is hot;

[0015] (4) Slowly cool to -5°C to 0°C and stir for 0.5-1h to crystallize;

[0016] (5) After the crystallization is completed, the crystal form I is obtained by filtration and drying.

[0017] Preferably, the crystallization solvent is one or more of n-heptane, n-hexane, petroleum ether and ethyl acetate.

[0018] Preferably, the added ratio of activated carbon is 1%-10%.

[0019] Preferably, the added ratio of activated carbon is 2%-6%.

[0020] Different from the prior art, the above technical solution has a simple crystallization process, generates less waste liquid, is environmentally friendly, and the prepared 2-methyl-3-trifluoromethylaniline crystal form I is not easy to absorb moisture and has good stability. The crystal form does not change after being placed at 25±1°C for 60 days. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the X-ray powder diffraction pattern of 2-methyl-3-trifluoromethylaniline crystalline form I;

[0022] Figure 2 The X-ray powder diffraction pattern of 2-methyl-3-trifluoromethylaniline crystal form I placed in a constant temperature box at 25±1°C for 1 month;

[0023] Figure 3 This is the X-ray powder diffraction of 2-methyl-3-trifluoromethylaniline Form I placed in a constant temperature box at 25±1°C for 2 months. DETAILED DESCRIPTION

[0024] In order to explain the technical content, structural features, achieved objectives and effects of the technical solution in detail, the following is a detailed description in conjunction with specific embodiments and accompanying drawings.

[0025] Reference to "embodiment" herein means that the specific features, structures or characteristics described in conjunction with the embodiment may be included in at least one embodiment of the present application. The term "embodiment" appearing in various places in the specification does not necessarily refer to the same embodiment, nor does it particularly limit its independence or association with other embodiments. In principle, in the present application, as long as there is no technical contradiction or conflict, the various technical features mentioned in the embodiments can be combined in any way to form a corresponding implementable technical solution.

[0026] Unless otherwise defined, the technical terms used in this document have the same meanings as those generally understood by those skilled in the art to which this application belongs; the use of relevant terms in this document is only for describing specific embodiments and is not intended to limit this application.

[0027] In the description of this application, the term "and / or" is an expression used to describe the logical relationship between objects, indicating that three relationships may exist, for example, A and / or B, which means: A exists, B exists, and A and B exist at the same time. In addition, the character " / " in this article generally indicates that the objects before and after are in an "or" logical relationship.

[0028] In the present application, terms such as “first” and “second” are merely used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship of quantity, priority or sequence between these entities or operations.

[0029] Without further limitations, in this application, the words "include", "comprises", "has" or other similar expressions used in the sentences are intended to cover non-exclusive inclusion. These expressions do not exclude the presence of additional elements in the process, method or product including the elements, so that the process, method or product including a series of elements may include not only those limited elements, but also other elements not explicitly listed, or also include elements inherent to such process, method or product.

[0030] Similar to the understanding in the Examination Guidelines, in this application, expressions such as "greater than", "less than", "exceed" and the like are understood to exclude the number itself; expressions such as "above", "below", "within" and the like are understood to include the number itself. In addition, in the description of the embodiments of this application, "multiple" means more than two (including two), and similar expressions related to "multiple" are also understood in this way, such as "multiple groups", "multiple times", etc., unless otherwise clearly and specifically limited.

[0031] XRPD test method: Instrument model: Empyrean DY1602; Radiation source: X-ray tube; Scanning range: 5-90°; Scanning rate: 8° / min.

[0032] Example 1

[0033] Add 25kg of crude 2-methyl-3-trifluoromethylaniline, 25kg of n-heptane and 0.5kg of activated carbon to a 100L reactor. Heat to 60-70°C at a uniform rate while stirring, and keep stirring for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5°C to 0°C, stir for 1h for crystallization. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, with a GC purity of 99.46%, chromaticity: 87APHA, and appearance: white needle-shaped crystals.

[0034] Example 2

[0035] Add 25kg of crude 2-methyl-3-trifluoromethylaniline, 25kg of petroleum ether and 1.0kg of activated carbon to a 100L reactor. Heat to 60-70°C at a uniform rate while stirring, and keep warm and stir for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5°C to 0°C, stir for 1h to crystallize. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, with a GC purity of 99.55%, a chromaticity of 69APHA, and an appearance of white needle-shaped crystals.

[0036] Example 3

[0037] Add 25kg of crude 2-methyl-3-trifluoromethylaniline, 25kg of ethyl acetate and 2kg of activated carbon to a 100L reactor. Heat to 60-70°C at a uniform rate while stirring, and keep stirring for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5°C to 0°C, stir for 1h to crystallize. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, with a GC purity of 99.62%, a chromaticity of 53APHA, and an appearance of white needle-shaped crystals.

[0038] Example 4

[0039] Add 25kg of crude 2-methyl-3-trifluoromethylaniline, 25kg of n-hexane and 2.5kg of activated carbon to a 100L reactor. Heat to 60-70°C at a uniform rate while stirring, and keep stirring for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5°C to 0°C, stir for 1h for crystallization. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, with a GC purity of 99.73%, chromaticity: 44APHA, and appearance: white needle-shaped crystals.

[0040] Example 5

[0041] Add 25kg of crude 2-methyl-3-trifluoromethylaniline, 5kg of n-heptane, 20kg of ethyl acetate and 1.5kg of activated carbon to a 100L reactor. Heat to 60-70°C at a uniform rate while stirring, and keep stirring for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5°C to 0°C, stir for 1h for crystallization. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, with a GC purity of 99.89%, a chromaticity of 57APHA, and an appearance of white needle-shaped crystals.

[0042] Example 6

[0043] Add 25kg 2-methyl-3-trifluoromethylaniline crude product, 5kg n-hexane, 20kg petroleum ether and 0.25kg activated carbon to a 100L reactor. Heat to 60-70℃ at a uniform rate while stirring, keep warm and stir for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5℃~0℃, stir for 1h for crystallization. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, GC purity 99.78%, color: 93APHA, appearance: white needle-shaped crystals.

[0044] Example 7

[0045] Add 25kg of crude 2-methyl-3-trifluoromethylaniline, 5kg of n-hexane, 20kg of petroleum ether and 0.25kg of activated carbon to a 100L reactor. Heat to 60-70°C at a uniform rate while stirring, and keep stirring for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5°C to 0°C, stir for 1h for crystallization. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, with a GC purity of 99.23%, chromaticity: 88APHA, and appearance: white needle-shaped crystals.

[0046] Example 8

[0047] Add 25kg of crude 2-methyl-3-trifluoromethylaniline, 25kg of n-hexane and 1kg of activated carbon to a 100L reactor. Heat to 60-70°C at a uniform rate while stirring, and keep stirring for 1h after the material is dissolved. Then, filter and remove the activated carbon while hot. Slowly cool to -5°C to 0°C, stir for 1h to crystallize. After the crystallization is completed, filter and dry to obtain pure 2-methyl-3-trifluoromethylaniline, with a GC purity of 99.82%, a chromaticity of 53APHA, and an appearance of white needle-shaped crystals.

[0048] The corresponding crystalline structure materials can be obtained according to the above embodiments, and embodiments 1-5 are preferred.

[0049] Crystal 25℃ accelerated stability test:

[0050] The 2-methyl-3-trifluoromethylaniline sample obtained in Example 1-5 was placed in a constant temperature box at 25±1°C for 2 months, and then taken out for product testing. The test results are as follows:

[0051]

[0052] Preferred Example 5 Samples were subjected to X-ray powder diffraction tests before and after accelerated stability, see Figure 1-3 It can be seen that the characteristic peaks of the crystalline form I of 2-methyl-3-trifluoromethylaniline have no obvious changes, indicating that it is not easy to absorb moisture and has good stability.

[0053] It should be noted that, although the above embodiments have been described in this article, the patent protection scope of the present invention is not limited thereby. Therefore, based on the innovative concept of the present invention, changes and modifications made to the embodiments described herein, or equivalent structures or equivalent process changes made using the contents of the present invention specification and drawings, directly or indirectly applying the above technical solutions to other related technical fields, are all included in the patent protection scope of the present invention.

Claims

1. A crystalline form I of 2-methyl-3-trifluoromethylaniline, characterized in that: The X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ values ​​of 14.20°±0.2°, 16.30°±0.2°, 17.31°±0.2°, 19.31°±0.2°, 20.52°±0.2°, 23.40°±0.2°, 24.30°±0.2°, 24.82°±0.2°, 27.03°±0.2°, and 33.79°±0.2°.

2. A crystalline form I of 2-methyl-3-trifluoromethylaniline according to claim 1, characterized in that: It has an XRPD pattern substantially the same as that of Figure 1 of the accompanying drawings of the specification.

3. A crystalline form I of 2-methyl-3-trifluoromethylaniline according to claim 1, characterized in that: It is white needle-shaped crystals.

4. A method for preparing a crystalline form I of 2-methyl-3-trifluoromethylaniline according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: (1) Adding crude 2-methyl-3-trifluoromethylaniline, a crystallization solvent and activated carbon into a reaction bottle; (2) While stirring, the temperature is raised to 60-70°C at a uniform rate, and after the material is dissolved, the temperature is kept and stirred for 0.5-1h; (3) After the insulation is completed, filter and remove the activated carbon while it is hot; (4) Slowly cool to -5°C to 0°C and stir for 0.5-1h to crystallize; (5) After the crystallization is completed, the crystal form I is obtained by filtration and drying.

5. The method for preparing the crystalline form I of 2-methyl-3-trifluoromethylaniline according to claim 4, characterized in that: The crystallization solvent is one or more of n-heptane, n-hexane, petroleum ether and ethyl acetate.

6. The method for preparing the crystalline form I of 2-methyl-3-trifluoromethylaniline according to claim 4, characterized in that: The added ratio of the activated carbon is 1%-10%.

7. The method for preparing the crystalline form I of 2-methyl-3-trifluoromethylaniline according to claim 6, characterized in that: The added ratio of the activated carbon is 2%-6%.

Images