A solvate of retinoic acid and its preparation method

Abstract

This invention discloses a solvate of rememega-2 and its preparation method. The rememega-2 solvate (compound II) provided by this invention has a purity of up to 99.15% compared with the existing rememega-2 methyl tert-butyl ether solvate. The preparation method includes the following steps: adding crude rememega-2 to a binary solvent, heating to 45℃~75℃, adding an antisolvent, stirring, crystallizing, cooling and filtering, and drying under reduced pressure to obtain rememega-2 solvate (compound II). Then, placing rememega-2 solvate (compound II) in ethanol and stirring to obtain rememega-2 (compound I). This route is simple to operate, the process is stable, and it is easy to scale up. Moreover, the rememega-2 (compound I) prepared by this solvate (compound II) has a purity of up to 99.66%, which is higher than that of rememega-2 (compound I) prepared by the existing rememega-2 methyl tert-butyl ether solvate. It also has better fluidity, does not caking, is easy to transfer, and is convenient for later production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a solvate of remedigpa and its preparation method. Background Technology

[0002] Rimegepant (Compound I) is a potent, selective, competitive, orally active calcitonin gene-related peptide (CGRP) antagonist for the acute treatment of migraine in adults. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on February 27, 2020. Its structural formula is as follows:

[0003]

[0004] Remegpam exhibits extremely poor solubility in common solvents, and existing synthetic routes suffer from cumbersome purification processes and low yields. Patent CN116554164A provides a solvate of remegpam and a method for preparing high-purity remegpam, with the following structural formula:

[0005]

[0006] Wherein: X is methyl tert-butyl ether or isopropyl ether.

[0007] Although the yield and purity of retinoic acid prepared using this solvate in patent CN116554164A are improved, the purity of the prepared retinoic acid is still not high enough, and the fluidity is poor. It will clump during storage, and morphological observation also shows agglomeration and static electricity problems, which are not conducive to transfer and subsequent production. Summary of the Invention

[0008] Purpose of the invention: The purpose of this invention is to overcome the shortcomings of the existing technology and provide a solvate of retinoic acid and its preparation method.

[0009] To achieve the above objectives, the technical solution provided by the present invention is as follows:

[0010] The first aspect of this application provides a solvate (II) of rememepam:

[0011]

[0012] Wherein: X is 2-methyltetrahydrofuran, tetrahydrofuran or 1,4-dioxane.

[0013] In some embodiments, the present invention provides a solvate (II) of retinoic acid, wherein X is 2-methyltetrahydrofuran, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.3°±0.2°, 4.7°±0.2°, 12.9°±0.2°, 15.3°±0.2°, 17.2°±0.2°, 18.3°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 21.1°±0.2°, and 22.8°±0.2°.

[0014] In some embodiments, the present invention provides a solvate (II) of retinoic acid, wherein the X-ray powder diffraction pattern obtained by Cu-Kα radiation is as follows: Figure 1 As shown.

[0015] In some embodiments, the present invention provides a solvate (II) of retrimazole, wherein X is tetrahydrofuran, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.4°±0.2°, 5.2°±0.2°, 12.5°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 18.0°±0.2°, 19.9°±0.2°, and 20.4°±0.2°.

[0016] In some embodiments, the present invention provides a solvate (II) of retinoic acid, wherein the X-ray powder diffraction pattern obtained by Cu-Kα radiation is as follows: Figure 4 As shown.

[0017] In some embodiments, the present invention provides a solvate (II) of retinoic acid, wherein X is 1,4-dioxane, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.4°±0.2°, 5.2°±0.2°, 12.5°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 18.0°±0.2°, 19.9°±0.2°, and 20.4°±0.2°.

[0018] In some embodiments, the present invention provides a solvate (II) of retinoic acid, wherein the X-ray powder diffraction pattern obtained by Cu-Kα radiation is as follows: Figure 7 As shown.

[0019] The second aspect of this application provides a method for preparing a solvate (II) of retinoic acid, characterized by comprising the following steps:

[0020]

[0021] Wherein: X is 2-methyltetrahydrofuran, tetrahydrofuran, or 1,4-dioxane; the crude compound I is dissolved in a binary solvent, heated to 45℃~75℃, an antisolvent is added, the temperature is lowered, the mixture is stirred to crystallize, filtered and dried to obtain Remegan solvate (II), wherein the binary solvent is a mixture of N,N-dimethylformamide and 2-methyltetrahydrofuran or a mixture of N,N-dimethylformamide and tetrahydrofuran or a mixture of N,N-dimethylformamide and 1,4-dioxane, the antisolvent is n-heptane or toluene, and the volume ratio of N,N-dimethylformamide: 2-methyltetrahydrofuran or tetrahydrofuran or 1,4-dioxane: antisolvent is in the range of 3:7.5N15:9~15.

[0022] A third aspect of this application provides a method for preparing remedypa, comprising the following steps:

[0023]

[0024] Wherein: X is 2-methyltetrahydrofuran, tetrahydrofuran, or 1,4-dioxane; in the step of preparing compound II from crude compound I, crude compound I is dissolved in a binary solvent, and compound II is obtained by adding an antisolvent to the system; the binary solvent is a mixed solvent of N,N-dimethylformamide and 2-methyltetrahydrofuran, or a mixed solvent of N,N-dimethylformamide and tetrahydrofuran, or a mixed solvent of N,N-dimethylformamide and 1,4-dioxane; the antisolvent is n-heptane or toluene, and the volume ratio of N,N-dimethylformamide: 2-methyltetrahydrofuran or tetrahydrofuran or 1,4-dioxane: antisolvent is in the range of 3:7.5 to 15:9 to 15; in the step of preparing compound I from compound II, the mass ratio of compound II to ethanol is in the range of 1:3.9 to 7.9. In some embodiments, the crude compound I described in this application has a main compound purity of 89.16%, a maximum single impurity of 5.71%, and a content of 79%.

[0025] Beneficial Effects: This invention discloses a solvate of retimetrozine and its preparation method. The retimetrozine solvate (compound II) provided by this invention has a purity of up to 99.15% compared with the existing retimetrozine methyl tert-butyl ether solvate. The preparation method includes the following steps: adding crude retimetrozine to a binary solvent, heating to 45℃~75℃, adding an antisolvent, stirring, crystallizing, cooling and filtering, and drying under reduced pressure to obtain retimetrozine solvate (compound II). Then, the retimetrozine... Remegapan (Compound I) is obtained by stirring the solvate of memegapan in ethanol. This route is simple to operate, the process is stable, the product has high purity and high yield, and it is easy to scale up. Moreover, the purity of remegapan (Compound I) prepared by this solvate (Compound II) is as high as 99.66%, which is higher than that of remegapan (Compound I) prepared by the existing methyl tert-butyl ether solvate. It has better fluidity, is not prone to caking, is easy to transfer, and is convenient for later production.

[0026] The abbreviations for the reaction reagents mentioned in the instructions are as follows:

[0027] DMF: N,N-dimethylformamide;

[0028] 2-MeTHF: 2-Methyltetrahydrofuran;

[0029] n-Heptane: n-Heptane. Attached Figure Description

[0030] Figure 1 The X-ray powder diffraction (XRPD) pattern of the solvate of rimexazol 2-methyltetrahydrofuran;

[0031] Figure 2 Differential scanning calorimetry (DSC) curve of rimexazol 2-methyltetrahydrofuran solvate;

[0032] Figure 3 Thermogravimetric (TGA) plot of the 2-methyltetrahydrofuran solvate of rimexazol;

[0033] Figure 4 The X-ray powder diffraction (XRPD) pattern of the remexazol tetrahydrofuran solvate is shown.

[0034] Figure 5 Differential scanning calorimetry (DSC) curve of the remexazol tetrahydrofuran solvate;

[0035] Figure 6 Thermogravimetric (TGA) plot of the remdesivir tetrahydrofuran solvate;

[0036] Figure 7 The X-ray powder diffraction (XRPD) pattern of the 1,4-dioxane solvate of rimexazol;

[0037] Figure 8 Differential scanning calorimetry (DSC) curve of 1,4-dioxane solvate of rimexazol;

[0038] Figure 9 Thermogravimetric (TGA) plot of 1,4-dioxane solvate of rimexazol;

[0039] Figure 10 Microscopic observation results of the compound of formula I obtained in Example 6;

[0040] Figure 11 Microscopic observation results of compound I obtained in Comparative Example 1. Detailed Implementation

[0041] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented under the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0042] The terms used in this invention are explained as follows:

[0043] The term XRPD refers to X-ray powder diffraction. In this invention, the powder X-ray diffraction testing instrument involved is a Bruker D2 Phaser. 2nd Powder diffractometer; Test conditions: Cu-Kα radiation, 30kV, 10mA, 3-40°.

[0044] The term DSC refers to Differential Scanning Calorimeter. In this invention, the differential scanning calorimeter involved is the American TADSC25; test conditions: 20-300℃, 10℃ / min; N2 (60mL / min).

[0045] The term TGA refers to thermogravimetric analyzer. In this invention, the thermogravimetric analyzer involved is the American TATGA55; the test conditions are: room temperature - 300℃, 10℃ / min; N2 (50mL / min).

[0046] In the context of this invention, the diffraction angle 2θ (also known as 2-theta or diffraction peak) values ​​in X-ray powder diffraction patterns are all expressed in degrees (°).

[0047] When referring to spectra and / or data in figures, the term "diffraction peak" refers to a feature that a person skilled in the art would not attribute to background noise.

[0048] The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern of the crystal is subject to experimental error. The measurement of the 2θ or diffraction peaks in the X-ray powder diffraction pattern may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be ±0.2 units. Therefore, the value of the 2θ or diffraction peaks cannot be considered absolute.

[0049] The differential scanning calorimetry (DSC) curve of the crystal has experimental errors. The position and peak value of the endothermic peak may vary slightly between one machine and another, and between one sample and another. The experimental error or difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. Therefore, the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

[0050] The thermogravimetric analysis (TGA) curves of the crystals are subject to experimental error. The endothermic curves or weight loss rates may vary slightly between different machines and between different samples. The experimental error or difference may be less than or equal to 0.4%, 0.3%, 0.2%, or 0.1%. Therefore, the thermogravimetric analysis curves or their weight loss rates cannot be considered absolute.

[0051] Example 1: Preparation of Remepiride 2-methyltetrahydrofuran solvate

[0052] 1.0 kg of crude compound I (purity of main compound: 89.16%, maximum single impurity: 5.71%, content: 79%) was weighed into a 50 L double-glass jacketed reactor. 3 L of N,N-dimethylformamide and 7.5 L of 2-methyltetrahydrofuran were added. The mixture was heated to 75 °C to dissolve completely, followed by the addition of 7.5 L of 2-methyltetrahydrofuran. The system was cooled to 45 °C and stirred for 2 hours. Then, 10.0 L of n-heptane was added, and the mixture was kept at this temperature and stirred for approximately 1 hour. The temperature was then further lowered to 4 °C and stirred for 1–2 hours. The solid was separated and dried under reduced pressure at 40 °C to obtain 778.9 g of solid. XRPD analysis confirmed that the obtained solid was rimexazol 2-methyltetrahydrofuran solvate with a purity of 99.15%. The characteristic XRPD peaks and patterns of rimexazol 2-methyltetrahydrofuran solvate are shown in Table 1 and [Table 2 missing in original text]. Figure 1 As shown:

[0053] Table 1

[0054]

[0055]

[0056] The DSC chromatogram of the 2-methyltetrahydrofuran solvate of rimexazol is shown below. Figure 2As shown, the 2-methyltetrahydrofuran solvate of Remepiride exhibits endothermic peaks when heated to 28.3℃ (initial temperature), 154.3℃ (initial temperature), and 189.6℃ (initial temperature).

[0057] The TGA chromatogram of the 2-methyltetrahydrofuran solvate of rimexazol is shown below. Figure 3 As shown, the 2-methyltetrahydrofuran solvate of Remepiride exhibits a mass loss of approximately 12.0% when heated to 200.0℃ (instrument error ±0.2%).

[0058] Example 2: Preparation of Remepiride Tetrahydrofuran Solvate

[0059] 100g of crude compound I (purity of main compound: 89.16%, maximum single impurity: 5.71%, content: 79%) was weighed into a 5-L double-glass jacketed reactor. 200.0mL of N,N-dimethylformamide and 1000.0mL of tetrahydrofuran were added. The system was heated to 75℃ to dissolve the impurities. After cooling to 45℃, 1000.0mL of tetrahydrofuran and 1000.0mL of n-heptane were added to induce crystallization for several hours. The mixture was then cooled to 4℃ and stirred for several hours. The solid was separated and dried under reduced pressure at 40℃ to obtain 41.4g of solid. XRPD analysis confirmed that the solid was rimexazol tetrahydrofuran solvate with a purity of 98.62%. The characteristic XRPD peaks and patterns of rimexazol tetrahydrofuran solvate are shown in Table 2 and [Table data missing]. Figure 4 As shown:

[0060] Table 2

[0061]

[0062]

[0063] The DSC chromatogram of the remdesivir tetrahydrofuran solvate is shown below. Figure 5 As shown, the remifentan tetrahydrofuran solvate exhibits endothermic peaks when heated to 61.0℃ (initial temperature) and 248.9℃ (initial temperature), and an exothermic peak when heated to 195.1℃ (initial temperature).

[0064] The TGA chromatogram of the remdesivir tetrahydrofuran solvate is shown below. Figure 6 As shown, the mass loss of the rimex tetrahydrofuran solvate is approximately 2.2% when heated to 75.0℃ (instrument error ±0.2%) and approximately 4.2% when heated to 150.0℃ (instrument error ±0.2%).

[0065] Example 3: Preparation of Remepiride 1,4-dioxane solvate

[0066] 100.0 g of crude compound of formula I (purity of main compound: 89.16%, maximum single impurity: 5.71%, content: 79%) was weighed into a 5-L double-glass jacketed reactor. 200.0 mL of N,N-dimethylformamide and 1000.0 mL of 1,4-dioxane were added. The system was heated to 75°C to dissolve the solid. After cooling to 45°C, 1000.0 mL of n-heptane was added to induce crystallization for several hours. The mixture was then cooled to 4°C and stirred for several hours. The solid was separated and dried under reduced pressure at 40°C to obtain 50.3 g of solid. XRPD analysis confirmed that the solid was 1,4-dioxane solvate of rememegapan, with a purity of 98.81%. The characteristic XRPD peaks and patterns of rememegapan 1,4-dioxane solvate are shown in Table 3 below. Figure 7 As shown.

[0067] Table 3

[0068]

[0069]

[0070] The DSC chromatogram of the 1,4-dioxane solvate of rimexazol is shown below. Figure 8 As shown, the 1,4-dioxane solvate of rimex exhibits endothermic peaks when heated to 65.2℃ (initial temperature), 143.8℃ (initial temperature), and 182.9℃ (initial temperature).

[0071] The TGA chromatogram of the 1,4-dioxane solvate of retinoic acid is shown below. Figure 9 As shown, the 1,4-dioxane solvate of remeraquinone, when heated to 195.0 °C, exhibits a mass loss of approximately 12.2% (instrument error ±0.2%).

[0072] Example 4: Preparation and Screening of Remepiride Solubilides

[0073] (1) Solvate screening

[0074] 20.0 g of crude compound I (purity of main compound: 89.16%, maximum single impurity: 5.71%, content: 79%) was weighed into a 100-mL double-glass jacketed reactor. N,N-dimethylformamide and the corresponding solvent were added and the mixture was heated to dissolve the solid. Then, n-heptane was added, and the system was cooled to 45°C to crystallize for several hours. After that, the temperature was further lowered to 4°C and stirred for several hours. The solid was separated and dried under reduced pressure at 40°C. The experimental results are shown in Table 4.

[0075] Table 4

[0076] batch Crystal form Yield (%) purity(%) Batch 1 Remepiqua 2-methyltetrahydrofuran solvate 84.7 99.08 Batch 2 Remepiquat tetrahydrofuran solvate 72.3 98.60 Batch 3 Remepiride 1,4-dioxane solvate 77.3 98.79

[0077] The experimental results above show that the preparation of 2-methyltetrahydrofuran solvate of Remepiride has the most significant purification effect and the highest yield on the crude product of Formula I. Therefore, the 2-methyltetrahydrofuran solvate of Formula I is selected as the intermediate for purifying the crude product of Formula I.

[0078] (2) Screening of antisolvents

[0079] 20.0 g of crude compound I (purity of main compound: 89.16%, maximum single impurity: 5.71%, content: 79%) was weighed into a 100-mL double-jacketed glass reactor. N,N-dimethylformamide and 2-methyltetrahydrofuran were added and the mixture was heated to dissolve the solid. Subsequently, different antisolvents were added, and the system was cooled to 45°C to crystallize for several hours. Then, the temperature was further lowered to 4°C and stirred for several hours. The solid was separated and dried under reduced pressure at 40°C. The experimental results are shown in Table 5.

[0080] Table 5

[0081] batch antisolvent Yield (%) Crystal form purity(%) Batch 1 n-Heptane 81.1 Remepiqua 2-methyltetrahydrofuran solvate 99.13 Batch 2 Toluene 36.8 Remepiqua 2-methyltetrahydrofuran solvate 99.02

[0082] The experimental results show that the yield and purity of the sample obtained by using n-heptane as the antisolvent are relatively high. Therefore, n-heptane is preferred as the antisolvent for preparing compound I, 2-methyltetrahydrofuran solvate.

[0083] (3) Solvent ratio screening for the preparation of compound I 2-methyltetrahydrofuran solvate

[0084] 20.0 g of crude compound I (purity of main compound: 89.16%, maximum single impurity: 5.71%, content: 79%) was weighed into a 100-mL double-jacketed glass reactor. N,N-dimethylformamide and 2-methyltetrahydrofuran were added and heated to dissolve the solid. The system was then cooled to 45°C to crystallize. After stirring for several hours, n-heptane was added. The temperature was further lowered to 4°C and stirred for several hours. The solid was separated and dried under reduced pressure at 40°C. The experimental results are shown in Table 6.

[0085] Table 6

[0086]

[0087]

[0088] The experimental results show that the 2-methyltetrahydrofuran solvate of Formula I prepared in a solvent ratio of N,N-dimethylformamide / 2-methyltetrahydrofuran / n-heptane (3:15:10, v / v / v) has the highest purity. Therefore, the solvent ratio of N,N-dimethylformamide / 2-methyltetrahydrofuran / n-heptane (3:15:10, v / v / v) is preferred for preparation.

[0089] Example 5: Preparation of Compound I from Remepiride 2-Methyltetrahydrofuran Solvate

[0090] 20 g of the 2-methyltetrahydrofuran solvate prepared in Example 4 was weighed into a 500-mL double-jacketed glass reactor. Different volumes of ethanol were added, and the mixture was heated to 65°C and stirred for 2 hours. The temperature was then lowered to 25°C and stirred for another 2 hours. The solid was separated and dried under reduced pressure at 45°C overnight. The mass ratio of compound II to ethanol ranged from 1:3.9 to 7.9, and the ethanol density was 0.789 g / mL. The results, converted to the volume ratio of ethanol to the mass ratio of the rememepam solvate, are shown in Table 7.

[0091] Table 7

[0092] batch Ethanol volume (V / M) Yield (%) purity(%) Batch 1 5 71.3 99.29 Batch 2 6 71.8 99.42 Batch 3 7 83.8 99.27 Batch 4 10 85.6 99.58

[0093] The experimental results show that the product yield and purity of the 2-methyltetrahydrofuran solvate of Formula I obtained by pulping in 10 V / M ethanol are the highest. Therefore, the preferred pulping ethanol volume for preparing Formula I from the 2-methyltetrahydrofuran solvate of Formula I is 10 V / M.

[0094] Example 6: Preparation of high-purity Formula I compound (from rimexazol 2-methyltetrahydrofuran solvate)

[0095] 778.0 g of the 2-methyltetrahydrofuran solvate of rememepam prepared in Example 1 was weighed into a 10-L double-jacketed glass reactor, and 7.78 L of ethanol was added. The mixture was heated to 65°C and stirred for 2 hours. Then, the temperature was lowered to 25°C and stirred for another 2 hours. The solid was separated and dried under vacuum at 45°C overnight to obtain 621.0 g of compound I, with a yield of 90.6%. HPLC analysis showed a purity of 99.66%.

[0096] Example 7: Preparation of high-purity Formula I compound (from rimegarbane tetrahydrofuran solvate)

[0097] 41.4 g of the rimegarbane tetrahydrofuran solvate obtained in Example 2 was weighed into a 1-L double-jacketed glass reactor, and 414.0 mL of ethanol was added. The mixture was heated to 65°C and stirred for 2 hours. Then, the temperature was lowered to 25°C and stirred for another 2 hours. The solid was separated and dried under vacuum at 45°C overnight to obtain 34.3 g of compound I, with a yield of 94.04%. HPLC analysis showed a purity of 99.21%.

[0098] Example 8: Preparation of high-purity Formula I compound (from rimegarbane 1,4-dioxane solvate)

[0099] 50.3 g of the 1,4-dioxane solvate of rememepiride prepared in Example 3 was weighed into a 1-L double-jacketed glass reactor. 500.3 mL of ethanol was added, and the mixture was heated to 65°C and stirred for 2 hours. The temperature was then lowered to 25°C and stirred for another 2 hours. The solid was separated and dried under vacuum at 45°C overnight to obtain 39.2 g of compound I, with a yield of 90.7%. HPLC analysis showed a purity of 99.39%.

[0100] Comparative Example 1: Compound of Formula I was prepared from the methyl tert-butyl ether solvate of patent CN116554164A.

[0101] Following the preparation method described in Examples 4 to 7 of patent CN1 16554164A, 100.0 g of crude compound of formula I (purity of main compound: 89.16%, maximum single impurity: 5.71%, content: 79%) was weighed into a 3-L double-layered glass-jacketed reactor. 400.0 mL of N,N-dimethylformamide was added and the mixture was heated to dissolve the solid. Then, 2000.0 mL of methyl tert-butyl ether was added. The system was cooled to 45°C for several hours to allow crystallization, and then further cooled to 4°C with stirring for several hours. The solid was separated and dried under reduced pressure at 40°C to obtain 82.0 g. XRPD analysis confirmed that the obtained solid was a solvate of methyl tert-butyl ether of formula I. HPLC analysis showed a purity of 98.58%.

[0102] The methyl tert-butyl ether solvate of formula I was weighed into a 1-L double-jacketed glass reactor, and 820.0 mL of ethanol was added. The mixture was heated to 65°C and stirred for 2 hours. Then, the temperature was lowered to 25°C and stirred for another 2 hours. The solid was separated and dried under vacuum at 45°C overnight to obtain 60.0 g. XRPD analysis confirmed that the obtained solid was the compound of formula I, with a yield of 88.7%. HPLC analysis showed a purity of 99.38%.

[0103] Purification of compound I in Comparative Example 2

[0104] The preparation methods and product quality of the compounds of formula I obtained in Example 6 and Comparative Example 1 are compared and summarized, and the results are shown in Table 8:

[0105] Table 8

[0106]

[0107] The comparison results show that, in preparing high-purity Formula I compounds, the purity of the intermediates and the purity of the final product obtained by the preparation method used in this patent are both superior to those in patent CN116554164A; the yield of the final product obtained by the preparation method used in this patent is comparable to that of the method in patent CN116554164A; and the flowability and properties of the final product obtained by the preparation method used in this patent are superior to those of the Formula I compounds obtained by the method in patent CN116554164A.

[0108] Comparison of the fluidity of Compound I in Example 3

[0109] The powder properties of a sample affect its flowability; better flowability of the intermediate facilitates transfer and is more beneficial for the production of the active pharmaceutical ingredient. The flowability of the compound sample of Formula I prepared in Example 6 of this patent and the compound sample of Formula I prepared in Comparative Example 1 were compared using a Hausner-Nabi test. The flowability evaluation results are shown in Table 9.

[0110] Methods for testing loose density and tapped density: This experiment uses a tapper and the fixed volume method is followed. The specific procedure is as follows: The weighed powder is placed into a 10-mL graduated cylinder, which is then fixed to a support. The cylinder is set to vibrate at 55±5 times per minute for 6-8 minutes. The volume change of the powder in the graduated cylinder is measured. The ratio of the powder mass to the volume of the material before tapping is the loose density of the powder, and the ratio of the powder mass to the volume of the material after tapping is the tapped density of the powder.

[0111] The methods for converting Hausner ratio and compressibility are as follows, and the descriptions of Hausner ratio and liquidity are shown in Table 10:

[0112] Hausner ratio of material = tapped density / loose density

[0113] Material compressibility = (tap density - loose density) / tap density

[0114] Table 9

[0115] batch <![CDATA[Bulk density (g / cm 3 )]]> <![CDATA[Tap density (g / cm 3 )]]> Hausner ratio Compression Compound of Formula I prepared in Example 6 0.362 0.441 1.22 0.179 Compound of Formula I prepared in Comparative Example 1 0.336 0.462 1.38 0.273

[0116] Table 10

[0117] Hausnabi Liquidity Description 1.00-1.11 The liquidity is very good. 1.12-1.18 Good liquidity 1.19-1.25 Good or moderate liquidity 1.26-1.34 Liquidity is acceptable 1.35-1.45 Poor liquidity 1.46-1.59 Very poor liquidity >1.60 Liquidity is extremely poor.

[0118] The experimental results show that the compound of formula I prepared in Example 6 of this patent has good or moderate flowability, while the compound of formula I prepared in Comparative Example 1 has poor flowability. Therefore, the flowability of rememepam prepared from the 2-methyltetrahydrofuran solvate is better than that of rememepam prepared from the methyl tert-butyl ether solvate.

[0119] Morphological study of compound I in Comparative Example 4

[0120] The compounds of formula I obtained in Example 6 and Comparative Example 1 were subjected to microscopic morphological studies. The results of the microscopic observations are shown in the figure below. Figure 10 and Figure 11 The Formula I compound prepared in Example 6 is rod-shaped, with relatively dispersed particles and a large particle size, with most particles ranging from 130 to 200 μm and an aspect ratio of 3 to 5. The Formula I compound prepared in Comparative Example 1 is rod-shaped, exhibits agglomeration, and has a particle size range mainly from 10 to 50 μm, with an aspect ratio ranging from 2 to 5.

[0121] The above specific embodiments further illustrate the purpose, technical solution and beneficial effects of this application. It should be understood that the above are only specific embodiments of this application and are not intended to limit the scope of protection of this application. Any modifications, equivalent substitutions, improvements, etc., made on the basis of the technical solution of this application should be included within the scope of protection of this application.

Claims

1. A solvate (II) of rimexazol, characterized in that: Wherein: X is 2-methyltetrahydrofuran, tetrahydrofuran or 1,4-dioxane.

2. The solvate of remeglib (II) according to claim 1, characterized in that, X is 2-methyltetrahydrofuran, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.3°±0.2°, 4.7°±0.2°, 12.9°±0.2°, 15.3°±0.2°, 17.2°±0.2°, 18.3°±0.2°, 19.1°±0.2°, 19.5°±0.2°, 21.1°±0.2°, and 22.8°±0.2°.

3. The solvate of remeglib (II) according to claim 2, characterized in that, The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown in Figure 1.

4. The solvate of remeglib (II) according to claim 1, characterized in that, X is tetrahydrofuran, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.4°±0.2°, 5.2°±0.2°, 12.5°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 18.0°±0.2°, 19.9°±0.2°, and 20.4°±0.2°.

5. The solvate of remeglib (II) according to claim 4, characterized in that, The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown in Figure 4.

6. The solvate of remeglib (II) according to claim 1, characterized in that, The X is 1,4-dioxane, and its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 4.4°±0.2°, 5.2°±0.2°, 12.5°±0.2°, 13.2°±0.2°, 15.4°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 18.0°±0.2°, 19.9°±0.2°, and 20.4°±0.2°.

7. The solvate of remeglib (II) according to claim 6, characterized in that, The X-ray powder diffraction pattern obtained using Cu-Kα radiation is shown in Figure 7.

8. A process for the preparation of a solvate (II) of remegping according to any one of claims 1 to 7, characterized in that, Includes the following steps: Wherein: X is 2-methyltetrahydrofuran, tetrahydrofuran, or 1,4-dioxane; the crude compound I is dissolved in a binary solvent, heated to 45℃~75℃, an antisolvent is added, the temperature is lowered, the mixture is stirred to crystallize, filtered and dried to obtain Remegan solvate (II), wherein the binary solvent is a mixed solvent of N,N-dimethylformamide and 2-methyltetrahydrofuran or a mixed solvent of N,N-dimethylformamide and tetrahydrofuran or a mixed solvent of N,N-dimethylformamide and 1,4-dioxane.

9. The method for preparing the solvate (II) of Remepiride according to claim 8, wherein the antisolvent is n-heptane or toluene, and the volume ratio of N,N-dimethylformamide:2-methyltetrahydrofuran or tetrahydrofuran or 1,4-dioxane:antisolvent is in the range of 3:7.5-15:9-15.

10. A process for the preparation of remegapam characterized in that, Includes the following steps: Wherein: X is 2-methyltetrahydrofuran, tetrahydrofuran, or 1,4-dioxane; in the step of preparing compound II from crude compound I, crude compound I is dissolved in a binary solvent, and compound II is obtained by adding an antisolvent to the system; the binary solvent is a mixed solvent of N,N-dimethylformamide and 2-methyltetrahydrofuran, or a mixed solvent of N,N-dimethylformamide and tetrahydrofuran, or a mixed solvent of N,N-dimethylformamide and 1,4-dioxane; the antisolvent is n-heptane or toluene; the volume ratio of N,N-dimethylformamide: 2-methyltetrahydrofuran or tetrahydrofuran or 1,4-dioxane: antisolvent is in the range of 3:7.5 to 15:9 to 15; in the step of preparing compound I from compound II, the mass ratio of compound II to ethanol is in the range of 1:3.9 to 7.9.

Images