A method for preparing a high purity doxazosin mesylate f crystal form

Abstract

The present application relates to a kind of preparation methods of high-purity doxazosin mesylate F crystal form, N-1,4-benzodioxane-2-carbonyl piperazine is condensed with 2-chloro-4-amino-6,7-dimethoxyquinazoline, after reaction, cooling, filtration, filter cake is washed using potassium carbonate aqueous solution, then using N,N-dimethylformamide is heated and dissolved, using water or methanol is crystallized, cooling, filtration, washing, drying, obtain doxazosin;Doxazosin and methanesulfonic acid are reacted in n-pentanol or iso-pentanol, after reaction is completed, crystallization, cooling, filtration, washing, drying, obtain doxazosin mesylate F crystal form.The doxazosin mesylate F crystal form prepared by the preparation method of the present application has less impurities, high purity, ensures the stability of the crystal form, has low equipment requirement and low production cost.The present application has high yield and has been used for industrial trial production.

Description

Technical Field

[0001] This invention relates to a method for preparing high-purity doxazosin mesylate F crystal form, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Doxazosin mesylate, chemically named 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxane-2-formyl)piperazine mesylate, has the following chemical structural formula:

[0003]

[0004] Doxazosin mesylate is a selective alpha-receptor blocker that works by blocking alpha1-receptors, thereby dilating blood vessels, reducing vascular resistance, and lowering blood pressure. Unlike non-selective alpha-receptor blockers, no drug tolerance has been observed with long-term use of this product, and tachycardia and elevated plasma renin levels are rare during maintenance therapy. By selectively blocking alpha-adrenergic receptors in the prostatic smooth muscle matrix, capsule, and bladder neck, this product can improve urodynamics and clinical symptoms in patients with symptomatic benign prostatic hyperplasia.

[0005] There are many reported synthetic routes for doxazosin mesylate. Among them, the synthetic route for preparing doxazosin by coupling reaction with piperazine as the center has the advantages of simple operation, safe process and high product yield.

[0006] Doxazosin mesylate is prepared by reacting doxazosin with methanesulfonic acid to form a salt. However, choosing different reaction solvents can lead to different crystal forms of doxazosin mesylate.

[0007] Current literature reports that doxazosin mesylate has different crystal forms, including A, B, C, D, E, F, M, I, II, III, and IV. These crystal forms can interconvert under heating conditions, but the conditions for this interconversion are uncertain. Foreign patent EP0848001 reports crystal form F and its preparation method.

[0008] The experiments in this patent application show that doxazosin mesylate (F crystal form) has moderate solubility; about 7.5 mg of this crystal form can be dissolved in 1 ml of purified water, and about 5.0 to 9.0 mg of this crystal form can be dissolved in 1 ml of acetate buffer solution at pH 4.5. When granulated using this crystal form, the release rate of simulated intestinal fluid after a meal can reach more than 90% after 24 hours, and the release rate of simulated gastric fluid after a meal is close to 90% after 28 hours. All indications suggest that the bioavailability of this crystal form has its own advantages over other crystal forms.

[0009] According to the report in EP0848001, when solvents such as ethanol, isopropanol, n-propanol, and n-butanol are used for crystal form preparation, abnormal crystal forms are obtained. For example, when using ethanol for multiple preparations of crystal form F according to the process in patent EP0848001, one or two batches will produce crystal form III or a mixture of crystal form III and crystal form F. When isopropanol, n-propanol, n-butanol, and n-pentanol are used, the DSC peak shape of the prepared crystal form is poor (e.g., Figure 5 , Figure 7 , Figure 9 , Figure 3 , Figure 11 , Figure 12 , Figure 13 , Figure 14 ), and through the XRD spectrum (e.g. Figure 6 , Figure 8 , Figure 10 , Figure 4 Analysis revealed no X-ray diffraction characteristic peaks of other crystal forms, thus concluding that the poor DSC peak shape was due to the presence of mixed crystals of amorphous and F-type crystals.

[0010] Based on this, the present invention is proposed. Summary of the Invention

[0011] This invention provides a method for preparing high-purity doxazosin mesylate F crystal form. To address the issue of interconversion of various crystal forms under heating conditions and the resulting instability in the preparation process of doxazosin mesylate F crystal form reported in the literature, this invention provides a simple, feasible method for preparing doxazosin mesylate F crystal form with high purity. The specific technical solution is as follows:

[0012] A method for preparing high-purity doxazosin mesylate F crystal form includes the following steps:

[0013] (1) Doxazosin was prepared by condensation reaction of N-1,4-benzodioxane-2-carbonylpiperazine with 2-chloro-4-amino-6,7-dimethoxyquinazoline.

[0014]

[0015] (2) The doxazosin obtained in step (1) is reacted with methanesulfonic acid in an alcohol solvent (such as n-pentanol, isopentanol, n-hexanol, isohexanol, heptanol or octanol as solvent) to prepare doxazosin methanesulfonic acid.

[0016]

[0017] Furthermore, the specific steps of step (1) are as follows:

[0018] Add n-butanol to a reaction flask, start stirring, add N-1,4-benzodioxane-2-carbonylpiperazine and 2-chloro-4-amino-6,7-dimethoxyquinazoline, heat to reflux (110-116℃) and maintain the temperature for reaction. After the reaction is complete, cool to 70-80℃ and filter. Wash the filter cake with potassium carbonate aqueous solution (measure wettability and dryness). Then dissolve it with N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone by heating, then crystallize with water or methanol, cool, filter, wash and dry to obtain doxazosin in sand-like granules.

[0019] The specific steps for step (2) are as follows:

[0020] Add the doxazosin prepared in step (1) and the alcohol solvent to the reaction flask in sequence, start stirring, heat to 120-135℃, then add methanesulfonic acid, keep warm and stir to precipitate crystals, cool to room temperature, filter, wash and dry to obtain doxazosin methanesulfonic acid, which is white sand-like particles.

[0021] Furthermore, the crude doxazosin obtained by washing with potassium carbonate aqueous solution needs to be dissolved in highly polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and then crystallized using one of the following undesirable solvents: water, methanol, or ethanol. During the salt formation reaction, the selected refining solvent is (a high-boiling-point saturated alcohol of C5 or higher, i.e., the alcohol solvent), preferably isoamyl alcohol or n-pentanol; the salt formation temperature is selected as 120–135°C, preferably 120–130°C; the amount of methanesulfonic acid is 1.0–1.1 eq, preferably 1.0–1.02 eq; and the amount of alcohol solvent is 8–10V (based on doxazosin, for example, if the mass of doxazosin is 25.00 g, the amount of alcohol solvent is 250 ml).

[0022] Before salt formation, doxazosin needs to be dissolved in a good solvent and crystallized in a bad solvent. The salt formation step uses high-boiling-point saturated alcohols of C5 and above, and the salt formation temperature and the amount of methanesulfonic acid and solvent are controlled.

[0023] The inventors discovered during their research that:

[0024] 1) To prepare a stable doxazosin mesylate F crystal form with good DSC peak shape, a combination of highly polar solvent / poor solvent is required, preferably N,N-dimethylformamide / water combination, to purify the crude doxazosin and reduce the influence of doxazosin on the crystal form purity of the F crystal form obtained by salt formation.

[0025] As in Examples 1 and 2, comparing doxazosin prepared using the above combination of highly polar solvent / poor solvent with doxazosin prepared without the above combination: one is a sandy particle, and the other is a white powder, although both can achieve a liquid phase purity of over 99%. Because liquid phase detection methods have limitations (e.g., in ICH, components below the reporting limit of 0.05% are not integrated, and there are slight differences in the content of inorganic salts between batches of doxazosin), using a combination of highly polar solvent / poor solvent can reduce the impact of undetectable trace substances in the crude doxazosin on the formation of F-type crystal nuclei during subsequent salt formation, thus directly affecting the peak shape of the prepared F-type DSC (e.g., ...). Figure 1 DSC and Figure 3 The DSC (Digital Sequence Conversion) is the crystal purity of the F crystal form. Therefore, using a combination of highly polar solvents / poor solvents can ensure the stability of the F crystal form prepared in subsequent processes (the purification yield can reach about 95%).

[0026] 2) The preparation of stable doxazosin mesylate F crystal form with good DSC peak shape requires high temperature. Selecting saturated alcohols of C5 and above with higher viscosity and higher boiling point as salting solvents and performing salting at high temperature (above 120℃) will reduce the interconversion of crystal forms, making salting and crystallization more favorable to the F crystal form. Furthermore, the F crystal form of doxazosin mesylate can be prepared without the addition of seed crystals.

[0027] Ethanol boiling point 78.4℃ < isopropanol boiling point 82.5℃ < n-propanol boiling point 97.2℃ < n-butanol boiling point 117.7℃ < isoamyl alcohol boiling point 131-132℃ < n-pentanol boiling point 137-139℃ < n-hexanol 157℃; Examples 6, 7, 8, 13, 16, and 17 used DSC data of the F-crystal form obtained by preparing doxazosin mesylate from isopropanol, n-propanol, n-butanol, and n-pentanol near their boiling points; as in Examples 9, 10, and 1 Items 1, 12, 13, 16, and 17 describe the DSC results of the F-crystal form of doxazosin mesylate obtained by preparing it using n-pentanol at different temperatures (90°C, 95°C, 100°C, 112°C, 120°C, 125°C, and 135°C). As mentioned above, when high-boiling-point C5 and higher saturated alcohols are selected for the preparation of the F-crystal form of doxazosin mesylate at temperatures above 120°C, the resulting DSC peak shapes of doxazosin mesylate are generally good (e.g., ...). Figure 15 DSC, Figure 17 DSC and Figure 19 (DSC).

[0028] Because the prepared doxazosin mesylate F crystals are sand-like particles with a particle size greater than 100 μm, if the selected salt-forming solvent has a higher boiling point (such as n-hexanol), the high-boiling-point solvent will be more difficult to remove as it is trapped in the crystal nuclei. Higher boiling points increase the difficulty of removal, which is detrimental to large-scale industrial production. Considering that the addition of methanesulfonic acid to the system will release heat by about 5°C, n-pentanol and isoamyl alcohol are preferred.

[0029] 3) To prepare doxazosin mesylate F crystal form with a liquid phase purity greater than or equal to 99.8%, it should be noted that high temperature and excessive methanesulfonic acid during the salt formation process of doxazosin mesylate will promote the formation of degradation impurity G in the salt formation reaction. The structural formula of impurity G is shown in formula G, which will affect the purity of the product. When the amount of methanesulfonic acid is too small, an abnormal reaction occurs, resulting in incomplete salt formation; when the amount of methanesulfonic acid is too large, the risk of degradation impurities increases. (Examples 1, 3, 4, and 5 show the experimental results using n-pentanol at 130°C with methanesulfonic acid amounts of 1.0 eq, 1.02 eq, 1.1 eq, and 1.2 eq, respectively; Examples 13, 14, and 15 show the experimental results using n-pentanol at 120°C with methanesulfonic acid amounts of 1.3 eq, 1.1 eq, and 1.02 eq, respectively; Examples 13, 16, and 17 show the experimental results using n-pentanol with 1.3 eq of methanesulfonic acid at 120°C, 125°C, and 135°C.)

[0030]

[0031] Ultimately, it was found that the combination of highly polar solvent / poor solvent is preferably one of N,N-dimethylformamide, dimethylacetamide, or N-methylpyrrolidone, more preferably N,N-dimethylformamide; the dissolution temperature is selected as 65-75°C; the poor solvent is preferably one of water or methanol or ethanol solvents, more preferably water.

[0032] The preferred salt-forming solvent (alcohol solvent) is n-pentanol or isopentanol; the salt-forming temperature is 120–135℃, preferably 120–130℃; the amount of methanesulfonic acid is 1.0–1.1 eq, preferably 1.0–1.02 eq; and the amount of alcohol solvent is 8–10 V.

[0033] The beneficial effects of this invention are:

[0034] 1. The doxazosin mesylate F crystal form prepared by the preparation method of the present invention has fewer impurities, higher purity, and ensures the stability of the crystal form. It also has low equipment requirements and low production costs.

[0035] 2. The present invention has a high yield and has been used in industrial pilot production. Attached Figure Description

[0036] Figure 1 The DSC spectrum is shown in Example 1;

[0037] Figure 2 The XRD pattern is shown in Example 1;

[0038] Figure 3 The DSC spectrum is shown in Example 2;

[0039] Figure 4 The XRD pattern is shown in Example 2;

[0040] Figure 5 The DSC spectrum is shown in Example 6;

[0041] Figure 6 The XRD pattern is shown in Example 6;

[0042] Figure 7 The DSC spectrum is shown in Example 7;

[0043] Figure 8 The XRD pattern is shown in Example 7;

[0044] Figure 9 The DSC spectrum in Example 8;

[0045] Figure 10 The XRD pattern is shown in Example 8;

[0046] Figure 11 The DSC spectrum in Example 9;

[0047] Figure 12 The DSC spectrum in Example 10;

[0048] Figure 13 The DSC spectrum in Example 11;

[0049] Figure 14 The DSC spectrum in Example 12;

[0050] Figure 15 The DSC spectrum in Example 13;

[0051] Figure 16 The XRD pattern is shown in Example 13;

[0052] Figure 17 The DSC spectrum in Example 16;

[0053] Figure 18 The XRD pattern is shown in Example 16;

[0054] Figure 19 The DSC spectrum in Example 17;

[0055] Figure 20 The image shown is the XRD pattern from Example 17. Detailed Implementation

[0056] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0057] Example 1

[0058] Preparation of doxazosin:

[0059] Add 1210 g of n-butanol to a 2 L reaction flask, start stirring, and add 80 g of N-1,4-benzodioxane-2-carbonylpiperazine and 75.5 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline. Heat to reflux (110-116 °C) and maintain the temperature. After the reaction is complete, cool to 70-80 °C and filter. Wash the filter cake with potassium carbonate aqueous solution, dry the washed filter cake to obtain crude doxazosin, and then dissolve it with 945 g of N,N-dimethylformamide by heating to 65-75 °C. After dissolution, add 945 ml of water, cool, filter, wash, and dry to obtain doxazosin (as a granular solid). (HPLC: 99.95%, yield 90%).

[0060] Preparation of doxazosin mesylate:

[0061] Add 25.00 g (0.05 mol, 1.0 eq) of the prepared doxazosin and 250 ml (10 V / W, V / W refers to the volume-to-mass ratio, the same below) of n-pentanol to the reaction flask, start stirring, heat to 130 °C, and add 5.46 g (0.07 mol, 1.02 eq) of mesylate all at once. After the addition is complete, slowly cool down, filter at an internal temperature of 50 °C, wash, and dry to obtain doxazosin mesylate F crystal form (HPLC: 99.9%, yield 95%, DSC and XRD detection results are shown in the figure). Figure 1 , 2 (As shown).

[0062] Example 2

[0063] Preparation of doxazosin:

[0064] Add 1210 g of n-butanol to a 2 L reaction flask, start stirring, and add 80 g of N-1,4-benzodioxane-2-carbonylpiperazine and 75.5 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline. Heat to reflux (110-116 °C) and maintain the temperature. After the reaction is complete, cool to 70-80 °C and filter. Wash the filter cake with potassium carbonate aqueous solution, and dry the washed filter cake to obtain crude doxazosin as a white powder (HPLC: 99.85%, yield 95%).

[0065] Preparation of doxazosin mesylate:

[0066] Add 25.00 g (0.05 mol, 1.0 eq) of the crude doxazosin prepared above and 250 ml (10 V / W) of n-pentanol to the reaction flask, start stirring, heat to 130 °C, and add 5.46 g (0.07 mol, 1.02 eq) of mesylate all at once. After the addition is complete, slowly cool, filter at an internal temperature of 50 °C, wash, and dry to obtain doxazosin mesylate F crystal form. (HPLC: 99.9%, yield 98%, DSC and XRD results are shown in [reference needed]) Figure 3 , 4 ).

[0067] Example 3

[0068] Preparation of doxazosin mesylate:

[0069] 25.00 g (0.055 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-pentanol were added to a reaction flask. Stirring was started, and the mixture was heated to 130 °C. Then, 5.32 g (0.055 mol, 1.0 eq) of methanesulfonic acid was added in one go. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. (Yield 96%, HPLC: 99.90%).

[0070] Example 4

[0071] Preparation of doxazosin mesylate:

[0072] 25.00 g (0.055 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-pentanol were added to a reaction flask. Stirring was started, and the mixture was heated to 130 °C. Then, 5.86 g (0.06 mol, 1.1 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form (yield 94%, HPLC: 99.51%).

[0073] Example 5

[0074] Preparation of doxazosin mesylate:

[0075] 25.00 g (0.055 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-pentanol were added to the reaction flask. Stirring was started, and the mixture was heated to 130 °C. Then, 6.39 g (0.066 mol, 1.2 eq) of methanesulfonic acid was added in one go. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form (yield 94%, HPLC: 98.99%).

[0076] Example 6

[0077] 25.00 g (0.05 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of isopropanol were added to the reaction flask. Stirring was started, and the mixture was heated to 80 °C. Then, 6.92 g (0.07 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the heating was turned off, and the mixture was slowly cooled. The mixture was filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form, which appeared as sand-like particles. The yield was 97.58%, HPLC: 99.80%, and the DSC and XRD results are shown in the figure. Figure 5 , 6 .

[0078] Example 7

[0079] Preparation of doxazosin mesylate:

[0080] 25.00 g (0.05 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-propanol were added to the reaction flask. Stirring was started, and the mixture was heated to 95 °C. Then, 6.92 g (0.07 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the heating was immediately stopped, and the mixture was slowly cooled. The mixture was filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 94%, HPLC: 99.38%, and DSC and XRD results are shown below. Figure 7 , 8 .

[0081] Example 8

[0082] Preparation of doxazosin mesylate:

[0083] 25.00 g (0.05 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-butanol were added to the reaction flask. Stirring was started, and the mixture was heated to 110 °C. Then, 6.92 g (0.07 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 92%, HPLC: 99.36%, and DSC and XRD results are shown in the figure. Figure 9 , 10 .

[0084] Example 9

[0085] Preparation of doxazosin mesylate:

[0086] 10.00 g (0.022 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 100 ml (10 V / W) of n-pentanol were added to the reaction flask. Stirring was started, and the mixture was heated to 90 °C. Then, 2.77 g (0.029 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 94%, HPLC: 99.58%, and DSC results are shown in [Figure number missing]. Figure 11 .

[0087] Example 10

[0088] Preparation of doxazosin mesylate:

[0089] 10.00 g (0.022 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 100 ml (10 V / W) of n-pentanol were added to the reaction flask. Stirring was started, and the mixture was heated to 95 °C. Then, 2.77 g (0.029 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 95%, HPLC: 99.35%, and DSC results are shown below. Figure 12 .

[0090] Example 11

[0091] Preparation of doxazosin mesylate:

[0092] 10.00 g (0.022 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 100 ml (10 V / W) of n-pentanol were added to a reaction flask. Stirring was started, and the mixture was heated to 100 °C. Then, 2.77 g (0.029 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 93%, HPLC: 99.30%, and DSC results are shown in [Figure number missing]. Figure 13 .

[0093] Example 12

[0094] Preparation of doxazosin mesylate:

[0095] 10.00 g (0.022 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 100 ml (10 V / W) of n-pentanol were added to the reaction flask. Stirring was started, and the mixture was heated to 112 °C. Then, 2.77 g (0.029 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 94%, HPLC: 99.26%, and DSC results are shown below. Figure 14 .

[0096] Example 13

[0097] Preparation of doxazosin mesylate:

[0098] 25.00 g (0.05 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-pentanol were added to the reaction flask. Stirring was started, and the mixture was heated to 120 °C. Then, 6.92 g (0.07 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 93%, HPLC: 99.04%, and DSC and XRD results are shown below. Figure 15 , 16 .

[0099] Example 14

[0100] Preparation of doxazosin mesylate:

[0101] 25.00 g (0.05 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-pentanol were added to a reaction flask. Stirring was started, and the mixture was heated to 120 °C. Then, 5.81 g (0.06 mol, 1.1 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. (Yield: 94%, HPLC: 99.86%).

[0102] Example 15

[0103] Preparation of doxazosin mesylate:

[0104] 25.00 g (0.05 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 mL (10 V / W) of n-pentanol were added to a reaction flask. Stirring was started, and the mixture was heated to 120 °C. Then, 5.39 g (0.056 mol, 1.02 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. Yield: 93%, HPLC: 99.87%.

[0105] Example 16

[0106] Preparation of doxazosin mesylate:

[0107] 25.00 g (0.05 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-pentanol were added to the reaction flask. Stirring was started, and the mixture was heated to 125 °C. Then, 6.92 g (0.07 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 92.57%, HPLC: 98.97%, and the DSC and XRD results are shown in the figure. Figure 17 , 18 .

[0108] Example 17

[0109] Preparation of doxazosin mesylate:

[0110] 25.00 g (0.055 mol, 1.0 eq) of doxazosin prepared according to the method of Example 1 and 250 ml (10 V / W) of n-pentanol were added to the reaction flask. Stirring was started, and the mixture was heated to 135 °C. Then, 6.92 g (0.07 mol, 1.3 eq) of methanesulfonic acid was added in one batch. After the addition was complete, the mixture was slowly cooled, filtered at an internal temperature of 50 °C, washed, and dried to obtain doxazosin mesylate F crystal form. The yield was 93.73%, HPLC: 98.08%, and the DSC and XRD results are shown in the figure. Figure 19 , 20 .

[0111] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing high-purity doxazosin mesylate F crystal form, characterized in that... Includes the following steps: Step S1: Doxazosin was prepared by condensation reaction of N-1,4-benzodioxane-2-carbonylpiperazine and 2-chloro-4-amino-6,7-dimethoxyquinazoline. Step S2: Doxazosin and methanesulfonic acid are reacted in an alcohol solvent to prepare doxazosin methanesulfonate F crystal form; In step S1, the solvent used in the reaction is n-butanol; the reaction temperature is 110~116℃. In step S2, the alcohol solvent is n-pentanol or isopentanol; the reaction temperature is 120~135℃; the equivalent ratio of methanesulfonic acid to doxazosin is (1.0~1.1):1; In step S1, after the reaction is complete, the temperature is lowered to 70-80°C, filtered, and the filter cake is washed with potassium carbonate aqueous solution. Then, it is dissolved by heating with N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, followed by crystallization with water or methanol, cooling, filtering, washing, and drying to complete the purification of doxazosin.

2. The method for preparing high-purity doxazosin mesylate F crystal form according to claim 1, characterized in that: In step S2, after the reaction is complete, crystals are precipitated, the temperature is lowered to 50±2℃, filtered, washed, and dried to obtain the purified doxazosin mesylate F crystal form.

3. The method for preparing high-purity doxazosin mesylate F crystal form according to claim 1, characterized in that: In step S2, the volume-to-mass ratio of the alcohol solvent to doxazosin is (8~10):1.

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