CN117777116A - Preparation method of high-purity doxazosin mesylate F crystal form - Google Patents
Preparation method of high-purity doxazosin mesylate F crystal form Download PDFInfo
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- CN117777116A CN117777116A CN202311780608.6A CN202311780608A CN117777116A CN 117777116 A CN117777116 A CN 117777116A CN 202311780608 A CN202311780608 A CN 202311780608A CN 117777116 A CN117777116 A CN 117777116A
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- doxazosin
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- 239000013078 crystal Substances 0.000 title claims abstract description 81
- 229960000220 doxazosin mesylate Drugs 0.000 title claims abstract description 74
- VJECBOKJABCYMF-UHFFFAOYSA-N doxazosin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 VJECBOKJABCYMF-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 66
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims abstract description 55
- 229960001389 doxazosin Drugs 0.000 claims abstract description 47
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 33
- 238000001914 filtration Methods 0.000 claims abstract description 29
- 238000010438 heat treatment Methods 0.000 claims abstract description 28
- 238000005406 washing Methods 0.000 claims abstract description 27
- 238000001035 drying Methods 0.000 claims abstract description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 24
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims abstract description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012065 filter cake Substances 0.000 claims abstract description 8
- FLUPDJNTYCSBJZ-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxin-3-yl(piperazin-1-yl)methanone Chemical compound C1OC2=CC=CC=C2OC1C(=O)N1CCNCC1 FLUPDJNTYCSBJZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- HWIIAAVGRHKSOJ-UHFFFAOYSA-N 2-chloro-6,7-dimethoxyquinazolin-4-amine Chemical compound ClC1=NC(N)=C2C=C(OC)C(OC)=CC2=N1 HWIIAAVGRHKSOJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 3
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 18
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 238000001816 cooling Methods 0.000 abstract description 25
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 238000009835 boiling Methods 0.000 description 15
- 238000001514 detection method Methods 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 10
- 238000002441 X-ray diffraction Methods 0.000 description 9
- 239000002245 particle Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
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- 210000002307 prostate Anatomy 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
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- -1 4-amino-6, 7-dimethoxy-2-quinazolinyl Chemical group 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
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- 239000002160 alpha blocker Substances 0.000 description 1
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- 229910017053 inorganic salt Inorganic materials 0.000 description 1
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method of high-purity doxazosin mesylate F crystal form, which comprises the steps of carrying out condensation reaction on N-1, 4-benzodioxane-2-carbonyl piperazine and 2-chloro-4-amino-6, 7-dimethoxy quinazoline, cooling, filtering after the reaction is finished, washing a filter cake by using a potassium carbonate aqueous solution, heating and dissolving the filter cake by using N, N-dimethylformamide, crystallizing by using water or methanol, cooling, filtering, washing and drying to obtain doxazosin; and (3) reacting the doxazosin and methanesulfonic acid in n-amyl alcohol or isoamyl alcohol, crystallizing after the reaction is finished, cooling, filtering, washing and drying to obtain the doxazosin mesylate F crystal form. The doxazosin mesylate F crystal form prepared by the preparation method has the advantages of less impurities, high purity, ensured stability of the crystal form, low equipment requirement and low production cost. The invention has high yield and is used for industrial production.
Description
Technical Field
The invention relates to a preparation method of a high-purity doxazosin mesylate F crystal form, belonging to the technical field of drug synthesis.
Background
Doxazosin mesylate (doxazosin mesylate), chemical name 1- (4-amino-6, 7-dimethoxy-2-quinazolinyl) -4- (1, 4-benzodioxane-2-formyl) piperazine mesylate, chemical formula shown below:
doxazosin mesylate is a drug for selecting an alpha receptor blocker, and achieves the effects of dilating blood vessels, reducing vascular resistance and lowering blood pressure by blocking alpha 1-receptors. Unlike non-selective alpha-blockers: the drug resistance is not observed after long-term application, and the heart beat speed is rarely seen in the maintenance treatment process, so that the plasma renin is increased. By selectively blocking the smooth muscle matrix of the prostate, the capsule and the alpha-adrenergic receptor of the bladder neck, the product can improve the urodynamics and clinical symptoms of symptomatic prostate hyperplasia patients.
The synthetic routes of doxazosin mesylate reported in the literature are more, wherein the synthetic routes for preparing doxazosin by taking piperazine as a center for a coupling reaction have the advantages of simple operation, safe process and high product yield.
The doxazosin mesylate is prepared by salifying doxazosin and methanesulfonic acid. However, the selection of different reaction solvents may result in the formation of different crystalline forms of doxazosin mesylate.
The current literature reports that doxazosin mesylate has different crystal forms of A, B, C, D, E, F, M, I, II, III, IV and the like, but the various crystal forms can be mutually converted under the heating condition, but the conversion condition is not definite. The form F and a process for the preparation of this form are reported in foreign patent EP 0848001.
Experiments of the patent application show that the doxazosin mesylate (F crystal form) has moderate solubility, 1ml of purified water can be dissolved for about 7.5mg of the crystal form, and 1ml of acetate buffer solution with pH of 4.5 can be dissolved for about 5.0-9.0 mg of the crystal form; by using the crystal form for granulating, the release of the simulated intestinal juice after meal for 24 hours can reach more than 90 percent, and the release of the simulated gastric juice after meal for 28 hours is close to 90 percent, so that various signs show that the bioavailability of the crystal form has own advantages compared with other crystal forms.
According to the report of EP0848001, when solvents such as ethanol, isopropanol, n-propanol, n-butanol and the like are used for preparing the crystal forms, the obtained crystal forms are abnormal, for example, when ethanol is used for preparing the F crystal form for a plurality of times according to the process of the patent EP0848001, 1 to 2 batches of prepared crystal forms are III crystal forms or mixed crystal of III crystal forms and F crystal forms; when isopropanol, n-propanol, n-butanol and n-pentanol are used, the DSC peak type of the prepared F crystal form is poor (as shown in fig. 5, 7, 9, 3, 11, 12, 13 and 14), and by analysis of the XRD spectrograms (as shown in fig. 6, 8, 10 and 4), no X-ray diffraction characteristic peak of other crystal forms is found, so that the reason for poor DSC peak type is that mixed crystals of amorphous and F crystal forms appear.
Based on this, the present invention has been proposed.
Disclosure of Invention
The invention provides a preparation method of a high-purity doxazosin mesylate F crystal form, which aims to solve the problem that various crystal forms in the prior art can be mutually converted under the heating condition, and the process for preparing the doxazosin mesylate F crystal form is unstable. The specific technical scheme is as follows:
the preparation method of the high-purity doxazosin mesylate F crystal form comprises the following steps:
(1) The doxazosin is prepared by adopting N-1, 4-benzodioxane-2-carbonyl piperazine and 2-chloro-4-amino-6, 7-dimethoxy quinazoline to carry out condensation reaction.
(2) And (2) reacting the doxazosin obtained in the step (1) with methanesulfonic acid to obtain the doxazosin mesylate by using an alcohol solvent (single alcohol such as n-amyl alcohol, isoamyl alcohol, n-hexyl alcohol, isoamyl alcohol, heptanol or octyl alcohol is used as a solvent).
Further, the specific implementation of the step (1) is as follows:
n-butanol is added into a reaction bottle, stirring is started, N-1, 4-benzodioxane-2-carbonyl piperazine and 2-chloro-4-amino-6, 7-dimethoxy quinazoline are added, heating is carried out until reflux (110-116 ℃) is carried out, and thermal insulation reaction is carried out. And after the reaction is finished, cooling to 70-80 ℃ and filtering. The filter cake was washed (dry and wet, dry) with aqueous potassium carbonate. Then heating and dissolving the doxazosin by using N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone, then crystallizing the doxazosin by using water or methanol, cooling, filtering, washing and drying to obtain the doxazosin in the form of sandy particles.
The specific method of the step (2) comprises the following steps:
sequentially adding the doxazosin prepared in the step (1) and an alcohol solvent into a reaction bottle, starting stirring, heating to 120-135 ℃, then adding methanesulfonic acid, carrying out heat preservation, stirring and crystallization, cooling to room temperature, filtering, washing and drying to obtain the doxazosin mesylate in the form of white sandy particles.
Further, the crude doxazosin obtained by washing with aqueous potassium carbonate solution is dissolved in a large polar solvent such as N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and then is crystallized by using one of poor solvents such as water, methanol, and ethanol. In the salification reaction, the selected refining solvent is (high boiling point saturated alcohol with more than C5 and C5, namely the alcohol solvent), preferably isoamyl alcohol or n-amyl alcohol, and the salification temperature is 120-135 ℃, preferably 120-130 ℃; the amount of methanesulfonic acid to be used is 1.0 to 1.1eq, preferably 1.0 to 1.02eq; the amount of the alcohol solvent is 8 to 10V (based on doxazosin, for example, the mass of the doxazosin is 25.00g, and the amount of the alcohol solvent is 250 ml).
Before salifying, benign solvent dissolution and poor solvent crystallization are carried out on doxazosin, saturated alcohols with high boiling points of C5 and above are used in the salifying step, and the salifying temperature and the dosage of methanesulfonic acid and the solvent are controlled.
The inventors found in the study that:
1) And the doxazosin mesylate F crystal form with stable preparation and better DSC peak type is prepared, a combination of a large-polarity solvent/poor solvent, more preferably an N, N-dimethylformamide/water combination is required to be used, the crude doxazosin is purified, and the influence of the doxazosin on the crystal form purity of the F crystal form obtained by salifying is reduced.
As in examples 1 and 2, doxazosin prepared using the above combination of highly polar solvent/poor solvent was compared to doxazosin prepared without the above combination: one of the two is in sand-like particles and the other is in white powder, although the purity of the liquid phase of the two can reach more than 99 percent. Because the liquid phase detection method has limitations (such as no integral can be performed in ICH for less than 0.05% report limit, and the tiny content difference of inorganic salt between batches in doxazosin, etc.), the combination of the solvent with large polarity/poor solvent can reduce the influence of undetected tiny substances in the doxazosin crude product on the formation of F crystal nucleus in the subsequent salification process due to the limitations of the detection method, thereby directly influencing the peak form of the prepared F crystal DSC (such as DSC in figure 1 and DSC in figure 3), namely the crystal purity of the F crystal DSC. Therefore, the combination of the solvent with large polarity and the poor solvent can ensure the stability of the F crystal form prepared in the subsequent process (the refining yield can reach about 95 percent).
2) The doxazosin mesylate F crystal form with stable preparation and better DSC peak type is prepared, the requirement on temperature is higher, saturated alcohols with higher viscosity and higher boiling point and more than C5 are selected as salifying solvents to form salt at high temperature (more than 120 ℃), so that the mutual conversion of the crystal forms is reduced, the salifying crystallization is more favorable for the progress toward the F crystal form, and the doxazosin mesylate of the F crystal form can be prepared without adding seed crystals.
The boiling point of ethanol is 78.4 ℃ less than the boiling point of isopropanol and 82.5 ℃ less than the boiling point of n-propanol and 97.2 ℃ less than the boiling point of n-butanol and 117.7 ℃ less than the boiling point of isoamyl alcohol and 131-132 ℃ less than the boiling point of n-amyl alcohol and 137-139 ℃ less than the boiling point of n-hexanol and 157 ℃; examples 6,7, 8, 13, 16 and 17 used DSC conditions of the F crystal form prepared by doxazosin mesylate of isopropanol, n-propanol, n-butanol and n-pentanol near the boiling point thereof; DSC cases of the F crystal forms prepared by using n-amyl alcohol at different temperatures (90 ℃, 95 ℃, 100 ℃, 112 ℃,120 ℃, 125 ℃, 135 ℃) are described in examples 9, 10, 11, 12, 13, 16, 17; as described above, when the doxazosin mesylate F crystal form was prepared at 120 ℃ or higher using saturated alcohols having a high boiling point of C5 and C5 or higher, the DSC peak forms of the doxazosin mesylate obtained were both good (e.g., DSC in fig. 15, DSC in fig. 17, and DSC in fig. 19).
As the prepared doxazosin mesylate F crystal form is sandy particles, the particle size is more than 100 mu m, if the boiling point of the selected salifying solvent is higher (such as n-hexanol), the solvent with high boiling point is more difficult to remove when being wrapped in crystal nucleus, and the higher the boiling point is, the more difficult to remove is, thus being unfavorable for industrial mass production. N-pentanol and isoamyl alcohol are preferred, considering that the addition of the methanesulfonic acid system gives off heat around 5 ℃.
3) And preparing a doxazosin mesylate F crystal form with the liquid phase purity of more than or equal to 99.8%, wherein the high temperature and excessive methanesulfonic acid in the salification process of the doxazosin mesylate can promote the generation of degraded impurity G in the salification reaction, and the structural formula of the impurity G is shown as a formula G, so that the purity of a product is influenced. When the dosage of the methanesulfonic acid is too small, abnormal reaction occurs, and salt formation is insufficient; when the amount of methanesulfonic acid used is too large, the risk of degradation of impurities increases; (examples 1, 3, 4 and 5 are examples of the use of n-amyl alcohol at 130℃and the use of methanesulfonic acid at 1.0eq, 1.02eq, 1.1eq and 1.2 eq; examples 13, 14 and 15 are examples of the use of n-amyl alcohol at 120℃and the use of methanesulfonic acid at 1.3eq, 1.1eq and 1.02eq; examples 13, 16 and 17 are examples of the use of n-amyl alcohol at 1.3eq and the use of methanesulfonic acid at 120℃and 125℃and 135 ℃).
It was finally found that a combination of highly polar solvents/poor solvents, preferably: one of N, N-dimethylformamide, dimethylacetamide or N-methylpyrrolidone, more preferably: n, N-dimethylformamide; the dissolution temperature is selected to be 65-75 ℃; the poor solvent is preferably: water or one of methanol and ethanol solvents, more preferably: and (3) water.
The salt forming solvent (alcohol solvent) is preferably n-amyl alcohol or isoamyl alcohol; the salification temperature is 120-135 ℃, preferably 120-130 ℃; the amount of methanesulfonic acid to be used is 1.0 to 1.1eq, preferably 1.0 to 1.02eq; the use level of the alcohol solvent is 8-10V.
The invention has the beneficial effects that:
1. the doxazosin mesylate F crystal form prepared by the preparation method has the advantages of less impurities, high purity, ensured stability of the crystal form, low equipment requirement and low production cost.
2. The invention has high yield and is used for industrial production.
Drawings
FIG. 1 is a DSC chart of example 1;
FIG. 2 is an XRD pattern for example 1;
FIG. 3 is a DSC chart of example 2;
FIG. 4 is an XRD pattern for example 2;
FIG. 5 is a DSC chart of example 6;
FIG. 6 is an XRD pattern for example 6;
FIG. 7 is a DSC chart of example 7;
FIG. 8 is an XRD pattern for example 7;
FIG. 9 is a DSC chart in example 8;
FIG. 10 is an XRD pattern for example 8;
FIG. 11 is a DSC chart in example 9;
FIG. 12 is a DSC chart in example 10;
FIG. 13 is a DSC chart in example 11;
FIG. 14 is a DSC chart in example 12;
FIG. 15 is a DSC chart in example 13;
FIG. 16 is an XRD pattern for example 13;
FIG. 17 is a DSC chart of example 16;
FIG. 18 is an XRD pattern for example 16;
FIG. 19 is a DSC chart in example 17;
figure 20 is an XRD pattern in example 17.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
Preparation of doxazosin:
into a 2L reaction flask, 1210g of n-butanol was added, stirring was turned on, and 80. 80g N-1, 4-benzodioxane-2-carbonyl piperazine and 75.5g of 2-chloro-4-amino-6, 7-dimethoxyquinazoline were added. Heating to reflux (110-116 deg.C) and thermal reacting. And after the reaction is finished, cooling to 70-80 ℃ and filtering. Washing the filter cake by using a potassium carbonate aqueous solution, drying the washed filter cake to obtain a coarse product of doxazosin, heating to 65-75 ℃ by using 945g of N, N-dimethylformamide to dissolve, adding 945ml of water after dissolving, cooling, filtering, washing and drying to obtain the doxazosin (in the form of sandy solid). (HPLC: 99.95%, yield 90%).
Preparation of doxazosin mesylate:
25.00g (0.05 mol,1.0 eq) of doxazosin prepared above and 250ml (10V/W, V/W means volume mass ratio, the same applies below) of n-pentanol are added into a reaction bottle, stirring is started, heating is carried out to 130 ℃, and 5.46g (0.07 mol,1.02 eq) of methanesulfonic acid is added at one time. After the addition, slowly cooling, filtering at an internal temperature of 50 ℃, washing, and drying to obtain doxazosin mesylate F crystal form (HPLC: 99.9%, yield 95%, DSC, XRD detection results are shown in figures 1 and 2).
Example 2
Preparation of doxazosin:
into a 2L reaction flask, 1210g of n-butanol was added, stirring was turned on, and 80. 80g N-1, 4-benzodioxane-2-carbonyl piperazine and 75.5g of 2-chloro-4-amino-6, 7-dimethoxyquinazoline were added. Heating to reflux (110-116 deg.C) and thermal reacting. And after the reaction is finished, cooling to 70-80 ℃ and filtering. The filter cake was washed with aqueous potassium carbonate and the washed filter cake was dried to give a crude doxazosin as a white powdery solid (HPLC: 99.85%, yield 95%).
Preparation of doxazosin mesylate:
25.00g (0.05 mol,1.0 eq) of the crude doxazosin product prepared above and 250ml (10V/W) of n-amyl alcohol are added into a reaction bottle, stirring is started, heating is carried out to 130 ℃, and 5.46g (0.07 mol,1.02 eq) of methanesulfonic acid are added at one time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. (HPLC: 99.9%, yield 98%, DSC, XRD detection results are shown in FIGS. 3, 4).
Example 3
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.055 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 130℃and 5.32g (0.055 mol,1.0 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. (yield 96%, HPLC: 99.90%).
Example 4
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.055 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 130℃and 5.86g (0.06 mol,1.1 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. (yield 94%, HPLC: 99.51%).
Example 5
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.055 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 130℃and 6.39g (0.066 mol,1.2 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. (yield 94%, HPLC: 98.99%).
Example 6
Into a reaction flask were charged 25.00g (0.05 mol,1.0 eq) of doxazosin prepared in the manner of example 1, 250ml (10V/W) of isopropanol, and the mixture was stirred and heated to 80℃with a single addition of 6.92g (0.07 mol,1.3 eq) of methanesulfonic acid. After the addition, the heating is closed, the temperature is slowly reduced, the filtration, the washing and the drying are carried out at the internal temperature of 50 ℃ to obtain the doxazosin mesylate F crystal form which is in the form of sandy particles. The yield is 97.58%, the HPLC is 99.80%, and the DSC and XRD detection results are shown in figures 5 and 6.
Example 7
Preparation of doxazosin mesylate:
into a reaction flask, 25.00g (0.05 mol,1.0 eq) of doxazosin prepared in the manner of example 1 and 250ml (10V/W) of n-propanol were added, stirring was started, heating was carried out to 95℃and 6.92g (0.07 mol,1.3 eq) of methanesulfonic acid was added at a time. And immediately closing the heating after the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing, and drying to obtain the doxazosin mesylate F crystal form. The yield is 94%, HPLC is 99.38%, and DSC and XRD detection results are shown in figures 7 and 8.
Example 8
Preparation of doxazosin mesylate:
into a reaction flask, 25.00g (0.05 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 250ml (10V/W) of n-butanol were added, stirring was started, heating was carried out to 110℃and 6.92g (0.07 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. The yield is 92%, the HPLC is 99.36%, and the DSC and XRD detection results are shown in figures 9 and 10.
Example 9
Preparation of doxazosin mesylate:
into a reaction flask, 10.00g (0.022 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 100ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 90℃and 2.77g (0.029 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. Yield 94%, HPLC:99.58%, DSC detection result is shown in FIG. 11.
Example 10
Preparation of doxazosin mesylate:
into a reaction flask, 10.00g (0.022 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 100ml (10V/W) of n-pentanol were added, stirring was started, heating was raised to 95℃and 2.77g (0.029 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. The yield was 95%, HPLC:99.35%, and DSC detection results are shown in FIG. 12.
Example 11
Preparation of doxazosin mesylate:
into a reaction flask, 10.00g (0.022 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 100ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 100℃and 2.77g (0.029 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. Yield 93%, HPLC:99.30%, DSC detection result is shown in FIG. 13.
Example 12
Preparation of doxazosin mesylate:
into the reaction flask, 10.00g (0.022 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 100ml (10V/W) of n-amyl alcohol were added, stirring was started, heating was carried out to 112℃and 2.77g (0.029 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. Yield 94%, HPLC:99.26%, DSC detection result is shown in FIG. 14.
Example 13
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.05 mol,1.0 eq) of doxazosin prepared in the manner of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 120℃and 6.92g (0.07 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. The yield is 93%, HPLC is 99.04%, and DSC and XRD detection results are shown in figures 15 and 16.
Example 14
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.05 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 120℃and 5.81g (0.06 mol,1.1 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. Yield 94%, HPLC: 99.86%).
Example 15
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.05 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 120℃and 5.39g (0.056 mol,1.02 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. Yield 93%, 99.87% by HPLC.
Example 16
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.05 mol,1.0 eq) of doxazosin prepared in the manner of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 125℃and 6.92g (0.07 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. The yield is 92.57%, the HPLC is 98.97%, and the DSC and XRD detection results are shown in figures 17 and 18.
Example 17
Preparation of doxazosin mesylate:
into the reaction flask, 25.00g (0.055 mol,1.0 eq) of doxazosin prepared in the method of example 1 and 250ml (10V/W) of n-pentanol were added, stirring was started, heating was carried out to 135℃and 6.92g (0.07 mol,1.3 eq) of methanesulfonic acid was added at a time. After the addition, slowly cooling, filtering at the internal temperature of 50 ℃, washing and drying to obtain the doxazosin mesylate F crystal form. The yield is 93.73%, the HPLC is 98.08%, and the DSC and XRD detection results are shown in figures 19 and 20.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (10)
1. The preparation method of the high-purity doxazosin mesylate F crystal form is characterized by comprising the following steps:
s1, performing condensation reaction on N-1, 4-benzodioxane-2-carbonyl piperazine and 2-chloro-4-amino-6, 7-dimethoxy quinazoline to prepare doxazosin;
and S2, reacting doxazosin and methanesulfonic acid in an alcohol solvent to prepare the doxazosin mesylate F crystal form.
2. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in the step S2, the alcohol solvent is one of n-amyl alcohol, isoamyl alcohol, n-hexyl alcohol, isoamyl alcohol, heptyl alcohol and octyl alcohol.
3. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in step S2, the alcohol solvent is n-amyl alcohol or isoamyl alcohol.
4. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in step S1, the solvent used in the reaction is n-butanol.
5. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in step S1, the reaction temperature is 110 to 116 ℃.
6. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in the step S1, after the reaction is finished, the temperature is reduced to 70-80 ℃, the filtration is carried out, a filter cake is washed by using a potassium carbonate aqueous solution, then N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone are used for heating and dissolving, then water or methanol is used for crystallization, the temperature is reduced, the filtration, the washing and the drying are carried out, and the purification of the doxazosin is completed.
7. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in step S2, the reaction temperature is 120-135 ℃.
8. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in the step S2, after the reaction is completed, crystallization is carried out, the temperature is reduced to 50+/-2 ℃, and the purified doxazosin mesylate F crystal form is obtained after filtration, washing and drying.
9. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in step S2, the equivalent ratio of methanesulfonic acid to doxazosin is (1.0-1.1): 1.
10. The method for preparing the high-purity doxazosin mesylate F crystal form of claim 1, which is characterized in that: in the step S2, the volume-mass ratio between the alcohol solvent and the doxazosin is (8-10): 1.
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