CN111662353A - Preparation method of fluticasone furoate crystal form 1 - Google Patents
Preparation method of fluticasone furoate crystal form 1 Download PDFInfo
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- CN111662353A CN111662353A CN201910165737.1A CN201910165737A CN111662353A CN 111662353 A CN111662353 A CN 111662353A CN 201910165737 A CN201910165737 A CN 201910165737A CN 111662353 A CN111662353 A CN 111662353A
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- fluticasone furoate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a preparation method of a furoic acid fluticasone crystal form 1, which comprises the following steps: under the heating condition, the fluticasone furoate is mixed with an organic solvent, cooled and crystallized after crystal transformation, and separated to obtain the fluticasone furoate crystal form 1, wherein the organic solvent is toluene or xylene. The crystal habit of the fluticasone furoate crystal form 1 prepared by the invention is a tetragonal pyramid, the fluidity is better, the yield is higher, the operation is simple and convenient, and the method is suitable for industrialization.
Description
Technical Field
The invention particularly relates to a preparation method of a furoic acid fluticasone crystal form 1.
Background
The glucocorticoid inhalation drug Fluticasone furoate (Fluticasone furoate) has the chemical name of (6 α, 11 β, 16 α, 17 α) -6, 9-difluoro-17- [ [ (fluoromethyl) thio]Carbonyl radical]-11-hydroxy-16-methyl-3-oxoandrost-1, 4-dien-17-yl 2-furancarboxylate with the molecular formula C27H29F3O6S, developed by Kurarin Schker, is indicated for allergic rhinitis or asthma, and has the following structural formula:
US7101866 discloses the chemical structure of fluticasone furoate, polymorphs and processes for their preparation. The reported crystal forms of fluticasone furoate include the following three, and five solvates (2-butanone, isopropanol, tetrahydrofuran, acetone or N, N-dimethylformamide) are reported:
the crystalline forms of fluticasone furoate include: crystalline forms 1, 2, 3 characterized by an X-ray powder diffraction (XRPD) pattern as: the 2 theta of the characteristic absorption peak of the crystal form 1 is 18.9 degrees, the 2 theta of the characteristic absorption peak of the crystal form 2 is 18.4 degrees and 21.5 degrees, and the 2 theta of the characteristic absorption peak of the crystal form 3 is 18.6 degrees and 19.2 degrees; the absorption peaks of the crystal forms 2 and 3 at 2 theta of 7 degrees are much higher than that of the crystal form 1.
Form 1 is the most thermodynamically stable form and is non-hygroscopic. For form 1, there are two crystal habits: tetragonal pyramid type and needle-shaped crystal, and tetragonal pyramid type has better fluidity, and is beneficial to preparing solid aerosol powder.
US7101866 reports a method for preparing crystal form 1, but does not describe the crystal habit of the method for preparing crystal form 1, and reports that a mixed solvent system is adopted: good solvents (ethyl acetate, methyl isobutyl ketone or acetone) and poor solvents (isooctane or toluene), complex preparation process, difficult solvent recovery, lower yield and higher cost.
In order to better meet the pharmaceutical requirements, the development of a preparation process of the bulk drug with low cost and high yield has higher commercial practical value and better meets the requirements of green chemistry. Therefore, a preparation method of the fluticasone furoate crystal form 1, which is simple to operate, low in cost, small in reagent dosage, environment-friendly, high in yield and suitable for industrial production, needs to be found to overcome many defects in the prior art.
Disclosure of Invention
The invention provides a novel preparation method of a furoic acid fluticasone crystal form 1, aiming at overcoming the defects of high cost, large reagent dosage, more three wastes, complex reaction operation, low yield and unsuitability for industrial production of the preparation method of the furoic acid fluticasone crystal form 1 in the prior art, and the solid crystal habit prepared by the method is a tetragonal pyramid type with better fluidity. The preparation method of the furoic acid fluticasone crystal form 1 has the advantages of simple operation, low cost, less reagent dosage, less three wastes and high yield, and is suitable for industrial production.
The invention provides a preparation method of a furoic acid fluticasone crystal form 1, which comprises the following steps: under the heating condition, mixing the fluticasone furoate with an organic solvent, carrying out cooling crystallization after crystal transformation, and separating to obtain the fluticasone furoate crystal form 1.
Wherein, the raw material of the fluticasone furoate is preferably in a crystal form 2, a crystal form 3 or a solvate. Wherein the furoic acid fluticasone solvate comprises 2-butanone, isopropanol, tetrahydrofuran, acetone or N, N-dimethylformamide.
The organic solvent is preferably one or more of toluene and xylene.
The preferable dosage of the organic solvent is 5-50 mL/g, and the more preferable dosage is 10-30 mL/g.
The preferable temperature of the heating condition is 80 to 140 ℃, and the more preferable temperature is 80 to 120 ℃.
The cooling temperature is preferably 50 ℃ or lower, more preferably 0 to 30 ℃, and most preferably 0 to 20 ℃.
The mixing step of the fluticasone furoate and the organic solvent and the cooling crystallization step are preferably carried out under stirring or standing conditions, and are more preferably carried out under stirring conditions.
The cooling crystallization time is more than 30 minutes, and the more preferable time is 2 to 6 hours.
The separation comprises the operations of further post-treatment: filtering, washing and drying. Wherein the washing is carried out using the same solvent. The drying is preferably oven drying, more preferably oven drying at 60 deg.C.
According to the preparation method of the fluticasone furoate crystal form 1, the prepared solid crystal nodule is a pure tetragonal pyramid type, and according to the preparation method of the crystal form 1 in US7101866, the prepared solid crystal nodule is a mixture of the tetragonal pyramid type and a needle shape.
The raw material fluticasone furoate crystal form 2, the crystal form 3 or the solvate can be used for preparing the crystal form 1, and the specific preparation method can be seen in US 7101866.
The room temperature in the invention means that the ambient temperature is 10-30 ℃.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method of the furoic acid fluticasone crystal form 1 has the advantages of simple operation, less reagent dosage, less three wastes, high yield, low cost and suitability for industrial production, and the prepared solid crystal habit is a pure tetragonal pyramid form.
Drawings
Figure 1 is a powder diffraction pattern of fluticasone furoate crystalline form 1 prepared with toluene solvent,
figure 2 is a powder diffraction pattern of fluticasone furoate crystalline form 1 prepared with a diphenyl solvent,
figure 3 is a microscope image of fluticasone furoate solid pica prepared with toluene solvent,
fig. 4 is a microscope image of fluticasone furoate solid pica prepared with a diphenyl solvent.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Mixing the solid fluticasone furoate crystal form 2 (0.5g) and toluene 2.5mL in a 50mL reaction bottle, heating to 110 ℃, stirring for 30 minutes, naturally cooling to 30 ℃, stirring for 6 hours, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product fluticasone furoate crystal form 1(0.46g), wherein the yield is 92.0%, and the product is anhydrous or non-solvated crystalline form. The crystal form 1 of the fluticasone furoate is determined by characterization and identification of X-ray powder diffraction (XRPD), the result is shown in figure 1 and table 1, the solid crystal form is a pure tetragonal pyramid form by microscope detection, and the result is shown in figure 3.
TABLE 1 XRD characteristic peaks of fluticasone furoate form 1
Example 2
Mixing the solid fluticasone furoate crystal form 3 (0.5g) and 25mL of toluene in a 50mL reaction bottle, heating to 80 ℃, standing for 30 minutes, naturally cooling to 30 ℃, standing for 6 hours, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product fluticasone furoate crystal form 1(0.44g), wherein the yield is 88.0 percent, and the white crystal product fluticasone furoate crystal form is anhydrous or non-solvating crystal form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was determined microscopically as pure tetragonal pyramid form.
Example 3
Mixing the solid fluticasone furoate crystal form 2 (0.5g) and 5mL of xylene in a 50mL reaction bottle, heating to 140 ℃, stirring for 60 minutes, naturally cooling to 0 ℃, stirring for 2 hours, filtering, washing with a small amount of xylene, and drying at 60 ℃ for 8 hours to obtain a white crystal product fluticasone furoate crystal form 1(0.45g), wherein the yield is 90.0%, and the white crystal product fluticasone furoate crystal form is anhydrous or non-solvation crystal form. The characterization result of X-ray powder diffraction (XRPD) is shown in figure 2, and the solid crystal nodule is a pure tetragonal pyramid type by microscope detection, and the result is shown in figure 4.
Example 4
Mixing the fluticasone furoate 2-butanone solvate (0.5g) and 5mL of xylene in a 50mL reaction bottle, heating to 120 ℃, stirring for 30 minutes, naturally cooling to 20 ℃, stirring for 30 minutes, filtering, washing with a small amount of xylene, and drying at 60 ℃ for 8 hours to obtain a white crystal product fluticasone furoate crystal form 1(0.44g), wherein the yield is 88.0 percent and the white crystal product fluticasone furoate is in an anhydrous or non-solvated crystalline form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was determined microscopically as pure tetragonal pyramid form.
Example 5
Mixing a furoic acid fluticasone isopropanol solvate (0.5g) and 10mL of toluene in a 50mL reaction bottle, heating to 100 ℃, standing for 30 minutes, naturally cooling to 0 ℃, standing for 4 hours, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product, namely a furoic acid fluticasone crystal form 1(0.45g), wherein the yield is 90.0%, and the product is in an anhydrous or non-solvated crystalline form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was determined microscopically as pure tetragonal pyramid form.
Example 6
Mixing a furoate fluticasone tetrahydrofuran solvate (0.5g) and 10mL of toluene in a 50mL reaction bottle, heating to 110 ℃, stirring for 30 minutes, naturally cooling to 0 ℃, stirring for 4 hours, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product, namely the furoate fluticasone crystal form 1(0.45g), wherein the yield is 90.0%, and the product is in an anhydrous or non-solvated crystalline form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was determined microscopically as pure tetragonal pyramid form.
Example 7
Mixing a furoic acid fluticasone acetone solvate (0.5g) and 10mL of toluene in a 50mL reaction bottle, heating to 80 ℃, stirring for 30 minutes, naturally cooling to 0 ℃, stirring for 4 hours, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product, namely the furoic acid fluticasone crystal form 1(0.44g), wherein the yield is 88.0 percent, and the product is in an anhydrous or non-solvated crystalline form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was determined microscopically as pure tetragonal pyramid form.
Example 8
Mixing the solid fluticasone furoate crystal form 2 (100g) and 1000ml of toluene in a 2L reaction bottle, heating to 110 ℃, stirring for 30 minutes, naturally cooling to 20 ℃, stirring for 6 minutes, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product fluticasone furoate crystal form 1(92.5g), wherein the yield is 92.5 percent and the white crystal product is in an anhydrous or non-solvated crystalline form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was determined microscopically as pure tetragonal pyramid form.
Comparative example 1
Mixing the solid of the fluticasone furoate crystal form 2 (0.5g) and 10mL of ethyl acetate in a 50mL reaction bottle, refluxing and heating until the mixture is dissolved, stirring for 30 minutes, adding 20mL of toluene, separating out the solid, distilling the solvent at 100 ℃, naturally cooling to 30 ℃, stirring for 4 hours, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product of the fluticasone furoate crystal form 1(0.38g), wherein the yield is 76.0 percent and the white crystal product is in an anhydrous or non-solvated crystalline form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was microscopically determined as a mixture of tetragonal pyramid and acicular crystals (small amount of acicular crystal impurities).
Comparative example 2
Mixing the solid of the fluticasone furoate crystal form 2 (0.5g) and 10mL of acetone in a 50mL reaction bottle, refluxing and heating until the mixture is dissolved, stirring for 30 minutes, adding 20mL of toluene, separating out the solid, distilling the solvent at 100 ℃, naturally cooling to 30 ℃, stirring for 4 hours, filtering, washing with a small amount of toluene, and drying at 60 ℃ for 8 hours to obtain a white crystal product of the fluticasone furoate crystal form 1(0.36g), wherein the yield is 72.0 percent and the white crystal product is in an anhydrous or non-solvation crystal form. Characterization by X-ray powder diffraction (XRPD) as in example 1, the solid crystal habit was microscopically determined as a mixture of tetragonal pyramid and acicular crystals (mostly acicular crystal impurities).
Claims (9)
1. A preparation method of a furoic acid fluticasone crystal form 1 is characterized by comprising the following steps: under the heating condition, mixing the fluticasone furoate with an organic solvent, carrying out cooling crystallization after crystal transformation, and separating to obtain the fluticasone furoate crystal form 1.
2. The process according to claim 1, wherein the fluticasone furoate is form 2, form 3 or a solvate.
3. The fluticasone furoate solvate of claim 2 comprising 2-butanone, isopropanol, tetrahydrofuran, acetone, or N, N-dimethylformamide.
4. The method of claim 1, wherein the organic solvent is one or more of toluene and xylene.
5. The method according to claim 1, wherein the organic solvent is used in an amount of 5 to 50 mL/g.
6. The production method according to claim 1, wherein the heating temperature is 80 ℃ to 140 ℃.
7. The process according to claim 1, wherein the cooling is carried out to a temperature of 50 ℃ or less, preferably 0 to 30 ℃.
8. The process according to claim 1, wherein the step of mixing the fluticasone furoate with the organic solvent and the step of cooling for crystallization are carried out under stirring or standing conditions, preferably under stirring conditions.
9. The process according to claim 1, wherein the cooling crystallization time is 30 minutes or more, preferably 2 to 6 hours.
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