CN107540720B - 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H and preparation method and application thereof - Google Patents
3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a new crystal form of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid, namely a crystal form H, and also provides a preparation method of the crystal form H of the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid. The 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H disclosed by the invention does not contain a crystallization solvent or water, has a good crystallization form, is good in stability, is not easy to absorb moisture, is suitable for recrystallization purification, and can effectively remove impurities.
Description
Technical Field
The invention provides a new crystal form of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid, in particular to a crystal form H of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid, and a preparation method and application thereof. Belongs to the field of medicine technology.
Background
Farnesoid X Receptors (FXRs), originally orphan nuclear receptors, were first identified from a murine liver cDNA library (B.M Forman et al, cell.81: 687-6931995), which are members of the family of ligand-activated transcription factor nuclear receptors, including receptors for steroids, retinoids, and thyroid hormones (D.J. Mangelsdorf et al, Cell, 83: 841-8501995).
As described in WO0037077, several natural bile acids (in particular chenocholic acid, deoxycholic acid, lithocholic acid and related complexes with taurine and glycine) bind together and activate FXR at physiological concentrations.
Obeticholic Acid (Obeticholic Acid, chemical name 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic Acid), also known as 6-ethyl chenodeoxycholic Acid, is a novel derivative of chenodeoxycholic Acid (CDCA) in human primary bile acids, is a natural ligand of the farnesoid derivative X receptor (FXR), is used for the treatment or prevention of FXR mediated diseases or conditions, cardiovascular diseases or cholestatic liver diseases, and can be used for lowering HDL cholesterol, lowering triglycerides in mammals or inhibiting fibrosis.
International patent publication WO02072598 discloses obeticholic acid compounds, indications, formulations, and methods of preparation. The preparation method comprises the following steps:
the method mainly comprises four steps:
the first step is as follows: 3, 4-dihydroxypyrrole and 3 alpha-hydroxy-7-ketocarbonyl-5 beta-cholic-24-acid react to generate an intermediate 3 alpha-tetrahydropyrrolyloxy-7-ketocarbonyl-5 beta-cholic-24-acid with the yield of 74 percent under the catalysis of p-toluenesulfonic acid and dioxane as a solvent. The work-up purification was carried out by means of silica gel column chromatography.
The second step is that: the intermediate 3 alpha-tetrahydropyrrole oxy-7-ketocarbonyl-5 beta-chola-24-acid is reacted with bromoethane at-78 ℃ under the condition of LDA as alkali to obtain an intermediate II with the yield of 12%. The work-up purification was carried out by means of silica gel column chromatography.
The third step: and reducing carbonyl of the intermediate II by using sodium borohydride to obtain an intermediate III with the yield of 81%.
The fourth step: and hydrolyzing the intermediate III by using sodium hydroxide to obtain the product obeticholic acid with the yield of 43%.
In the patent method, the intermediate is purified by silica gel column chromatography for many times, and the process route is not suitable for industrial production. In addition, the patent does not investigate the crystal form of obeticholic acid.
International patent publication WO2013192097 (congeneric patent publication CN201380043964, US2013345188) reports 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystal forms a, C, D, F, G and amorphous form 1; protects the intermediate crystal form C and the process for preparing the amorphous crystal form 1 (medicinal crystal form). The crystal form C is suitable for recrystallization purification, contains a crystallization solvent, is a hydrate or a solvate, and can be converted into the amorphous crystal form 1 again after purification.
Disclosure of Invention
Obeticholic acid is used as a steroid compound, contains a plurality of chiral centers, and is difficult to avoid the generation of chiral isomer impurities in the synthesis process, so that a crystal form which has a good crystal form, good stability, difficult moisture absorption, suitability for recrystallization purification and capability of effectively removing impurities is very necessary to be found.
The invention provides a new crystal form, namely a crystal form H, which has good stability and is not easy to absorb moisture, is suitable for recrystallizing and purifying obeticholic acid (3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid), is easy to crystallize, and effectively removes impurities. The invention also provides a method for preparing the crystal form H.
The technical problem of the invention is realized by the following technical scheme:
the invention provides a 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H, which is characterized in that: the diffraction angle 2 theta of the X-ray powder diffraction pattern has characteristic peaks at about +/-0.2 degrees of 4.9 degrees, 5.2 degrees, 7.2 degrees, 7.6 degrees, 8.9 degrees and 9.9 degrees.
Preferably, the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystalline form H is characterized by: the diffraction angle 2 theta of the X-ray powder diffraction pattern has characteristic peaks at about +/-0.2 degrees of 4.9 degrees, 5.2 degrees, 6.2 degrees, 7.2 degrees, 7.6 degrees, 8.9 degrees, 9.3 degrees and 9.9 degrees.
Preferably, the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystalline form H is characterized by: the diffraction angle 2 theta of the X-ray powder diffraction pattern has characteristic peaks at about +/-0.2 degrees of 4.9 degrees, 5.2 degrees, 6.2 degrees, 7.2 degrees, 7.6 degrees, 8.9 degrees, 9.3 degrees, 9.9 degrees, 10.9 degrees, 12.4 degrees, 14.4 degrees, 14.8 degrees and 15.2 degrees.
Preferably, the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystalline form H is characterized by: the diffraction angle 2 theta of the X-ray powder diffraction pattern is about +/-0.2 DEG and has characteristic peaks at 4.9 DEG, 5.2 DEG, 6.2 DEG, 7.2 DEG, 7.6 DEG, 8.9 DEG, 9.3 DEG, 9.9 DEG, 10.9 DEG, 12.4 DEG, 14.4 DEG, 14.8 DEG, 15.2 DEG, 16.0 DEG, 16.4 DEG, 16.7 DEG, 17.9 DEG, 18.9 DEG, 19.5 DEG, 20.5 DEG, 21.2 DEG, 24.6 DEG and 25.0 DEG +/-0.2 deg.
More preferably, said crystalline form H of 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid is characterized by: having an X-ray powder diffraction pattern substantially as shown in figure 1.
Preferably, the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid is crystalline form H, characterized by a DSC having an endothermic peak at 81.7-101.7 ℃.
Preferably, the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H is characterized in that DSC has an endothermic peak at 85-93 ℃. Typical endothermic or exothermic peaks on a DSC chart will include an onset (onset), a peak (peak), and an end (end), where the endothermic peak is referred to as a peak (peak). Wherein the crystal form H presents an endothermic peak between 85 ℃ and 93 ℃.
More preferably, said 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystalline form H, characterized by: has DSC pattern as shown in figure 2.
Preferably, the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystalline form H is characterized by: has an infrared spectrum as shown in figure 3.
The invention also provides a preparation method of the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H, which comprises the following steps:
(1) dissolving the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid solid into an organic solvent to obtain a 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid solution, wherein the organic solvent is selected from one or more of an alcohol solvent, an ester solvent and an alkane solvent;
(2) stirring and dissolving at the temperature of 40-80 ℃.
(3) Cooling and crystallizing at 0-30 ℃;
(4) separating the solids from the suspension; preferably, the separation further comprises filtration, washing with the organic solvent of step (1);
(5) drying the separated solid to obtain a crystal form H of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid; preferably, drying is performed by using a drying oven; the drying temperature is preferably from 30 to 80 ℃. Because the product has low melting point, the temperature can be programmed for drying.
The organic solvent in the step (1) is selected from isopropanol, butanol, isobutanol, tert-butanol, amyl alcohol, 2-amyl alcohol and other higher alcohols; the ester solvent is selected from ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, amyl acetate, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate, ethyl butyrate, propyl butyrate, isopropyl butyrate, butyl butyrate and the like, and other small polar ester solvents; the alkane solvent is selected from n-hexane, n-heptane, mixed heptane, cyclohexane, n-octane, isooctane, dodecane, etc., and other higher alkanes. Wherein, the alcohol solvent belongs to a good solvent, the alkane solvent belongs to a poor solvent, and the solubility of the ester solvent is intermediate. In order to balance between removal of impurities and improvement of yield, the ratio between the good solvent and the poor solvent may be adjusted as necessary.
The combination of solvents in step (1) may be a combination of 2 and more than 2 solvents. Wherein the alcohol solvent, the alkane belongs to poor solvent, and the ester solvent has intermediate solubility to the product.
In the actual production, in the crystallization process in the step (3), a proper amount of seed crystals can be optionally added, or no seed crystals can be optionally added. If the seed crystal is added, the dosage of the seed crystal is 0.1-50%, preferably 1-10%.
As another object of the present invention, there is also provided the use of crystalline form H of 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid as described above in the preparation of a medicament for the treatment or prevention of a disease associated with FXR mediation, preferably for the treatment or prevention of cardiovascular disease or cholestatic liver disease, or for lowering HDL cholesterol, lowering triglycerides in mammals, or inhibiting fibrosis.
As another aspect of the present invention, there is also provided a pharmaceutical composition comprising 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid and pharmaceutically conventional excipients, wherein the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid is mainly the above-mentioned crystalline form H of 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid, and preferably, the crystalline form H of 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid is 2.5% to 25% by weight of the pharmaceutical composition.
In the above pharmaceutical composition, the dosage of the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystal form H may be a dosage of clinical obeticholic acid, for example, in a unit preparation, the 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystal form H may be 1mg, 5mg, 7.5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 40mg, 50mg, or the like.
The pharmaceutical composition can be a common pharmaceutical formulation in the field, such as tablets, capsules, granules, oral liquid, injection, powder injection and the like.
The crystal form H of the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid is different from the existing crystal form A, C, D, F, G and the crystal form 1 (amorphous) of the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid, and the specific performance is shown in the following table 1.
TABLE 13 comparison of the different crystal forms of alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid
Five different solid forms of obeticholic acid have been reported, wherein obeticholic acid crystalline form A, C or D is a mixed hydrate/solvate containing water and various organic solvents in varying amounts, which upon heating, simultaneously lose crystallinity and solvent, and these solvated forms are not suitable for further development as pharmaceutical ingredients. Obeticholic acid crystalline form F or G is difficult to scale up for industrial reproduction and the process is difficult to repeat, and the recrystallization process uses nitromethane, a toxic solvent that can explode if activated by amines, alkali metals, strong acids or high temperatures or adiabatic compression.
The 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H provided by the invention is a new crystal form of obeticholic acid, does not contain crystal water or a crystal solvent, has a higher melting point (85-93 ℃), is stable in physical property, is easy to separate and purify obeticholic acid, and is beneficial to preparing pure obeticholic acid and a pharmaceutical preparation thereof.
The 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H of the invention has the stability investigation data at room temperature for 6 months as shown in the following table 2.
TABLE 23 stability test data for alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H
And (4) conclusion: the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H is inspected at room temperature for 6 months, and the sample is stable.
Drawings
FIG. 1: x-ray powder diffraction pattern (XRPD) of crystalline form H of 3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid.
FIG. 2: differential Scanning Calorimetry (DSC) curve of 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystal form H.
FIG. 3: is the infrared spectrum (IR) of the crystal form H of the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid.
FIG. 4: is the hydrogen spectrum of the crystal form H of the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid ()1H-NMR)。
FIG. 5: is the carbon spectrum of the crystal form H of the 3 alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid (13C-NMR)。
FIG. 6: the simulated powder pattern, experimental pattern of WO2013192097 protection and XRPD of obeticholic acid form G overlap.
FIG. 7: an XRPD pattern of form C protected by WO 2006122977.
FIG. 8: a DSC-TGA profile of form C protected by WO 2013192097.
Detailed Description
The following examples are presented to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention in any manner.
The analysis and detection conditions of the invention are as follows:
1. x-ray powder diffraction was measured by Rigaku D/max 2550VB-pc diffractometer using Cu/K-alphal (
) Radiation, power: the 40kV multiplied by 100mA collects relevant diffraction data in the range of 2 theta 0-60 degrees, the step width is 0.02 degrees, and the scanning speed is 6 degrees/min.
2. DSC is detected by German relaxation-resistant DSC200F3, the temperature range is 30-350 ℃, the heating rate is 10.0K/min, the hole is sealed, and the nitrogen environment is adopted.
3. Infrared Spectrum (IR) was measured by PE spectrum RXI at 23 ℃ and 54% humidity.
EXAMPLE 1.3 preparation of alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid (crude)
Reference is made to the preparation process reported in the above document WO 2013192097: 3 alpha-hydroxy-7-ketocarbonyl-5 beta-chola-24-acid (KICA) is used as a starting material, and is subjected to esterification reaction under the catalysis conditions of methanol and sulfuric acid to generate methyl ester to obtain a methyl esterification intermediate 1; li [ N (CH)3)2)2]Reacting with trimethylchlorosilane at-10 to-30 ℃, and protecting 3-hydroxy with silane to obtain an intermediate 3. Adding acetaldehyde into the intermediate 3 at a temperature of between 50 ℃ below zero and 70 ℃ below zero to react to obtain a vinyl intermediate 4, and directly using the intermediate 4 solution in the next step. Intermediate 4 was hydrolyzed under 30% sodium hydroxide and neutralized to give intermediate 5 in an overall yield of 47.5% (starting from KLCA). The intermediate 5 is subjected to catalytic hydrogenation under the condition of 5 percent palladium-carbon to obtain an intermediate 6 with the yield of 81.2 percent. And (3) carrying out reduction reaction on the intermediate 6 by sodium borohydride at 85-110 ℃ to obtain a crude product of obeticholic acid, wherein the yield is 77.9%.
Example 2.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
10g of the crude product was dissolved in 80mL of ethyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. And (3) after solid is separated out, dropwise adding 80mL of n-heptane, and continuously stirring at 0-5 ℃ for crystallization for more than 2 h. Filtration gave 8g of a white solid in 80% yield and 99.5% purity (HPLC) of form H. The XRPD spectrum is shown in figure 1, the DSC spectrum is shown in figure 2, the IR spectrum is shown in figure 3, the hydrogen spectrum is shown in figure 4, and the carbon spectrum is shown in figure 5.
Example 3 preparation of crystalline form H of alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid
10g of the crude product was dissolved in 80mL of isopropyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. And (3) after solid is separated out, 80mL of mixed heptane is dripped, and stirring and crystallization are continuously carried out at the temperature of 0-5 ℃ for more than 2 h. Filtration gave 9g of a white solid in 90% yield and 99.6% purity (HPLC) of form H.
Example 4.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
10g of the crude product are dissolved in 80mL of butyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. And (3) after solid is separated out, dropwise adding 80mL of n-heptane, and continuously stirring at 0-5 ℃ for crystallization for more than 2 h. Filtration gave 8g of a white solid in 80% yield and 99.1% purity (HPLC) of form H.
Example 5.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
10g of the crude product was dissolved in 80mL of ethyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. After solid is separated out, 80mL of n-octane is added dropwise, and the mixture is stirred and crystallized for more than 2 hours at the temperature of 0-5 ℃. Filtration gave 6g of white solid, 60% yield, 99.4% purity (HPLC) of form H.
Example 6.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
10g of the crude product are dissolved in 80mL of butyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. After solid is separated out, 80mL of n-octane is added dropwise, and the mixture is stirred and crystallized for more than 2 hours at the temperature of 0-5 ℃. Filtration gave 6.8g of a white solid in 68% yield and 99.4% purity (HPLC) of form H.
Example 7.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
10g of the crude product was dissolved in 80mL of isopropyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. After solid is separated out, 80mL of n-octane is added dropwise, and the mixture is stirred and crystallized for more than 2 hours at the temperature of 0-5 ℃. Filtration gave 7.5g of a white solid in 75% yield and 99.3% purity (HPLC) of form H.
Example 8.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
10g of the crude product was dissolved in 80mL of ethyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. Adding 0.1g of seed crystal, precipitating solid, then dropwise adding 80mL of octane, and continuously stirring at 0-5 ℃ for crystallization for more than 2 h. Filtration gave 8g of a white solid in 80% yield and 99.5% purity (HPLC) of form H.
Example 9.3 preparation of alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystalline form H
And heating and dissolving 10g of crude product with a mixture of 80mL of ethyl acetate and 80mL of heptane, filtering while the mixture is hot, cooling the filtrate to 20-30 ℃, adding 0.1g of seed crystal, dropwise adding the seed crystal after solid is separated out, and continuously stirring and crystallizing at 0-5 ℃ for more than 2 hours. Filtration gave 8g of a white solid in 70% yield and 99.5% purity (HPLC) of form H.
Example 10.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
And heating and dissolving 10g of crude product with a mixture of 80mL of butyl acetate and 80mL of octane, filtering while the mixture is hot, cooling the filtrate to 20-30 ℃, adding 0.1g of seed crystal, dropwise adding the seed crystal after separating out solids, and continuously stirring and crystallizing at 0-5 ℃ for more than 2 hours. Filtration gave 8g of a white solid in 82% yield and 99.5% purity (HPLC) of form H.
Example 11.3 preparation of alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystalline form H
And heating and dissolving 10g of crude product with a mixture of 80mL of butyl acetate and 90mL of heptane, filtering while the mixture is hot, cooling the filtrate to 0-10 ℃, dropwise adding the filtrate after solid is separated out, and continuously stirring and crystallizing at 0-5 ℃ for more than 2 hours. Filtration gave 8g of a white solid in 80% yield and 99.5% purity (HPLC) of form H.
Example 12.3 preparation of crystalline form H of α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid
10g of the crude product was dissolved in 80mL of isopropyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. Adding 0.1g of seed crystal, precipitating solid, dropwise adding 80mL of mixed heptane, and continuously stirring at 0-5 ℃ for crystallization for more than 2 h. Filtration gave 9.1g of a white solid in 91% yield and 99.6% purity (HPLC) of form H.
Example 13.3 preparation of alpha, 7 alpha-dihydroxy-6 alpha-ethyl-5 beta-cholanic acid crystalline form H
10g of the crude product are dissolved in 80mL of butyl acetate. Heating to dissolve, filtering while hot, and cooling the filtrate to 20-30 ℃. Adding 0.1g of seed crystal, precipitating solid, then dropwise adding 80mL of n-heptane, and continuously stirring at 0-5 ℃ for crystallization for more than 2 h. Filtration gave 8.2g of a white solid, yield 82%, purity (HPLC) 99.4% of form H.
Claims (1)
1.3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholanic acid crystal form H, characterized by: the diffraction angle of the X-ray powder diffraction pattern thereof is 4.9 degrees, 5.2 degrees, 6.2 degrees, 7.2 degrees, 7.6 degrees, 8.9 degrees, 9.3 degrees, 9.9 degrees, 10.9 degrees, 12.4 degrees, 14.4 degrees, 14.8 degrees, 15.2 degrees, 16.0 degrees, 16.4 degrees, 16.7 degrees, 17.9 degrees, 18.9 degrees, 19.5 degrees, 20.5 degrees, 21.2 degrees, 24.6 degrees and 25.0 degrees at 2 theta +/-0.2 degrees, the DSC has a characteristic peak at 85-93 degrees, and has an X-ray powder diffraction pattern as shown in figure 1 and a DSC pattern as shown in figure 2.
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| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
| CN105175473A (en) * | 2015-08-19 | 2015-12-23 | 丽珠医药集团股份有限公司 | Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof |
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| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
| CN105175473A (en) * | 2015-08-19 | 2015-12-23 | 丽珠医药集团股份有限公司 | Obeticholic acid crystal form I, preparation method, pharmaceutical composition, and application thereof |
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