CN110818758B - Crystallization process of promestrene crystal - Google Patents
Crystallization process of promestrene crystal Download PDFInfo
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- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a crystallization process of a promestrene crystal. Crystallizing the crude product of the promestrene by adopting a main solvent, a cosolvent and organic acid to obtain the promestrene crystal. The crystallization process is safe and environment-friendly, is simple and convenient to operate, improves the quality and yield, has the refining yield of 93-95 percent and the purity of more than 99.98 percent, and is suitable for industrial production; the prepared columnar crystal has small static electricity, small viscosity, good fluidity, large crystal grains, uniform granules, high wet and heat stability, high preparation success rate and high bioavailability, and reduces the generation of side effects of the medicine.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a crystallization process of a promestrene crystal.
Background
Promestriene (Promestriene) is a topical estrogen supplement developed by the pharmaceutical factory of Damanli, Moringa (purchased in 1999 by the company Merck), approved in the United states patent in 1977, whose formulation was mainly marketed in France in 1975 as Geobaifen (Colpotrophine) and in France in 1978 as Colophorm (Delipoderm). Promestriene, climbazole (soft promestrene capsules and creams) and copaxone (cloquindol/promestrene vaginal tablets) are collected by a Martindale pharmaceutical handbook, have been clinically used in more than 40 foreign countries for more than 40 years, and currently become first-line medicines for treating vaginal infection and atrophic vaginitis in many countries, and clinical practice shows that the medicines are safe and effective and have good tolerance for patients.
The chemical structure of promestrene is as follows:
the synthesis process reported by the pharmaceutical factory of dary america in mornago in the patent filed in 1971 (GB1337198A) is: firstly, using sodium ethoxide to synthesize an intermediate 3-propoxy-17 beta-hydroxy estra-1, 3, 5(10) -triene prepared by reacting metallic sodium with absolute ethyl alcohol, secondly, synthesizing the promestrene, namely firstly using sodium hydride and dimethyl sulfoxide to prepare a dimethyl sulfoxide sodium solution, treating the 3-propoxy-17 beta-hydroxy estra-1, 3, 5(10) -triene by the dimethyl sulfoxide sodium solution, then using dimethyl sulfate to perform methyl etherification to prepare the promestrene, and finally using ethyl alcohol to repeatedly recrystallize to obtain the promestrene product, wherein the molar yield is 78%.
An improved research on a synthetic method of a prolestrene intermediate estradiol 3-n-propyl ether is disclosed in Shanxi university school newspaper (Nature science edition), 2008, 31(2), Tejianto, Xitong sister-in-law, wherein sodium hydroxide and n-tetrabutylammonium hydrogen sulfate are adopted as phase transfer catalysts to replace sodium ethoxide, estradiol 3-n-propyl ether is synthesized under mild conditions, then the reaction with dimethyl sulfate is carried out in the presence of sodium hydride to prepare the prolestrene, ethanol is used for recrystallization, white flaky crystals are obtained, and the yield is 84.7%.
Improved research on a propestrene (promestrene) synthesis method, Guangdong chemical industry, 2014, 16 th stage, Yangjing and the like disclose a propestrene synthesis method, wherein methyl iodide is used for replacing dimethyl sulfate to serve as a methylation reagent to prepare the propestrene, and the propestrene is synthesized simply and conveniently under mild conditions. The synthesis route uses a proper amount of ethanol for recrystallization, and the molar yield is 85.6 percent.
Chinese patent CN110003298A discloses a method for synthesizing promestrylene, wherein ethanol dissolution, activated carbon decoloration, cooling crystallization, filtration and drying are adopted in the synthesis process to obtain the promestrylene.
There are a number of documents and patents that have been developed to date on the synthesis of promestrene, but no studies have been made on the appearance of promestrene crystals. All the promestrene crystals obtained by ethanol refining in the prior art are white flaky crystals, and researches show that the flaky crystals and the preparation method thereof have the following defects:
1. the flaky crystal has large static electricity, high viscosity, small crystal grains, poor fluidity and poor stability.
2. The preparation obtained by the flaky crystal has unstable pharmaceutical characteristics, low preparation success rate and low bioavailability, and is only suitable for a few preparation types such as tablets or creams.
3. The purification yield is only 80% because the promestrene and the ethanol are easy to form intermolecular hydrogen bonds, so that the solubility is increased, and a large amount of promestrene is remained in the purification mother liquor, thereby causing great pollution to the environment and increasing the potential safety hazard.
Therefore, it is desirable to provide a process for crystallizing promestrene crystals to solve the above problems.
Disclosure of Invention
The invention aims to provide a crystallization process of a promestrene crystal, which is safe and environment-friendly, is simple and convenient to operate, improves the quality and yield, and is suitable for industrial production; the prepared crystal has small static electricity, small viscosity, good fluidity, large crystal grain, uniform granule, high wet and heat stability, high preparation success rate and high bioavailability, and is suitable for various dosage forms such as tablets, powder, colloid, ointment and the like.
The crystallization process of the promestrene crystal adopts a main solvent, a cosolvent and organic acid to crystallize a promestrene crude product to obtain the promestrene crystal.
The main solvent is ethylene glycol isopropyl ether.
The mass ratio of the crude promestrene to the main solvent is 1: 2-5.
The cosolvent is one of 1, 4-dioxane, methyl tert-butyl ether or tetrahydrofuran, preferably 1, 4-dioxane.
The mass ratio of the crude promestrene to the cosolvent is 1: 0.1-1.0.
The organic acid is formic acid.
The mass ratio of the crude promestrene to the organic acid is 1: 0.001-0.005.
The crystallization mode is combined crystallization of gradient cooling and ultrasonic oscillation.
The gradient is a 5-6 deg.C decrease every 25-35 minutes, preferably a 5 deg.C decrease every 30 minutes.
The ultrasonic wave is generated by an ultrasonic wave generating device with the frequency of 10-30KHz and the power of 100-500W, preferably 20KHz and 200W.
The crystallization process of the promestrene crystal comprises the following steps:
(1) under the protection of nitrogen at room temperature, adding a crude product of promestrene into a main solvent, adding a cosolvent and organic acid, heating to dissolve, decoloring and filtering, and stirring and cooling a filtrate to a metastable zone under the action of ultrasonic oscillation;
(2) stopping ultrasonic oscillation, then adding crystal seeds, preserving heat, stirring, crystallizing and then ultrasonically oscillating;
(3) then carrying out gradient cooling, and carrying out ultrasonic oscillation and heat preservation stirring in the gradient cooling process;
(4) stirring at constant temperature, filtering, leaching the obtained filter cake, and drying under reduced pressure to obtain the promestrene crystal.
In the step (1), the temperature rise is 60-65 ℃.
In the step (1), medicinal carbon is adopted for decolorization, and the mass ratio of the promestrene crude product to the medicinal carbon is 1: 0.001-0.005.
In the step (1), the stirring speed is 30-40 Hz.
The temperature of the metastable zone in the step (1) is 41-43 ℃.
In the step (2), the seed crystal is a powdery crystal obtained by grinding the promestrene flaky crystal.
In the step (2), the mass ratio of the promestrene crude product to the seed crystal is 1: 0.0001-0.0002.
In the step (2), the heat preservation, stirring and crystallization time is 1.8-2.2 hours, preferably 2.0 hours.
In the step (2), the stirring speed is 30-40 Hz.
The ultrasonic oscillation time in the step (2) is 4-6 minutes, preferably 5 minutes.
In the step (2), the ultrasonic frequency is 10-30 KHz.
The ultrasonic oscillation time in the step (3) is 0.5 to 1.5 minutes, preferably 1.0 minute.
In the step (3), the ultrasonic frequency is 10-30 KHz.
The heat preservation stirring time in the step (3) is 25 to 35 minutes, and preferably 30 minutes.
The stirring rate in step (3) is 30-40Hz, preferably 30 Hz.
In the step (3), the temperature is reduced to-5 to-10 ℃ in a gradient way.
The heat preservation stirring time in the step (4) is 1.8 to 2.2 hours, preferably 2.0 hours.
In the step (4), the stirring speed is 30-40 Hz.
And (4) leaching by adopting ethanol, wherein the temperature of the ethanol is-5 to-10 ℃, and the mass ratio of the crude promestrene to the ethanol is 1: 0.5-1.0.
In the step (4), the reduced pressure drying pressure is-0.09-0.1 MPa, the reduced pressure drying temperature is 40-50 ℃, and the reduced pressure drying time is 6-8 hours.
The crystallization process of the promestrene crystal comprises the following specific steps:
(1) under the protection of nitrogen at room temperature, adding a crude product of promestrene into a main solvent, adding a cosolvent and organic acid, heating to dissolve, decoloring and filtering, and stirring and cooling a filtrate to a metastable zone under the action of ultrasonic oscillation;
(2) stopping ultrasonic oscillation, then adding crystal seeds, preserving heat, stirring, crystallizing and then ultrasonically oscillating;
(3) then, starting gradient temperature reduction at 41-43 ℃ in a metastable zone, stirring and cooling to 36-37 ℃, then carrying out heat preservation stirring and ultrasonic oscillation, then carrying out heat preservation stirring, continuing stirring and cooling to 31-32 ℃, then carrying out heat preservation stirring and ultrasonic oscillation, then carrying out heat preservation stirring, continuing stirring and cooling to 26-27 ℃, then carrying out heat preservation stirring and ultrasonic oscillation, then carrying out heat preservation stirring, continuing stirring and cooling to 21-22 ℃, then carrying out heat preservation stirring and ultrasonic oscillation, then carrying out heat preservation stirring, continuing stirring and cooling to 16-17 ℃, then carrying out heat preservation stirring and ultrasonic oscillation, then carrying out heat preservation stirring, continuing stirring and cooling to 11-12 ℃, then carrying out heat preservation stirring and ultrasonic oscillation, then carrying out heat preservation stirring, continuing stirring and cooling to 6-7 ℃, then carrying out heat preservation stirring and ultrasonic oscillation, then carrying out heat preservation stirring, continuously stirring and cooling to 1-2 ℃, then keeping the temperature and stirring and carrying out ultrasonic oscillation, then keeping the temperature and stirring, and finally stirring and cooling to-5 to-10 ℃.
(4) Stirring at-5 deg.C to-10 deg.C, filtering, leaching the obtained filter cake, and drying under reduced pressure to obtain promestrene columnar crystal.
Researches find that solvents such as ethanol and methanol easily form intermolecular hydrogen bonds with the promestrylene, so that the solubility is increased, and the yield is low. Due to the influence of steric hindrance, the ethylene glycol isopropyl ether and the promestrene are difficult to form intermolecular hydrogen bonds, and the molecular size is large, so that the molecular distance is increased, and the ethylene glycol isopropyl ether can be effectively separated at low temperature, thereby improving the yield.
The cosolvent is added to increase the solubility of the promestrylene in the ethylene glycol isopropyl ether by virtue of the principle of 'similar phase dissolution', so that the solvent loss, potential safety hazards and the like caused by high-temperature dissolution are avoided.
The research finds that the crystal growth of the promestrene is columnar crystal habit when the organic acid is added, and the crystal growth is flaky crystal habit when the organic acid is not added. Compared with acetic acid, propionic acid, oxalic acid and the like, the formic acid is used as the organic acid, so that the columnar crystal habit is more complete, the crystal grains are larger, the static electricity is reduced, the fluidity is good and the like, and the formic acid is easy to remove and has no residue after cooling crystallization and leaching, and has no influence on the stability and the efficacy of the medicine.
The cooling crystallization mode is combined crystallization of gradient cooling and ultrasonic oscillation. Because of the uneven size of the crystal obtained by natural cooling, the crystal grown by gradient cooling at each time is vibrated by ultrasonic waves to generate cavitation bubbles, the bubbles expand and grow, a liquid flow which moves rapidly is generated during crushing, the larger crystal is crushed, part of the crushed crystal is dissolved, most of the crushed crystal is used as new crystal seeds to grow into the crystal, the growth rate of the crystal is equal, and the size is even.
A large amount of crystals can be separated out when the temperature is reduced to-5 to-10 ℃, impurities and residual solvents can be effectively removed when ethanol with the temperature of-5 to-10 ℃ is used for leaching, the product purity is improved, and the yield is not influenced.
The invention has the following beneficial effects:
1. the crystallization process is safe and environment-friendly, is simple and convenient to operate, improves the quality and yield, has the refining yield of 93-95 percent and the purity of more than 99.98 percent, and is suitable for industrial production.
2. The columnar crystal prepared by the invention has small static electricity, small viscosity, good fluidity, large crystal grains, uniform granules, high wet and heat stability, high preparation success rate and high bioavailability, and reduces the generation of side effects of the medicine.
3. The columnar crystal prepared by the invention is suitable for various dosage forms such as tablets, powder, colloid, ointment and the like.
Drawings
FIG. 1 is a diagram showing the morphology of a sheet crystal of promestrene obtained in comparative example 1.
FIG. 2 is a histogram of the columnar crystals of promestrene obtained in example 1.
Detailed Description
The present invention is further described below with reference to examples.
Comparative example 1
Adding 100 g of a crude product of promestrylene into a 1000ml four-mouth bottle under the protection of nitrogen at room temperature, adding 500 g of absolute ethyl alcohol, stirring and heating to 82 ℃ for refluxing and clearing, adding 0.1 g of medicinal carbon, stirring for 30 minutes under heat preservation, filtering while the solution is hot, stirring the filtrate, cooling to 25 ℃ for crystallization, stirring for 2 hours under heat preservation, continuously cooling to 0-5 ℃, stirring for 2 hours under heat preservation, filtering, rinsing with 50 g of cold ethanol, and drying the obtained solid for 6 hours under vacuum at 40 ℃ to obtain 83.21 g of a promestrylene sheet crystal, as shown in figure 1. The yield was 83.21%, the HPLC purity was 99.96%.
The plate crystal is ground into powder and is reserved as seed crystal for standby.
Example 1
Adding 10 g of a promestrene crude product and 50 g of ethylene glycol isopropyl ether into a 100ml four-mouth bottle under the protection of nitrogen at room temperature, adding 1 g of 1, 4-dioxane and 0.02 g of formic acid, heating to 65 ℃ for dissolution, adding 0.02 g of medicinal carbon for decolorization and filtration, stirring and cooling the filtrate to 41 ℃ within 2 hours under the action of 20KHz and 200W ultrasonic waves, stopping ultrasonic oscillation, adding 0.001 g of seed crystal, stirring and crystallizing for 2 hours under heat preservation, then ultrasonic oscillation for 5 minutes, then carrying out gradient cooling, stirring and cooling to 36 ℃ within 30 minutes, then carrying out heat preservation stirring and ultrasonic oscillation for 1 minute, then carrying out heat preservation stirring for 30 minutes, continuously stirring and cooling to 31 ℃ within 30 minutes, carrying out heat preservation stirring for 1 minute, then carrying out heat preservation stirring for 30 minutes, continuously cooling to 26 ℃, 21 ℃, 16 ℃, 11 ℃, 6 ℃, repeating the processes, continuously stirring and cooling to 1 ℃ within 30 minutes, then stirring while maintaining the temperature and shaking with ultrasound for 1 minute, then stirring while maintaining the temperature for 30 minutes, and finally stirring until the temperature is reduced to-8 ℃ within 47 minutes. Stirring for 2 hours under heat preservation, filtering, leaching the obtained filter cake with 10 g-7 ℃ ethanol, and drying under reduced pressure at 40 ℃ to obtain 9.40 g of promestrene columnar crystal, as shown in figure 2. The yield was 94.00% and the HPLC purity was 99.98%.
Example 2
Under the protection of nitrogen at room temperature, adding 20 g of a promestrene crude product and 80 g of ethylene glycol isopropyl ether into a 250ml four-opening bottle, adding 4 g of 1, 4-dioxane and 0.05 g of formic acid, heating to 64 ℃ for dissolution, adding 0.04 g of medicinal carbon for decolorization and filtration, stirring and cooling the filtrate to 42 ℃ under the action of 20KHz and 200W ultrasonic waves, stopping ultrasonic oscillation, adding 0.002 g of seed crystal, carrying out heat preservation stirring crystallization for 2 hours, then carrying out ultrasonic oscillation for 5 minutes, then carrying out gradient cooling, stirring within 30 minutes, cooling to 37 ℃, then carrying out heat preservation stirring and ultrasonic oscillation for 1 minute, then carrying out heat preservation stirring for 30 minutes, stirring within 30 minutes, cooling to 27 ℃, 22 ℃, 17 ℃, 12 ℃ and 7 ℃ respectively, repeating the above processes, continuously stirring and cooling to 2 ℃ within 30 minutes, then stirring while maintaining the temperature and shaking with ultrasonic waves for 1 minute, then stirring while maintaining the temperature for 30 minutes, and finally stirring and cooling to-6 ℃ within 42 minutes. Stirring for 2 hours under the condition of heat preservation, filtering, leaching the obtained filter cake with 20 g of ethanol with the temperature of 6 ℃, and drying under reduced pressure at the temperature of 45 ℃ to obtain 18.66 g of promestrene columnar crystal. The yield was 93.30%, the HPLC purity was 99.98%.
Example 3
Adding 50 g of a promestrylene crude product and 150 g of ethylene glycol isopropyl ether into a 250ml four-mouth bottle under the protection of nitrogen at room temperature, adding 30 g of methyl tert-butyl ether and 0.15 g of formic acid, heating to 63 ℃ for dissolution, adding 0.14 g of medicinal carbon for decolorization and filtration, stirring and cooling a filtrate to 43 ℃ under the action of 20KHz and 200W ultrasonic waves, stopping ultrasonic oscillation, adding 0.005 g of seed crystal, carrying out heat preservation stirring and crystallization for 2 hours, carrying out ultrasonic oscillation for 5 minutes, then carrying out gradient cooling, stirring and cooling to 37 ℃ within 30 minutes, carrying out heat preservation stirring and ultrasonic oscillation for 1 minute, carrying out heat preservation stirring for 30 minutes, continuing stirring and cooling to 2 ℃ within 30 minutes, then carrying out heat preservation stirring and ultrasonic oscillation for 1 minute, carrying out heat preservation stirring and ultrasonic oscillation for 30 minutes, continuing to cool to 27 ℃, 22 ℃, 17 ℃, 12 ℃ and 7 ℃ respectively, repeating the processes, continuing stirring and cooling to 2 ℃ within 30 minutes, then carrying out heat preservation, then stirring for 30 minutes under heat preservation, and finally cooling to-5 ℃ within 35 minutes under stirring. Stirring for 2 hours under the condition of heat preservation, filtering, leaching the obtained filter cake with 50 g of ethanol at the temperature of 10 ℃, and drying under reduced pressure at the temperature of 50 ℃ to obtain 46.98 g of promestrene columnar crystal. The yield was 93.96%, the HPLC purity was 99.98%.
Example 4
Adding 50 g of a crude product of promestrylene and 200 g of ethylene glycol isopropyl ether into a 500ml four-mouth bottle under the protection of nitrogen at room temperature, adding 40 g of tetrahydrofuran and 0.16 g of formic acid, heating to 62 ℃ for dissolution, adding 0.2 g of medicinal carbon for decolorization and filtration, stirring and cooling filtrate to 42 ℃ under the action of 20KHz and 200W of ultrasonic waves, stopping ultrasonic oscillation, adding 0.01 g of seed crystal, carrying out heat preservation stirring and crystallization for 2 hours, carrying out ultrasonic oscillation for 5 minutes, then carrying out gradient cooling, stirring and cooling to 37 ℃ within 30 minutes, carrying out heat preservation stirring and ultrasonic oscillation for 1 minute, carrying out heat preservation stirring for 30 minutes, continuing stirring and cooling to 2 ℃ within 30 minutes, then carrying out heat preservation stirring and ultrasonic oscillation for 1 minute, carrying out heat preservation stirring and ultrasonic oscillation for 30 minutes, continuing to cool to 27 ℃, 22 ℃, 17 ℃, 12 ℃ and 7 ℃ respectively, repeating the above processes, continuing stirring and cooling to 2 ℃ within 30 minutes, then carrying out heat preservation stirring and, then stirring is carried out for 30 minutes under the condition of heat preservation, and finally the temperature is reduced to-7 ℃ within 48 minutes. Stirring for 2 hours under the condition of heat preservation, filtering, leaching the obtained filter cake with 40 g-9 ℃ ethanol, and drying under reduced pressure at 46 ℃ to obtain 47.49 g of promestrene columnar crystal. The yield was 94.98%, the HPLC purity was 99.99%.
Example 5
Adding 100 g of a promestrene crude product and 200 g of ethylene glycol isopropyl ether into a 500ml four-mouth bottle under the protection of nitrogen at room temperature, adding 100 g of 1, 4-dioxane and 0.5 g of formic acid, heating to 60 ℃ for dissolution, adding 0.5 g of medicinal carbon for decolorization and filtration, stirring and cooling the filtrate to 41 ℃ under the action of 20KHz and 200W ultrasonic waves, stopping ultrasonic oscillation, adding 0.01 g of seed crystal, carrying out heat preservation stirring crystallization for 2 hours, then carrying out ultrasonic oscillation for 5 minutes, then carrying out gradient cooling, stirring within 30 minutes and cooling to 36 ℃, then carrying out heat preservation stirring and ultrasonic oscillation for 1 minute, then carrying out heat preservation stirring for 30 minutes, stirring within 30 minutes and cooling to 26 ℃, 21 ℃, 16 ℃, 11 ℃ and 6 ℃ respectively, repeating the above processes, continuously stirring and cooling to 1 ℃ within 30 minutes, then stirring under heat preservation and ultrasonic oscillation for 1 minute, then stirring under heat preservation for 30 minutes, and finally stirring and cooling to-9 ℃ within 54 minutes. Stirring for 2 hours under the condition of heat preservation, filtering, leaching the obtained filter cake with 50 g of ethanol with the temperature of 8 ℃, and drying under reduced pressure at the temperature of 48 ℃ to obtain 94.88 g of promestrene columnar crystals. The yield was 94.88%, the HPLC purity was 99.99%.
Protameline columnar crystal stability experiment:
the promestrene samples prepared in examples 1-5 and comparative example 1 were sealed in a stability testing box at 30 ℃ and 55% humidity. Samples were taken for 0, 30, 45, 60, 75, and 90 days to determine the change in HPLC purity, and the stability data of promestrene crystals are shown in Table 1.
TABLE 1 comparison of crystal stability data for Proestrone in examples 1-5 and comparative example 1
As can be seen from Table 1, the purity of examples 1 to 5 varied only 0.03 to 0.06% in 90 days, whereas that of comparative example 1 varied 0.31% in 90 days. It is known to those skilled in the art that the smaller the change in purity at the same time, the more stable the crystal is. And the purity change of the comparative example 1 is more than 5 times larger than that of the examples 1-5 within 90 days, so that the promestrene crystal prepared by the invention has better stability.
Claims (1)
1. A process for crystallizing a crystal of promestrene, characterized by comprising the steps of:
(1) under the protection of nitrogen at room temperature, adding a crude product of promestrene into a main solvent, adding a cosolvent and organic acid, heating to dissolve, decoloring and filtering, and stirring and cooling a filtrate to a metastable zone under the action of ultrasonic oscillation;
(2) stopping ultrasonic oscillation, then adding crystal seeds, preserving heat, stirring, crystallizing and then ultrasonically oscillating;
(3) then carrying out gradient cooling, and carrying out ultrasonic oscillation and heat preservation stirring in the gradient cooling process;
(4) stirring at a constant temperature, filtering, leaching the obtained filter cake, and drying under reduced pressure to obtain a promestrene crystal;
the main solvent is ethylene glycol isopropyl ether;
the mass ratio of the crude promestrene to the main solvent is 1: 2-5;
the cosolvent is one of 1, 4-dioxane, methyl tert-butyl ether or tetrahydrofuran;
the mass ratio of the crude product of the promestrene to the cosolvent is 1: 0.1-1.0;
the organic acid is formic acid;
the mass ratio of the crude promestrene to the organic acid is 1: 0.001-0.005;
the gradient cooling is 5-6 ℃ every 25-35 minutes, and the ultrasonic wave is generated by an ultrasonic wave generating device with the frequency of 10-30KHz and the power of 100 and 500W.
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| CN110003298A (en) * | 2019-03-22 | 2019-07-12 | 中国人民解放军军事科学院防化研究院 | A kind of synthetic method of Promestriene |
| CN110218234A (en) * | 2019-07-08 | 2019-09-10 | 北京金城泰尔制药有限公司 | The synthesis technology of Promestriene |
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| CN110003298A (en) * | 2019-03-22 | 2019-07-12 | 中国人民解放军军事科学院防化研究院 | A kind of synthetic method of Promestriene |
| CN110218234A (en) * | 2019-07-08 | 2019-09-10 | 北京金城泰尔制药有限公司 | The synthesis technology of Promestriene |
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| Title |
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| 普罗雌烯(promestriene)合成方法改进研究;杨静等;《广东化工》;20141231;第41卷(第282期);第21-22页 * |
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