CN110845407B - Preparation method of chloroquinate crystal - Google Patents
Preparation method of chloroquinate crystal Download PDFInfo
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- CN110845407B CN110845407B CN201911196862.5A CN201911196862A CN110845407B CN 110845407 B CN110845407 B CN 110845407B CN 201911196862 A CN201911196862 A CN 201911196862A CN 110845407 B CN110845407 B CN 110845407B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
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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 belongs to the technical field of medicines, and particularly relates to a preparation method of a chloroquinate crystal. And (3) refining the crude product of the chloroquinate by adopting a high-molecular surfactant and a solvent to obtain a chloroquinate crystal. The crystal prepared by the invention has good fluidity, stable crystal, easy pulverization and good pharmaceutical property, and is suitable for multiple dosage forms; the prepared chloroquinalder flaky crystal and columnar crystal can be uniformly mixed with the promestrene flaky crystal, so that the stability of the drug effect of the preparation is improved; the preparation method is safe, environment-friendly, simple and convenient to operate and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a chloroquinate crystal.
Background
Cloquinadol is a broad-spectrum bacteriostatic agent. The structural formula is as follows:
It was extensively studied by many pharmaceutical facilities in europe as early as the 50 s, and found to have antimicrobial pathogen activity against fungi, trichomonas, bacteria (G + and G-), chlamydia and mycoplasma, and is a broad spectrum bacteriostatic. The earliest was developed and produced by the pharmaceutical factory of Morage Theramex, and the preparation method disclosed in the first place is that 8-hydroxy-2-methylquinoline is used as a raw material, 20% hydrochloric acid is used as a solvent, and the raw material is synthesized by one-step chlorination reaction under the condition of introducing chlorine.
The synthesis of the chloroquinadol, journal of Chinese medicine industry, 2008, 39(10), Tejiangtong, discloses a synthetic process of the chloroquinadol by using formic acid to replace hydrochloric acid as a solvent. Adding 2-methyl-8-light-radical oualin and formic acid into a reaction bottle, stirring until the mixture is dissolved, cooling to 0-5 ℃, introducing chlorine, stirring at room temperature for reaction until the reaction is complete when the color is not changed any more by using a diazobenzene-acetic acid solution, driving chlorine for 0.5h under the condition of reduced pressure at room temperature, and then recovering the formic acid under reduced pressure. The residue was treated with water and 20% sodium bisulfite solution until no color change was detected by starch potassium iodide paper. And (4) carrying out suction filtration, washing a filter cake with water, drying under reduced pressure, and then recrystallizing with ethanol to obtain yellow needle crystals.
Chinese patent CN108341776A discloses a process for synthesizing cloquindol, which comprises the steps of taking 8-hydroxy-2-methylquinoline as a raw material, taking chlorine atoms in an active state generated by the reaction of sodium hypochlorite and hydrochloric acid as a chlorinated raw material, and generating the cloquindol through one-step chlorination reaction; the process uses sodium hypochlorite as a chlorinated raw material instead of chlorine.
Chinese patent CN110143919A discloses a process for synthesizing chloroquinate, which comprises using 8-hydroxy-2-methylquinoline and N-chlorosuccinimide as raw materials, using Lewis acid as a catalyst, and carrying out one-step chlorination reaction under the conditions of solvent and dark place to generate the chloroquinate.
At present, a great deal of literature and patents are available for studying the synthesis process of chloroquinate, but the appearance of chloroquinate polymorph is not studied. In the prior art, the refined solvent of the chloroquinate is methanol and ethanol, the chloroquinate crystals obtained by crystallization are all yellow needle-shaped crystals, and researches show that the needle-shaped crystals have poor liquidity, uneven dispersion, difficult pulverization and poor drug property.
China imported in 1997 for use of cloquindol/promestrene vaginal tablets (trade name "Colubetryn"), Chinese patent CN1600315A discloses a cloquindol/promestrene soft capsule composition for vagina, which is a cloquindol/promestrene soft capsule for vagina and contains a main drug of cloquindol/promestrene and a proper amount of solvent, surfactant and the like to form an opaque liquid suitable for vagina. Chinese patent CN102038688A discloses a self-emulsifying microemulsion soft capsule for cloquindol-promestrene vagina and a preparation method thereof, the self-emulsifying microemulsion soft capsule for the cloquindol-promestrene vagina is a soft capsule for the vagina which has no local stimulation and good melting time limit, and the system is a uniform transparent solution formed by the cloquindol, the promestrene, an oil phase, a surfactant and a cosurfactant.
Cloquindol is often used in combination with promestrene, which is a lamellar crystal, and the needle-shaped crystals of cloquindol and the lamellar crystal of promestrene cannot be uniformly mixed, resulting in poor stability of the drug effect of the preparation.
Disclosure of Invention
The invention aims to provide a preparation method of a chloroquinate crystal, which is safe, environment-friendly, simple and convenient to operate, suitable for industrial production, good in flowability of the prepared crystal, stable in crystal, easy to crush, good in pharmacy and suitable for multiple dosage forms.
The preparation method of the cloquindol crystal adopts a high molecular surfactant and a solvent to refine a crude product of the cloquindol to obtain the cloquindol crystal.
The polymer surfactant is sorbitan ester surfactant, preferably tween-80 or span-60, and more preferably tween-80.
The mass ratio of the crude chloroquinader to the high molecular surfactant is 1: 0.001-0.005.
The ratio of the crude chloroquinader to the solvent is 1:5-10, wherein the crude chloroquinader is counted by g, and the solvent is counted by ml.
The solvent is acetone or acetonitrile, preferably acetone.
When the solvent is acetone, the preparation method of the cloquindol crystal comprises the steps of adding a crude cloquindol product into the solvent under the protection of nitrogen, heating to dissolve, decoloring, then performing heat filtration, stirring and cooling filtrate, adding purified water and a high molecular surfactant, preserving heat, standing and growing crystals, then performing gradient cooling, stirring and crystallizing, then filtering, leaching, and drying under reduced pressure to obtain the cloquindol crystal.
The mass ratio of the crude product of the chloroquinader to the purified water is 1: 2-6.
When the solvent is acetonitrile, the preparation method of the cloquindol crystal comprises the steps of adding a crude cloquindol product into the solvent under the protection of nitrogen, heating to dissolve, decoloring, then carrying out heat filtration, stirring and cooling filtrate, adding a high molecular surfactant, keeping the temperature, standing, growing crystals, then carrying out gradient cooling, stirring and crystallizing, then filtering, leaching, and drying under reduced pressure to obtain the cloquindol crystal.
The temperature rise is 56-82 ℃.
The decolorization is realized by adopting medicinal carbon, and the mass ratio of the crude chloroquinader to the medicinal carbon is 1: 0.01-0.05.
The stirring speed of the filtrate is 20-50 Hz.
The stirring blade is in a helical blade turbine type, so that the flow field is mainly axial, the shearing is small, the flow is large, the nucleation is weakened, and the crystal growth is promoted.
Standing and growing the crystal at the temperature of 30-60 ℃ for 10-20 hours.
The gradient cooling is that the temperature is reduced to 15-25 ℃ at the rate of 5 ℃ per 1 hour, the temperature is kept and stirred for 1-2 hours, and then the temperature is reduced to-5-15 ℃ at the rate of 10 ℃ per 1 hour.
The stirring speed is 20-50 Hz.
The gradient cooling can change crystal habit, prevent crystal fracture, make its crystal appearance no longer be acicular, and the gradient cooling can avoid exploding and separating moreover, improves crystal purity.
The stirring crystallization temperature is-5-15 ℃, the stirring crystallization time is 6-10 hours, and the stirring speed in the stirring crystallization is 20-50 Hz.
The leaching is performed by adopting absolute ethyl alcohol, and the temperature of the absolute ethyl alcohol is-5-15 ℃.
The reduced pressure drying temperature is 30-60 deg.C, preferably 40-50 deg.C.
Research shows that in the preparation process of the chloroquinalder crystal, when no high molecular surfactant is added, the precipitated crystal is needle-shaped. After the addition of the high molecular surfactant, the crystal habit is changed, so that the appearance of the precipitated crystal is changed. In order to avoid the influence of the added high molecular surfactant on the purity of the precipitated crystals, an ionic surfactant cannot be selected, and a nonionic surfactant is selected. The nonionic surfactant is divided into polyoxyethylene type and polyhydric alcohol type, and experiments show that crystals precipitated by adding polyoxyethylene type (such as alkylphenol ethoxylates, polyoxyethylene fatty acid, etc.) are still needle-shaped crystals, crystals precipitated by adding polyhydric alcohol type (such as Tween-80, span-60, hydroxyethyl cellulose, polyacrylamide, polyvinylpyrrolidone, etc.) are one or more of needle-shaped crystals, sheet-shaped crystals or columnar crystals, but the crystal precipitated by adding hydroxyethyl cellulose, polyacrylamide, polyvinylpyrrolidone and the like is a mixed crystal of two or three of needle-shaped crystal, flaky crystal or columnar crystal, the crystal precipitated by adding the sorbitan esters such as the Tween-80, the span-60 and the like is a crystal with a single shape, wherein the crystal precipitated by adding the Tween-80 is more stable.
Further research shows that under the condition of adding sorbitan ester surfactants such as tween-80, span-60 and the like, methanol, ethanol, THF, 1,4 dioxane, DMF and the like are used as solvents, and the refined chloroquindol is needle-shaped crystal; taking acetone as a solvent, and taking the refined chloroquinadol as a flaky crystal; acetonitrile is used as a solvent, and the refined chloroquinadol is a columnar crystal. When acetonitrile is used as a solvent, no purified water is added, and therefore, the yield is not affected.
According to the classical nucleation theory, if the surface energy of a certain crystal phase is small, the energy barrier for becoming a critical nucleus is low, and thus has a relatively high nucleation rate. The interaction energy of the solvent and different crystal faces is different, so that the relative growth rate of the crystal faces is changed, and the growth morphology of the crystal is influenced and changed. When acetone and acetonitrile are used as solvents, different intermolecular forces are generated between the acetone and the acetonitrile and different crystal faces, so that different crystal shapes can be grown.
The X-ray diffraction method detects that unit cell parameters such as diffraction angles of the flaky crystal, the columnar crystal and the needle crystal are completely consistent, parameters such as infrared absorption spectrum absorption band frequency, peak shape, peak position and peak intensity are also completely consistent, and analysis results such as DSC, DTA, TGA and the like are also the same, so that the flaky crystal, the columnar crystal and the needle crystal are of the same crystal form.
The appearance of the chloroquinate crystal prepared by the invention is sheet-shaped or columnar.
The invention has the following beneficial effects:
1. the crystal prepared by the invention has good fluidity, stable crystal, easy pulverization and good pharmaceutical property, and is suitable for multiple dosage forms.
2. The cloquindol flaky crystal and the columnar crystal prepared by the invention can be uniformly mixed with the promestrene flaky crystal, so that the stability of the drug effect of the preparation is improved.
3. The preparation method of the chloroquinalder crystal is safe, environment-friendly, simple and convenient to operate and suitable for industrial production.
4. Aiming at the defects of the needle-shaped crystal of the chloroquinate in practical application, the invention prepares the flaky crystal and the columnar crystal of the chloroquinate and improves the refining yield of the chloroquinate and the stability of the drug effect of the preparation of the chloroquinate. The yield of the cloquinalder refined product is 95-98%, and the purity is more than 99.9%.
Drawings
FIG. 1 is a morphology chart of the layered crystal of chloroquinader prepared in example 1.
FIG. 2 is a topographical map of the chloroquinalder columnar crystals prepared in example 3.
FIG. 3 is a morphology chart of needle-shaped crystals of chloroquinate prepared in comparative example 1.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
Adding 10g of crude chloroquinader into 50ml of acetone under the protection of nitrogen, heating to 56 ℃ for dissolution, adding 0.1g of medicinal activated carbon for decolorization, then carrying out hot filtration, stirring and cooling the filtrate, wherein the stirring speed is 30Hz, the temperature is reduced to 45-50 ℃, adding 20g of purified water, adding 0.01g of Tween-80, carrying out heat preservation and standing for crystal growth for 10 hours, then cooling to 15-25 ℃ at the speed of 5 ℃ per 1 hour, carrying out heat preservation and stirring for 2 hours, then cooling to 0-5 ℃ at the speed of 10 ℃ per 1 hour, stirring for crystallization for 6 hours, filtering, carrying out leaching with 0-5 ℃ of absolute ethyl alcohol, and carrying out vacuum drying on the obtained solid at 40-50 ℃ for 6 hours to obtain 9.5g of flaky chloroquinader crystals. The purification yield was 95% and the purity was 99.93%. The morphology of the chloroquinaldine flaky crystal is shown in figure 1.
Example 2
Adding 50g of crude chloroquinate into 500ml of acetone under the protection of nitrogen, heating to 56 ℃ for dissolution, adding 1g of medicinal activated carbon for decolorization, then carrying out heat filtration, stirring and cooling the filtrate, wherein the stirring speed is 20Hz, the temperature is reduced to 30-45 ℃, adding 250g of purified water, adding 0.1g of Tween-80, carrying out heat preservation and standing for crystal growth for 20 hours, then cooling to 15-25 ℃ at the speed of 5 ℃ per 1 hour, carrying out heat preservation and stirring for 2 hours, then cooling to-5-0 ℃ at the speed of 10 ℃ per 1 hour, stirring for 8 hours, carrying out filtration, carrying out leaching with anhydrous ethanol at the temperature of-5-0 ℃, carrying out vacuum drying on the obtained solid at the temperature of 40-50 ℃ for 8 hours, and obtaining 49g of flaky chloroquinate crystals. The purification yield was 98% and the purity was 99.96%.
Example 3
Under the protection of nitrogen, 200g of crude chloroquinader is added into 1600ml of acetonitrile, the temperature is raised to 82 ℃ for dissolution, 10g of medicinal active carbon is added for decolorization, then heat filtration is carried out, the filtrate is stirred and cooled, the stirring speed is 50Hz, the temperature is reduced to 55-60 ℃, 1g of Tween-80 is added, the mixture is kept warm and kept stand for growing crystals for 15 hours, then the temperature is reduced to 15-25 ℃ at the speed of 5 ℃ per 1 hour, the mixture is kept warm and stirred for 1 hour, then the temperature is reduced to 5-10 ℃ at the speed of 10 ℃ per 1 hour, the mixture is stirred and crystallized for 10 hours, the mixture is filtered, the mixture is rinsed with absolute ethyl alcohol at the temperature of 5-10 ℃, the obtained solid is dried for 10 hours under vacuum at the temperature of 40-. The purification yield was 96.5% and the purity was 99.95%. The morphology of the chloroquinadol columnar crystal is shown in figure 2.
Example 4
Adding 500g of crude chloroquinader into 3000ml of acetone under the protection of nitrogen, heating to 56 ℃ for dissolving, adding 15g of medicinal activated carbon for decoloring, then carrying out heat filtration, stirring and cooling the filtrate, wherein the stirring speed is 40Hz, the temperature is reduced to 50-55 ℃, adding 2500g of purified water, adding 1.5g of Tween-80, carrying out heat preservation and standing for crystallization for 12 hours, then cooling to 15-25 ℃ at the speed of 5 ℃ per 1 hour, carrying out heat preservation and stirring for 1.5 hours, then cooling to 0-5 ℃ at the speed of 10 ℃ per 1 hour, stirring for crystallization for 9 hours, filtering, carrying out leaching by using absolute ethyl alcohol at the temperature of 0-5 ℃, carrying out vacuum drying on the obtained solid at the temperature of 40-50 ℃ for 6 hours, and obtaining 489g of flaky chloroquinader crystal. The purification yield was 97.8% and the purity was 99.94%.
Example 5
Under the protection of nitrogen, 500g of crude chloroquinader is added into 5000ml of acetonitrile, the temperature is raised to 82 ℃ for dissolution, 25g of medicinal activated carbon is added for decolorization, then heat filtration is carried out, the filtrate is stirred and cooled, the stirring speed is 35Hz, the temperature is reduced to 45-50 ℃, 2.5g of Tween-80 is added, the mixture is kept warm and kept still for growing crystals for 18 hours, then the temperature is reduced to 15-25 ℃ at the speed of 5 ℃ per 1 hour, the mixture is kept warm and stirred for 1 hour, then the temperature is reduced to 10-15 ℃ at the speed of 10 ℃ per 1 hour, the mixture is stirred and crystallized for 7 hours, filtration is carried out, 10-15 ℃ absolute ethyl alcohol is used for leaching, and the obtained solid is dried in vacuum at 40-50 ℃ for 10 hours, so as to. The purification yield was 96% and the purity was 99.96%.
Comparative example 1
Under the protection of nitrogen, 10g of crude chloroquinate is added into 50ml of ethanol, the temperature is raised to 78 ℃ for dissolution, 0.1g of medicinal activated carbon is added for decolorization, then the hot filtration is carried out, the filtrate is stirred and cooled to 0-5 ℃, the stirring is carried out for crystallization for 6 hours, the filtration is carried out, the anhydrous ethanol at 0-5 ℃ is used for leaching, the obtained solid is dried in vacuum at 40-50 ℃ for 6 hours, and 9.08g of needle-shaped chloroquinate crystals are obtained. The purification yield was 90.8% and the purity was 99.91%. The morphology of the needle-shaped crystal of chloroquinalder is shown in figure 3.
Comparative example 2
Adding 10g of crude chloroquinader into 50ml of acetone under the protection of nitrogen, heating to 56 ℃ for dissolution, adding 0.1g of medicinal activated carbon for decolorization, then carrying out heat filtration, stirring and cooling the filtrate, wherein the stirring speed is 30Hz, the temperature is reduced to 45-50 ℃, adding 20g of purified water, adding 0.01g of alkylphenol ethoxylate, carrying out heat preservation and standing for crystal growth for 10 hours, then carrying out gradient cooling, cooling to 15-25 ℃ at the speed of 5 ℃ per 1 hour, carrying out heat preservation and stirring for 2 hours, then cooling to 0-5 ℃ at the speed of 10 ℃ per 1 hour, stirring for crystal growth for 6 hours, filtering, carrying out rinsing with 0-5 ℃ of absolute ethyl alcohol, and carrying out vacuum drying on the obtained solid at 40-50 ℃ for 6 hours to obtain 9.41g of needle-shaped chloroquinader crystals. The purification yield was 94.1% and the purity was 99.92%.
Comparative example 3
Adding 10g of crude chloroquinader into 50ml of 1, 4-dioxane under the protection of nitrogen, heating to 101 ℃ for dissolution, adding 0.1g of medicinal activated carbon for decolorization, then carrying out heat filtration, stirring and cooling the filtrate, wherein the stirring speed is 30Hz, the temperature is reduced to 45-50 ℃, adding 20g of purified water, adding 0.01g of Tween-80, keeping the temperature and standing for crystal growth for 10 hours, then carrying out gradient cooling, cooling to 15-25 ℃ at the speed of 5 ℃ per 1 hour, stirring for 1 hour at the temperature of 10 ℃ per 1 hour, cooling to 0-5 ℃ at the temperature, stirring for crystal growth for 6 hours, filtering, carrying out leaching by using absolute ethyl alcohol at the temperature of 0-5 ℃, and carrying out vacuum drying on the obtained solid at the temperature of 40-50 ℃ for 6 hours to obtain 9.51g of needle-shaped chloroquinader crystals. The purification yield was 95.1% and the purity was 99.91%.
Stability test of chloroquinate crystals:
samples of chloroquinate prepared in example 1, example 2, example 3, example 4, example 5 and comparative example 1 were sealed in a stability testing cabinet at 30 ℃ and 55% humidity. Samples were taken at 0, 30, 45, 60, 75, and 90 days to check for changes in HPLC purity, and the data relating to the purity of cloquindol are shown in Table 1.
TABLE 1 comparative data on stability of the crystalline cloquindol crystals of examples 1-5 and comparative example 1
As can be seen from table 1, example 2, example 3, example 4 and example 5 had a purity change of only 0.03% within 90 days, while comparative example 1 had a purity change of 0.1% within 90 days. Thus, the smaller the change in purity over the same time, the more stable the crystal is.
Claims (5)
1. A preparation method of a cloquindol crystal is characterized in that a high molecular surfactant and a solvent are adopted to refine a cloquindol crude product to obtain the cloquindol crystal;
the high molecular surfactant is a sorbitan ester surfactant;
the solvent is acetone or acetonitrile;
when the solvent is acetone, the preparation method of the cloquindol crystal comprises the steps of adding a crude cloquindol product into the solvent under the protection of nitrogen, heating to dissolve, decoloring, then carrying out hot filtration, stirring and cooling filtrate, adding purified water and a high molecular surfactant, carrying out heat preservation, standing and crystallization, then carrying out gradient cooling, stirring and crystallization, then filtering, leaching, and drying under reduced pressure to obtain the cloquindol crystal;
when the solvent is acetonitrile, the preparation method of the cloquindol crystal comprises the steps of adding a crude cloquindol product into the solvent under the protection of nitrogen, heating to dissolve, decoloring, then carrying out hot filtration, stirring and cooling the filtrate, adding a high-molecular surfactant, carrying out heat preservation, standing, crystallizing, then carrying out gradient cooling, stirring and crystallizing, then filtering, leaching, and drying under reduced pressure to obtain the cloquindol crystal;
standing and growing the crystal at the temperature of 30-60 ℃ for 10-20 hours;
the gradient cooling is that the temperature is reduced to 15-25 ℃ at the rate of 5 ℃ per 1 hour, the temperature is kept and stirred for 1-2 hours, and then the temperature is reduced to-5-15 ℃ at the rate of 10 ℃ per 1 hour;
the stirring crystallization temperature is-5 to 15 ℃, and the stirring crystallization time is 6 to 10 hours.
2. The method for producing a crystal of chloroquinate as claimed in claim 1, wherein the polymeric surfactant is tween-80 or span-60.
3. The method for preparing a crystal of chloroquinate according to claim 1, wherein the mass ratio of the crude chloroquinate to the polymeric surfactant is 1: 0.001-0.005.
4. The method for preparing a crystal of chloroquinate as claimed in claim 1, wherein the ratio of the crude chloroquinate to the solvent is 1:5-10, the crude chloroquinate is calculated by g, and the solvent is calculated by ml.
5. The process for producing a crystal of chloroquinate as claimed in claim 1, wherein the mass ratio of the crude chloroquinate to the purified water is 1:2 to 6.
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| CH229982A (en) * | 1942-06-04 | 1943-11-30 | Ag J R Geigy | Process for the preparation of 5,7-dichloro-8-oxychinaldine. |
| RO58660A2 (en) * | 1972-02-08 | 1975-09-15 | ||
| CN108341776B (en) * | 2018-04-13 | 2021-04-09 | 北京金城泰尔制药有限公司沧州分公司 | Process for synthesizing chloroquinate |
| CN110143919B (en) * | 2019-07-08 | 2020-11-27 | 北京金城泰尔制药有限公司 | Synthesis process of chloroquinate |
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