CN107488178B - Preparation method of high-purity pralatrexate intermediate - Google Patents
Preparation method of high-purity pralatrexate intermediate Download PDFInfo
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- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a high-purity pralatrexate intermediate. On the basis of PLQS-3 preparation, a crystallization solvent is used to obtain a PLQS-3 crude product, a single solvent is used to heat and wash the crude product, the hot crude product is filtered to obtain high-purity PLQS-3, the PLQS-3 is hydrolyzed at a certain temperature by using a proper amount of inorganic alkali liquor, the hydrolyzed solution is added with excessive hydrochloric acid to form hydrochloride, and the hydrochloride thereof is continuously refined by using solvents such as absolute ethyl alcohol and the like to obtain the high-purity PLQS-4 hydrochloride. The purification of the PLQS-3 crude product is beneficial to improving the purity of the PLQS-4, and the invention can be well applied to the production process of the pralatrexate.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a high-purity pralatrexate intermediate.
Background
Pralatrexate (Pralatrexate), trade name Folotyn, is the first new targeted folic acid formulation approved by the FDA for the treatment of peripheral T-cell lymphoma. The chemical name of pralatrexate is 10-propargyl-10-deazaaminopterin. By Joseph i.degew; j William T.Colwell et al, Synthesis and antagonist Activity of 10-propagyl-10-deazaaminopterin J.medical chem.36: 2228-one 2231 (1993). It was also studied next by Sirotaak et al and O' Connor et al. The molecular structure is shown as follows:
the synthesis of pralatrexate is carried out by taking p-carboxylphenylacetic acid as initial raw material and carrying out a series of chemical conversions. First, intermediate methyl 4-formate phenylacetate (PLQS-1), intermediate methyl a-propargyl- (4-formate) -phenylacetate (PLQS-2), intermediate 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroate (PLQS-3), intermediate 10-propargyl-10-carboxy-4-deoxy-4-amino-10-deazapteroate (PLQS-4), intermediate 10-propargyl-4-deoxy-4-amino-10-deazapteroate (PLQS-5), intermediate 10-propargyl-10-deazaaminopterin dimethyl ester (PLQS-6), finally, the final product of pralatrexate is obtained.
The intermediate 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester (PLQS-3) is characterized in that 6- (bromomethyl) -2, 4-pteridine diamine hydrobromide (PLQS-B) is introduced in the synthesis process, and the synthesized (PLQS-3) has relatively low purity due to the active chemical property of the 6- (bromomethyl) -2, 4-pteridine diamine hydrobromide. And new impurities are generated in the hydrolysis process of the PLQS-3, so that the PLQS-4 is lower in purity; the method for obtaining the PLQS-3 crude product in the prior art is to pour the reaction solution into purified water to adjust the pH value to be neutral, precipitate solid and filter to obtain the PLQS-3 crude product, but the PLQS-3 crude product obtained by the technology is sticky and is not suitable for filtering; for refining the crude product PLQS-3, WO2014016740A2 uses a mixed solvent of methanol, dichloromethane and isopropanol with a certain proportion to drip hydrobromic acid to form salt and refine the salt, but the method needs to form the salt at low temperature and the refining time is longer; therefore, the problem of improving the purity of PLQS-3 and PLQS-4 or preparing a new intermediate is urgently needed to be solved.
Disclosure of Invention
The invention uses crystallization solvent to obtain PLQS-3 crude product on the basis of PLQS-3 preparation, uses single solvent to heat and wash the crude product, filters the crude product while the product is hot to obtain high-purity PLQS-3, the PLQS-3 uses a proper amount of inorganic alkali liquor to hydrolyze at a certain temperature, the hydrolysis solution is added with excessive hydrochloric acid to make the hydrolysis solution become hydrochloride, and the hydrochloride thereof is continuously refined by absolute ethyl alcohol to obtain high-purity PLQS-4 hydrochloride.
The inventors have conducted further studies on the crystallization solvent and the detergent solvent of PLQS-3 through intensive studies and researches, and also conducted further studies on the hydrolysis temperature, the alkali dosage, the crystallization pH value, the refining solvent and the solvent dosage of PLQS-3.
Specifically, the invention is realized by the following technical scheme:
(1) α -propargyl- (4-methyl formate) -methyl phenylacetate (PLQS-2) reacts with NaH to remove hydrogen, electrophilic substitution reaction is carried out on the hydrogen and 6- (bromomethyl) -2, 4-pteridine diamine hydrobromide, after the reaction is finished, reaction liquid is poured into a crystallization solvent, crystallization and filtration are carried out, a PLQS-3 crude product is obtained, then the crude product is heated and refluxed by a washing solvent, natural cooling, crystallization, filtration and drying are carried out, and a coffee solid intermediate 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deaza pteroate (PLQS-3) is obtained;
(2) 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester (PLQS-3), dropwise adding a sodium hydroxide solution under the condition of taking water as a solvent for hydrolysis, dropwise adding hydrochloric acid after the hydrolysis is finished, adjusting the pH value of a reaction solution to be 3.0-3.8, filtering to obtain a solid, dissolving the solid into a refined solvent, heating, dissolving and refluxing, filtering while hot, cooling and crystallizing a filtrate, and obtaining a high-purity intermediate 10-propargyl-10-carboxyl-4-deoxy-4-amino-10-deazapteroic acid (PLQS-4) hydrochloride.
The crystallization solvent is selected from one of methyl tert-butyl ether, diethyl ether and isopropyl ether; preferably diethyl ether.
The volume ratio of the reaction liquid to the crystallization solvent is 1: 3-10 ml/ml, preferably 1: 5.
the washing solvent is selected from one of absolute methanol, absolute ethanol, isopropanol and acetone; anhydrous methanol is preferred.
The mass-volume ratio of the PLQS-3 crude product to the washing solvent is as follows: 1: 5-15 g/ml, preferably 1: 10.
the hydrolysis temperature of PLQS-3 is as follows: 0-25 ℃; preferably 15 deg.c.
The mole ratio of PLQS-3 to sodium hydroxide is as follows: 1: 3-15; preferably 1: 10.
the molar concentration of the sodium hydroxide solution is as follows: 0.1-1.5 mol/L; preferably 1.0 mol/L.
The crystallization pH is preferably 3.5.
The refined solvent is selected from one of absolute methanol, absolute ethanol and isopropanol; preferably anhydrous ethanol.
The mass-volume ratio of the hydrochloride of PLQS-4 to the refined solvent is as follows: 1: 5-12 g/ml; preferably 1: 10.
compared with the prior art, the invention has the following technical effects:
(1) after the crystallization solvent is added, the solid is separated out quickly, and compared with the method of adding purified water, the viscosity of the solid is reduced, the suction filtration is easy, the post-treatment time is shortened, and the working efficiency is improved.
(2) By utilizing the property that the PLQS-3 is slightly soluble in a washing solvent and the impurities are easily soluble, the crude product of the PLQS-3 is heated, refluxed and refined, and the purity of the obtained solid is higher and reaches more than 98.5 percent.
(3) Adding PLQS-4 into concentrated hydrochloric acid to form salt, refining to obtain solid with purity of about 96%, and refining and recrystallizing with anhydrous ethanol to obtain the product with purity of 99%.
Detailed Description
The benefits of the present invention will now be further illustrated by the following examples, which are intended for the purpose of illustration only and should not be construed as limiting the invention, and all such obvious modifications and variations that may be apparent to those skilled in the art are intended to be included within the scope of the invention.
Example 1
Under the protection of inert gas, 400ml of DMF and 32.5g of NaH are added into a 1L three-necked bottle, when the internal temperature is reduced to-5-0 ℃, the dropping of the anhydrous DMF solution of PLQS-2 (50 g of PLQS-2 is dissolved in 65ml of anhydrous DMF) is started, and the dropping speed is controlled so that the internal temperature is not higher than 0 ℃. After the dripping is finished, continuously stirring for 1h at the temperature of 0-5 ℃, cooling, slowly dripping 600ml of anhydrous DMF solution of PLQS-B when the internal temperature is reduced to-20 to-10 ℃, and controlling the dripping speed to ensure that the internal temperature is not higher than-10 ℃ (finishing the dripping within about 2-3 h). After dripping, continuously keeping the temperature and stirring for 0.5h, after the reaction is finished, pouring the reaction solution into 5L of anhydrous ether, separating out solids, continuously stirring for 0.5h, carrying out suction filtration, adding 2.0L of anhydrous methanol into a filter cake, heating and refluxing for 2h, naturally cooling to room temperature, carrying out suction filtration, and carrying out vacuum drying on the solids at 50 ℃ to obtain 68.3g of coffee solids with the purity of: 98.9% and a yield of 80%.
Example 2
Under the protection of inert gas, 400ml of DMF and 32.5g of NaH are added into a 1L three-necked bottle, when the internal temperature is reduced to-5-0 ℃, the dropping of the anhydrous DMF solution of PLQS-2 (50 g of PLQS-2 is dissolved in 65ml of anhydrous DMF) is started, and the dropping speed is controlled so that the internal temperature is not higher than 0 ℃. After the dripping is finished, continuously stirring for 1h at the temperature of 0-5 ℃, cooling, slowly dripping 600ml of anhydrous DMF solution of PLQS-B when the internal temperature is reduced to-20 to-10 ℃, and controlling the dripping speed to ensure that the internal temperature is not higher than-10 ℃ (finishing the dripping within about 2-3 h). After dripping, continuing to keep the temperature and stir for 0.5h, after the reaction is finished, pouring the reaction liquid into 5L of methyl tert-butyl ether, separating out solids, continuing to stir for 0.5h, performing suction filtration, adding 2.0L of absolute ethyl alcohol into a filter cake, heating and refluxing for 2h, naturally cooling to room temperature, performing suction filtration, and performing vacuum drying on the solids at 50 ℃ to obtain 65.2g of coffee solids with the purity of: 98.5% and a yield of 76.4%.
Example 3
Adding 65g of PLQS-3 and 650ml of purified water into a 3L three-necked flask, cooling to about 10 ℃, dropwise adding 1.55L of 1mol/L sodium hydroxide aqueous solution under stirring, continuing to perform heat preservation reaction for 24-30 h after dropwise adding, sampling HPLC, after the reaction is completed, dropwise adding concentrated hydrochloric acid into the reaction solution at room temperature until the pH value is 3.5, separating out solids, stirring for 2h, filtering, adding 10 times of absolute ethyl alcohol into a filter cake, heating and refluxing for 1h, filtering out insoluble substances, naturally cooling the filtrate, stirring and crystallizing, when the solids are separated out, continuously stirring and crystallizing for 2h in an ice bath, performing suction filtration, washing the filter cake with 50ml of absolute ethyl alcohol, drying after filtration, and placing in a 50 ℃ oven to dry to constant weight to obtain 60.65g of brown yellow solids, wherein the purity is: 98.7% and yield 84.3%.
Example 4
Adding 65g of PLQS-3 and 650ml of purified water into a 3L three-necked flask, cooling to about 10 ℃, dropwise adding 1.55L of 1mol/L sodium hydroxide aqueous solution under stirring, continuing to perform heat preservation reaction for 24-30 h after dropwise adding, sampling HPLC, after the reaction is completed, dropwise adding concentrated hydrochloric acid into the reaction solution at room temperature until the pH value is 3.8, separating out solids, stirring for 2h, filtering, adding 10 times of absolute ethyl alcohol into a filter cake, heating and refluxing for 1h, filtering out insoluble substances, naturally cooling the filtrate, stirring and crystallizing, when the solids are separated out, continuously stirring and crystallizing for 2h in an ice bath, performing suction filtration, washing the filter cake with 50ml of absolute ethyl alcohol, drying after filtration, and placing in a 50 ℃ oven to dry to constant weight to obtain 57.92g of brown yellow solids, wherein the purity is: 98.2% and a yield of 80.5%.
Example 5
Adding 65g of PLQS-3 and 650ml of purified water into a 3L three-necked bottle, keeping the temperature at about 30 ℃, dropwise adding 1.55L of 1mol/L sodium hydroxide aqueous solution under stirring, continuing to keep the temperature and react for 14-20 h after the dropwise adding is finished, sampling HPLC, after the reaction is finished, dropwise adding concentrated hydrochloric acid into the reaction solution at room temperature until the pH value is 3.5, separating out solids, stirring for 2h, filtering, adding 5 times of absolute ethyl alcohol into a filter cake, heating and refluxing for 1h, filtering out insoluble substances, naturally cooling the filtrate, stirring and crystallizing, when the solids are separated out, continuously stirring and crystallizing for 2h in an ice bath, carrying out suction filtration, washing the filter cake with 50ml of absolute ethyl alcohol, drying in a 50 ℃ oven to constant weight after being filtered out, obtaining 57.78g of brown yellow solids, wherein the purity is: 98.1% and a yield of 80.3%.
Example 6
Adding 65g of PLQS-3 and 650ml of purified water into a 3L three-necked flask, cooling to about 10 ℃, dropwise adding 0.78L of 1mol/L sodium hydroxide aqueous solution under stirring, continuing to perform heat preservation reaction for 30-40 h after dropwise adding, sampling HPLC, after the reaction is completed, dropwise adding concentrated hydrochloric acid into the reaction solution at room temperature until the pH value is 3.5, separating out solids, stirring for 2h, filtering, adding 10 times of absolute ethyl alcohol into a filter cake, heating and refluxing for 1h, filtering out insoluble substances, naturally cooling the filtrate, stirring and crystallizing, when the solids are separated out, continuously stirring and crystallizing for 2h in an ice bath, performing suction filtration, washing the filter cake with 50ml of absolute ethyl alcohol, drying after filtration, and placing in a 50 ℃ oven to dry to constant weight to obtain 59.9g of brown yellow solids, wherein the purity is as follows: 98.5% and yield 83.3%.
Example 7
Adding 65g of PLQS-3 and 650ml of purified water into a 3L three-necked bottle, cooling to about 10 ℃, dropwise adding 1.55L of 1mol/L sodium hydroxide aqueous solution under stirring, continuing to perform heat preservation reaction for 24-30 h after dropwise adding, sampling HPLC, after the reaction is completed, dropwise adding concentrated hydrochloric acid into the reaction solution at room temperature until the pH value is 3.8, separating out solids, stirring for 2h, filtering, adding 12 times of absolute ethyl alcohol into a filter cake, heating and refluxing for 1h, filtering out insoluble substances, naturally cooling the filtrate, stirring and crystallizing, when the solids are separated out, continuously stirring and crystallizing for 2h in an ice bath, performing suction filtration, washing the filter cake with 50ml of absolute ethyl alcohol, drying after filtration, and putting into a 50 ℃ oven to dry to constant weight to obtain 56.33g of brown yellow solids, wherein the purity is: 98.9% and yield 78.3%.
Example 8
Adding 65g of PLQS-3 and 650ml of purified water into a 3L three-necked flask, cooling to about 10 ℃, dropwise adding 1.55L of 1mol/L sodium hydroxide aqueous solution under stirring, continuing to perform heat preservation reaction for 24-30 h after dropwise adding, sampling HPLC, after the reaction is completed, dropwise adding concentrated hydrochloric acid into the reaction solution at room temperature until the pH value is 3.5, separating out solids, stirring for 2h, filtering, adding 5 times of absolute ethyl alcohol into a filter cake, heating and refluxing for 1h, filtering out insoluble substances, naturally cooling the filtrate, stirring and crystallizing, when the solids are separated out, continuously stirring and crystallizing for 2h in an ice bath, performing suction filtration, washing the filter cake with 50ml of absolute ethyl alcohol, drying after filtration, and placing in a 50 ℃ oven to dry to constant weight to obtain 61.5g of brown yellow solids, wherein the purity is: 98.0% and 85.5% yield.
Example 9
Adding 65g of PLQS-3 and 650ml of purified water into a 3L three-necked flask, cooling to about 10 ℃, dropwise adding 1.55L of 1mol/L sodium hydroxide aqueous solution under stirring, continuing to perform heat preservation reaction for 24-30 h after dropwise adding, sampling HPLC, after the reaction is completed, dropwise adding concentrated hydrochloric acid into the reaction solution at room temperature until the pH value is 3.5, separating out solids, stirring for 2h, filtering, adding 12 times of absolute ethyl alcohol into a filter cake, heating and refluxing for 1h, filtering out insoluble substances, naturally cooling the filtrate, stirring and crystallizing, when the solids are separated out, continuously stirring and crystallizing for 2h in an ice bath, performing suction filtration, washing the filter cake with 50ml of absolute ethyl alcohol, drying after filtration, putting into a 50 ℃ oven to dry to constant weight to obtain 57.9g of brown yellow solids, wherein the purity is as follows: 99.2% and 80.5% yield.
Claims (8)
1. A preparation method of a high-purity pralatrexate intermediate is characterized by comprising the following steps:
(1) α -propargyl- (4-methyl formate) -methyl phenylacetate (PLQS-2) reacts with NaH to remove hydrogen, electrophilic substitution reaction is carried out on the hydrogen and 6- (bromomethyl) -2, 4-pteridine diamine hydrobromide, after the reaction is finished, reaction liquid is poured into a crystallization solvent, crystallization and filtration are carried out, a PLQS-3 crude product is obtained, then the crude product is heated and refluxed by a washing solvent, natural cooling, crystallization, filtration and drying are carried out, and a coffee solid intermediate 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deaza pteroate (PLQS-3) is obtained;
(2) 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester (PLQS-3), dropwise adding a sodium hydroxide solution for hydrolysis in the presence of water as a solvent, dropwise adding hydrochloric acid after hydrolysis is finished, adjusting the pH value of a reaction solution to 3.0-3.8, filtering to obtain a solid, dissolving the solid in a refined solvent, heating, dissolving and refluxing, filtering while hot, cooling and crystallizing a filtrate to obtain a hydrochloride of a high-purity intermediate 10-propargyl-10-carboxyl-4-deoxy-4-amino-10-deazapteroic acid (PLQS-4);
the crystallization solvent in the step (1) is selected from one of methyl tert-butyl ether, diethyl ether and isopropyl ether;
the washing solvent in the step (1) is selected from one of absolute methanol, absolute ethanol, isopropanol and acetone.
2. The method according to claim 1, wherein the volume ratio of the reaction solution to the crystallization solvent in the step (1) is 1: 3-10 ml/ml.
3. The method of claim 1, wherein the mass-to-volume ratio of crude PLQS-3 to washing solvent in step (1) is 1: 5-15 g/ml.
4. The method of claim 1, wherein the hydrolysis temperature in step (2) is: 0-25 ℃.
5. The process according to claim 1, wherein the molar ratio of intermediate (PLQS-3) to sodium hydroxide in step (2) is: 1: 3 to 15.
6. The method of claim 1, wherein the molar concentration of sodium hydroxide in step (2) is: 0.1 to 1.5 mol/L.
7. The method according to claim 1, wherein the refining solvent in the step (2) is one selected from the group consisting of absolute methanol, absolute ethanol and isopropanol.
8. The process according to claim 1, wherein the mass-to-volume ratio of the hydrochloride of PLQS-4 to the refining solvent in step (2) is: 1: 5-12 g/ml.
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| CN102984940A (en) * | 2010-06-02 | 2013-03-20 | 阿罗斯治疗公司 | Methods for treating methotrexate-resistant disorders with 10-propargyl-10-deazaaminopterin |
| CN104628728A (en) * | 2013-11-08 | 2015-05-20 | 深圳海王药业有限公司 | Pralatrexate preparation method |
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| WO2013177713A1 (en) * | 2012-05-31 | 2013-12-05 | Alphora Research Inc. | Process for preparation of an antifolate agent |
| US9440979B2 (en) * | 2012-07-23 | 2016-09-13 | Fresenius Kabi Oncology Limited | Process for the preparation of pralatrexate |
| WO2014068599A2 (en) * | 2012-11-02 | 2014-05-08 | Hetero Research Foundation | Process for pralatrexate |
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| CN102984940A (en) * | 2010-06-02 | 2013-03-20 | 阿罗斯治疗公司 | Methods for treating methotrexate-resistant disorders with 10-propargyl-10-deazaaminopterin |
| CN104628728A (en) * | 2013-11-08 | 2015-05-20 | 深圳海王药业有限公司 | Pralatrexate preparation method |
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