CN111499590A - Preparation method of high-purity cis-2, 6-dimethylmorpholine - Google Patents
Preparation method of high-purity cis-2, 6-dimethylmorpholine Download PDFInfo
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- CN111499590A CN111499590A CN202010263369.7A CN202010263369A CN111499590A CN 111499590 A CN111499590 A CN 111499590A CN 202010263369 A CN202010263369 A CN 202010263369A CN 111499590 A CN111499590 A CN 111499590A
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Abstract
The invention relates to the technical field of pharmaceutical chemistry synthesis, and discloses a preparation method of high-purity cis-2, 6-dimethylmorpholine, which comprises the steps of salifying a mixture of cis-2, 6-dimethylmorpholine rich in cis-2, 6-dimethylmorpholine, trans-2, 6-dimethylmorpholine, cis-2, 5-dimethylmorpholine and trans-2, 5-dimethylmorpholine with micromolecular aliphatic carboxylic acid in an ester solvent, and recrystallizing to obtain cis-2, 6-dimethylmorpholine carboxylate; then the cis-2, 6-dimethyl morpholine is dissociated by strong alkaline substances to obtain high-purity cis-2, 6-dimethyl morpholine. According to the method, environment-friendly ethyl acetate, isopropyl acetate and butyl acetate are used as reaction solvents and are also used as recrystallization solvents, pollution is reduced, green production is convenient to achieve, impurity content is effectively controlled, the purity of finished products reaches over 99.9%, and the used acid and solvents are environment-friendly and suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a preparation method of high-purity cis-2, 6-dimethylmorpholine.
Background
2, 6-dimethyl morpholine is an important pesticide and medical intermediate, and is indispensable in synthesizing bactericides such as bactericide of kresoxim-methyl, moroxydine, propimorph, fenpropimorph and antifungal medicine of amorolfine hydrochloride. For propiolin, the activity of inhibiting germs by cis isomer is obviously higher than that by trans isomer, and the activity of the cis isomer and the trans isomer mixture is lower. In the field of medicine, the molecular structure of propiolin refers to cis-isomers. In addition, for preparing the antifungal drug amorolfine hydrochloride (see the following structural formula), high-purity cis-2, 6-dimethylmorpholine is required to be used as a reaction raw material. The european pharmacopoeia specifies that the trans-amorolfine (trans-isomer) content must not be greater than 0.2%. This requires the preparation of cis-2, 6-dimethylmorpholine of a purity of 99.8% or more. Therefore, the research on the preparation method of the high-purity cis-2, 6-dimethylmorpholine has important practical significance.
The preparation method of the 2, 6-dimethyl morpholine mixture can be implemented by reference (US3083202), and is generally implemented by using diisopropanolamine as a raw material and dehydrating at high temperature under the catalysis of concentrated sulfuric acid, and the generated product is a mixture, and besides cis-2, 6-dimethyl morpholine, a certain amount of trans-2, 6-dimethyl morpholine, cis-2, 5-dimethyl morpholine and trans-2, 5-dimethyl morpholine are generally contained, wherein cis-2, 6-dimethyl morpholine in the mixture is the main component (see the following reaction formula).
Since the cis-isomer and trans-isomer of 2, 6-dimethylmorpholine have different boiling points, wherein the boiling point of the cis-isomer is 142- & ltwbr & gt 143 ℃, and the boiling point of the trans-isomer is 148.1-148.5 ℃, patent (US4212972) indicates that the cis-2, 6-dimethylmorpholine can be collected at 80-81 ℃ and the trans-2, 6-dimethylmorpholine can be collected at 87-89 ℃ by controlling the vacuum degree in a fractionating column with 60 theoretical plates, thereby obtaining the cis-2, 6-dimethylmorpholine with 54% yield. Because the boiling points of cis-isomer and trans-isomer are similar, cis-2, 6-dimethylmorpholine with trans-isomer content less than 0.2 percent can not be obtained by the method, thus the requirement of medical use can not be met.
In addition, patent (CN101270098A) reports the use of a mixture of cis, trans-2, 6-dimethylmorpholine and an inorganic or organic acid to form a salt, followed by recrystallization twice to obtain a cis-2, 6-dimethylmorpholine salt, and finally liberating with a strong base to obtain cis-2, 6-dimethylmorpholine. However, the patent also has a plurality of defects, such as high requirement on raw materials, and the cis-product content in the raw materials needs to reach more than 90 percent; if the salt is formed in toluene, xylene, chloroform and dichloromethane, the solvent has high toxicity; the used organic acids such as phenylglycine, o-chlorobenzoic acid, m-chlorophenylglycine and the like are expensive; the obtained cis-2, 6-dimethylmorpholine content is lower, and the cis-2, 6-dimethylmorpholine content cannot be used for preparing amorolfine hydrochloride (the trans-2, 6-dimethylmorpholine content cannot be larger than 0.2%).
Therefore, the need of developing a preparation method which has low requirements on reaction raw materials, can obtain cis-2, 6-dimethylmorpholine with the purity of more than 99.8 percent, meets the requirement of medicine, is environment-friendly, simple to operate, low in cost and convenient for realizing green production is needed in the field.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a preparation method of high-purity cis-2, 6-dimethylmorpholine.
(II) technical scheme
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of high-purity cis-2, 6-dimethylmorpholine comprises the following steps:
(1) forming salt with micromolecular fatty acid in ester solvent by cis-2, 6-dimethyl morpholine, trans-2, 6-dimethyl morpholine and a mixture of cis-2, 5-dimethyl morpholine and trans-2, 5-dimethyl morpholine which are rich in cis-2, 6-dimethyl morpholine, and collecting crystals;
(2) recrystallizing the crystal obtained in the step (1) for one to two times by using the same ester solvent;
(3) dissociating the cis-2, 6-dimethyl morpholine carboxylate obtained in the step (2) by using a strong alkaline substance to obtain high-purity cis-2, 6-dimethyl morpholine, wherein the content of the cis-2, 6-dimethyl morpholine can reach more than 99.9%.
Preferably, the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate or butyl acetate.
Preferably, the salt formation temperature in step (1) is from 25 to 80 ℃, more preferably from 30 to 50 ℃.
Preferably, the small molecular fatty acid in the step (1) is one or more of acetic acid, propionic acid or butyric acid; more preferably acetic acid.
Preferably, in the step (1), the molar ratio of the cis-2, 6-dimethylmorpholine to the small molecular fatty acid is cis-2, 6-dimethylmorpholine: 1 (1-2).
Preferably, the strongly alkaline substance in step (3) is one or more of sodium hydroxide, potassium hydroxide or the like.
(III) advantageous effects
Compared with the prior art, the invention provides a preparation method of high-purity cis-2, 6-dimethylmorpholine, which has the following beneficial effects:
(1) the cis-and trans-2, 6-dimethylmorpholine in the reaction raw materials has low proportion requirement and wide application range.
(2) Cheap micromolecular fatty acid such as acetic acid, propionic acid, butyric acid and the like is used as a salifying reagent, so that the production cost is effectively controlled.
(3) The environment-friendly ethyl acetate, isopropyl acetate and butyl acetate are used as reaction solvents and are also used as recrystallization solvents, so that the pollution is reduced, and the green production is convenient to realize.
(4) The cis-2, 6-dimethylmorpholine with the purity of more than 99.9 percent is obtained by simple and convenient operations such as salt formation, recrystallization, dissociation and the like, and meets the requirement of medical use.
(5) The method disclosed by the invention is simple to operate, low in energy consumption, low in cost, environment-friendly and suitable for industrial production.
Drawings
FIG. 1 is a structural formula of cis-2, 6-dimethylmorpholine according to the present invention;
FIG. 2 is a flow diagram of the present invention for preparing cis-2, 6-dimethylmorpholine carboxylate;
FIG. 3 is a reaction diagram showing the liberation of cis-2, 6-dimethylmorpholine carboxylate under basic conditions according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Preparation of cis-2, 6-dimethylmorpholine, trans-2, 6-dimethylmorpholine, a mixture of cis-2, 5-dimethylmorpholine and trans-2, 5-dimethylmorpholine.
Adding 400g of concentrated sulfuric acid and 24g of water into a 2L four-neck flask, adding 200g of diisopropanolamine in batches under stirring, heating to 178-180 ℃, keeping the temperature and stirring for 3.5-5h, keeping the temperature, reducing the temperature, adding 300ml of water for dilution, then dropwise adding 33.3% of liquid alkali, adjusting the pH to 13-14, separating, carrying out reduced pressure distillation on the oily matter, collecting fractions, adding 130g of solid NaOH into the fractions after distillation, dissolving and clearing under stirring to separate the system into layers, adding 20g of solid NaOH into the upper product layer, stirring, and separating to obtain 150g of a product, wherein the yield is 82% (according to GC analysis, the molar ratio of each component in the product is cis-2, 6-dimethylmorpholine to trans-2, 6-dimethylmorpholine to cis-2, 5-dimethylmorpholine to trans-2, 5-dimethylmorpholine to 11.0: 3.0: 6.0).
Example 2
Adding 46g of 2, 6-dimethylmorpholine (containing 80% of cis-2, 6-dimethylmorpholine), 160ml of ethyl acetate, heating to 35-40 ℃ under stirring, adding 26g of acetic acid dropwise, cooling to-3-3 ℃, keeping the temperature and stirring for 2.5-3.0h, carrying out suction filtration, drying to obtain 53g of cis-2, 6-dimethylmorpholine acetate (yield 75%), recrystallizing the crystals with ethyl acetate twice to obtain 43g of pure cis-2, 6-dimethylmorpholine acetate, adjusting pH to 14 with liquid alkali, extracting with 50ml of × 2 chloroform twice, drying a chloroform layer with anhydrous potassium carbonate, filtering to remove potassium carbonate, concentrating under reduced pressure to obtain 28g of cis-2, 6-dimethylmorpholine, and carrying out Gas Chromatography (GC) with purity of 99.9% and yield of 60%.
Example 3
46g of 2, 6-dimethylmorpholine (with the cis-2, 6-dimethylmorpholine content being 80%), 165ml of isopropyl acetate are added, the temperature is raised to 40-45 ℃ under stirring, 26g of acetic acid is added dropwise, the mixture is stirred at room temperature for crystallization for 2h, then cooled to-2-3 ℃, kept warm and stirred for 2.5-3.0h, suction filtration is carried out, 55g of cis-2, 6-dimethylmorpholine acetate is obtained after drying (the salt formation yield is 78%), the crystals are recrystallized twice by using isopropyl acetate to obtain 45g of pure cis-2, 6-dimethylmorpholine acetate, the pH value is adjusted to 14 by using 33.3% potassium hydroxide solution, 40ml of × 2 chloroform is used for extraction twice, the chloroform layer is dried by using anhydrous potassium carbonate, the potassium carbonate is removed by filtration, and the mixture is concentrated under reduced pressure to obtain 28g of cis-2, 6-dimethylmorpholine with the GC purity being 100.0% and the GC yield being 60%.
Example 4
46g of 2, 6-dimethylmorpholine (cis-2, 6-dimethylmorpholine content: 80%), 190ml of butyl acetate are added, the temperature is raised to 50-55 ℃ under stirring, 26g of acetic acid is added dropwise, the mixture is stirred at room temperature for crystallization for 2h, then cooled to-2-3 ℃, kept warm and stirred for 2.5-3.0h, suction filtration is carried out, and drying is carried out to obtain 52g of cis-2, 6-dimethylmorpholine acetate (salt formation yield: 74%), the crystals are recrystallized twice by using butyl acetate to obtain 42g of pure cis-2, 6-dimethylmorpholine acetate, the pH value is adjusted to 14 by using 20.0% sodium hydroxide solution, 50ml of × 2 chloroform is used for extraction twice, the chloroform layer is dried by anhydrous magnesium sulfate, magnesium sulfate is removed by filtration, reduced pressure concentration is carried out to obtain 27g of cis-2, 6-dimethylmorpholine, the GC purity is 99.9%, and the yield is 59%.
Example 5
46g of 2, 6-dimethylmorpholine (cis-2, 6-dimethylmorpholine content: 80%), 170ml of ethyl acetate are added, the temperature is raised to 40-45 ℃ under stirring, 33g of propionic acid is added dropwise, the mixture is stirred at room temperature for crystallization for 2h, then cooled to-5-0 ℃, kept warm and stirred for 3.0-3.5h, suction filtration is carried out, drying is carried out to obtain 45g of cis-2, 6-dimethylmorpholine propionate (salt formation yield: 60%), recrystallization is carried out once with ethyl acetate to obtain 39g of pure cis-2, 6-dimethylmorpholine propionate, pH is adjusted to 14 with liquid alkali, 50ml of × 2 chloroform is used for extraction twice, the chloroform layer is dried with anhydrous sodium sulfate, sodium sulfate is removed by filtration, decompression concentration is carried out to obtain 23g of cis-2, 6-dimethylmorpholine, GC purity is 100.0%, and yield is 50%.
Example 6
Adding 46g of 2, 6-dimethylmorpholine (containing 80% of cis-2, 6-dimethylmorpholine) and 170ml of isopropyl acetate into a reaction bottle, heating to 40-45 ℃ under stirring, dropping 33g of propionic acid, stirring at room temperature for crystallization for 2h, cooling to-5-0 ℃, keeping the temperature and stirring for 2.5-3.0h, performing suction filtration, recrystallizing with isopropyl acetate for one time to obtain 39g of pure cis-2, 6-dimethylmorpholine propionate, adjusting the pH to 14 with 20% potassium hydroxide solution, extracting with 50ml of × 2 chloroform twice, drying the chloroform layer with anhydrous potassium carbonate, filtering to remove the potassium carbonate, and concentrating under reduced pressure to obtain 23g of cis-2, 6-dimethylmorpholine with the purity of 100.0% GC and the yield of 51%.
Example 7
46g of 2, 6-dimethylmorpholine (cis-2, 6-dimethylmorpholine content: 80%), 190ml of butyl acetate are added, the temperature is raised to 40-45 ℃ under stirring, 33 propionic acid is added dropwise, the mixture is stirred at room temperature for crystallization for 2h, then cooled to-5-0 ℃, kept warm and stirred for 3.0-3.5h, suction filtration is carried out, butyl acetate is used for recrystallization for one time, 38g of pure cis-2, 6-dimethylmorpholine propionate is obtained, 33.3% potassium hydroxide solution is used for regulating the pH value to 14, 50ml of × 2 chloroform is used for extraction for two times, a chloroform layer is dried by anhydrous potassium carbonate, potassium carbonate is removed by filtration, 23g of cis-2, 6-dimethylmorpholine is obtained by decompression and concentration, the GC purity is 99.9%, and the yield is 50%.
Example 8
Adding 115g of 2, 6-dimethylmorpholine (cis-2, 6-dimethylmorpholine: trans-2, 6-dimethylmorpholine: cis-2, 5-dimethylmorpholine: trans-2, 5-dimethylmorpholine: 92: 6.0: 0.3: 1.7) into a reaction flask, adding 400ml of ethyl acetate, heating to 30-40 ℃ under stirring, dropping 65g of acetic acid, stirring at room temperature for crystallization for 2h, cooling to-2-3 ℃, stirring at constant temperature for 2.5-3.0h, suction filtering, recrystallizing with ethyl acetate to obtain pure cis-2, 6-dimethylmorpholine acetate 142g, adjusting pH to 14 with 33.3% sodium hydroxide solution, extracting twice with 100ml of × 2 chloroform, drying the chloroform layer with anhydrous potassium carbonate, filtering to remove potassium carbonate, and concentrating under reduced pressure to obtain 92g of cis-2, 6-dimethylmorpholine, 100.0% of purity and 80% GC yield.
Example 9
Adding 115g of 2, 6-dimethylmorpholine (cis-2, 6-dimethylmorpholine: trans-2, 6-dimethylmorpholine: cis-2, 5-dimethylmorpholine: trans-2, 5-dimethylmorpholine: 92: 6.0: 0.3: 1.7) into a reaction flask, adding 400ml of isopropyl acetate, heating to 30-40 ℃ under stirring, dropping 65g of acetic acid, stirring at room temperature for crystallization for 2h, cooling to-2-3 ℃, stirring at constant temperature for 2.5-3.0h, suction filtering, recrystallizing with ethyl acetate to obtain pure cis-2, 6-dimethylmorpholine acetate 142g, adjusting pH to 14 with 33.3% sodium hydroxide solution, extracting twice with 100ml of × 2 chloroform, drying the chloroform layer with anhydrous potassium carbonate, filtering to remove potassium carbonate, and concentrating under reduced pressure to obtain 90g of cis-2, 6-dimethylmorpholine, 100.0% of purity and GC yield 78%.
The various starting materials and reagents used in the examples were all commercially available unless otherwise specified.
The purification principle of the present invention is that cis-2, 6-dimethylmorpholine salt is insoluble in the ester solvent of the present invention, and the other three compounds are soluble in the ester solvent (as shown below), thereby achieving the technical effects of the present invention.
Claims (6)
1. A preparation method of high-purity cis-2, 6-dimethylmorpholine is characterized by comprising the following steps:
(1) forming salt with micromolecular fatty acid in ester solvent by cis-2, 6-dimethyl morpholine, trans-2, 6-dimethyl morpholine and a mixture of cis-2, 5-dimethyl morpholine and trans-2, 5-dimethyl morpholine which are rich in cis-2, 6-dimethyl morpholine, and collecting crystals;
(2) recrystallizing the crystal obtained in the step (1) for one to two times by using the same ester solvent;
(3) dissociating the cis-2, 6-dimethyl morpholine carboxylate obtained in the step (2) by using a strong alkaline substance to obtain high-purity cis-2, 6-dimethyl morpholine.
2. The method for preparing high-purity cis-2, 6-dimethylmorpholine according to claim 1, wherein the ester solvent is one or more selected from ethyl acetate, isopropyl acetate and butyl acetate.
3. The process according to claim 1, wherein the salt formation temperature in step (1) is 25-80 ℃, more preferably 30-50 ℃.
4. The method for preparing high-purity cis-2, 6-dimethylmorpholine according to claim 1, wherein the small-molecule fatty acid in step (1) is one or more of acetic acid, propionic acid or butyric acid; more preferably acetic acid.
5. The method for preparing high-purity cis-2, 6-dimethylmorpholine according to claim 1, wherein the molar ratio of cis-2, 6-dimethylmorpholine to small-molecule fatty acid in step (1) is cis-2, 6-dimethylmorpholine: and (1-2) a small-molecular fatty acid.
6. The method for preparing high-purity cis-2, 6-dimethylmorpholine according to claim 1, wherein the strong alkaline substance in step (3) is one or more of sodium hydroxide, potassium hydroxide or the like.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3083202A (en) * | 1960-06-06 | 1963-03-26 | Monsanto Chemicals | Isomerization of 2, 6-dimethylmorpholine |
| US4212972A (en) * | 1978-07-14 | 1980-07-15 | Basf Aktiengesellschaft | Preparation of cis-2,6-dimethylmorpholine |
| CN101270098A (en) * | 2008-05-08 | 2008-09-24 | 上海思协化工科技有限公司 | Method for preparing high-purity cis-2,6-dimethyl morpholine |
| CN110950818A (en) * | 2019-12-18 | 2020-04-03 | 浙江海翔药业股份有限公司 | Method for purifying cis-2, 6-dimethyl morpholine |
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2020
- 2020-04-07 CN CN202010263369.7A patent/CN111499590A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3083202A (en) * | 1960-06-06 | 1963-03-26 | Monsanto Chemicals | Isomerization of 2, 6-dimethylmorpholine |
| US4212972A (en) * | 1978-07-14 | 1980-07-15 | Basf Aktiengesellschaft | Preparation of cis-2,6-dimethylmorpholine |
| CN101270098A (en) * | 2008-05-08 | 2008-09-24 | 上海思协化工科技有限公司 | Method for preparing high-purity cis-2,6-dimethyl morpholine |
| CN110950818A (en) * | 2019-12-18 | 2020-04-03 | 浙江海翔药业股份有限公司 | Method for purifying cis-2, 6-dimethyl morpholine |
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