CN115710221A - Synthesis method of montelukast sodium intermediate - Google Patents
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- CN115710221A CN115710221A CN202211510227.1A CN202211510227A CN115710221A CN 115710221 A CN115710221 A CN 115710221A CN 202211510227 A CN202211510227 A CN 202211510227A CN 115710221 A CN115710221 A CN 115710221A
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Abstract
The invention relates to a synthesis method of a montelukast sodium intermediate, belonging to the technical field of drug synthesis. In order to solve the problem of improving the purity of the product, a method for synthesizing a montelukast sodium intermediate is provided, which comprises the steps of carrying out a condensation reaction on a compound shown in a formula 7 and a compound shown in a formula 6 in an organic solvent to obtain a compound shown in a formula 5, carrying out a reaction on the compound shown in the formula 5 and a compound shown in a formula 4 in the organic solvent under the action of a catalyst and a phase transfer catalyst to obtain a compound shown in a formula 3, carrying out a selective reduction reaction on the compound shown in the formula 3 under the catalysis of a reducing agent to obtain a compound shown in a formula 2, and carrying out a reaction on the compound shown in the formula 2 and a methyl magnesium halide to obtain a final product; the method has the advantages of short reaction route, low production cost, high product generation rate, high product purity and the like.
Description
Technical Field
The invention relates to a method for synthesizing a montelukast sodium intermediate, and belongs to the field of preparation of pharmaceutical intermediates.
Background
Montelukast Sodium (Monte lukast Sodium), chemically known as Sodium 1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinoline) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropaneacetate, is a leukotriene receptor antagonist, inhibits the biosynthesis of leukotriene, and is pharmaceutically useful as an antiasthmatic agent, an antiallergic agent, etc.
The compound of formula 1, 2- [3- (S) - [3- (2- (7-chloro-2-quinolinyl) ethenyl) phenyl ] -3-hydroxypropyl ] phenyl-2-propanol, is an important intermediate for the preparation of montelukast sodium and has the following chemical formula:
in patent CN101638381A, a method for synthesizing montelukast sodium intermediate is disclosed, in which 3-cyanobenzaldehyde and 7-chloroquinaldine are condensed to obtain an intermediate compound, namely 3- (2- (7-chloro-2-quinolyl) vinyl) benzonitrile, and then the intermediate compound is reacted with a compound, namely 2- (2-o- (2-haloethyl) phenylpropyl) tetrahydropyrane ether to generate a final product, namely 2- (2- (3- (2- (7-chloro-2-quinolyl) vinyl) phenyl) -3-oxopropyl) phenyl) propanol, the reaction route has many steps and a long production flow path, and the synthesis route is as follows:
in patent WO2008035086, a synthetic method for preparing montelukast sodium intermediate from (S) -1- (3-bromophenyl) -3- [2- (1-hydroxy-1-methylethyl) -phenyl ] methyl formate is disclosed, which has low conversion rate and low overall yield and purity when converting ester group into tertiary alcohol group, resulting in high production cost and being not beneficial to industrial production, and the preparation route is as follows:
the above documents show that they have the disadvantages of multiple reaction steps, long production flow, and low yield and purity of the product. The production cost is high.
Therefore, a synthesis method with short reaction route, high product yield and high product purity is urgently needed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthesis method of a montelukast sodium intermediate, and solves the problem of how to realize a preparation method for improving the purity of a product.
The invention aims to realize the following technical scheme, and the method for synthesizing the montelukast sodium intermediate comprises the following steps:
s1: carrying out a condensation reaction of a compound of formula 7 and a compound of formula 6 in an organic solvent to produce a compound of formula 5;
s2: reacting a compound shown in formula 5 with a compound shown in formula 4 in an organic solvent under the action of a catalyst and a phase transfer catalyst to generate a compound shown in formula 3;
s3: the compound shown in the formula 3 is subjected to a selective reduction reaction under the catalysis of a reducing agent to generate a compound shown in the formula 2;
s4: the compound of formula 2 is reacted with a catalyst to form the final product.
The synthetic route of the compound of the formula 5 is as follows:
the synthetic route of the compound of the formula 1 is as follows:
wherein the halogen X is chlorine.
The intermediate compound shown in the formula 5 is obtained by condensing 7-chloroquinaldine and 3-iodobenzaldehyde at high temperature, all reaction raw materials can be directly obtained from the outside, independent preparation is not needed, the time and the cost for synthesizing the raw materials are saved, the compound shown in the formula 5 and the compound shown in the formula 4, namely the 2- (3-oxopropyl) methyl benzoate are reacted to generate the compound shown in the formula 3, the compound shown in the formula 3 is selectively reduced by using a reducing agent, the obtained compound shown in the formula 2 and methyl magnesium halide are reacted to generate a final product, the whole reaction route is short, a large amount of artificial preparation intermediate products and various raw materials are not needed to be consumed, the production flow is shortened, the yield is high, the product purity is high, meanwhile, part of byproducts can be recycled to prepare the reaction raw materials for reuse after the reaction, and the production cost is reduced.
In the above method for synthesizing montelukast sodium intermediate, the organic solvent in the step S1 is preferably one of acetic anhydride, trifluoroacetic anhydride or acetic anhydride. Most preferably, acetic anhydride has the greatest solubility as the reaction solvent.
In the above method for synthesizing the montelukast sodium intermediate, preferably, the organic solvent used in the step S2 is one of tetrahydrofuran, toluene, and dioxane. Most preferably, the addition of tetrahydrofuran is the fastest reaction.
In the synthesis method of the montelukast sodium intermediate, the catalyst in the step S2 can be preferably one of palladium acetate, palladium trifluoroacetate and palladium carbon. Most preferably, palladium acetate is used as the catalyst, which reduces the production of by-products and production costs.
In the above method for synthesizing the montelukast sodium intermediate, the phase transfer catalyst in the step S2 may be preferably one of benzyltriethylammonium bromide, tetrabutylammonium bromide and tetrapropylammonium bromide. Most preferably, benzyltriethylammonium bromide is used in higher product purity.
In the above method for synthesizing the montelukast sodium intermediate, the reaction in the step S2 preferably takes place in an alkaline environment, and triethylamine, piperidine or pyrrolidine may be used. Most preferably, triethylamine is selected, so that few by-products are generated, and the purity of the product is high.
In the synthesis method of the montelukast sodium intermediate, preferably, the reducing agent in the step S3 is (-) -diisopinocampheylchloroborane.
In the above method for synthesizing the montelukast sodium intermediate, the catalyst in the S4 step is preferably an organic titanium reagent. Most preferably, the organic titanium reagent is prepared using anhydrous titanium tetrachloride.
In the above method for synthesizing the montelukast sodium intermediate, the reaction solvent in the S4 step is preferably toluene or xylene. Most preferably, toluene is selected for greater product yield.
In the synthesis method of the montelukast sodium intermediate, preferably, the iodine in the solution can be recovered after the step S3 to prepare the compound of formula 6, so that the production cost can be reduced, and the post-treatment difficulty can be reduced.
In summary, compared with the prior art, the invention has the following advantages:
1. production raw materials can be purchased from the outside, manpower and material resources are not consumed for independent preparation, and meanwhile, part of raw materials can be recycled after the reaction is finished, so that the production cost can be reduced, and the post-treatment difficulty can be reduced;
2. the reaction route of the invention has higher conversion rate, so the product generation rate is higher, and most of the reaction is a directional reaction under the action of a catalyst, so the byproducts are less, and the product purity is higher;
3. in the invention, a large amount of highly toxic compounds such as acetonitrile and the like are not used, and the reaction conditions are strictly controlled, so that substances harmful to workers are reduced in the reaction process, and the safety is higher.
Drawings
FIG. 1 is a general synthetic route according to the present invention;
FIG. 2 shows the structural formula of the compound of formula 1 according to the present invention.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
Preparation of the compound of formula 5:
44.4g of the compound of formula 7 (0.25 mol) and 37.53g of the compound of formula 6 (0.25 mol) were dissolved in 300mL of acetic anhydride, heated to 70 ℃, stirred for reaction for 24h, concentrated under reduced pressure, extracted 3 times with 500mL of ethyl acetate, filtered, and the filter cake was washed with 200mL of a saturated saline solution and 200mL of ethyl acetate in this order, and dried by adding 20g of anhydrous sodium sulfate to obtain 67.29g of the compound of formula 5 with a yield of 86.9% and a purity of 98.1%.
Example 2
Preparation of the compound of formula 3:
37.27g of the compound of formula 5 (0.1 mol), 29.9g of the compound of formula 4 (0.18 mol), 38.11g of benzyltriethylammonium bromide (0.14 mol), 12g of anhydrous magnesium sulfate (0.1 mol) were dissolved in tetrahydrofuran (300 mL), and to the resulting solution were added 4.5g of palladium acetate (0.02 mol) and 13.15g of triethylamine (0.13 mol) under nitrogen protection, the solution was heated to 50 ℃, stirred for reaction for 4 hours, 50mL of water was added, 200mL of ethyl acetate was extracted 3 times, 200mL of saturated sodium chloride was washed, concentrated, purified by column chromatography (petroleum ether: ethyl acetate = 10), and concentrated to give 40.8g of the compound of formula 3 with a yield of 89.5% and a purity of 95.3%.
Example 3
Preparation of the compound of formula 2:
dissolving 45.59g of a compound (0.1 mol) of a formula 3 in 500mL of dichloromethane in a reaction bottle, adding 32mLN and N-diisopropylethylamine, cooling to-15 ℃, stirring for reaction for 30min, slowly dropwise adding 148mL of (-) -diisopinocampheylchloroborane n-heptane solution, preserving heat for reaction for 8h, heating to 25 ℃ after the reaction is finished, adding 25mL of triethylamine, stirring for 2h, adding 500mL of saturated sodium chloride solution, standing for layering, extracting for 3 times by 300mL of dichloromethane, combining organic phases, washing by 200mL of saturated saline, evaporating a solvent, adding 250mL of toluene, dissolving at 55 ℃, cooling to room temperature, stirring for 12h, filtering, washing a filter cake by 50mL of n-heptane for 2 times, drying at 50 ℃ under reduced pressure to obtain 40.85g of a compound (2) of a formula 2, wherein the purity is 89.2%, and the purity is 98.8%.
Example 4
Preparation of the compound of formula 1:
under the protection of nitrogen, 18.96g of anhydrous titanium tetrachloride (0.1 mol) and 50mL of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to 0 ℃,30 mL of 3M methyl magnesium chloride tetrahydrofuran solution is dripped, the temperature is controlled to 15 ℃, and the reaction is carried out for 20min, so as to obtain the organic titanium reagent.
In another reaction flask, 45.8g of the compound of formula 2 (0.1 mol) and 200mL of toluene were added and stirred until it was clear. And (3) dropwise adding an organic titanium reagent into the solution, and reacting for 5 hours at the temperature of 0-10 ℃ after dropwise adding. 200mL of aqueous ammonia acetate solution was added to the reaction mixture, and the mixture was allowed to stand for layering, and the organic phase was washed successively with 200mL of 10% sodium carbonate solution, 200mL of 5% sodium sulfite aqueous solution and 200mL of saturated brine. Adding 90mL of ethanol, stirring, crystallizing for 2h, filtering, and drying to obtain 43.65 of the compound shown as the formula 1, wherein the yield is 95.1%, and the purity is 99.3%.
Example 5
The recovery of iodine and the preparation of 3-iodobenzaldehyde are as follows:
adding 20.1g of triethylamine hydroiodide into a reaction bottle, adding 100mL of water for dissolving, filtering, adding a potassium hydroxide solution into the filtrate for adjusting the pH value to 10, extracting triethylamine and other organic impurities by using dichloromethane, separating out a water phase, concentrating, adding 100mL of ethanol, cooling and crystallizing to generate 9g of potassium iodide. Titrimetric analysis, total recovery 89%.
Adding 7.66g of m-aminobenzaldehyde, 25mL of concentrated hydrochloric acid and 100mL of water into a three-neck flask, cooling in an ice bath, stirring, dropwise adding 3.9g of sodium nitrite solution at the temperature of not higher than 5 ℃, and continuously stirring for reacting for 2 hours to obtain the diazonium salt solution after the dropwise adding is finished. Slowly adding 9.28g of potassium iodide into the diazonium salt solution, continuously reacting for 30min, performing suction filtration, washing with water, and drying to obtain 10.0g of 3-iodobenzaldehyde with the total yield of 76%.
Example 6
44.4g of 7-chloroquinaldine of the formula 8 and 37.53g of 3-carboxybenzaldehyde of the compound of the formula 7 are dissolved in 500mL of trifluoroacetic anhydride, the mixture is heated to 50-140 ℃, stirred and reacted for 24 hours, the acetic anhydride solvent is evaporated under reduced pressure, 500mL of ethyl acetate is extracted for 3 times, the filtration is carried out, 200mL of saturated saline solution and mL of ethyl acetate are used for washing a filter cake, 20g of anhydrous sodium sulfate is added for drying, and the vacuum concentration is carried out, so that 64.03g of the compound of the formula 6 is obtained, the yield is 82.7%, and the purity is 96.6%.
Example 7
44.4g of 7-chloroquinaldine of formula 8 and 37.53g of 3-carboxybenzaldehyde of formula 7 are dissolved in 500mL of acetic anhydride, heated to 50-140 ℃, stirred for reaction for 24h, the acetic anhydride solvent is evaporated under reduced pressure, 500mL of ethyl acetate is extracted for 3 times, filtered, the filter cake is washed with 200mL of saturated saline solution and mL of ethyl acetate, 20g of anhydrous sodium sulfate is added for drying, and vacuum concentration is carried out to obtain 65.5g of the compound of formula 6 with yield of 84.6% and purity of 97.2%.
Example 8
37.27g of the compound of formula 5, 29.9g of the compound of formula 4, 38.11g of tetrabutylammonium bromide and 12g of anhydrous magnesium sulfate were dissolved in 300mL of toluene, 6.45g of palladium trifluoroacetate and 11.07g of piperidine were added to the resulting solution under nitrogen protection, the solution was heated to 50 ℃ and stirred for reaction for 4 hours, 50mL of water was added, 200mL of ethyl acetate was extracted 3 times, 200mL of saturated sodium chloride was washed, concentrated, column chromatography purification (petroleum ether: ethyl acetate =10
Example 9
37.27g of the compound of formula 5, 29.9g of the compound of formula 4, 37.28g of tetrapropylammonium bromide and 12g of anhydrous magnesium sulfate were dissolved in 300mL of dioxane, 2.13g of palladium on carbon and 9.25g of pyrrolidine were added to the resulting solution under a nitrogen atmosphere, the solution was heated to 50 ℃, stirred and reacted for 4 hours, 50mL of water was added, 200mL of ethyl acetate was extracted 3 times, 200mL of saturated sodium chloride was washed, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 10)
Example 10
Under the protection of nitrogen, 18.96g of anhydrous titanium tetrachloride and 50mL of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to 0 ℃,30 mL of 3M methyl magnesium chloride tetrahydrofuran solution is added dropwise, the temperature is controlled at 15 ℃ and the reaction is carried out for 20min, so as to obtain the organic titanium reagent.
In another reaction flask, 45.8g of the compound of formula 2 and 200mL of xylene were added and stirred until it was clear. And (3) dropwise adding an organic titanium reagent into the solution, and reacting for 5 hours at 0-10 ℃ after dropwise adding. 200mL of aqueous ammonia acetate solution was added to the reaction mixture, and the mixture was allowed to stand for separation, and the organic phase was washed successively with 200mL of 10% sodium carbonate solution, 200mL of 5% sodium sulfite aqueous solution and 200mL of saturated brine. Adding 90mL of ethanol, stirring, crystallizing for 2h, filtering, and drying to obtain 42.36 of the compound shown as the formula 1, wherein the yield is 92.3%, and the purity is 98.1%.
Comparative example
This example is an example of the published patent CN102442948B
A process for the preparation of the compound 2- (2- (3 (S) -chloro-3- (3- (2- (7-chloro-2-quinolinyl) - (E) vinyl) phenyl) propyl) phenyl) -2-propanol of formula III:
2- (2- (3 (R) -hydroxy-3- (3- (2- (7-chloro-2-quinolyl) - (E) vinyl) phenyl) propyl) phenyl) -2-propanol (25.1g, 55mmol), DMF (400 mL) and diisopropylethylamine (17.74g, 137.5 mmol) were added to a reaction flask in this order at room temperature (25-30 ℃) under argon atmosphere and stirred until completely dissolved. The temperature of the system was reduced to-10 ℃ in a cold salt bath, methanesulfonyl chloride (15.6 g,137.5 mmol) was added dropwise over 30 minutes, and then the reaction was carried out at that temperature for 10 hours. (TLC or HPLC monitoring of the starting material reaction completed); lithium chloride (11.7 g, 275mmol) was added in one portion, the ice bath was removed, the temperature was naturally returned to room temperature, and the reaction was continued for 14 hours. The TLC tracks the completion of the reaction. Ice water 300mL of ethyl acetate (60 mL. Times.3) was added and the organic phases were combined. The organic phase was washed successively with saturated brine and water. Dried over anhydrous sodium sulfate. Concentrating the organic phase to 1/5 of the original volume, adding 500mL petroleum ether, stirring for half an hour, standing overnight, filtering, and drying to obtain 16.1g of a white solid of the compound of formula III with a yield of 61.5%
Compared with the preparation method in the invention, the yield in the embodiment is lower, so that the production cost is higher, and the large-scale production is not facilitated.
The embodiments of the invention are not limited to the above-described examples, and various changes and modifications in form and detail may be made by one skilled in the art without departing from the spirit and scope of the invention, which is considered to fall within the scope of the invention.
Claims (10)
1. A synthetic method of a montelukast sodium intermediate is characterized in that the preparation method comprises the following steps:
s1: carrying out a condensation reaction of the compound of formula 7 and the compound of formula 6 in an organic solvent to produce a compound of formula 5;
s2: in an organic solvent, the compound of the formula 5 and the compound of the formula 4 react under the action of a catalyst and a phase transfer catalyst to generate the compound of the formula 3
S3: the compound shown in the formula 3 is subjected to a selective reduction reaction under the catalysis of a reducing agent to generate a compound shown in the formula 2;
s4: the compound of formula 2 is reacted with a methyl magnesium halide to produce the final product.
2. The method for synthesizing the montelukast sodium intermediate according to claim 1, wherein: and in the step S1, the organic solvent is one of acetic anhydride, trifluoroacetic anhydride or acetic anhydride.
3. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: in the step S2, one of tetrahydrofuran, toluene or dioxane is used as an organic solvent.
4. The method for synthesizing the montelukast sodium intermediate according to claim 1, wherein: the catalyst in the step S2 can be one of palladium acetate, palladium trifluoroacetate or palladium carbon.
5. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: the phase transfer catalyst in the step S2 can be one of benzyltriethylammonium bromide, tetrabutylammonium bromide and tetrapropylammonium bromide.
6. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: the reaction in the step S2 is carried out in an alkaline environment, and triethylamine, piperidine or pyrrolidine can be selected.
7. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: in the step S3, the reducing agent is (-) -diisopinocampheylchloroborane.
8. The method for synthesizing the montelukast sodium intermediate according to claim 1, wherein: and the catalyst in the step S4 is an organic titanium reagent.
9. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: and the reaction solvent in the step S4 is toluene or xylene.
10. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: after the step S3 is finished, the iodine in the solution can be recovered to prepare the compound shown in the formula 6.
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| CN116375639A (en) * | 2023-04-19 | 2023-07-04 | 南京欧信医药技术有限公司 | Method for preparing montelukast sodium intermediate by micro-channel method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116375639A (en) * | 2023-04-19 | 2023-07-04 | 南京欧信医药技术有限公司 | Method for preparing montelukast sodium intermediate by micro-channel method |
| CN116375639B (en) * | 2023-04-19 | 2024-05-28 | 南京欧信医药技术有限公司 | Method for preparing montelukast sodium intermediate by micro-channel method |
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