CN111302996A - Preparation method of high-chiral-purity chloromalastine fumarate - Google Patents
Preparation method of high-chiral-purity chloromalastine fumarate Download PDFInfo
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- CN111302996A CN111302996A CN202010194711.2A CN202010194711A CN111302996A CN 111302996 A CN111302996 A CN 111302996A CN 202010194711 A CN202010194711 A CN 202010194711A CN 111302996 A CN111302996 A CN 111302996A
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of high-chiral-purity chloromalastine fumarate, which comprises the following five steps: step 1: resolving the compound N-methyl-2- (2-hydroxyethyl) pyrrolidine in the formula 2 by using D-arginine as a resolving agent to obtain a compound in a formula 3; step 2: reacting the compound shown in the formula 3 with thionyl chloride for chlorination to obtain a compound shown in a formula 4; and step 3: reacting the compound shown in the formula 4 with 1- ((4-chlorphenyl) -1-phenyl) ethanol shown in the formula 5 under the condition that sodium amide is strong alkali to obtain a compound shown in the formula 6; and 4, step 4: the compound shown in the formula 6 is resolved by tartaric acid to remove chiral isomer impurities, and a compound shown in a formula 7 is obtained; and 5: salifying the compound of formula 7 with fumaric acid to obtain the compound of formula 1, clemastine fumarate. The chloromalastine fumarate bulk drug prepared by the invention has high chiral purity, the product quality meets the requirements of injection drugs specified in pharmacopoeia, the process is simple and easy to control, the operability is strong, and the industrial production can be realized.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of high-chiral-purity chloromalestine fumarate.
Background
The clemastine fumarate is a second-generation novel H1 receptor antagonist, and has the advantages of quick response, strong antihistamine effect, long effect duration and good antihistamine effect. For the release of histamine induced by allergen, clemastine fumarate not only antagonizes histamine at the H1 receptor level, but also exerts the function of inhibiting the release of histamine to mast cells, and can exert a good antihistaminic effect. The antihistaminic composition is mainly used for clinically treating urticaria, eczema and allergic skin diseases caused by histamine, and is one of the best antihistaminic medicaments recognized in the world at present. Clemastine fumarate, the chinese chemical name (R- (R, R)) -1-methyl-2- (2- (1- (4-chlorophenyl) -1-phenylethoxy) ethyl) -pyrrolidine (E) -2-butenedioate.
Because two chiral centers exist in the molecular structure of the clemastine fumarate, the chiral purity of the clemastine fumarate becomes an important quality index, and the difficulty of synthesis, resolution and purification of the clemastine fumarate is increased. In the synthetic process routes reported in the past, most of the process methods (for example, patent CN 201710374858) adopt racemic N-methyl-2- (2-hydroxyethyl) pyrrolidine and racemic 1- ((4-chlorophenyl) -1-phenyl) ethanol to react to obtain clemastine containing three chiral isomers, and the clemastine fumarate is obtained by resolving tartaric acid to remove the three chiral isomers and then salifying with fumaric acid. In another patent, namely the original research route CN201710374858, the resolved N-methyl-2- (2-hydroxyethyl) pyrrolidine and the resolved 1- ((4-chlorophenyl) -1-phenyl) ethanol are reacted to obtain chloromastidine fumarate with a single configuration, but the method uses expensive catalyst and chiral auxiliary agent, and the production cost is high. In addition, in patent CN201710374858, racemic N-methyl-2- (2-hydroxyethyl) pyrrolidine reacts with resolved 1- ((4-chlorophenyl) -1-phenyl) ethanol, and after tartaric acid resolution, clemastine fumarate with a single configuration is obtained, and the method uses expensive catalyst and chiral auxiliary agent, involves tartaric acid resolution, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of high-chiral-purity chloromalestine fumarate, the prepared chloromalestine fumarate bulk drug has high chiral purity, the product quality meets the requirements of injection drugs specified in pharmacopoeia, the process is simple and easy to control, the operability is strong, and industrial production can be realized, so that the problems in the background art are solved.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of high-chiral-purity clemastine fumarate comprises the following five steps:
step 1: resolving the compound N-methyl-2- (2-hydroxyethyl) pyrrolidine in the formula 2 by using D-arginine as a resolving agent to obtain a compound in a formula 3;
step 2: reacting the compound shown in the formula 3 with thionyl chloride for chlorination to obtain a compound shown in a formula 4;
and step 3: reacting the compound shown in the formula 4 with 1- ((4-chlorphenyl) -1-phenyl) ethanol shown in the formula 5 under the condition that sodium amide is strong alkali to obtain a compound shown in the formula 6;
and 4, step 4: the compound shown in the formula 6 is resolved by tartaric acid to remove chiral isomer impurities, and a compound shown in a formula 7 is obtained;
and 5: salifying the compound of formula 7 with fumaric acid to obtain the compound of formula 1, clemastine fumarate.
Further, the resolving agent adopted in the step 1 is D-arginine, and the resolving agent adopted in the step 1 is D-arginine.
Further, the chlorination reagent adopted in the step 2 is thionyl chloride, the chlorination reaction solvent adopted is dichloromethane, and the post-treatment mode adopted after the reaction is reduced pressure concentration.
Further, the strong base used in step 3 is sodium amide, and the reaction solvent used is toluene, wherein the equivalent ratio of sodium amide to the compound of formula 3 is 2: 1-5: 1, optimally, the equivalent ratio of sodium amide to compound of formula 3 is 3: 1.
further, after the reaction in the step 3 is finished, salt is formed with succinic acid, the salt forming solvent is absolute ethyl alcohol, the temperature of the salt forming reaction is 65 +/-5 ℃, after the salt formation with succinic acid in the step 3 is finished, the compound of the formula 6 is obtained by adopting a cooling crystallization method, and the cooling crystallization temperature range is-5 +/-5 ℃.
Further, in the step 4, a NaOH aqueous solution is used as an alkali reagent to dissociate the clemastine succinate to obtain free clemastine, the dissociative agent is tartaric acid, and the pH control range of the dissociated solution is 12-14.
Further, after the free clemastine is extracted by using petroleum ether as an extraction solvent after the free clemastine is obtained in the step 4, the post-treatment mode adopts reduced pressure concentration, acetone and water are used as a resolution solvent after the reduced pressure concentration in the step 4 is finished, and the volume ratio of the acetone to the water is 20: 1.
further, in the step 5, NaOH aqueous solution is used as an alkali reagent to dissociate the chloromastemistine tartrate to obtain free chloromastemistine, the free chloromastemistine is salified with fumaric acid, and the pH control range of the dissociated solution is 12-14.
Further, after the free clemastine is obtained in the step 5, petroleum ether is used as an extraction solvent to extract the free clemastine, and a post-treatment mode adopts reduced pressure concentration.
Further, methanol is adopted as a salt forming solvent after the vacuum concentration in the step 5 is finished.
Compared with the prior art, the invention has the beneficial effects that: the invention provides a preparation method of high chiral purity chloromalastine fumarate, which comprises the steps of splitting N-methyl-2- (2-hydroxyethyl) pyrrolidine by using D-arginine as a splitting agent for the first time, reacting sodium amide serving as strong base with racemic 1- ((4-chlorphenyl) -1-phenyl) ethanol after chlorination to obtain chloromalastine succinate and epimers thereof, splitting by using chloromalastine tartrate for the first time, and finally converting into a salt form to obtain the chloromalastine fumarate. The chloromalastine fumarate bulk drug prepared by the process method has high chiral purity, the product quality meets the requirements of injection drugs specified in pharmacopoeia, the process is simple and easy to control, the operability is strong, and the industrial production can be realized.
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FIG. 1 is a flow chart of the preparation process of 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 drawings in 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.
A method for preparing high chiral purity clemastine fumarate is shown in figure 1, and comprises the following five steps:
step 1: resolving N-methyl-2- (2-hydroxyethyl) pyrrolidine of a compound shown in a formula 2 by using D-arginine as a resolving agent to obtain a compound shown in a formula 3, wherein the resolving agent is D-arginine, and the resolving agent is D-arginine;
step 2: reacting the compound shown in the formula 3 with thionyl chloride for chlorination to obtain a compound shown in a formula 4, wherein the adopted chlorination reagent is thionyl chloride, the adopted chlorination reaction solvent is dichloromethane, and the post-treatment mode adopted after the reaction is reduced pressure concentration;
and step 3: reacting the compound of formula 4 with 1- ((4-chlorophenyl) -1-phenyl) ethanol, a compound of formula 5, under the condition that sodium amide is a strong base to obtain a compound of formula 6, wherein the strong base is sodium amide, and the reaction solvent is toluene, wherein the equivalent ratio of the sodium amide to the compound of formula 3 is 2: 1-5: 1, optimally, the equivalent ratio of sodium amide to compound of formula 3 is 3: 1, salifying with succinic acid after the reaction is finished, wherein a salifying reaction solvent is absolute ethyl alcohol, the salifying reaction temperature is 65 +/-5 ℃, and the compound shown in the formula 6 is obtained by adopting a cooling crystallization method after salifying with succinic acid in the step 3, wherein the cooling crystallization temperature range is-5 +/-5 ℃;
and 4, step 4: the compound of formula 6 is subjected to tartaric acid resolution to remove chiral isomer impurities, a compound of formula 7 is obtained at the same time, NaOH aqueous solution is used as an alkali reagent to dissociate chloromastemitin succinate to obtain free chloromastemitin, the resolving agent is tartaric acid, the pH control range of the dissociated solution is 12-14, after the free chloromastemitin is obtained, petroleum ether is used as an extraction solvent to extract the free chloromastemitin, the post-treatment mode is reduced pressure concentration, acetone and water are used as the resolving solvent after the reduced pressure concentration in the step 4 is finished, and the volume ratio of the acetone to the water is 20: 1;
and 5: salifying the compound of the formula 7 and fumaric acid to obtain a compound of a formula 1, dissociating the chloromalastine tartrate to obtain free chloromalastine by using NaOH aqueous solution as an alkali reagent, salifying the dissociated chloromalastine and the fumaric acid, controlling the pH value of the dissociated solution within the range of 12-14, extracting the free chloromalastine by using petroleum ether as an extraction solvent after the free chloromalastine is obtained, performing reduced pressure concentration in a post-processing mode, and using methanol as a salifying solvent after the reduced pressure concentration is finished.
The following examples show the preparation of the compounds of formula 1, 3, 4, 5, 6 by way of 5 examples.
Example 1
Preparation of the Compound of formula 3
Dissolving 2.4kg of N-methyl-2- (2-hydroxyethyl) pyrrolidine in 1.6kg of methanol to obtain a feed liquid A, sequentially adding 7.9kg of methanol, 6.2kg of D-arginine and 335g of purified water into a 30L reaction kettle, stirring and heating to 60 +/-5 ℃, dripping the feed liquid A into the reaction system, adding after 0.5-1 hour, keeping 60 +/-5 ℃ and stirring for 0.5 hour after finishing dripping, cooling to 40 +/-5 ℃, stirring and crystallizing for 0.5 hour, cooling to 25 +/-5 ℃, stirring and crystallizing for 0.5 hour, finally cooling to 5 +/-5 ℃, stirring for 2 hours, centrifuging to obtain white crystal powder, blowing and drying at 50 ℃ for 4 hours to obtain white crystal powder, adding the obtained white solid powder into 39.9kg of dichloromethane, regulating the pH to 13-14 with 20% of sodium hydroxide under the stirring at 0 +/-5 ℃, keeping the temperature and stirring for 1 hour, filtering, leaching with 4kg of dichloromethane, standing the filtrate for 20 minutes, separating, adding the water phase and 4kg of dichloromethane into a 30L reaction kettle, stirring for 10 minutes, standing for 20 minutes, separating, combining organic phases, and concentrating the filtrate at 40 ℃ under reduced pressure until no condensate is formed, thus obtaining a light yellow oily substance, namely the compound of the formula 3.
Example 2
Preparation of the Compound of formula 4
Adding 670g of the compound shown in the formula 3 and 2.6L of dichloromethane into a 30L reaction kettle, cooling to 0 +/-5 ℃ under stirring, dropwise adding a solution of thionyl chloride and 800ml of dichloromethane, keeping the temperature of the system at 5 +/-5 ℃, heating to 25 +/-5 ℃ after dropwise adding, stirring for 2 hours, monitoring the reaction by TLC (methanol: dichloromethane =1:3, iodine is shown), sampling at intervals of 1 hour, monitoring the reaction by TLC until the reaction is complete, concentrating the reaction solution at 40 +/-5 ℃ under reduced pressure until no condensate exists, adding 1.5L of ethyl acetate, and continuing to concentrate until no condensate exists, thus obtaining the compound shown in the formula 4.
Example 3
Preparation of Compounds of formula 5
1L of toluene was added to the compound of formula 4 obtained in example 2 above, and concentration was continued until no condensate was formed. Toluene 3L, 1- (4-chlorophenyl) -1-phenyl) ethanol and sodium amide were added to a 30L reactor, stirred, heated to 40 ± 5 ℃ for 1 hour, heated to 60 ± 5 ℃, the resulting pale yellow solid and toluene 2L turbid suspension were added in 5 portions, heated to 80 ± 5 ℃, stirred for 4 hours with constant temperature, monitored by TLC (dichloromethane: methanol =5: 1), sampling TLC every 1 hour to monitor the reaction until the reaction is complete, cooling to 25 +/-5 ℃, filtering, concentrating the filtrate at 60 +/-5 ℃ under reduced pressure until no condensate exists, adding 1L of absolute ethanol, continuing to concentrate until no condensate exists, adding 5L of absolute ethanol, heating to 65 +/-5 ℃, adding succinic acid, keeping the temperature at 65 +/-5 ℃, stirring for 30 minutes, cooling to 20 +/-5 ℃, stirring for 2 hours, cooling to-5 +/-5 ℃ after solid is separated out, stirring for 2 hours, centrifuging, and drying by air blowing at 45 +/-5 ℃ for 8 hours to obtain a white solid, namely the compound of formula 5.
Example 4
Preparation of the Compound of formula 6
Preparing a sodium hydroxide solution: purified water 1870ml and sodium hydroxide 468g are added into the material barrel, stirred and dissolved for standby.
4L of purified water and the compound of formula 5, namely the clemastine succinate are added into a 100L reaction kettle, and the prepared sodium hydroxide solution is dripped to adjust the pH value to 12-13. Adding 13L of petroleum ether for extraction, adding 1kg of anhydrous sodium sulfate into the organic phase, drying for 1 hour, filtering, concentrating the filtrate at 45 +/-5 ℃ under reduced pressure until no condensate exists, stopping concentration, adding 7.3L of acetone water (20: 1), heating to 50 +/-5 ℃, adding L-tartaric acid, stirring for 30 minutes, cooling to 25 +/-5 ℃, keeping the temperature at 25 +/-5 ℃, stirring for 2 hours, centrifuging to obtain a white solid, adding 8.8L of acetone water (20: 1) into a 100L reaction kettle, heating to reflux, stirring for 30 minutes, cooling to 25 +/-5 ℃, stirring for 2 hours, centrifuging, and drying for 4 hours by blowing at 50 +/-5 ℃ to obtain the white solid, namely the compound shown in the formula 6.
Example 5
Preparation of the Compound of formula 1
Preparing a sodium hydroxide solution: 432ml of purified water and 108g of sodium hydroxide are added into a material barrel, stirred and dissolved for standby.
Adding 1.6L of the compound of formula 6, namely chloromalastine tartrate and purified water into a 100L reaction kettle, and slowly dropwise adding a prepared sodium hydroxide solution to adjust the pH value to 12-13. Adding petroleum ether, stirring for 20 min, standing for 20 min, separating, adding anhydrous sodium sulfate into organic phase, and drying for 1 hr. Filtering, and concentrating the filtrate at 45 + -5 deg.C under reduced pressure until no condensate is obtained. Adding methanol, heating to 60 + -5 deg.C, adding fumaric acid, stirring at 60 + -5 deg.C for 30 min, cooling to 0 + -5 deg.C, and stirring for 2 hr. Centrifuging, and drying by blowing air at 40 +/-5 ℃ to obtain a white solid, namely the compound of the formula 1, namely the chloromalestine fumarate.
In summary, the preparation method of high chiral purity chloromalastine fumarate of the present invention firstly proposes that D-arginine is used as a resolving agent to resolve N-methyl-2- (2-hydroxyethyl) pyrrolidine, then sodium amide is used as a strong base to react with racemic 1- ((4-chlorophenyl) -1-phenyl) ethanol after chlorination to obtain chloromalastine succinate and its epimer, and then chloromalastine tartrate is used to perform primary resolution, and finally the chloromalastine fumarate is obtained through salt conversion. The chloromalastine fumarate bulk drug prepared by the process method has high chiral purity, the product quality meets the requirements of injection drugs specified in pharmacopoeia, the process is simple and easy to control, the operability is strong, and the industrial production can be realized.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. A preparation method of high-chiral-purity chloromalastine fumarate is characterized by comprising the following five steps:
step 1: resolving the compound N-methyl-2- (2-hydroxyethyl) pyrrolidine in the formula 2 by using D-arginine as a resolving agent to obtain a compound in a formula 3;
step 2: reacting the compound shown in the formula 3 with thionyl chloride for chlorination to obtain a compound shown in a formula 4;
and step 3: reacting the compound shown in the formula 4 with 1- ((4-chlorphenyl) -1-phenyl) ethanol shown in the formula 5 under the condition that sodium amide is strong alkali to obtain a compound shown in the formula 6;
and 4, step 4: the compound shown in the formula 6 is resolved by tartaric acid to remove chiral isomer impurities, and a compound shown in a formula 7 is obtained;
and 5: salifying the compound of formula 7 with fumaric acid to obtain the compound of formula 1, clemastine fumarate.
2. The method for preparing high chiral purity clemastine fumarate according to claim 1, wherein the resolving agent used in step 1 is D-arginine, and the resolving agent used in step 1 is D-arginine.
3. The method for preparing chloromastemitine fumarate with high chiral purity as claimed in claim 1, wherein the chlorinating agent used in step 2 is thionyl chloride, the chlorinating solvent used is dichloromethane, and the post-treatment after the reaction is vacuum concentration.
4. The method for preparing clemastine fumarate with high chiral purity according to claim 1, wherein the strong base used in the step 3 is sodium amide, the reaction solvent used is toluene, and the equivalent ratio of the sodium amide to the compound of the formula 3 is 2: 1-5: 1, optimally, the equivalent ratio of sodium amide to compound of formula 3 is 3: 1.
5. the method for preparing high chiral purity clemastine fumarate according to claim 1, wherein the reaction in step 3 is completed and then salt formation is carried out with succinic acid, the salt formation reaction solvent is absolute ethyl alcohol, the salt formation reaction temperature is 65 +/-5 ℃, the compound of formula 6 is obtained by adopting a cooling crystallization method after the salt formation with succinic acid in step 3 is completed, and the cooling crystallization temperature range is-5 +/-5 ℃.
6. The method for preparing high chiral purity clemastine fumarate according to claim 1, wherein in step 4, clemastine succinate is dissociated by using NaOH aqueous solution as an alkali reagent to obtain free clemastine, and then the dissociated clemastine is resolved, wherein the resolving agent is tartaric acid, and the pH control range of the dissociated solution is 12-14.
7. The method for preparing high chiral purity clemastine fumarate according to claim 1, wherein after the free clemastine is obtained in step 4, petroleum ether is used as an extraction solvent to extract the free clemastine, a post-treatment mode is vacuum concentration, acetone and water are used as resolution solvents after the vacuum concentration in step 4 is finished, and the volume ratio of the acetone to the water is 20: 1.
8. the method for preparing high chiral purity clemastine fumarate according to claim 1, wherein in step 5, clemastine tartrate is dissociated by using NaOH aqueous solution as an alkali reagent to obtain free clemastine tartrate, and the dissociated clemastine tartrate is salified with fumaric acid, wherein the pH control range of the solution after the dissociation is 12-14.
9. The method for preparing high chiral purity clemastine fumarate according to claim 1, wherein the free clemastine is obtained in step 5, extracted by using petroleum ether as an extraction solvent, and then subjected to vacuum concentration.
10. The method for preparing clemastine fumarate with high chiral purity according to claim 1, wherein methanol is used as a salt-forming solvent after the vacuum concentration in step 5.
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|---|---|---|---|---|
| CN114324673A (en) * | 2022-01-12 | 2022-04-12 | 山东百诺医药股份有限公司 | Analysis method for simultaneously determining chloromalastine fumarate and isomers thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5191253A (en) * | 1975-02-05 | 1976-08-10 | Kogakukatsusei 11 mechiru 22 okishechiruupirorijinno seiho | |
| HU208670B (en) * | 1991-06-04 | 1993-12-28 | Budapesti Mueszaki Egyetem | Process for separating and clean ing 1-methyl-2-pyrrolidinyl ethanol enenthiomers |
| WO2009094457A2 (en) * | 2008-01-22 | 2009-07-30 | Auspex Pharmaceuticals | Substituted benzhydrylethers |
| CN103387528A (en) * | 2013-08-01 | 2013-11-13 | 刘怀振 | Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof |
| PL218348B1 (en) * | 2011-06-01 | 2014-11-28 | Politechnika Warszawska | Process for the preparation of enantiomers of 2 - (1-methyl-2-pyrrolidino) ethanol |
| CN107011228A (en) * | 2017-05-24 | 2017-08-04 | 浙江诚意药业股份有限公司 | A kind of preparation method of clemastine fumarate |
-
2020
- 2020-03-19 CN CN202010194711.2A patent/CN111302996A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5191253A (en) * | 1975-02-05 | 1976-08-10 | Kogakukatsusei 11 mechiru 22 okishechiruupirorijinno seiho | |
| HU208670B (en) * | 1991-06-04 | 1993-12-28 | Budapesti Mueszaki Egyetem | Process for separating and clean ing 1-methyl-2-pyrrolidinyl ethanol enenthiomers |
| WO2009094457A2 (en) * | 2008-01-22 | 2009-07-30 | Auspex Pharmaceuticals | Substituted benzhydrylethers |
| PL218348B1 (en) * | 2011-06-01 | 2014-11-28 | Politechnika Warszawska | Process for the preparation of enantiomers of 2 - (1-methyl-2-pyrrolidino) ethanol |
| CN103387528A (en) * | 2013-08-01 | 2013-11-13 | 刘怀振 | Resolution method of N-methyl-2(2-hydroxyethyl)pyrrolidine and application thereof |
| CN107011228A (en) * | 2017-05-24 | 2017-08-04 | 浙江诚意药业股份有限公司 | A kind of preparation method of clemastine fumarate |
Non-Patent Citations (1)
| Title |
|---|
| MARIA LX.，等: "New Method of Optical Activation for Racemic Bases", 《TCMHEDRON LERRERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114324673A (en) * | 2022-01-12 | 2022-04-12 | 山东百诺医药股份有限公司 | Analysis method for simultaneously determining chloromalastine fumarate and isomers thereof |
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