CN111484445A - Method for synthesizing intermediate of high-purity Wumei ammonium bromide - Google Patents
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- CN111484445A CN111484445A CN202010319312.4A CN202010319312A CN111484445A CN 111484445 A CN111484445 A CN 111484445A CN 202010319312 A CN202010319312 A CN 202010319312A CN 111484445 A CN111484445 A CN 111484445A
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a method for synthesizing 1- (2-chloroethyl) piperidine-4-formate and quinuclidine-4-carboxylic ester which are midbodies of Umeclinium bromide. The method purifies the crude products of the intermediates 1- (2-chloroethyl) piperidine-4-formic ether and quinuclidine-4-carboxylic ester by molecular distillation or rectification under reduced pressure to obtain the high-purity medical intermediate. The purification cost can be effectively reduced and the yield can be improved by molecular distillation or vacuum rectification, and the product purity can reach more than 99 percent. The synthesis method disclosed by the invention is adopted for preparing the 1- (2-chloroethyl) piperidine-4-formic ether and the quinuclidine-4-carboxylic ester, the process route is short, the large-scale production is easy to realize, and the yield is high. The invention has the characteristics of novel process, high yield, low cost, high product purity and the like.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a novel method for synthesizing a high-purity Wumei ammonium bromide intermediate.
Background
Ultramipramine (Umeclinium bromide) is a long-acting muscarinic choline receptor antagonist (L AMA), a me-beter class of novel chemical entity, and can be used for treating asthma and Chronic Obstructive Pulmonary Disease (COPD). Ultramine bromide has the following structure:
1- (2-chloroethyl) piperidine-4-formate and quinuclidine-4-carboxylate are used as important intermediates of ammonium umei bromide, and have wide market demands.
In order to overcome the defects of long reaction route, low reaction activity, low conversion rate, more reaction byproducts and the like in the synthesis of 1- (2-chloroethyl) -4-piperidine formate and quinuclidine-4-carboxylate, the company designs and develops a new process route which uses 4-piperidine formate as a raw material and carries out two-step one-pot reaction through epoxy ring opening and chlorination.
The 1- (2-chloroethyl) -4-piperidine formic ether prepared by the process is subjected to further cyclization to prepare quinuclidine-4-carboxylic ester through the hydrogen extraction of alkali.
1- (2-chloroethyl) piperidine-4-carboxylate and quinuclidine-4-carboxylate are oils, and there are two main methods for obtaining 1- (2-chloroethyl) piperidine-4-carboxylate and quinuclidine-4-carboxylate with high purity according to current literature reports:
the first method is column chromatography separation and purification, the yield of the scheme is low, the consumption of solvent is large, and the scheme needs to face troubles in stability in the process of column chromatography, and 1- (2-chloroethyl) piperidine-4-formic ester and quinuclidine-4-carboxylic ester can be degraded to different degrees along with the prolonging of column chromatography time, so that the method is difficult to industrialize.
The second method is to form hydrochloride from 1- (2-chloroethyl) piperidine-4-carboxylic acid ester and quinuclidine-4-carboxylic acid ester by hydrogen chloride, and crystallize after forming solid. Firstly, the solution or gas of hydrogen chloride is used in the scheme, any scheme needs to face operational difficulty, meanwhile, partial impurities can be salified simultaneously in the salifying process, and the impurities are difficult to remove by subsequent crystallization. And the yield of the method is generally lower, and alkali hydrolysis is needed in the subsequent use process, so that the risk of ester group hydrolysis is increased.
In summary, no cheap, efficient and high-quality separation and purification method for 1- (2-chloroethyl) piperidine-4-formate and quinuclidine-4-carboxylate exists at present.
Disclosure of Invention
In view of the deficiencies of the prior art solutions, the inventors of the present invention have conducted a targeted study and improvement on 1- (2-chloroethyl) piperidine-4-carboxylate and quinuclidine-4-carboxylate:
since both 1- (2-chloroethyl) piperidine-4-carboxylate and quinuclidine-4-carboxylate are oily substances and have high boiling points, and the solution of salt formation and column chromatography has certain defects, the inventors of the present invention consider to use a reduced pressure distillation scheme for purification.
Gram-level and hectogram reactions achieve better reaction results, and yield and purity are obviously reduced in the process of further amplification. The inventor of the present invention has studied and found that the distillation time is greatly increased along with the scale-up of the batch, and 1- (2-chloroethyl) piperidine-4-carboxylic acid ester and quinuclidine-4-carboxylic acid ester are unstable at high temperature, so that the yield and purity are reduced along with degradation during the distillation process.
After further investigation, the inventors of the present invention have found that the degradation during distillation is mainly due to oxidation, for which case the addition of antioxidants is attempted during distillation, and that high boiling antioxidants such as β n-octadecyl- (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate, pentaerythritol tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate ], 1,1, 3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, dilauryl thiodipropionate are used in order to avoid the antioxidants from distilling out during distillation.
After adding enough antioxidant, the oxidation of the distillation substrate is effectively controlled, the viscosity of the substrate is effectively controlled, and the kilogram-level production also obtains ideal yield and purity.
Based on the research results, the invention provides a novel method for synthesizing an intermediate of high-purity wumei ammonium bromide, which comprises the step of adding an oxidant with a high boiling point, and simultaneously using a distillation or rectification method to separate and purify 1- (2-chloroethyl) piperidine-4-formic ester and quinuclidine-4-carboxylic ester so as to synthesize the intermediate of high-purity wumei ammonium bromide.
The invention is realized by the following technical scheme:
a method for synthesizing an intermediate of high-purity ammonium umei bromide is used for separating and purifying 1- (2-chloroethyl) piperidine-4-formic ester and quinuclidine-4-carboxylic ester by using a molecular distillation or reduced pressure distillation method. The method specifically comprises the following steps:
(1) separation and purification of 1- (2-chloroethyl) piperidine-4-formic ether:
(2) separation and purification of quinuclidine-4-carboxylate:
the separation and purification method in step (1) may be molecular distillation with addition of a high boiling point antioxidant, the high boiling point antioxidant used includes at least one of β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionic acid n-octadecyl ester, tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionic acid ] pentaerythritol ester, 1,1, 3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, dilauryl thiodipropionate, and the molecular distillation equipment used includes one of a static molecular distiller, a falling film molecular distiller, a wiped film molecular distiller, a scraper molecular distiller, and a centrifugal molecular distiller.
The separation and purification mode of the step (1) can also be vacuum distillation with high boiling point antioxidant, the boiling point of 1- (2-chloroethyl) piperidine-4-formate is reduced by vacuum, the stability of 1- (2-chloroethyl) piperidine-4-formate in the distillation process is improved, the used high boiling point antioxidant comprises at least one of β - (3, 5-di-tert-butyl-4-hydroxyphenyl) n-octadecyl propionate, tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate ] pentaerythritol ester, 1,1, 3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane and dilauryl thiodipropionate, and the purity of 1- (2-chloroethyl) piperidine-4-formate is improved by a rectifying tower, the used rectifying device comprises one of a plate rectifying tower and a filler rectifying tower, and can adopt a continuous rectifying mode, also can adopt a batch rectifying mode, and preferably adopt continuous rectifying mode.
The separation and purification method in step (2) may be molecular distillation with addition of a high boiling point antioxidant, the high boiling point antioxidant used includes, but is not limited to, β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionic acid n-octadecyl ester, tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionic acid ] pentaerythritol ester, 1,1, 3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, dilauryl thiodipropionate, and the molecular distillation equipment used includes one of a static molecular still, a falling film molecular still, a wiped film molecular distillation apparatus, and a centrifugal molecular distillation apparatus.
The separation and purification method in step (2) may also be vacuum distillation with the addition of high boiling point antioxidant, the boiling point of 1- (2-chloroethyl) piperidine-4-formate is reduced by vacuum, the stability of 1- (2-chloroethyl) piperidine-4-formate in the distillation process is improved, the high boiling point antioxidant used includes, but is not limited to β - (3, 5-di-tert-butyl-4-hydroxyphenyl) n-octadecyl propionate, tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate ] pentaerythritol ester, 1,1, 3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, dilauryl thiodipropionate, and the purity of 1- (2-chloroethyl) piperidine-4-formate is improved by a rectification column, the rectification device used includes one of a plate rectification column and a filler rectification column, and a continuous rectification mode may be adopted, or a batch rectification mode may be adopted, and continuous rectification is preferred.
R in the structural formula is an aliphatic chain substituent with less than or equal to 6 carbons. In a preferred embodiment of the technical solution of the present invention, R is one of methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-butyl.
The invention provides a method for synthesizing 1- (2-chloroethyl) piperidine-4-formic ether and quinuclidine-4-carboxylic ester, which uses distillation or rectification to separate and purify 1- (2-chloroethyl) piperidine-4-formic ether and quinuclidine-4-carboxylic ester,
according to one embodiment of the invention, the distillation is molecular distillation and the rectification is vacuum rectification; preferably, the 1- (2-chloroethyl) piperidine-4-carboxylic acid ester and quinuclidine-4-carboxylic acid ester are separated and purified by molecular distillation.
According to one embodiment of the invention, an antioxidant is added to the distillate to be distilled or to the distillate to be rectified.
According to one embodiment of the invention, the antioxidant is a high boiling antioxidant.
According to one embodiment of the present invention, for example, the high boiling antioxidant comprises at least one of β n-octadecyl- (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate, pentaerythrityl tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate ], 1, 3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, and dilauryl thiodipropionate.
According to one embodiment of the present invention, R in the above formula is an aliphatic chain substituent of less than or equal to 6 carbons;
according to an embodiment of the present invention, R is one of methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-butyl.
According to one embodiment of the invention, the rectification is a continuous or batch rectification; preferably, the rectification is a continuous rectification.
According to an embodiment of the invention, the distillation uses equipment comprising one of a static molecular still, a falling film molecular still, a wiped film molecular distillation device, a scraped molecular distillation device, and a centrifugal molecular distillation device; the device used for rectification comprises one of a plate-type rectifying tower and a packing rectifying tower.
According to one embodiment of the invention, 1- (2-chloroethyl) piperidine-4-carboxylic acid ester is purified by molecular distillation using the following parameters: the vacuum degree is 0.1 Pa-100 Pa, the distance between the condenser and the evaporator is 10 mm-100 mm, the temperature of the evaporator is 80-160 ℃, and the temperature of the condenser is-20-50 ℃;
according to one embodiment of the invention, for example, the molecular distillation uses the parameters: the vacuum degree is 0.1 Pa-1 Pa, the distance between the condenser and the evaporator is 20 mm-50 mm, the temperature of the evaporator is 100-130 ℃, and the temperature of the condenser is 0-30 ℃.
According to one embodiment of the present invention, quinuclidine-4-carboxylate is purified by molecular distillation using the following parameters: the vacuum degree is 0.1 Pa-100 Pa, the distance between the condenser and the evaporator is 10 mm-100 mm, the temperature of the evaporator is 50-120 ℃, and the temperature of the condenser is-30-50 ℃;
according to one embodiment of the invention, for example, the molecular distillation uses the parameters: the vacuum degree is 0.1 Pa-1 Pa, the distance between the condenser and the evaporator is 20 mm-50 mm, the temperature of the evaporator is 60-100 ℃, and the temperature of the condenser is-5-15 ℃.
Based on the technical scheme, the invention has the following beneficial technical effects:
(1) by adopting the method for synthesizing the intermediate of high-purity Wumei ammonium bromide, the purity of 1- (2-chloroethyl) piperidine-4-formic ether and quinuclidine-4-carboxylic ester can be improved to more than 99%; the purity is generally 95% and not more than 98% by adopting a common column chromatography or salifying purification method.
(2) According to the invention, the 1- (2-chloroethyl) piperidine-4-formic ether and quinuclidine-4-carboxylic ester are purified by using a distillation or rectification process, and in the obtained product, the amount of impurities such as inorganic salt, acid-base impurities, moisture and the like which can influence the content and stability of the product is greatly reduced, so that the product has the advantages of high stability, stable content, clear and transparent appearance and the like.
(3) The method for synthesizing the intermediate of high-purity Wumei ammonium bromide greatly improves the purification efficiency by using molecular distillation and reduced pressure distillation, obtains higher yield and is suitable for industrial large-scale production.
Drawings
FIG. 1 is a graph showing the results of chromatography of ethyl 1- (2-chloroethyl) -4-piperidinecarboxylate obtained in example 1 of the present invention;
FIG. 2 is a graph showing the results of chromatography of quinuclidine-4-carboxylic acid ethyl ester obtained in example 1 of the present invention;
FIG. 3 is a graph showing the results of chromatography of methyl 1- (2-chloroethyl) -4-piperidinecarboxylate obtained in example 2 of the present invention;
FIG. 4 is a graph showing the results of chromatography on methyl 1- (2-chloroethyl) -4-piperidinecarboxylate obtained in example 2 of the present invention.
Detailed Description
To facilitate understanding of the invention by those skilled in the art, the invention is further described below with reference to specific examples, which are not intended to limit the scope of the invention.
Example 1
Preparation of 1- (2-chloroethyl) -4-piperidinecarboxylic acid ethyl ester
Adding 12 kg of 4-ethyl piperidinecarboxylate and dichloromethane into a reaction kettle in sequence, stirring uniformly, heating to a material temperature of 40-45 ℃, slowly introducing ethylene oxide, controlling the internal temperature not to exceed 45 ℃, reacting for 5-7 hours, sampling, controlling the temperature during sampling, cooling to 35 ℃ after the reaction is completed, adding triethylamine, dropwise adding thionyl chloride, keeping the temperature, continuing to react for 1-2 hours after the dropwise adding is completed, sampling, controlling the temperature during sampling, dropwise adding a sodium carbonate aqueous solution, stirring, standing, carrying out phase separation, collecting an organic phase, distilling under reduced pressure until no obvious liquid is distilled off to obtain a crude product of 1- (2-chloroethyl) -4-ethyl piperidinecarboxylate, adding 1.5 kg of n-octadecyl β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate, and stirring uniformly.
And transferring the crude product to a falling film evaporator, wherein the vacuum degree is 0.1Pa, the distance between a condenser and the evaporator is 30mm, the temperature of the evaporator is 120 ℃, and the temperature of the condenser is 25 ℃. 12.75 kg of colorless clear liquid, namely 1- (2-chloroethyl) -4-ethyl piperidinecarboxylate, is obtained, the total yield is 76%, the purity is 99.45%, and the maximum content of unknown single impurity is 0.26%. The related chromatographic analysis results are shown in figure 1.
Preparation of quinuclidine-4-carboxylic acid ethyl ester
Sequentially adding 10 kg of 1- (2-chloroethyl) -4-piperidinecarboxylic acid ethyl ester and dichloromethane into a reaction kettle, uniformly stirring, heating to a material temperature of 40-45 ℃, adding a hexamethyldisilazane-based aminolithium solution, controlling the internal temperature not to exceed 45 ℃, continuing to react for 3-4 hours after the dropwise addition is finished, controlling in a sampling process, after the completion of the reaction is confirmed, cooling to 0 ℃, slowly dropwise adding glacial acetic acid, continuing to stir for 2 hours after the dropwise addition is finished, adding a sodium carbonate aqueous solution, stirring, standing, carrying out phase separation, collecting an organic phase, distilling under reduced pressure until no obvious liquid is distilled off to obtain a quinuclidine-4-carboxylic acid ethyl ester crude product, adding 1kg of β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionic acid n-octadecyl ester, and uniformly stirring.
And transferring the crude product to a falling film evaporator, wherein the vacuum degree is 0.1Pa, the distance between a condenser and the evaporator is 30mm, the temperature of the evaporator is 90 ℃, and the temperature of the condenser is 5 ℃. 6.67 kg of colorless clear liquid is quinuclidine-4-carboxylic acid ethyl ester, the total yield is 80%, the purity is 99.87%, and the maximum content of unknown single impurity is 0.13%. The related chromatographic analysis results are shown in figure 2.
Example 2
Preparation of methyl 1- (2-chloroethyl) -4-piperidinecarboxylate
20 kg of 4-methyl piperidine formate and toluene are sequentially added into a reaction kettle, the mixture is uniformly stirred, the mixture is heated to the material temperature of 55-65 ℃, ethylene oxide is slowly introduced, the internal temperature is controlled not to exceed 65 ℃, the reaction lasts for 5-7 hours, and sampling and central control are carried out. After the reaction is confirmed to be complete, cooling to 45 ℃, dropwise adding thionyl chloride, keeping the temperature for continuous reaction for 1-2 hours after the dropwise adding is finished, and sampling and controlling the temperature. And (3) after the reaction is confirmed to be finished, dropwise adding a sodium carbonate aqueous solution, stirring, standing, splitting phases, collecting an organic phase, distilling under reduced pressure until no obvious liquid is distilled off to obtain a crude product of the 1- (2-chloroethyl) -4-methyl piperidine formate, adding 4 kg of dilauryl thiodipropionate, and uniformly stirring.
Transferring the 1- (2-chloroethyl) -4-methyl piperidinecarboxylate crude product to a reaction kettle provided with a reduced pressure rectification column, wherein the theoretical plate number is 50. Carrying out vacuum rectification under 1Pa, collecting fractions when the temperature of the tower top reaches 92-98 ℃, and obtaining 18.18kg of light yellow transparent liquid, namely 1- (2-chloroethyl) -4-methyl piperidine formate, wherein the total yield is 65%, the purity is 99.24%, and the maximum unknown single impurity is 0.24%. The related chromatographic analysis results are shown in figure 3.
Preparation of quinuclidine-4-carboxylic acid methyl ester
Adding 15 kg of 1- (2-chloroethyl) -4-piperidinecarboxylic acid methyl ester and toluene into a reaction kettle in sequence, stirring uniformly, heating to a material temperature of 50-55 ℃, adding a 1, 8-diazabicycloundeca-7-ene solution, controlling the internal temperature not to exceed 55 ℃, continuing to react for 1-2 hours after the dropwise addition is finished, and sampling and controlling the temperature. After the reaction is confirmed to be complete, the temperature is reduced to 0 ℃, glacial acetic acid is slowly dripped, and stirring is continued for 2 hours after dripping is finished. Adding sodium carbonate aqueous solution, stirring, standing, phase splitting, collecting an organic phase, distilling under reduced pressure until no obvious liquid is distilled off to obtain a crude product of quinuclidine-4-carboxylic acid methyl ester, adding 3 kg of dilauryl thiodipropionate, and uniformly stirring.
And (3) transferring the quinuclidine-4-methyl carboxylate crude product to a reaction kettle provided with a reduced pressure rectification column, wherein the theoretical plate number is 30. Vacuum rectification is carried out under 1Pa, and when the temperature of the tower top reaches 72-75 ℃, fractions are collected to obtain 9.51kg of light yellow transparent liquid, namely 1- (2-chloroethyl) -4-piperidinecarboxylic acid methyl ester, wherein the total yield is 76%, the purity is 99.81%, and the maximum unknown single impurity is 0.19%. The related chromatographic analysis results are shown in figure 4.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
2. the method according to claim 1, wherein the distillation is molecular distillation and the rectification is vacuum rectification; preferably, the 1- (2-chloroethyl) piperidine-4-carboxylic acid ester and quinuclidine-4-carboxylic acid ester are separated and purified by molecular distillation.
3. The process according to claim 1 or 2, characterized in that an antioxidant is added to the distillate to be distilled or to the distillate to be rectified.
4. The method according to claim 3, wherein the antioxidant is a high boiling point antioxidant, preferably the high boiling point antioxidant comprises at least one of β n-octadecyl- (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate, pentaerythritol tetrakis [ β - (3, 5-di-tert-butyl-4-hydroxyphenyl) propionate ], 1, 3-tris (2-methyl-4-hydroxy-5-tert-butylphenyl) butane, and dilauryl thiodipropionate, and preferably the high boiling point antioxidant has a boiling point of 260 ℃ or higher.
5. The process of claim 1 or 2, wherein R in the formula is an aliphatic chain substituent of less than or equal to 6 carbons;
preferably, R is one of methyl, ethyl, n-propyl, isopropyl, tert-butyl and n-butyl.
6. The method according to claim 1 or 2, characterized in that the rectification is a continuous or batch rectification; preferably, the rectification is a continuous rectification.
7. The method according to claim 1 or 2, wherein the distillation is carried out using an apparatus comprising one of a static molecular still, a falling film molecular still, a wiped film molecular still, and a centrifugal molecular still; the device used for rectification comprises one of a plate-type rectifying tower and a packing rectifying tower.
8. The process according to claim 2, characterized in that 1- (2-chloroethyl) piperidine-4-carboxylic acid ester is purified by molecular distillation using the following parameters: the vacuum degree is 0.1 Pa-100 Pa, the distance between the condenser and the evaporator is 10 mm-100 mm, the temperature of the evaporator is 80-160 ℃, and the temperature of the condenser is-20-50 ℃;
preferably, the parameters used for molecular distillation are: the vacuum degree is 0.1 Pa-1 Pa, the distance between the condenser and the evaporator is 20 mm-50 mm, the temperature of the evaporator is 100-130 ℃, and the temperature of the condenser is 0-30 ℃.
9. The process according to claim 2, characterized in that the quinuclidine-4-carboxylate is purified by molecular distillation using the parameters: the vacuum degree is 0.1 Pa-100 Pa, the distance between the condenser and the evaporator is 10 mm-100 mm, the temperature of the evaporator is 50-120 ℃, and the temperature of the condenser is-30-50 ℃;
preferably, the parameters used for molecular distillation are: the vacuum degree is 0.1 Pa-1 Pa, the distance between the condenser and the evaporator is 20 mm-50 mm, the temperature of the evaporator is 60-100 ℃, and the temperature of the condenser is-5-15 ℃.
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CN102040602A (en) * | 2004-04-27 | 2011-05-04 | 葛兰素集团有限公司 | Muscarinic acetylcholine receptor antagonists |
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CN110167931A (en) * | 2016-11-14 | 2019-08-23 | 好利安科技有限公司 | The method for preparing umeclidinium |
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