CN113735816A - Method for preparing chiral alcohol from ketone by using microchannel reactor - Google Patents
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- CN113735816A CN113735816A CN202111085778.3A CN202111085778A CN113735816A CN 113735816 A CN113735816 A CN 113735816A CN 202111085778 A CN202111085778 A CN 202111085778A CN 113735816 A CN113735816 A CN 113735816A
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- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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Abstract
The invention relates to a method for preparing chiral alcohol from ketone by using a microchannel reactor, belonging to the technical field of synthesis of drug intermediates, wherein the ketone is N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) tert-butyl carbamate, and the chiral alcohol is (R) -tert-butyl (2- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) -2-hydroxyethyl). According to the method, a tetrahydrofuran solution of ketone is used as a raw material, a microchannel reactor is adopted to obtain the chiral alcohol through a Corey-Bakshi-Shibata reduction chiral reduction technology, the reaction condition is accurately controlled, the reaction time is short, the reaction selectivity is good, and the chiral purity of the product is high.
Description
Technical Field
The invention belongs to the field of synthesis of drug intermediates, and relates to a method for preparing chiral alcohol from ketone by using a microchannel reactor.
Background
(R) -tert-butyl (2- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) -2-hydroxyethyl) is a key chiral intermediate for the synthesis of vilanterol and salmeterol, and the chemical structural formula is as follows:
the existing process technology for synthesizing the chiral intermediate is mainly realized through Corey-Bakshi-Shibata reaction, and the specific synthetic process route is as follows:
the Corey-Bakshi-Shibata reaction, abbreviated as CBS reduction, also known as Itsuno-Corey reduction, is an organic reaction in which a ketone is stereoselectively reduced to an alcohol under the catalysis of a chiral boron isoxazolidine (CBS catalyst) and an ether solution of diborane. The reaction is widely applied to medicines and preparations, and is successfully applied to industrial production.
The literature (Organic & Biomolecular Chemistry,1(7), 1106-1111; 2003) reacts for 2 hours at 5 ℃ with a yield of 99%, unreported chemical purity and 96% chiral purity; in WO2014041565A2, the reaction is carried out for 1 hour at the temperature of minus 10 ℃, the yield is 70%, the chemical purity is 98.06%, the chiral purity is less than 96%, and the chiral S isomer accounts for 2.2%. The reaction is carried out for 2 hours in the literature (China journal of medical industry, 2020,51(10)1262-1265.) at the temperature of-12 ℃, the yield is 92%, the chemical purity is 99.45% and the chiral purity is 99.31%.
However, the process route mainly has the following defects: (1) the reaction temperature is low, and generally needs to be carried out at the temperature of between 10 and 15 ℃; (2) the heat release is severe in the reaction process, and the system temperature is difficult to control accurately in the reaction process; (3) the reaction selectivity is low, and the chiral purity is lower than 97%; (4) the reaction process needs to be strictly controlled to be operated without water.
The traditional process is carried out in a kettle type reactor, the chiral purity is low due to inaccurate reaction temperature control, uneven reaction stirring degree and the like, and therefore, the development of a preparation process which has good selectivity, good yield and high purity and is suitable for large-scale industrial production is urgently needed.
Disclosure of Invention
The invention discloses a method for preparing chiral alcohol from ketone by using a microchannel reactor, and provides a method for preparing (R) -tert-butyl (2- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) -2-hydroxyethyl) from N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamic acid tert-butyl ester by using the microchannel reactor aiming at the defects in the prior art. The method comprises the steps of respectively reducing the temperature of borane tetrahydrofuran solution and (R) -2-methyl-CBS-oxazaborolidine tetrahydrofuran solution to a certain temperature, introducing the mixture into a first microchannel reactor for mixing and reacting, introducing the obtained mixture into subsequent 2 microchannel reactors to obtain chiral reduction material flow, introducing the cooled ketone tetrahydrofuran solution into the subsequent 2 microchannel reactors, and performing a post-treatment process to obtain a chiral alcohol pure product, wherein the ketone in the ketone tetrahydrofuran solution is N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) tert-butyl carbamate, and the microchannel reactor is purchased from corning reactor technology Limited.
Preferably, the reaction residence time of the first microchannel reactor is 5-15S, the reaction temperature is-15 to-10 ℃, and the reaction pressure is 0-1.5 MPa; the reaction residence time of each microchannel reactor in the subsequent 2 microchannel reactors is 5-15S, and the reaction temperature is 12-15 ℃; the reaction pressure is 0-1.5 MPa.
Preferably, the post-treatment process is distillation, extraction, crystallization and filtration to obtain the chiral alcohol.
Preferably, the material of the mixing reaction module of the microchannel reactor is silicon carbide, stainless steel, alloy or ceramic, and the feeding modes of all materials of the microchannel reactor device are diaphragm pump-driven continuous feeding. The microchannel reactor is a microchannel reactor of Shandong Haimai chemical engineering Co., Ltd, and comprises a precooling module and a reaction module.
Preferably, the concentration of the borane tetrahydrofuran is 1mol/L, the concentration of the (R) -2-methyl-CBS-oxazole borane tetrahydrofuran is 1mol/L, and the solution of the ketone tetrahydrofuran is the solution of the ketone tetrahydrofuran with the concentration of 2 mol/L.
Preferably, the molar ratio of the (R) -2-methyl-CBS-oxazole borane to the borane tetrahydrofuran introduced into the first microchannel reactor mixing module 1 is 5-10: 100, the molar ratio of the ketone tetrahydrofuran solution to the borane tetrahydrofuran is 1: 1.1-1.4, the flow rate of borane tetrahydrofuran is 60mL/min, the flow rate of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran is 6mL/min, and the flow rate of the ketone tetrahydrofuran solution is 25 mL/min.
The invention has the following advantages:
(1) the method has the advantages of good reaction selectivity, chiral purity of more than 99.8 percent, high product yield of 96 percent, realization of rapid and effective mixing and reaction of reactants by setting reasonable reaction conditions and adopting proper reaction equipment, accurate control of residence time and reaction temperature, promotion of reaction conversion rate and selectivity and effective avoidance of side reaction.
(2) The reaction time is obviously improved, the original reaction time of 3 hours is reduced to 30S, the reaction efficiency is obviously improved, and the output of products in unit time is improved.
(3) The reaction safety is obviously improved, the effective control of the reaction process is realized, and the safety factor of the reaction is improved.
Drawings
FIG. 1 is a schematic diagram of the process of the present invention
Detailed Description
Example 1:
(1) the tetrahydrofuran concentrations of borane tetrahydrofuran and (R) -2-methyl-CBS-oxazole borane are both 1mol/L, and the tetrahydrofuran solution of ketone is configured to be 2mol/L, wherein the mass ratio of the ketone to the tetrahydrofuran is 1: 4, the ketone in the tetrahydrofuran solution of the ketone is tert-butyl N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamate, which is provided by Anhuidiqijia biological medicine, Inc.
(2) Setting the temperature value of a precooler in a microreactor device, setting the precooling temperature of a borane tetrahydrofuran solution to-13 ℃, setting the precooling temperature of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to-13 ℃, and setting the precooling temperature of a reaction zone to-15 ℃.
(3) And opening a flow regulating valve of a coolant inlet pipeline of the borane tetrahydrofuran heat exchanger and the (R) -2-methyl-CBS-oxazole borane tetrahydrofuran heat exchanger in the pre-cooling area, starting to regulate the temperature of the equipment, and sequentially opening the raw material conveying pump after the temperature of the equipment is reduced to a set value.
(4) After precooling of each zone in the device is completed, starting a borane tetrahydrofuran pump, observing temperature change in the reactor, starting the (R) -2-methyl-CBS-oxazole borane tetrahydrofuran pump when the temperature is stabilized at a set value, adjusting a needle valve on a heat exchange sheet pipeline in the reactor device at the moment, controlling the temperature in the reaction sheet under reaction conditions and keeping the temperature in a stable state, wherein the reaction temperature of the microchannel reactor is-13 ℃, the reaction time is 10s, and the reaction pressure is 0.3 MPa.
(5) Controlling the flow rate of borane tetrahydrofuran to be 60mL/min, controlling the flow rate of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to be 6mL/min, and controlling the molar ratio of (R) -2-methyl-CBS-oxazole borane to borane tetrahydrofuran to be 1: 10, enabling the flow rate of the tetrahydrofuran solution of the ketone to be 25mL/min, enabling the reacted mixture to sequentially pass through two microchannel reactors to obtain a chiral reduction material flow, enabling the obtained chiral reduction material flow and the tetrahydrofuran solution of the ketone cooled to-10 ℃ to pass through the two microchannel reactors again and react, wherein the molar ratio of the tetrahydrofuran solution of the ketone to the borane tetrahydrofuran is 1: 1.2.
(6) the reaction solution liquid chromatography tests that the conversion rate of the tetrahydrofuran solution of the ketone is 100 percent.
(7) Taking 7kg of reaction liquid, dripping 750g of methanol below 10 ℃ to quench reaction, concentrating the solvent in vacuum, adding 3kg of ethyl acetate and 3kg of water into the residue, stirring for 1 hour at 10 ℃, layering, washing the organic phase once with saturated saline water and water, drying the organic phase, concentrating until no fraction flows out, adding 1.5kg of petroleum ether, stirring overnight, filtering, and drying to obtain a white solid with the yield of 95%, the chemical purity of 99.92% and the chiral purity of 99.95%.
(8) After the experiment is finished, the equipment is cleaned, the pumps simultaneously convey the methanol, the equipment can be judged to be sand-cleaned when the solution at the outlet of the reactor is clear, and the specific operation process flow schematic diagram is shown as the attached figure 1.
Example 2:
(1) the tetrahydrofuran concentrations of borane tetrahydrofuran and (R) -2-methyl-CBS-oxazole borane are both 1mol/L, and the tetrahydrofuran solution of ketone is configured to be 2mol/L, wherein the mass ratio of the ketone to the tetrahydrofuran is 1: 3.
(2) setting the temperature value of a precooler in a microreactor device, setting the precooling temperature of a borane tetrahydrofuran solution to-10 ℃, setting the precooling temperature of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to-10 ℃, and setting the precooling temperature of a reaction zone to-12 ℃.
(3) Opening a flow regulating valve of a coolant inlet pipeline of a tetrahydrofuran solution heat exchanger of borane tetrahydrofuran and (R) -2-methyl-CBS-oxazole borane tetrahydrofuran and ketone in a pre-cooling area, starting to regulate the temperature of the equipment, and sequentially opening a raw material conveying pump after the temperature of the equipment is reduced to a set value.
(4) After precooling of each zone in the device is completed, starting a borane tetrahydrofuran pump, observing temperature change in the reactor, starting the (R) -2-methyl-CBS-oxazole borane tetrahydrofuran pump when the temperature is stabilized at a set value, adjusting a needle valve on a heat exchange sheet pipeline in the reactor device at the moment, controlling the temperature in the reaction sheet under reaction conditions and keeping the temperature in a stable state, wherein the reaction temperature of each microchannel reactor is-10 ℃, the reaction time is 8s, and the reaction pressure is 1.0 MPa.
(5) Controlling the flow rate of borane tetrahydrofuran to be 60mL/min, controlling the flow rate of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to be 6mL/min, and controlling the molar ratio of (R) -2-methyl-CBS-oxazole borane to borane tetrahydrofuran to be 1: and 15, enabling the flow of the tetrahydrofuran solution of the ketone to be 25mL/min, enabling the reacted mixture to sequentially pass through two microchannel reactors to obtain a chiral reduction material flow, enabling the obtained chiral reduction material flow and the tetrahydrofuran solution of the ketone cooled to-10 ℃ to pass through the two microchannel reactors again and react, wherein the molar ratio of the tetrahydrofuran solution of the ketone to the borane tetrahydrofuran is 1: 1.4.
(6) the reaction solution liquid chromatography tests that the conversion rate of the tetrahydrofuran solution of the ketone is 100 percent.
(7) Taking 7kg of reaction liquid, dripping 750g of methanol below 10 ℃ to quench reaction, concentrating the solvent in vacuum, adding 3kg of ethyl acetate and 3kg of water into the residue, stirring for 1 hour at 10 ℃, layering, washing the organic phase once with saturated saline water and water, drying the organic phase, concentrating until no fraction flows out, adding 1.5kg of petroleum ether, stirring overnight, filtering, and drying to obtain a white solid, wherein the yield is 95.7%, the chemical purity is 99.93%, and the chiral purity is 99.92%.
(8) After the experiment is finished, the equipment is cleaned, the pumps simultaneously convey the methanol, and the equipment can be judged to be sand-cleaned when the solution at the outlet of the reactor is clear.
Comparative example 1:
at room temperature, adding anhydrous THF (2.5L) and 1mol/L (R) -2-methyl-CBS-oxazaborolidine tetrahydrofuran solution (1mol/L, 0.65L) into a 30L glass reaction kettle, starting stirring, cooling to-13 ℃, and then dropwise adding 1mol/L BH at-12 to-10 DEG C3THF (1mol/L, 6.5L, 6.5mol), 30min after dropping, stirring was continued for 1 h. Adding ketone THF solution (1 kg of ketone, 4kg of THF) dropwise at a temperature not higher than-12 deg.C for 1 hr, and reacting for 2 hr. Methanol (1L) was added dropwise to quench the reaction, the reaction mixture was concentrated at 50 ℃ under reduced pressure to near dryness, and ethyl acetate (6L) was added. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Concentrating the filtrate at 40 deg.C under reduced pressure, adding petroleum ether (2L) for crystallization, filtering, and drying the filter cake at 40 deg.C under normal pressure to obtain white solid with yield of 82%, chemical purity of 98.35%, and chiral purity of 98.25%.
Comparative example 2:
(1) the tetrahydrofuran concentrations of borane tetrahydrofuran and (R) -2-methyl-CBS-oxazole borane are both 1mol/L, and the tetrahydrofuran solution of ketone is configured to be 2mol/L, wherein the mass ratio of the ketone to the tetrahydrofuran is 1: 4.
(2) setting the temperature value of a precooler in a microreactor device, setting the precooling temperature of a borane tetrahydrofuran solution to be-5 ℃, setting the precooling temperature of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to be-5 ℃, and setting the precooling temperature of a reaction zone to be 3 ℃.
(3) Opening a flow regulating valve of a coolant inlet pipeline of a tetrahydrofuran solution heat exchanger of borane tetrahydrofuran and (R) -2-methyl-CBS-oxazole borane tetrahydrofuran and ketone in a pre-cooling area, starting to regulate the temperature of the equipment, and sequentially opening a raw material conveying pump after the temperature of the equipment is reduced to a set value.
(4) After precooling of each zone in the device is completed, starting a borane tetrahydrofuran pump, observing temperature change in the reactor, starting the (R) -2-methyl-CBS-oxazole borane tetrahydrofuran pump when the temperature is stabilized at a set value, adjusting a needle valve on a heat exchange sheet pipeline in the reactor device at the moment, controlling the temperature in the reaction sheet under reaction conditions and keeping the temperature in a stable state, wherein the reaction temperature of each microchannel reactor is-5 ℃, the reaction time is 15s, and the reaction pressure is 0.3 MPa.
(5) Controlling the flow rate of borane tetrahydrofuran to be 60mL/min, controlling the flow rate of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to be 6mL/min, and controlling the molar ratio of (R) -2-methyl-CBS-oxazole borane to borane tetrahydrofuran to be 1: 10, enabling the flow rate of the tetrahydrofuran solution of the ketone to be 25mL/min, enabling the reacted mixture to sequentially pass through two microchannel reactors to obtain a chiral reduction material flow, enabling the obtained chiral reduction material flow and the tetrahydrofuran solution of the ketone cooled to-10 ℃ to pass through the two microchannel reactors again and react, wherein the molar ratio of the tetrahydrofuran solution of the ketone to the borane tetrahydrofuran is 1: 2.
(6) taking 7kg of reaction liquid, dripping 750g of methanol below 10 ℃ to quench reaction, concentrating the solvent in vacuum, adding 3kg of ethyl acetate and 3kg of water into the residue, stirring for 1 hour at 10 ℃, layering, washing the organic phase once with saturated saline water and water, drying the organic phase, concentrating until no fraction flows out, adding 1.5kg of petroleum ether, stirring overnight, filtering, and drying to obtain a white solid with the yield of 84%, the chemical purity of 97.78% and the chiral purity of 95.56%.
(7) After the experiment is finished, the equipment is cleaned, the pumps simultaneously convey the methanol, and the equipment can be judged to be sand-cleaned when the solution at the outlet of the reactor is clear.
Comparative example 3:
(1) the tetrahydrofuran concentrations of borane tetrahydrofuran and (R) -2-methyl-CBS-oxazole borane are both 1mol/L, and the tetrahydrofuran solution of ketone is configured to be 2mol/L, wherein the mass ratio of the ketone to the tetrahydrofuran is 1: 4.
(2) setting the temperature value of a precooler in a microreactor device, setting the precooling temperature of a borane tetrahydrofuran solution to-13 ℃, setting the precooling temperature of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to-13 ℃, and setting the precooling temperature of a reaction zone to-15 ℃.
(3) After precooling of each zone in the device is completed, starting a borane tetrahydrofuran pump, starting the (R) -2-methyl-CBS-oxazole borane tetrahydrofuran pump when the temperature is stabilized at a set value, and simultaneously introducing a ketone tetrahydrofuran solution cooled to-10 ℃, wherein the molar ratio of the ketone tetrahydrofuran solution to the borane tetrahydrofuran is 1: 1.2. at the moment, a needle valve on a pipeline of a heat exchange plate in the reactor device is adjusted, the temperature in the reaction plate is controlled under the reaction condition and is kept in a stable state, wherein the reaction temperature of the microchannel reactor is-13 ℃, the reaction time is 10s, and the reaction pressure is 0.3 MPa.
(5) Controlling the flow rate of borane tetrahydrofuran to be 60mL/min, controlling the flow rate of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran to be 6mL/min, and controlling the molar ratio of (R) -2-methyl-CBS-oxazole borane to borane tetrahydrofuran to be 1: 10, the flow rate of the tetrahydrofuran solution of the ketone is 25mL/min,
taking 7kg of reaction liquid, dripping 750g of methanol below 10 ℃ to quench reaction, concentrating the solvent in vacuum, adding 3kg of ethyl acetate and 3kg of water into the residue, stirring for 1 hour at 10 ℃, layering, washing the organic phase once with saturated saline water and water, drying the organic phase, concentrating until no fraction flows out, adding 1.5kg of petroleum ether, stirring overnight, filtering, and drying to obtain a white solid with the yield of 88.2%, the chemical purity of 98.12% and the chiral purity of 98.36%.
Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (7)
1. A method for preparing chiral alcohol from ketone by using a microchannel reactor, wherein the ketone is tert-butyl N- (2- (2, 2-dimethyl-4H-1, 3-benzodioxin-6-yl) -2-oxoethyl) carbamate, and the chiral alcohol is (R) -tert-butyl (2- (2, 2-dimethyl-4H-benzo [ D ] [1,3] dioxin-6-yl) -2-hydroxyethyl) carbamate, is characterized in that a borane tetrahydrofuran solution and a (R) -2-methyl-CBS-oxazaborolidine tetrahydrofuran solution are respectively introduced into a first microchannel reactor for mixing and reacting after being cooled, the obtained mixture is introduced into subsequent 2 microchannel reactors to obtain chiral reduction material flow, and the obtained chiral reduction material flow and the cooled tetrahydrofuran solution of the ketone enter 2 subsequent microchannel reactors, and the chiral alcohol is obtained through a post-treatment process.
2. The method for preparing chiral alcohol from ketone by using the microchannel reactor as claimed in claim 1, wherein the reaction residence time in the first microchannel reactor is 5-10S, the reaction temperature is-15 to-10 ℃, and the reaction pressure is 0-1.5 MPa; the reaction residence time of each microchannel reactor of the subsequent 2 microchannel reactors is 5-10S, and the reaction temperature is-15 to-10 ℃; the reaction pressure is 0-1.5 MPa.
3. The method of claim 1, wherein the post-treatment process comprises distillation, extraction, crystallization and filtration.
4. The method for preparing chiral alcohol from ketone by using the microchannel reactor as claimed in claim 1, wherein the material of the mixing reaction module of the microchannel reactor is silicon carbide, stainless steel, alloy or ceramic, and the feeding mode of each material of the microchannel reactor device is diaphragm pump driven continuous feeding.
5. The method for preparing chiral alcohol from ketone by using microchannel reactor as claimed in claim 1, wherein the mass ratio of ketone to tetrahydrofuran in the tetrahydrofuran solution of ketone is 1: 3 to 5.
6. The method for preparing the vilanterol key chiral intermediate by using the microchannel reactor as claimed in claim 1, wherein the concentration of borane tetrahydrofuran is 1mol/L, the concentration of (R) -2-methyl-CBS-oxazaborolidine tetrahydrofuran is 1mol/L, and the concentration of the tetrahydrofuran solution in the tetrahydrofuran solution of ketone is 2 mol/L.
7. The method for preparing chiral alcohol from ketone by using the microchannel reactor as claimed in claim 1, wherein the molar ratio of (R) -2-methyl-CBS-oxazole borane and borane tetrahydrofuran introduced into the first microchannel reactor is 5-10: 100, the molar ratio of the ketone tetrahydrofuran solution to the borane tetrahydrofuran is 1: 1.1-1.4, the flow rate of borane tetrahydrofuran is 60mL/min, the flow rate of (R) -2-methyl-CBS-oxazole borane tetrahydrofuran is 6mL/min, and the flow rate of the ketone tetrahydrofuran solution is 25 mL/min.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI791365B (en) * | 2021-01-15 | 2023-02-01 | 財團法人工業技術研究院 | Method for manufacturing alcohol compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014041565A2 (en) * | 2012-09-13 | 2014-03-20 | Laurus Labs Private Limited | An improved process for the preparation of vilanterol and intermediates thereof |
| CN107188813A (en) * | 2016-03-14 | 2017-09-22 | 益方生物科技（上海）有限公司 | Phenethanolamine derivative and its production and use |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014041565A2 (en) * | 2012-09-13 | 2014-03-20 | Laurus Labs Private Limited | An improved process for the preparation of vilanterol and intermediates thereof |
| CN107188813A (en) * | 2016-03-14 | 2017-09-22 | 益方生物科技（上海）有限公司 | Phenethanolamine derivative and its production and use |
Non-Patent Citations (3)
| Title |
|---|
| DIANE M. COE: "Potassium trimethylsilanolate induced cleavage of 1,3-oxazolidin-2 and 5-ones, and application to the synthesis of (R)-salmeterol", 《ORG. BIOMOL. CHEM.》 * |
| SONIA DE ANGELIS: "A convenient enantioselective CBS-reduction of arylketones in flow-microreactor systems", 《ORG. BIOMOL. CHEM.》 * |
| 张启龙: "维兰特罗关键手性中间体的合成工艺优化", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI791365B (en) * | 2021-01-15 | 2023-02-01 | 財團法人工業技術研究院 | Method for manufacturing alcohol compound |
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