CN108456235A - Microreactor prepares N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine - Google Patents
Microreactor prepares N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine Download PDFInfo
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- CN108456235A CN108456235A CN201810198387.4A CN201810198387A CN108456235A CN 108456235 A CN108456235 A CN 108456235A CN 201810198387 A CN201810198387 A CN 201810198387A CN 108456235 A CN108456235 A CN 108456235A
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- ethamine
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- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
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Abstract
The invention discloses a kind of continuous flow micro passage reactions to prepare N, and the method for N dimethyl (R) 1 [(S) 2 (diphenylphosphine) ferrocenyl] ethamine the described method comprises the following steps：N, the organic solvent solution of N dimethyl (R) 1 [(S) ferrocenyl] ethamine and the hexane solution of n-BuLi are passed through micro passage reaction thermostat module by metering pump respectively and carry out constant temperature processing, it is reacted subsequently into the first mixing module, reaction finishes, it is reacted into the second mixing module with diphenyl phosphine chloride, acidification, extraction, it is dry, distill to obtain product N, N dimethyl (R) 1 [(S) 2 (diphenylphosphine) ferrocenyl] ethamine crude product, crude product obtains product N through ethyl alcohol recrystallization, N dimethyl (R) 1 [(S) 2 (diphenylphosphine) ferrocenyl] ethamine.This method is easy to operate and safe, high income.
Description
Technical field
The present invention relates to chiral organic micromolecule catalysts to synthesize field, and in particular in continuous flow micro passage reaction
Prepare N, the method for N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine.
Background technology
The chiral phosphine ligands such as Xyliphos, Josiphos, TriFer with ferrocene frame having ferrocene frame are in asymmetric catalytic hydrogenation
Field is widely used (J.Am.Chem.Soc.2004,126,9918.；Angew.Chem.Int.Ed.2007,46,
4141), this high potency ligand of especially Xyliphos gives 2,000,000 turn over number, hydrogenation product in hydrogenation of imines reaction
79% ee values have been successfully applied to chiral herbicide gold all your industrialized production (Jianhua XIEs；Zhou Qilin .A cta
Chim.Sinica 2012,70,1427—1438)；N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] second
Amine is the important intermediate for synthesizing such chiral phosphine ligand.
The synthesis of N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine has document
(J.Am.Chem.Soc.1994,116(9),4062-4066；Adv.Syn.Catal.2002,344 (1), 17-31.) report, with
N, N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine is starting material, anti-with diphenyl phosphine chloride through n-BuLi lithiumation
Should after be acidified to obtain N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine, chemical equation is as follows：
This method operates in traditional glass reaction kettle, when n-BuLi is added dropwise, needs nitrogen protection, and system meeting
There is apparent heating, needs to control always rate of addition holding system temperature at 10 DEG C or so, operation process is complicated, overall reaction
Time reaches 8h or more, and has by-product generation, and product yield only has 65% or so.
Invention content
In view of the deficiencies of the prior art, it is short to provide a kind of reaction time for the technical problems to be solved of the present invention, operation letter
Just safety prepares N, the method for N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine in high yield.
N, N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine is during dropwise addition n-BuLi pulls out hydrogen lithiumation, to anti-
It answers the temperature requirement of system higher, needs temperature control to 10 DEG C or so, in reaction kettle whipping process, mass-and heat-transfer effect is poor, by-product
Object easily generates, and the reaction time is long, is up to 8h or more.In view of the above problems, we use continuous flow micro passage reaction pair
The preparation of N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine has carried out process optimization, greatly shortens
In the reaction time, improve reaction yield, the internal diameter of micro passage reaction is small (0.5-10mm), and mass-and heat-transfer efficiency is far above passing
System reaction kettle, is suitable for strong exothermal reaction.We carry out process certification, such as cardioid to different continuous current micro-reactor channel designs
Structure, T-type structure, Z-type structure, spherical structure or drops structure, achieve good effect.
The invention discloses a kind of continuous flow micro passage reactions to prepare N, N- dimethyl-(R) -1- [(S) -2- (diphenyl
Phosphine) ferrocenyl] ethamine method, it is characterised in that include the following steps：
(1) organic solvent solution of N, N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine and n-BuLi just oneself
Alkane solution is passed through micro passage reaction thermostat module by metering pump respectively and carries out constant temperature processing at 0 DEG C -30 DEG C；N, N- diformazan
The molar ratio of base-(R) -1- [(S)-ferrocenyl] ethamine and n-BuLi is 1:1~1.5；N, N- dimethyl-(R) -1-
N in the organic solvent solution of [(S)-ferrocenyl] ethamine, the quality point of N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine
Number is 10%~30%；A concentration of 1.6M~2.7M of the hexane solution of n-BuLi；N, N- dimethyl-(R) -1- [(S) -
Ferrocenyl] ethamine flow velocity by metering pump control in 10mL/min~120mL/min；The flow velocity of n-butyllithium solution passes through
Metering pump is controlled in 10mL/min~80mL/min；The organic solvent is tetrahydrofuran, 2- methyltetrahydrofurans, methyl- tert
Butyl ether, petroleum ether, hexamethylene or n-hexane；
(2) it after the completion of constant temperature processing procedure, is reacted into the first mixing module；The reaction process is in the first mixing module
Residence time is 1s~30s, and reaction temperature is 0 DEG C~30 DEG C；
(3) reaction solution of the first mixing module is reacted with diphenyl phosphine chloride in the second mixing module；This is anti-
It is 1s~30s to answer process residence time in the second mixing module, and reaction temperature is 20 DEG C~40 DEG C；N, N- dimethyl-(R)-
The molar ratio of 1- [(S)-ferrocenyl] ethamine and diphenyl phosphine chloride is 1:1~1.2；
(4) efflux that micro passage reaction exports is acidified to neutrality with concentrated hydrochloric acid, ethyl acetate aqueous layer extracted is organic
It is laminated and after, after being dried over anhydrous sodium sulfate, boil off solvent and obtain product N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine)
Ferrocenyl] ethamine crude product, crude product obtains product N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) two through ethyl alcohol recrystallization
Luxuriant iron-based] ethamine.
The invention discloses a kind of method that continuous flow micro passage reaction prepares difluoro piperonal, preferred embodiment includes
Following steps：
(1) t-butyl methyl ether solution of N, N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine and n-BuLi
Hexane solution is passed through micro passage reaction thermostat module by metering pump respectively and carries out constant temperature processing at 20 DEG C~30 DEG C；N,N-
The molar ratio of dimethyl-(R) -1- [(S)-ferrocenyl] ethamine and n-BuLi is 1:1~1.2；N, N- dimethyl-(R) -1-
N in the methyl tertiary butyl ether(MTBE) organic solvent solution of [(S)-ferrocenyl] ethamine, N- dimethyl-(R) -1- [(S)-ferrocenyl]
The mass fraction of ethamine is 15%~25%；A concentration of 1.6M~2.7M of the hexane solution of n-BuLi；N, N- dimethyl-
(R) flow velocity of -1- [(S)-ferrocenyl] ethamine is controlled by metering pump in 20mL/min~80mL/min；N-butyllithium solution
Flow velocity by metering pump control in 10mL/min~60mL/min；
(2) it after the completion of constant temperature processing procedure, is reacted into the first mixing module；The reaction process is in the first mixing module
Residence time is 3s~15s, and reaction temperature is 20 DEG C~30 DEG C；
(3) reaction solution of the first mixing module and diphenyl phosphine chloride are reacted in the second mixing module；This is anti-
It is 3s~15s to answer process residence time in the second mixing module, and reaction temperature is 30 DEG C~40 DEG C；N, N- dimethyl-(R)-
The molar ratio of 1- [(S)-ferrocenyl] ethamine and diphenyl phosphine chloride is 1:1~1.1；
(4) efflux that micro passage reaction exports is acidified to neutrality with concentrated hydrochloric acid, ethyl acetate aqueous layer extracted is organic
It is laminated and after, after being dried over anhydrous sodium sulfate, boil off solvent and obtain product N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine)
Ferrocenyl] ethamine crude product, crude product obtains product N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) two through ethyl alcohol recrystallization
Luxuriant iron-based] ethamine.
The beneficial effects are mainly as follows：
(1) the continuous flow micro passage reaction that uses of the present invention, the reaction time from document report 8 hours or more shorten to
More than ten seconds, reaction efficiency has been obviously improved it；
(2) continuous flow micro passage reaction prepares N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl]
Ethamine yield 82.4%, documents only have 65% or so, improve yield, reduce cost；
Description of the drawings
Fig. 1 continuous flow micro passage reactions prepare N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl]
The reaction process flow chart of ethamine；
Fig. 2 continuous flow micro passage reactions prepare N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl]
Ethamine schematic device：Isosorbide-5-Nitrae, 7- raw material storage tanks, 2,5,8- feed pumps, 3,6,9- pressure gauges, 10- microreactors, 11- heat exchange are situated between
Matter, 12- collection of products tanks；
Specific implementation mode
According to the process flow chart of Fig. 1 and the reactor assembly schematic diagram of Fig. 2, (1) is by raw material N, N- dimethyl-(R) -1-
It is micro- to inject continuous flow through metering pump according to a certain percentage for the organic solvent solution and n-BuLi of [(S)-ferrocenyl] ethamine
Constant temperature processing (heat transferring medium is conduction oil) is carried out in reactor thermostat module, whole process monitors pressure by pressure gauge；(2)
The organic solvent solution and n-BuLi of N, N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine enter after constant temperature is handled
The first mixing module of continuous flow micro passage reaction is reacted；The efflux and diphenyl phosphine chloride of (3) first mixing modules
It is reacted in the second mixing module；(4) efflux exported from micro passage reaction is acidified to neutrality, second with concentrated hydrochloric acid
Acetoacetic ester aqueous layer extracted after being dried over anhydrous sodium sulfate, boils off solvent and obtains product N, N- dimethyl-(R)-after organic layer merges
1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude product, product N, N- dimethyl-(R) -1- [(S)-are obtained through ethyl alcohol recrystallization
2- (diphenylphosphine) ferrocenyl] ethamine.
It further illustrates the present invention with reference to embodiments, the purpose is to be better understood on present disclosure institute body
The substantive distinguishing features of the existing present invention, therefore the cited case is not construed as limiting the scope of the invention.
Embodiment 1
(1) raw material storage tank 1,4 is respectively N, the methyl tertiary butyl ether(MTBE) of N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine
The hexane solution (2.7M) of solution (mass fraction 15%) and n-BuLi controls N, N- dimethyl-(R)-by metering pump
The flow velocity of the t-butyl methyl ether solution of 1- [(S)-ferrocenyl] ethamine is 50mL/min, the hexane solution of n-BuLi
Flow velocity is 12mL/min, and injection micro passage reaction thermostat module is handled in 25 DEG C of constant temperature；Enter microchannel plate after constant temperature processing
The first mixing module of device is answered to be reacted, 25 DEG C of reaction temperature, residence time 7.1s.
(2) efflux of the first mixing module is reacted with diphenyl phosphine chloride in the second mixing module, is passed through
The flow velocity that metering pump controls diphenyl phosphine chloride is 7mL/min, 35 DEG C of reaction temperature, residence time 6.5s.
(3) the efflux enriching hydrochloric acid of micro passage reaction is acidified to neutrality, ethyl acetate extraction, anhydrous sodium sulfate is done
It is dry, it boils off solvent and obtains brown solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude product, through second
Faint yellow solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine, N, N- bis- are obtained after alcohol recrystallization
Methyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude products are 1 with ethyl alcohol mass ratio:5；Yield 77.1%.
Embodiment 2
(1) raw material storage tank 1,4 is respectively N, the methyl tertiary butyl ether(MTBE) of N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine
The hexane solution (2.7M) of solution (mass fraction 15%) and n-BuLi controls N, N- dimethyl-(R)-by metering pump
The flow velocity of the t-butyl methyl ether solution of 1- [(S)-ferrocenyl] ethamine is 50mL/min, the hexane solution of n-BuLi
Flow velocity is 14mL/min, and injection micro passage reaction thermostat module is handled in 25 DEG C of constant temperature；Enter microchannel plate after constant temperature processing
The first mixing module of device is answered to be reacted, 25 DEG C of reaction temperature, residence time 10.7s.
(2) efflux of the first mixing module is reacted with diphenyl phosphine chloride in the second mixing module, is passed through
The flow velocity that metering pump controls diphenyl phosphine chloride is 7mL/min, 35 DEG C of reaction temperature, residence time 9.8s.
(3) the efflux enriching hydrochloric acid of micro passage reaction is acidified to neutrality, ethyl acetate extraction, anhydrous sodium sulfate is done
It is dry, it boils off solvent and obtains brown solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude product, through second
Faint yellow solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine, N, N- bis- are obtained after alcohol recrystallization
Methyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude products are 1 with ethyl alcohol mass ratio:5；Yield 82.4%.
Embodiment 3
(1) raw material storage tank 1,4 is respectively N, the methyl tertiary butyl ether(MTBE) of N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine
The hexane solution (1.8M) of solution (mass fraction 20%) and n-BuLi controls N, N- dimethyl-(R)-by metering pump
The flow velocity of the t-butyl methyl ether solution of 1- [(S)-ferrocenyl] ethamine is 75mL/min, the hexane solution of n-BuLi
Flow velocity is 39mL/min, and injection micro passage reaction thermostat module is handled in 25 DEG C of constant temperature；Enter microchannel plate after constant temperature processing
The first mixing module of device is answered to be reacted, 25 DEG C of reaction temperature, residence time 3.6s.
(2) efflux of the first mixing module is reacted with diphenyl phosphine chloride in the second mixing module, is passed through
The flow velocity that metering pump controls diphenyl phosphine chloride is 12mL/min, 35 DEG C of reaction temperature, residence time 3.4s.
(3) the efflux enriching hydrochloric acid of micro passage reaction is acidified to neutrality, ethyl acetate extraction, anhydrous sodium sulfate is done
It is dry, it boils off solvent and obtains brown solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude product, through second
Faint yellow solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine, N, N- bis- are obtained after alcohol recrystallization
Methyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude products are 1 with ethyl alcohol mass ratio:5；Yield 71.6%.
Embodiment 4
(1) raw material storage tank 1,4 is respectively N, the tetrahydrofuran solution of N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine
The hexane solution (2.7M) of (mass fraction 15%) and n-BuLi controls N, N- dimethyl-(R) -1- by metering pump
The flow velocity of the tetrahydrofuran solution of [(S)-ferrocenyl] ethamine is 50mL/min, and the flow velocity of the hexane solution of n-BuLi is
12mL/min, injection micro passage reaction thermostat module are handled in 25 DEG C of constant temperature；Enter micro passage reaction the after constant temperature processing
One mixing module is reacted, 25 DEG C of reaction temperature, residence time 10.9s.
(2) efflux of the first mixing module is reacted with diphenyl phosphine chloride in the second mixing module, is passed through
The flow velocity that metering pump controls diphenyl phosphine chloride is 7mL/min, 35 DEG C of reaction temperature, residence time 10.1s.
(3) the efflux enriching hydrochloric acid of micro passage reaction is acidified to neutrality, ethyl acetate extraction, anhydrous sodium sulfate is done
It is dry, it boils off solvent and obtains brown solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude product, through second
Faint yellow solid N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine, N, N- bis- are obtained after alcohol recrystallization
Methyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethamine crude products are 1 with ethyl alcohol mass ratio:5；Yield 77.4%.
Claims (2)
1. a kind of continuous flow micro passage reaction prepares N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] second
The method of amine, it is characterised in that include the following steps：
(1) organic solvent solution of N, N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine and the n-hexane of n-BuLi are molten
Liquid is passed through micro passage reaction thermostat module by metering pump respectively and carries out constant temperature processing at 0 DEG C -30 DEG C；N, N- dimethyl-
(R) molar ratio of -1- [(S)-ferrocenyl] ethamine and n-BuLi is 1:1~1.5；N, N- dimethyl-(R) -1- [(S)-two
Luxuriant iron-based] ethamine organic solvent solution in N, the mass fraction of N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine is
10%~30%；A concentration of 1.6M~2.7M of the hexane solution of n-BuLi；N, N- dimethyl-(R) -1- [(S)-two cyclopentadienyls
Iron-based] ethamine flow velocity by metering pump control in 10mL/min~120mL/min；The flow velocity of n-butyllithium solution passes through metering
Pump control is in 10mL/min~80mL/min；The organic solvent is tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertbutyl
Ether, petroleum ether, hexamethylene or n-hexane；
(2) it after the completion of constant temperature processing procedure, is reacted into the first mixing module；The reaction process stops in the first mixing module
Time is 1s~30s, and reaction temperature is 0 DEG C~30 DEG C；
(3) reaction solution of the first mixing module is reacted with diphenyl phosphine chloride in the second mixing module；The reaction
Journey residence time in the second mixing module is 1s~30s, and reaction temperature is 20 DEG C~40 DEG C；N, N- dimethyl-(R) -1-
The molar ratio of [(S)-ferrocenyl] ethamine and diphenyl phosphine chloride is 1:1~1.2；
(4) efflux that micro passage reaction exports is acidified to neutrality with concentrated hydrochloric acid, ethyl acetate aqueous layer extracted is organic laminated
After and, after being dried over anhydrous sodium sulfate, boils off solvent and obtain product N, N- dimethyl-(R) -1- [two cyclopentadienyls of (S) -2- (diphenylphosphine)
Iron-based] ethamine crude product, crude product obtains product N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocene through ethyl alcohol recrystallization
Base] ethamine.
2. continuous flow micro passage reaction according to claim 1 prepares N, N- dimethyl-(R) -1- [(S) -2- (hexichol
Base phosphine) ferrocenyl] ethamine crude product method, it is characterised in that include the following steps：
(1) t-butyl methyl ether solution of N, N- dimethyl-(R) -1- [(S)-ferrocenyl] ethamine and n-BuLi just oneself
Alkane solution is passed through micro passage reaction thermostat module by metering pump respectively and carries out constant temperature processing at 20 DEG C~30 DEG C；N, N- diformazan
The molar ratio of base-(R) -1- [(S)-ferrocenyl] ethamine and n-BuLi is 1:1~1.2；N, N- dimethyl-(R) -1-
N in the methyl tertiary butyl ether(MTBE) organic solvent solution of [(S)-ferrocenyl] ethamine, N- dimethyl-(R) -1- [(S)-ferrocenyl]
The mass fraction of ethamine is 15%~25%；A concentration of 1.6M~2.7M of the hexane solution of n-BuLi；N, N- dimethyl-
(R) flow velocity of -1- [(S)-ferrocenyl] ethamine is controlled by metering pump in 20mL/min~80mL/min；N-butyllithium solution
Flow velocity by metering pump control in 10mL/min~60mL/min；
(2) it after the completion of constant temperature processing procedure, is reacted into the first mixing module；The reaction process stops in the first mixing module
Time is 3s~15s, and reaction temperature is 20 DEG C~30 DEG C；
(3) reaction solution of the first mixing module and diphenyl phosphine chloride are reacted in the second mixing module；The reaction
Journey residence time in the second mixing module is 3s~15s, and reaction temperature is 30 DEG C~40 DEG C；N, N- dimethyl-(R) -1-
The molar ratio of [(S)-ferrocenyl] ethamine and diphenyl phosphine chloride is 1:1~1.1；
(4) efflux that micro passage reaction exports is acidified to neutrality with concentrated hydrochloric acid, ethyl acetate aqueous layer extracted is organic laminated
After and, after being dried over anhydrous sodium sulfate, boils off solvent and obtain product N, N- dimethyl-(R) -1- [two cyclopentadienyls of (S) -2- (diphenylphosphine)
Iron-based] ethamine crude product, crude product obtains product N, N- dimethyl-(R) -1- [(S) -2- (diphenylphosphine) ferrocene through ethyl alcohol recrystallization
Base] ethamine.
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| CN112759605A (en) * | 2021-01-26 | 2021-05-07 | 合肥立方制药股份有限公司 | Method for synthesizing Criboborol intermediate by using microchannel reactor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105254610A (en) * | 2015-11-06 | 2016-01-20 | 西安近代化学研究所 | Method for preparing difluoro piperonal by utilizing continuous flow microchannel reactor |
| CN107286202A (en) * | 2016-03-30 | 2017-10-24 | 上海茂晟康慧科技有限公司 | Synthetic method and the application of chiral Ugi ' s amine and its derivative and optical isomer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105254610A (en) * | 2015-11-06 | 2016-01-20 | 西安近代化学研究所 | Method for preparing difluoro piperonal by utilizing continuous flow microchannel reactor |
| CN107286202A (en) * | 2016-03-30 | 2017-10-24 | 上海茂晟康慧科技有限公司 | Synthetic method and the application of chiral Ugi ' s amine and its derivative and optical isomer |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112759605A (en) * | 2021-01-26 | 2021-05-07 | 合肥立方制药股份有限公司 | Method for synthesizing Criboborol intermediate by using microchannel reactor |
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