CN108911980A - The method that Kinetic Resolution is carried out to Alpha-hydroxy-beta-dicarbonyl compound enantiomer under the conditions of micro- reaction condition or popular response - Google Patents
The method that Kinetic Resolution is carried out to Alpha-hydroxy-beta-dicarbonyl compound enantiomer under the conditions of micro- reaction condition or popular response Download PDFInfo
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Abstract
A kind of method for carrying out Kinetic Resolution to Alpha-hydroxy-beta-dicarbonyl compound enantiomer under the conditions of micro- reaction condition or popular response, belongs to organic chemical synthesis technical field.The present invention is under the conditions of micro- reaction condition or popular response using Alpha-hydroxy-beta-dicarbonyl compound enantiomer as raw material, use chiral phosphorimide acid catalyst, it is acted on phenylhydrazine or substituted phenylhydrazines, isolates Alpha-hydroxy-beta-dicarbonyl compound of two kinds of single configurations with pharmaceutical active.At high cost, disadvantage that enantioselectivity is low in the prior art is changed, has the characteristics that technological operation is simple, fractionation is high-efficient, the reaction time is short, the pure product of high light can be obtained, realize successive reaction.
Description
Technical field
The invention belongs to organic chemical synthesis technical fields, and in particular under the conditions of a kind of micro- reaction condition or popular response
The method that Kinetic Resolution is carried out to Alpha-hydroxy-beta-dicarbonyl compound enantiomer.
Background technique
Chirality is a kind of universal phenomenon of nature, and in recent years, the industrialized production of chiral drug has obtained the hair of high speed
Exhibition, and Alpha-hydroxy-beta-dicarbonyl compound that this patent is related to is a kind of structure with optical activation, is that other are important for synthesis
The scaffold intermediate of functional molecular is prevalent in natural products and pesticide molecule structure.
Common chiral intermediate Alpha-hydroxy-beta-dicarbonyl compound is not generally the product of single configuration in market,
And the content of Related product is that single configuration product calculates, therefore, obtaining purer single configuration intermediate has important meaning
Justice.In recent years, to improve the effective body content of Alpha-hydroxy-beta-dicarbonyl compound, scientists have done many effort.Both at home and abroad
It is split in relation to Alpha-hydroxy-beta-dicarbonyl compound and the report of the process route of synthesis mainly contains following documents：
CN101503358A；W003002255；W003040083；Chem.Rev.1992,92,919-934；
J.Am.Chem.Soc.2000,122,8453-8463；Org.React.2003,62,1-356；
Proc.Natl.Acad.Sci.U.S.A.2004,101,5810-5814；Pure Appl.Chem.2006,78,391-396；
J.Am.Chem.Soc.2006,128,16488-16489；Togni,A.Helv.Chim.acta,2000,83,2425；Togni,
A.Proc.Natl.Acad.Sci.U.S.A.,2004,101,5810；Jorgensen,K.A.Chem.Eur.j.,2004,10,
2133；Shibata,N.Angew.Chem.Int.Ed.,2005,44,4204；Shi,M.Tetrahedro：Asymmetry,
2010,21,247；Bartoli,G.Angew.Chem.Int.Ed.,2005,44,6219；Chem.Commun.,2010,46,
1250；J.Am.Chem.Soc,2009,131,4562；Synlett2009,1 6,2659-2662；Tetrahedron 2012,
38,7973-7977；Eur.J.Org.Chem.2010,34,6526-6530；J.Org.Chem.2012,77,9610-9608 etc..
Substantially have following several by investigation to patent document and Macro or mass analysis, catalyst：Chiral ligand and gold
Belong to ion complex Lewis acid catalyst, TADDOLate-Ti catalyst, bisoxazoline ligand metal catalyst, small organic molecule
Catalyst, the cinchona alkaloid of non-metal ion and its derivative are organic catalyst, quaternary ammonium salt derived from quinine
Catalyst, lappaconitine and horse racing Luo Er drug and its derivative catalyst, chiral bronsted acid catalyst etc..It is wherein big absolutely
Majority all haves the shortcomings that catalyst efficiency is low, activity is low or selectivity is low；Although some catalyst can get high mapping choosing
The product of selecting property, but chiral ligand used or oxidant are expensive, operate also more complex；Additionally some oxidant toxicities
Greatly, be not suitable for industrial production.
Micro-reaction device is a kind of to can be used for being chemically reacted with what solid matrix manufactured by special micro-processing
Three-dimensional structure element, similar with tradition Chemical Engineering Technology, microreaction technology also uses reactor, mixer, heat exchanger etc. single
First component, but compared with traditional chemical plant installations, the fluid channel dimensions of micro-reaction device are very small, and specific surface area is very big,
Therefore the moment mixing and the accurate control to reaction temperature that reaction mass can be achieved in these micro-structural devices.Currently, adopting
Alpha-hydroxy-beta-dicarbonyl compound Kinetic Resolution is carried out with micro-reacting tcchnology to have not been reported.
Summary of the invention
The present invention is under the conditions of micro- reaction condition or popular response with Alpha-hydroxy-beta-dicarbonyl compound enantiomer
(rac-A1Or rac-A2) it is raw material, using chiral phosphorimide acid catalyst, acts on, isolate with phenylhydrazine or substituted phenylhydrazines
Alpha-hydroxy-beta-dicarbonyl compound (C of two kinds of single configurations with pharmaceutical active1And D1Or C2And D2).It changes existing
Disadvantage at high cost in technology, enantioselectivity is low improves the utilization rate and product yield of raw material, realizes successive reaction.
To achieve the above object, the technology used in the present invention route is as follows：
To Alpha-hydroxy-beta-dicarbonyl compound mapping under the conditions of a kind of micro- reaction condition or popular response of the present invention
The method that body carries out Kinetic Resolution, its step are as follows：
(1) by Alpha-hydroxy-beta-dicarbonyl compound enantiomer (rac-A1Or rac-A2), catalysts and solvents mixing, obtain
To homogeneous phase solution；
(2) phenylhydrazine or substituted phenylhydrazines (B) are dissolved in step (1) identical solvent, obtain homogeneous phase solution；
(3) Alpha-hydroxy-beta-dicarbonyl compound enantiomer Kinetic Resolution is reacted, and includes power in conventional reactor
Learn two methods of fractionation or one of Kinetic Resolution in microreactor；
1. Kinetic Resolution in conventional reactor：Hybrid reaction, reaction in three-necked flask by above two homogeneous phase solution
After obtain reaction solution；
2. Kinetic Resolution in microreactor：Above two homogeneous phase solution is injected separately into microreactor with metering pump simultaneously
In, the reaction solution of outflow is collected after reaction；
(4) reaction solution being collected into is concentrated into solvent to be completely dried, two kinds of single configurations is obtained after column chromatography for separation
Alpha-hydroxy-beta-dicarbonyl compound (C1And D1Or C2And D2)。
In step (1), shown in one of Alpha-hydroxy-beta-dicarbonyl compound enantiomer (rac-A) structural formula is following：
Wherein：R1=methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclohexyl, fluorine, chlorine, bromine
Or methoxyl group etc.；
R2、R3、R4It is identical or different, it is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, phenyl
Or benzyl etc..
N=1 or 2.
* it is expressed as chiral centre
Substituted phenylhydrazines structural formula is as follows：
Wherein：R5For fluorine, chlorine, bromine, iodine, nitro, ester group, cyano, methoxyl group, methyl, ethyl, propyl or butyl etc..
For the present invention with twin shaft chirality phosphorimide sour (Cat) for catalyst, structural formula is as follows：
Wherein：R6And R7It is identical or different, it is hydrogen atom, phenyl, 1 naphthalene, 2 naphthalenes, triphenyl silicon substrate or 3,5- bis- (three
Methyl fluoride) phenyl etc..
In step (1) and step (2), solvent be benzene, dimethylbenzene, mesitylene, halogeno-benzene class, ether, tetrahydrofuran, 1,
4- dioxane, methyl acetate, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, 1,2- dichloroethanes, methanol, second
Alcohol, isopropanol, n-hexane or petroleum ether etc..
Alpha-hydroxy-beta-dicarbonyl compound enantiomer concentration is 0.01~0.5mol/L, optimal concentration in step (1)
For 0.04~0.3mol/L；The concentration of phenylhydrazine or substituted phenylhydrazines is 0.01~1.0mol/L in step (2), and optimal concentration is
0.1~0.5mol/L；
Phenylhydrazine or substituted phenylhydrazines and Alpha-hydroxy-beta-dicarbonyl compound enantiomer molar ratio in step (1) in step (2)
It is 0.3~3：1, optimal molar ratio is 0.5~2：1；The dosage of catalyst is Alpha-hydroxy-beta-dicarbonyl compound enantiomer
0.1~20mol%, optimal dosage are 5~10mol% of Alpha-hydroxy-beta-dicarbonyl compound enantiomer；
In step (3), the reaction temperature of micro- reaction condition and popular response condition is -20 DEG C~50 DEG C, optimal reaction
Temperature is 0~20 DEG C；
In step (3), reaction time of micro- reaction condition is 5~120min, the reaction time of popular response condition is 5~
72h。
Method of the present invention utilizes the efficient hot mass transfer ability of microreactor, in conjunction with chiral phosphorimide acid catalysis,
Have that technological operation is simple, it is high-efficient to split relative to the reaction in conventional reactor, the reaction time is short, obtains two kinds of optical voidnesses
Single configuration intermediate, it will be apparent that the enantioselectivity for improving product improves the utilization rate and product yield of raw material, real
Successive reaction is showed.
Detailed description of the invention
Fig. 1 is reaction process schematic diagram of the invention.
Fig. 2 is tubular microreactors structural schematic diagram.
As described in Figure 1, the micro-reaction device of micro- reaction condition of the present invention is mainly by raw material storage tank, metering pump and micro- anti-
Device is answered to form.Raw material storage tank is glass storage tank, 10~1000mL of volume；Metering pump is that flow velocity (0~30mL/min) is adjustable
Metering pump；As shown in Fig. 2, microreactor (material is polytetrafluoroethylene (PTFE), titanium alloy, stainless steel) includes 2 feed inlets and one
Discharge port, the reaction channel aperture of microreactor are 0.2~5mm, and length is 10~1000cm.
As shown in Figure 1, Alpha-hydroxy-beta-dicarbonyl compound the enantiomer and the catalysis that raw material storage tank (glass) will be contained in respectively
The solution of the solution of agent, phenylhydrazine perhaps substituted phenylhydrazines injects microreactor by heating or cooling down hydraulic control by metering pump respectively
System is mixed and is reacted certain time at moderate temperatures, after the concentration of obtained reaction solution, through column chromatography for separation, obtain two kinds it is single
Alpha-hydroxy-beta-dicarbonyl compound of configuration.
Specific embodiment
In following case study on implementation, illustrations are carried out to the present invention in a manner of case study on implementation.Case study on implementation is retouched
Specific material proportion, process conditions and its result stated are merely to illustrate the present invention, want without that should will not limit right
Seek the present invention described in detail in book.
Embodiment 1：Popular response device carries out the chloro- 2- methoxycarbonyl group -2- hydroxide radical-1-indenone Kinetic Resolution reaction of 5-
In 250mL three-necked flask be added the chloro- 2- methoxycarbonyl group -2- hydroxide radical-1-indenone enantiomer of 5- (2.4g,
9.99mmol) with 200mL toluene, H is added8-Ph(R6=R7=phenyl) phosphorimide acid catalyst (0.50g, 0.5mmol), is stirred
Lower addition phenylhydrazine (1.08g, 9.99mmol) is mixed, is stirred to react for 24 hours at 20 DEG C.It is concentrated be completely dried to solvent, column chromatography (work
Skill parameter is that the volume ratio of petroleum ether and ethyl acetate is 1:1) after, chiral hydrazone compound C is obtained11.78g, yield 54.0%,
Ee value 87%；Obtain Alpha-hydroxy-beta-dicarbonyl compound D of single configuration11.10g, yield 46.0%, ee value 95%.
C1Hydrogen spectrum1H NMR(400MHz,CDCl3)：δ7.73(m,2H),7.30(m,2H),7.14(m,2H),7.04(m,
1H), 6.92 (m, 2H), 3.79 (s, 3H), 3.54 (dd, J=17.2Hz, 1H), 3.28 (dd, J=17.1,10.6Hz, 1H)
D1Hydrogen spectrum1H NMR(400MHz,CDCl3)：δ7.84(m,1H),7.17(m,2H),3.78(s,3H),3.74(d,J
=17.6Hz, 1H), 3.27 (d, J=17.5Hz, 1H).
Embodiment 2：The chloro- 2- methoxycarbonyl group -2- hydroxide radical-1-indenone Kinetic Resolution of 5- is carried out using micro-reaction device to react
By the chloro- 2- methoxycarbonyl group -2- hydroxide radical-1-indenone enantiomer (2.4g, 9.99mmol) of 5- and H8-Ph(R6=R7=benzene
Base) phosphorimide acid catalyst (0.50g, 0.5mmol) is dissolved in toluene, obtain homogeneous phase solution (200mL；By phenylhydrazine (1.08g,
It 9.99mmol) is dissolved in toluene, obtains homogeneous phase solution (100mL)；By both of which phase solution according to 2：1 flow velocity is infused with metering pump
In the tubular microreactors for entering long 150cm, internal diameter 2mm, 20 DEG C of reaction temperature, reaction time 30min, trickle is collected.Through
It is concentrated into that solvent is completely dried, (technological parameter is that the volume ratio of petroleum ether and ethyl acetate is 1 to column chromatography:1) after, chirality is obtained
Hydrazone compound C11.66g, yield 50.4%, ee value 92%.Obtain Alpha-hydroxy-beta-dicarbonyl compound D of single configuration1
1.19g, yield 49.5%, ee value 93%.
C1Hydrogen spectrum1H NMR(400MHz,CDCl3)δ7.73(m,2H),7.30(m,2H),7.14(m,2H),7.04(m,
1H), 6.92 (m, 2H), 3.79 (s, 3H), 3.54 (dd, J=17.2Hz, 1H), 3.28 (dd, J=17.1,10.6Hz, 1H)
D1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.84 (m, 1H), 7.17 (m, 2H), 3.78 (s, 3H), 3.74 (d, J=
17.6Hz, 1H), 3.27 (d, J=17.5Hz, 1H).
Embodiment 3：The Kinetic Resolution of 5- methyl -2- methoxycarbonyl group -2- hydroxide radical-1-indenone is carried out using micro-reaction device
Reaction
By 5- ethyl -2- methoxycarbonyl group -2- hydroxide radical-1-indenone enantiomer (2.2g, 9.99mmol) and H8-3,5-(CF3)2C6H3)[R6=R7=3,5- bis- (trifluoromethyl) phenyl] phosphorimide acid catalyst (0.77g, 0.5mmol) is dissolved in chloroform
In, obtain homogeneous phase solution (240mL)；Chlorophenyl hydrazine (0.89g, 4.99mmol) will be dissolved in chloroform, and obtain homogeneous phase solution
(60mL)；By both of which phase solution according to 4：1 flow velocity injects the tubular microreactors of long 200cm, internal diameter 3mm with metering pump
In, 10 DEG C of reaction temperature, reaction time 40min, collect trickle.It is concentrated be completely dried to solvent, column chromatography (technique ginseng
Number is that the volume ratio of petroleum ether and ethyl acetate is 1:1) after, chiral hydrazone compound C is obtained11.73g, yield 55.8%, ee value
82%；Another anomeric product D10.96g, yield 44.0%, ee value 97%.
C1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.69 (d, J=7.9Hz, 1H), 7.29 (m, 2H), 7.16 (m, 3H),
7.07(s,1H),3.78(s,2H),3.57–3.49(m,1H),3.32–3.24(m,1H),2.77–2.63(m,2H),1.34–
1.23(m,3H).
D1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.74 (d, J=7.9Hz, 1H), 7.31 (m, 1H), 3.76 (s, 3H),
3.75-3.67 (dd, J=16.3,10.6Hz, 1H), 3.22 (dd, J=14.0,9.6Hz, 1H), 2.82-2.68 (m, 2H),
1.36–1.25(m,3H)。
Embodiment 4：The Kinetic Resolution for carrying out the fluoro- 2 methoxycarbonyl group -2- hydroxide radical-1-indenone of 6- using micro-reaction device is anti-
It answers
By the fluoro- 2 methoxycarbonyl group -2- hydroxide radical-1-indenone (2.24g, 9.99mmol) of 6- and H8-1-Nap(R6=R7=1 naphthalene
Base) in the ether that is dissolved in of phosphorimide acid catalyst (0.60g, 0.5mmol), obtain homogeneous phase solution (150mL)；By phenylhydrazine
(1.42g, 9.99mmol) is dissolved in ether, obtains homogeneous phase solution (50mL)；By both of which phase solution according to 3：1 flow velocity is used tricks
Amount pump injects in the tubular microreactors of long 500cm, internal diameter 1mm, 0 DEG C of reaction temperature, reaction time 20min, collects efflux
Body.It is concentrated be completely dried to solvent, (technological parameter is that the volume ratio of petroleum ether and ethyl acetate is 1 to column chromatography:1) it after, obtains
To chiral hydrazone compound C11.96g, yield 56.9%, ee value 81%；Another anomeric product D11.0g, yield 43.0%, ee
Value 93%.
C1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.41 (dd, J=8.7,2.3Hz, 1H), 7.34-7.27 (m, 2H),
7.17 (m, 3H), 7.01 (td, J=8.6,2.4Hz, 1H), 6.93 (t, J=7.3Hz, 1H), 3.79 (s, 3H), 3.52 (dd, J
=16.8Hz, 1H), 3.27 (dd, J=16.8Hz, 1H)
D1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.52-7.39 (m, 3H), 3.78 (s, 3H), 3.71 (dd, J=
17.1Hz, 1H), 3.24 (dd, J=17.1Hz, 1H).
Embodiment 5：It is torn open using the dynamics that micro-reaction device carries out 5- methoxyl group -2- carbethoxyl group -2- hydroxide radical-1-indenone
Divide reaction
By 6- methyl -2- methoxycarbonyl group -2- hydroxide radical-1-indenone (2.34g, 9.99mmol) and H8-2-Nap(R6=R7=2
Naphthalene) phosphorimide acid catalyst (0.60g, 0.5mmol) is dissolved in ethyl alcohol, obtain homogeneous phase solution (180mL)；By phenylhydrazine
(1.08g, 9.99mmol) is dissolved in ether, obtains homogeneous phase solution (60mL)；By both of which phase solution according to 3：1 flow velocity is used tricks
Amount pump injects in the tubular microreactors of long 200cm, internal diameter 2mm, 5 DEG C of reaction temperature, reaction time 5min, collects efflux
Body.It is concentrated be completely dried to solvent, (technological parameter is that the volume ratio of petroleum ether and ethyl acetate is 1 to column chromatography:1) it after, obtains
To chiral hydrazone compound C11.68g, yield 46.2%, ee value 87%.Another anomeric product D11.25g, yield 53.7%,
Ee value 81%.
C1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.60 (s, 1H), 7.31 (dd, J=15.4,7.4Hz, 2H), 7.21-
7.10 (m, 4H), 6.91 (t, J=7.2Hz, 1H), 3.77 (s, 3H), 3.52 (d, J=16.9Hz, 1H), 3.27 (d, J=
16.8Hz,1H),2.43(s,3H).
D1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.62 (s, 1H), 7.52 (d, J=7.8Hz, 1H), 7.40 (d, J=
7.8Hz, 1H), 3.76 (s, 3H), 3.70 (d, J=17.1Hz, 1H), 3.22 (d, J=17.1Hz, 1H), 2.44 (s, 3H).
Embodiment 6：The Kinetic Resolution for carrying out the chloro- 2- methoxycarbonyl group -2- hydroxide radical-1-indenone of 6- using micro-reaction device is anti-
It answers
By the chloro- 2- methoxycarbonyl group -2- hydroxide radical-1-indenone (2.4g, 9.99mmol) of 6- and H8-Ph(R6=R7=phenyl) phosphorus
Acid imide acid catalyst (0.50g, 0.5mmol) is dissolved in ortho-xylene, obtains homogeneous phase solution (100mL)；By phenylhydrazine (2.1g,
It 19.4mmol) is dissolved in ortho-xylene, obtains homogeneous phase solution (50mL)；By both of which phase solution according to 2：1 flow velocity metering
Pump injects in the tubular microreactors of long 200cm, internal diameter 1.5mm, 15 DEG C of reaction temperature, reaction time 100min, collects outflow
Liquid.It is concentrated be completely dried to solvent, (technological parameter is that the volume ratio of petroleum ether and ethyl acetate is 1 to column chromatography:1) after,
Obtain chiral hydrazone compound C11.92g, yield 56.8%, ee value 79%.Another anomeric product D11.03g, yield 43.0%,
Ee value 92%.
C1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.88 (d, J=1.4Hz, 1H), 7.41 (dd, J=8.1,1.7Hz,
1H), 7.32 (d, J=8.2Hz, 2H), 7.15 (d, J=7.9Hz, 2H), 7.10 (d, J=8.1Hz, 1H), 6.93 (t, J=
7.3Hz, 1H), 3.79 (s, 3H), 3.50 (d, J=17.1Hz, 1H), 3.25 (d, J=17.2Hz, 1H).
D1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.93 (d, J=9.8Hz, 1H), 7.80 (dd, J=8.1,1.7Hz,
1H), 7.41 (d, J=8.2Hz, 1H), 3.77 (s, 3H), 3.69 (dd, J=17.4Hz, 1H), 3.22 (dd, J=17.4Hz,
1H)。
Embodiment 7：The Kinetic Resolution for carrying out 2- hydroxyl -3- carbonyl -3- phenylpropionic acid methyl ester using micro-reaction device is anti-
It answers
By 2- hydroxyl -3- carbonyl -3- phenylpropionic acid methyl ester (1.94g, 9.99mmol) and H8-SiPh3(R6=R7=triphen
Base silicon substrate) phosphorimide acid catalyst (0.86g, 0.5mmol) is dissolved in methyl acetate, obtain homogeneous phase solution (80mL)；It will be right
Procarbazine (0.61g, 4.99mmol) is dissolved in methyl acetate, obtains homogeneous phase solution (40mL)；By both of which phase solution according to
2：1 flow velocity is injected with metering pump in the tubular microreactors of long 100cm, internal diameter 3mm, and 10 DEG C of reaction temperature, the reaction time
30min collects trickle.It is concentrated be completely dried to solvent, (technological parameter is the body of petroleum ether and ethyl acetate to column chromatography
Product is than being 1:1) after, chiral hydrazone compound C is obtained21.42g, yield 47.6%, ee value 93%.Another anomeric product D2
1.00g, yield 52.0%, ee value 82%.
C2Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.93 (d, J=1.4Hz, 2H), 7.42 (m, 3H), 7.34 (m, 2H),
7.21 (m, 2H), 6.93 (t, J=7.3Hz, 1H), 4.17 (s, 1H), 3.79 (s, 3H).
D2Hydrogen spectrum1H NMR(500MHz,CDCl3)δ8.04-8.05(m,2H),7.59-7.62(m,1H),7.45-7.48
(m,2H),5.60(s,1H),4.42-4.49(brs,1H),3.68(s,3H)。
Embodiment 8：The Kinetic Resolution for carrying out the chloro- 2- methoxycarbonyl group -2- hydroxide radical-1-indenone of 4- using micro-reaction device is anti-
It answers
By 2- methoxycarbonyl group -2- hydroxide radical-1-indenone (2.06g, 9.99mmol) and H8-3,5-(CF3)2C6H3[R6=R7=
3,5- bis- (trifluoromethyl) phenyl] phosphorimide acid catalyst (0.77g, 0.5mmol) is dissolved in 1,2 dichloroethanes, it obtains
Phase solution (80mL)；Phenylhydrazine (1.08g, 9.99mmol) is dissolved in 1,2 dichloroethanes, homogeneous phase solution (20mL) is obtained；By two
Kind homogeneous phase solution is according to 4：1 flow velocity is injected with metering pump in the tubular microreactors of long 200cm, internal diameter 1mm, reaction temperature 20
DEG C, reaction time 120min collects trickle.It is concentrated be completely dried to solvent, column chromatography (technological parameter be petroleum ether with
The volume ratio of ethyl acetate is 1:1) after, chiral hydrazone compound C is obtained11.79g, yield 52.9%, ee value 83%.It is another
Anomeric product D11.13g, yield 47.0%, ee value 88%.
C1Hydrogen spectrum1H NMR(400MHz,CDCl3)δ7.81–7.68(m,2H),7.59–7.51(m,1H),7.35–7.31
(m, 2H), 7.24 (d, J=6.1Hz, 1H), 7.16 (d, J=8.4Hz, 2H), 6.91 (t, J=7.3Hz, 1H), 3.78 (s,
3H), 3.57 (d, J=17.0Hz, 1H), 3.32 (d, J=17.0Hz, 1H).
D1Hydrogen spectrum1H NMR (400MHz, CDCl3) δ 7.83 (d, J=7.7Hz, 1H), 7.70 (t, J=7.5Hz, 1H),
7.52 (d, J=7.7Hz, 1H), 7.46 (t, J=7.5Hz, 1H), 3.78 (d, J=2.2Hz, 1H), 3.77 (s, 3H), 3.74
(s, 1H), 3.28 (d, J=17.3Hz, 1H).
Claims (9)
1. carrying out dynamics to Alpha-hydroxy-beta-dicarbonyl compound enantiomer under the conditions of a kind of micro- reaction condition or popular response to tear open
The method divided, its step are as follows：
(1) Alpha-hydroxy-beta-dicarbonyl compound enantiomer, catalysts and solvents are mixed, obtains homogeneous phase solution；
(2) phenylhydrazine or substituted phenylhydrazines are dissolved in step (1) identical solvent, obtain homogeneous phase solution；
(3) Alpha-hydroxy-beta-dicarbonyl compound Kinetic Resolution react, include in conventional reactor Kinetic Resolution or
Two methods of one of Kinetic Resolution in microreactor；
1. Kinetic Resolution in conventional reactor：By above two homogeneous phase solution in three-necked flask hybrid reaction, after reaction
To reaction solution；
2. Kinetic Resolution in microreactor：Above two homogeneous phase solution is injected separately into microreactor with metering pump simultaneously,
The reaction solution of outflow is collected after reaction；
(4) reaction solution being collected into is concentrated into solvent to be completely dried, obtains the α-hydroxyl of two kinds of single configurations through column chromatography for separation
Base-beta-dicarbonyl compound C1And D1Or C2And D2；N=1 or 2；
2. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as described in claim 1 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：Alpha-hydroxy-beta-dicarbonyl compound enantiomer structural formula is as follows
One of shown in,
R1=methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, cyclohexyl, fluorine, chlorine, bromine or methoxyl group；
R2、R3、R4It is identical or different, it is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, phenyl or benzyl.
3. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as described in claim 1 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：Substituted phenylhydrazines structural formula is as follows,
R5For fluorine, chlorine, bromine, iodine, nitro, ester group, cyano, methoxyl group, methyl, ethyl, propyl or butyl.
4. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as described in claim 1 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：It is the structural formula using twin shaft chirality phosphorimide acid as catalyst
As follows,
R6And R7It is identical or different, it is hydrogen atom, phenyl, 1 naphthalene, 2 naphthalenes, triphenyl silicon substrate or 3,5- bis- (trifluoromethyl) benzene
Base.
5. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as described in claim 1 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：Solvent be benzene, dimethylbenzene, mesitylene, halogeno-benzene class, ether,
Tetrahydrofuran, 1,4- dioxane, methyl acetate, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, bis- chloroethene of 1,2-
Alkane, methanol, ethyl alcohol, isopropanol, n-hexane or petroleum ether.
6. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as described in claim 1 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：Alpha-hydroxy-beta-dicarbonyl compound enantiomer concentration is 0.01
The concentration of~0.5mol/L, phenylhydrazine or substituted phenylhydrazines is 0.01~1.0mol/L, phenylhydrazine or substituted phenylhydrazines and-two carbonyl of Alpha-hydroxy-β
The molar ratio of based compound enantiomer is 0.3~3:1, the dosage of catalyst is Alpha-hydroxy-beta-dicarbonyl compound enantiomer
0.1~20mol%.
7. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as claimed in claim 6 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：Alpha-hydroxy-beta-dicarbonyl compound enantiomer concentration is 0.04
The concentration of~0.3mol/L, phenylhydrazine or substituted phenylhydrazines is 0.1~0.5mol/L, phenylhydrazine or substituted phenylhydrazines and-two carbonyl of Alpha-hydroxy-β
The molar ratio of based compound enantiomer is 0.5~2:1, the dosage of catalyst is Alpha-hydroxy-beta-dicarbonyl compound enantiomer 5
~10mol%.
8. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as described in claim 1 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：The reaction temperature of micro- reaction condition and popular response condition is -20
~50 DEG C；The reaction time of micro- reaction condition is 5~120min, and the reaction time of popular response condition is 5~72h.
9. to Alpha-hydroxy-beta-dicarbonyl compound under the conditions of a kind of micro- reaction condition as claimed in claim 8 or popular response
The method of enantiomer progress Kinetic Resolution, it is characterised in that：The reaction temperature of micro- reaction condition and popular response condition be 0~
20℃。
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