CN108911980B - Method for kinetic resolution of alpha-hydroxy-beta-dicarbonyl compound enantiomer under micro-reaction condition or conventional reaction condition - Google Patents
Method for kinetic resolution of alpha-hydroxy-beta-dicarbonyl compound enantiomer under micro-reaction condition or conventional reaction condition Download PDFInfo
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Abstract
A method for carrying out kinetic resolution on an alpha-hydroxy-beta-dicarbonyl compound enantiomer under a micro-reaction condition or a conventional reaction condition belongs to the technical field of organic chemical synthesis. The invention uses alpha-hydroxyl-beta-dicarbonyl compound enantiomer as raw material under micro reaction condition or conventional reaction condition, uses chiral phosphorus imide acid catalyst to react with phenylhydrazine or substituted phenylhydrazine to separate two alpha-hydroxyl-beta-dicarbonyl compounds with pharmaceutical activity and single configuration. Overcomes the defects of high cost and low enantioselectivity in the prior art, has the characteristics of simple process operation, high resolution efficiency and short reaction time, can obtain a product with higher optical purity, and realizes continuous reaction.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for carrying out kinetic resolution on an alpha-hydroxy-beta-dicarbonyl compound enantiomer under a micro-reaction condition or a conventional reaction condition.
Background
Chirality is a common phenomenon in nature, in recent years, the industrial production of chiral drugs is developed at a high speed, and the alpha-hydroxy-beta-dicarbonyl compound related to the patent is an optically active structure, is a structural intermediate for synthesizing other important functional molecules, and is generally present in molecular structures of natural products and pesticides.
The common chiral intermediate alpha-hydroxy-beta-dicarbonyl compounds in the market are not single-configuration products generally, and the content of related products is calculated by the single-configuration products, so that the method has important significance for obtaining the purer single-configuration intermediate. In recent years, many efforts have been made by scientists to increase the content of active entities in α -hydroxy- β -dicarbonyl compounds. Reports on the process route for splitting and synthesizing the alpha-hydroxy-beta-dicarbonyl compound at home and abroad mainly contain the following documents: CN 101503358A; 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 apple 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.angelw.chem.int.ed., 2005,44, 4204; shi, m.tetrahedron: asymmetry,2010,21, 247; bartoli, g.angelw.chem.int.ed., 2005,44, 6219; commun.,2010,46, 1250; am chem soc,2009,131,4562; synlett2009, 16, 2659-; tetrahedron 2012,38, 7973-7977; Eur.J.org.chem.2010,34, 6526-6530; chem.2012,77,9610-9608, and the like.
Through research and summary analysis of published patent documents, the following catalysts are roughly available: chiral ligand and metal ion matched Lewis acid catalyst, TADDOLATE-Ti catalyst, bisoxazoline ligand-metal catalyst, organic small molecular catalyst, cinchona alkaloid without metal ion and derivatives thereof are organic catalyst, quaternary ammonium salt catalyst derived from cinchona alkaloid, lappaconitine, silole drug and derivatives thereof catalyst, chiral Bronsted acid catalyst and the like. Most of them have the disadvantages of low catalyst efficiency, low activity or low selectivity; although some catalysts can obtain products with high enantioselectivity, the chiral ligand or oxidant used is expensive and the operation is complicated; in addition, some oxidants have high toxicity and are not suitable for industrial production.
The micro-reaction device is a three-dimensional structural element which is manufactured by a special micro-processing technology and is used for carrying out chemical reaction on a solid matrix, and the micro-reaction device also uses unit components such as a reactor, a mixer, a heat exchanger and the like similar to the traditional chemical technology, but compared with the traditional chemical device, the micro-reaction device has very small fluid channel size and very large specific surface area, so that the micro-reaction device can realize the instant mixing of reaction materials and the precise control of reaction temperature. At present, the kinetic resolution of the alpha-hydroxy-beta-dicarbonyl compound by adopting a micro-reaction technology is not reported.
Disclosure of Invention
The invention uses alpha-hydroxy-beta-dicarbonyl compound enantiomer (rac-A) under micro reaction condition or conventional reaction condition1Or rac-A2) Uses chiral phosphorus imide acid catalyst as raw material, and makes it react with phenylhydrazine or substituted phenylhydrazine to separate out two alpha-hydroxy-beta-dicarbonyl compounds (C) with pharmaceutical activity and single configuration1And D1Or C2And D2). Overcomes the defects of high cost and low enantioselectivity in the prior art, improves the utilization rate of raw materials and the yield of products, and realizes continuous reaction.
In order to achieve the purpose, the technical route adopted by the invention is as follows:
the invention relates to a method for carrying out kinetic resolution on an alpha-hydroxy-beta-dicarbonyl compound enantiomer under a micro-reaction condition or a conventional reaction condition, which comprises the following steps:
(1) the enantiomer of alpha-hydroxy-beta-dicarbonyl compound (rac-A)1Or rac-A2) Mixing the catalyst and the solvent to obtain a homogeneous solution;
(2) dissolving phenylhydrazine or substituted phenylhydrazine (B) in the same solvent as the step (1) to obtain a homogeneous solution;
(3) the kinetic resolution reaction of the alpha-hydroxy-beta-dicarbonyl compound enantiomer comprises one of two methods of kinetic resolution in a conventional reactor or in a microreactor;
firstly, kinetic resolution in a conventional reactor: mixing the two homogeneous solutions in a three-neck flask for reaction to obtain a reaction solution;
kinetic resolution in the microreactor: simultaneously injecting the two homogeneous phase solutions into a microreactor by using a metering pump, and collecting the effluent reaction liquid after reaction;
(4) concentrating the collected reaction liquid until the solvent is completely dried, and obtaining two single-configuration alpha-hydroxy-beta-dicarbonyl after column chromatography separationBase compound (C)1And D1Or C2And D2)。
In the step (1), the structural formula of the enantiomer of the alpha-hydroxy-beta-dicarbonyl compound (rac-A) is shown as one of the following formulas:
wherein: r1Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclohexyl, fluoro, chloro, bromo, methoxy, or the like;
R2、R3、R4the same or different, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl or benzyl, etc.
n is 1 or 2.
Expressed as chiral centers
The structural formula of the substituted phenylhydrazine is shown as follows:
wherein: r5Fluorine, chlorine, bromine, iodine, nitro, ester group, cyano, methoxy, methyl, ethyl, propyl or butyl, etc.
The invention takes biaxial chiral phosphinimide acid (Cat) as a catalyst, and the structural formula is shown as follows:
wherein: r6And R7The same or different, hydrogen atom, phenyl group, 1 naphthyl group, 2 naphthyl group, triphenylsilyl group, 3, 5-bis (trifluoromethyl) phenyl group, or the like.
In the step (1) and the step (2), the solvent is benzene, xylene, mesitylene, halogenated benzenes, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methyl acetate, ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, methanol, ethanol, isopropanol, n-hexane or petroleum ether and the like.
In the step (1), the concentration of the alpha-hydroxy-beta-dicarbonyl compound enantiomer is 0.01-0.5 mol/L, and the optimal concentration is 0.04-0.3 mol/L; in the step (2), the concentration of phenylhydrazine or substituted phenylhydrazine is 0.01-1.0 mol/L, and the optimal concentration is 0.1-0.5 mol/L;
the molar ratio of phenylhydrazine or substituted phenylhydrazine in the step (2) to the enantiomer of the alpha-hydroxy-beta-dicarbonyl compound in the step (1) is 0.3-3: 1, the optimal molar ratio is 0.5-2: 1; the dosage of the catalyst is 0.1-20 mol% of the enantiomer of the alpha-hydroxy-beta-dicarbonyl compound, and the optimal dosage is 5-10 mol% of the enantiomer of the alpha-hydroxy-beta-dicarbonyl compound;
in the step (3), the reaction temperature of the micro-reaction condition and the conventional reaction condition is-20 ℃ to 50 ℃, and the optimal reaction temperature is 0 ℃ to 20 ℃;
in the step (3), the reaction time under the micro-reaction condition is 5-120 min, and the reaction time under the conventional reaction condition is 5-72 h.
The method utilizes the high-efficiency heat and mass transfer capability of the microreactor, combines the catalysis of chiral phosphoryl imide acid, has the advantages of simple process operation, high resolution efficiency and short reaction time compared with the reaction in a conventional reactor, obtains two optically pure intermediates with single configuration, obviously improves the enantioselectivity of products, improves the utilization rate of raw materials and the yield of the products, and realizes continuous reaction.
Drawings
FIG. 1 is a schematic diagram of the reaction scheme of the present invention.
FIG. 2 is a schematic structural diagram of a tubular microreactor.
As shown in FIG. 1, the micro-reaction apparatus of the micro-reaction conditions of the present invention is mainly composed of a raw material storage tank, a metering pump and a micro-reactor. The raw material storage tank is a glass storage tank, and the volume of the raw material storage tank is 10-1000 mL; the metering pump is a metering pump with adjustable flow rate (0-30 mL/min); as shown in FIG. 2, the micro-reactor (made of polytetrafluoroethylene, titanium alloy, stainless steel) comprises 2 feed inlets and a discharge outlet, the diameter of the reaction channel of the micro-reactor is 0.2-5 mm, and the length is 10-1000 cm.
As shown in fig. 1, an enantiomer of an α -hydroxy- β -dicarbonyl compound and a solution of a catalyst, and a solution of phenylhydrazine or substituted phenylhydrazine, which are respectively contained in a raw material storage tank (glass), are respectively injected into a microreactor through a metering pump, and are mixed and reacted for a certain time at a proper temperature controlled by heating or cooling liquid, and the obtained reaction liquid is concentrated and separated by column chromatography to obtain two α -hydroxy- β -dicarbonyl compounds with single configuration.
Detailed Description
In the following embodiments, the present invention is exemplified by way of the embodiments. The specific material ratios, process conditions and results described in the examples are illustrative only and should not be taken as limiting the invention as detailed in the claims.
Example 1: the conventional reaction device carries out the kinetic resolution reaction of 5-chloro-2-methoxycarbonyl-2-hydroxyl-1-indanone
In a 250mL three-necked flask, 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone enantiomer (2.4g, 9.99mmol) and 200mL of toluene were added, and H was added8-Ph(R6＝R7Phenyl-phosphorylimidic acid catalyst (0.50g, 0.5mmol) was added with stirring phenylhydrazine (1.08g, 9.99mmol) and the reaction was stirred at 20 ℃ for 24 h. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C11.78g, yield 54.0%, ee value 87%; obtaining the alpha-hydroxy-beta-dicarbonyl compound D with single configuration11.10g, yield 46.0%, ee 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)。
Example 2: utilizing a micro-reaction device to carry out the kinetic resolution reaction of 5-chloro-2-methoxycarbonyl-2-hydroxyl-1-indanone
5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone enantiomer (2.4g, 9.99mmol) and H8-Ph(R6＝R7Phenyl) phosphinimide acid catalyst (0.50g, 0.5mmol) was dissolved in toluene to give a homogeneous solution (200 mL; phenylhydrazine (1.08g, 9.99mmol) was dissolved in toluene to give a homogeneous solution (100 mL); the two homogeneous solutions were mixed as follows 2:1, injecting the mixture into a tubular microreactor with the length of 150cm and the inner diameter of 2mm by using a metering pump, reacting at the temperature of 20 ℃ for 30min, and collecting effluent liquid. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C11.66g, 50.4% yield, 92% ee. Obtaining the alpha-hydroxy-beta-dicarbonyl compound D with single configuration11.19g, 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)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)。
Example 3: utilizing a micro-reaction device to carry out the kinetic resolution reaction of 5-methyl-2-methoxycarbonyl-2-hydroxyl-1-indanone
5-Ethyl-2-methoxycarbonyl-2-hydroxy-1-indanone enantiomer (2.2g, 9.99mmol) and H8-3,5-(CF3)2C6H3)[R6＝R73, 5-bis (trifluoromethyl) phenyl]The phosphoramidite catalyst (0.77g, 0.5mmol) was dissolved in chloroform to give a homogeneous solution (240 mL); p-chlorophenylhydrazine (0.89g, 4.99mmol) was dissolved in chloroform to give a homogeneous solution (60 mL); the two homogeneous solutions were mixed as per 4: 1, injecting the mixture into a tubular micro-reactor with the length of 200cm and the inner diameter of 3mm by using a metering pump, reacting at the temperature of 10 ℃ for 40min, and collecting effluent liquid. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C11.73g, yield 55.8%, ee 82%; product D of another configuration10.96g, yield 44.0%, ee value 97%.
C1Hydrogen spectrum1H NMR(400MHz,CDCl3)δ7.69(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)δ7.74(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)。
Example 4: kinetic resolution reaction of 6-fluoro-2-methoxycarbonyl-2-hydroxy-1-indanone by using micro-reaction device
The reaction mixture of 6-fluoro-2-methoxycarbonyl-2-hydroxy-1-indanone (2.24g, 9.99mmol) and H8-1-Nap(R6＝R71 naphthyl) phosphinimide acid catalyst (0.60g, 0.5mmol) was dissolved in diethyl ether to give a homogeneous solution (150 mL); phenylhydrazine (1.42g, 9.99mmol) was dissolved in ether to give a homogeneous solution (50 mL); the two homogeneous solutions were mixed as follows 3:1, injecting the mixture into a tubular micro-reactor with the length of 500cm and the inner diameter of 1mm by using a metering pump, reacting at the temperature of 0 ℃ for 20min, and collecting effluent liquid. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C1 1.96g，Yield 56.9%, ee value 81%; product D of another configuration11.0g, yield 43.0%, ee 93%.
C1Hydrogen spectrum1H NMR(400MHz,CDCl3)δ7.41(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)δ7.52–7.39(m,3H),3.78(s,3H),3.71(dd,J＝17.1Hz,1H),3.24(dd,J＝17.1Hz,1H)。
Example 5: utilizing a micro-reaction device to carry out the kinetic resolution reaction of 5-methoxy-2-ethoxycarbonyl-2-hydroxy-1-indanone
The reaction mixture of 6-methyl-2-methoxycarbonyl-2-hydroxy-1-indanone (2.34g, 9.99mmol) and H8-2-Nap(R6＝R72-naphthyl) phosphinimidate catalyst (0.60g, 0.5mmol) was dissolved in ethanol to give a homogeneous solution (180 mL); phenylhydrazine (1.08g, 9.99mmol) was dissolved in ether to give a homogeneous solution (60 mL); the two homogeneous solutions were mixed as follows 3:1, injecting the mixture into a tubular micro-reactor with the length of 200cm and the inner diameter of 2mm by using a metering pump, reacting at the temperature of 5 ℃ for 5min, and collecting effluent liquid. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C11.68g, yield 46.2% and ee value 87%. Product D of another configuration11.25g, yield 53.7%, ee value 81%.
C1Hydrogen spectrum1H NMR(400MHz,CDCl3)δ7.60(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)δ7.62(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)。
Example 6: the micro reaction device is utilized to carry out the kinetic resolution reaction of 6-chloro-2-methoxycarbonyl-2-hydroxyl-1-indanone
The reaction mixture of 6-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone (2.4g, 9.99mmol) and H8-Ph(R6＝R7Phenyl) phosphinimide acid catalyst (0.50g, 0.5mmol) was dissolved in o-xylene to give a homogeneous solution (100 mL); phenylhydrazine (2.1g, 19.4mmol) was dissolved in o-xylene to give a homogeneous solution (50 mL); the two homogeneous solutions were mixed as follows 2:1, injecting the mixture into a tubular micro-reactor with the length of 200cm and the inner diameter of 1.5mm by using a metering pump, reacting at the temperature of 15 ℃ for 100min, and collecting effluent liquid. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C11.92g, 56.8% yield, 79% ee. Product D of another configuration11.03g, yield 43.0%, ee 92%.
C1Hydrogen spectrum of1H NMR(400MHz,CDCl3)δ7.88(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 spectrum of1H NMR(400MHz,CDCl3)δ7.93(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)。
Example 7: kinetic resolution reaction of 2-hydroxy-3-carbonyl-3-phenyl methyl propionate by using micro-reaction device
Methyl 2-hydroxy-3-carbonyl-3-phenylpropionate (1.94g, 9.99mmol) and H8-SiPh3(R6＝R7Triphenylsilyl) phosphorylideneThe amine acid catalyst (0.86g, 0.5mmol) was dissolved in methyl acetate to give a homogeneous solution (80 mL); p-methylphenylhydrazine (0.61g, 4.99mmol) was dissolved in methyl acetate to give a homogeneous solution (40 mL); the two homogeneous solutions were mixed as follows 2:1, injecting the mixture into a tubular microreactor with the length of 100cm and the inner diameter of 3mm by using a metering pump, reacting at the temperature of 10 ℃ for 30min, and collecting effluent liquid. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C21.42g, 47.6% yield, 93% ee. Product D of another configuration21.00g, yield 52.0%, ee 82%.
C2Hydrogen spectrum1H NMR(400MHz,CDCl3)δ7.93(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)。
Example 8: utilizing a micro-reaction device to carry out the kinetic resolution reaction of 4-chloro-2-methoxycarbonyl-2-hydroxyl-1-indanone
2-methoxycarbonyl-2-hydroxy-1-indanone (2.06g, 9.99mmol) and H8-3,5-(CF3)2C6H3[R6＝R73, 5-bis (trifluoromethyl) phenyl]The phosphinimide acid catalyst (0.77g, 0.5mmol) was dissolved in 1,2 dichloroethane to give a homogeneous solution (80 mL); phenylhydrazine (1.08g, 9.99mmol) was dissolved in 1,2 dichloroethane to give a homogeneous solution (20 mL); the two homogeneous solutions were mixed as per 4: 1, injecting the mixture into a tubular micro-reactor with the length of 200cm and the inner diameter of 1mm by using a metering pump, reacting at the temperature of 20 ℃ for 120min, and collecting effluent liquid. Concentrating until the solvent is completely dried, and performing column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain chiral hydrazone compound C11.79g, yield 52.9%, ee 83%. Alternative configurationProduct D11.13g, 47.0% yield, 88% ee.
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)δ7.83(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 (4)
1. A method for the kinetic resolution of the enantiomer of an α -hydroxy- β -dicarbonyl compound under microreaction conditions or conventional reaction conditions comprising the steps of:
(1) mixing an alpha-hydroxy-beta-dicarbonyl compound enantiomer, a catalyst and a solvent to obtain a homogeneous solution;
(2) dissolving phenylhydrazine or substituted phenylhydrazine in the same solvent as the step (1) to obtain a homogeneous solution;
(3) the kinetic resolution reaction of the alpha-hydroxy-beta-dicarbonyl compound comprises one of two methods of kinetic resolution in a conventional reactor or kinetic resolution in a microreactor;
firstly, kinetic resolution in a conventional reactor: mixing the two homogeneous solutions in a three-neck flask for reaction to obtain a reaction solution;
kinetic resolution in the microreactor: simultaneously injecting the two homogeneous phase solutions into a microreactor by using a metering pump, and collecting the effluent reaction liquid after reaction;
(4) concentrating the collected reaction solution until the solvent is completely dried, and separating by column chromatography to obtain two single-configuration alpha-hydroxy-beta-dicarbonyl compounds C1And D1；
Wherein, the structural formula of the alpha-hydroxy-beta-dicarbonyl compound enantiomer is shown as the following,
R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclohexyl, fluorine, chlorine, bromine or methoxy; r2Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl or benzyl
The structural formula of the substituted phenylhydrazine is shown as follows,
R3is fluorine, chlorine, bromine, nitro, methoxy or methyl;
the double-shaft chiral phosphorus imide acid is used as a catalyst, the structural formula is shown as follows,
R6and R7Identical or different and is a hydrogen atom, a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a triphenylsilyl group or a 3, 5-bis (trifluoromethyl) phenyl group;
the concentration of an alpha-hydroxy-beta-dicarbonyl compound enantiomer is 0.01-0.5 mol/L, the concentration of phenylhydrazine or substituted phenylhydrazine is 0.01-1.0 mol/L, the molar ratio of phenylhydrazine or substituted phenylhydrazine to the alpha-hydroxy-beta-dicarbonyl compound enantiomer is 0.3-3: 1, and the dosage of the catalyst is 0.1-20 mol% of the alpha-hydroxy-beta-dicarbonyl compound enantiomer;
the reaction temperature of the micro-reaction condition and the conventional reaction condition is-20-50 ℃; the reaction time under the micro-reaction condition is 5-120 min, and the reaction time under the conventional reaction condition is 5-72 h.
2. A method according to claim 1 for the kinetic resolution of the enantiomers of α -hydroxy- β -dicarbonyl compounds under microreaction or conventional reaction conditions, characterized in that: the solvent is benzene, xylene, mesitylene, halogenated benzenes, diethyl ether, tetrahydrofuran, 1, 4-dioxane, methyl acetate, ethyl acetate, dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, methanol, ethanol, isopropanol, n-hexane or petroleum ether.
3. A method according to claim 1 for the kinetic resolution of the enantiomers of α -hydroxy- β -dicarbonyl compounds under microreaction or conventional reaction conditions, characterized in that: the concentration of an alpha-hydroxy-beta-dicarbonyl compound enantiomer is 0.04-0.3 mol/L, the concentration of phenylhydrazine or substituted phenylhydrazine is 0.1-0.5 mol/L, the molar ratio of phenylhydrazine or substituted phenylhydrazine to the alpha-hydroxy-beta-dicarbonyl compound enantiomer is 0.5-2: 1, and the dosage of the catalyst is 5-10 mol% of the alpha-hydroxy-beta-dicarbonyl compound enantiomer.
4. A method according to claim 1 for the kinetic resolution of the enantiomers of α -hydroxy- β -dicarbonyl compounds under microreaction or conventional reaction conditions, characterized in that: the reaction temperature of the micro-reaction condition and the conventional reaction condition is 0-20 ℃.
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