CN105521826B - A kind of Zr catalyst and its prepare chiral alpha-hydroxy-beta -one ester compound method - Google Patents

A kind of Zr catalyst and its prepare chiral alpha-hydroxy-beta -one ester compound method Download PDF

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CN105521826B
CN105521826B CN201510895304.3A CN201510895304A CN105521826B CN 105521826 B CN105521826 B CN 105521826B CN 201510895304 A CN201510895304 A CN 201510895304A CN 105521826 B CN105521826 B CN 105521826B
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indenes
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孟庆伟
杨帆
刘广志
王亚坤
赵静喃
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Dalian University of Technology
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Abstract

Chiral cyclohexanediamine derivative is applied to prepare chiral alpha-hydroxy-beta -one ester compound method for the Zr catalyst of ligand the present invention relates to a kind of.This method includes in the presence of cyclohexanediamine derivative is the zirconium complex of ligand, beta-ketoester compounds contact in atent solvent with oxidant, catalyst amount is 0.5~50mol% of beta-ketoester compounds, oxidizer is 100~2000mol% of beta-ketoester compounds, reaction temperature is 0~100 DEG C, Alpha-hydroxy-beta-ketoester compounds yield is up to 99%, ee value highest 98%.Present invention uses the Zr catalysts that the cyclohexanediamine derivative being readily synthesized, price is low, property is stable is ligand, can effectively prepare chiral alpha-hydroxy-beta -one ester compound, obtain very high yield and good enantioselectivity.It is easy to operate, it is at low cost, it is suitble to industrialization.

Description

A kind of Zr catalyst and its prepare chiral alpha-hydroxy-beta -one ester compound method
Technical field
The invention belongs to asymmetry catalysis synthesis technical fields, are related to a kind of two-(2- hydroxyl-of chiral (1S, 2S)-hexamethylene Aryl methyl) amine derivative be the zirconium complex of ligand is catalyst, prepare Alpha-hydroxy-beta-ketoester compounds method.
Technical background
Some Alpha-hydroxy-beta-ketoester compounds with optical activation are important structural unit, widely exist in Natural products is used to prepare drug, pesticide and fine chemical product as intermediate.Prepare chiral alpha-hydroxy-beta -one acid esters chemical combination The catalysis oxidation beta-ketoester compounds that object is most ideal, simple, fast method is exactly enantioselectivity.Davis was in 1981 It reports for the first time and obtains chirality ɑ-hydroxy-beta-dicarbonyl compound method (Tetrahedron using Davis reagent Lett.1981,22,4385-4388), but this method is cumbersome, reaction condition is more harsh, uses excessive chiral oxygen Agent, higher cost are not suitable for production application.
In recent years, researchers report a large amount of asymmetric syntheses chiral alpha-hydroxy-beta -one ester compound Method.Including 1) metal complex；2) organic catalysis.For organic catalysis, document WO 03/040083 and J.Org.Chem.2004,69,8165-8167 to disclose with cinchona alkaloid and its derivative be organic catalyst, organic mistake Oxide is oxidant, prepares a kind of chiral alpha-method of hydroxy-beta-dicarbonyl compound, wherein oxidation products yield is generally 80-90%, corresponding selection are generally 50-80%ee.The fragrant oxygen alkamine catalyst of our seminar's independent developments (Tetrahedron.2012,38,7973-7977), and Diterpenoid Alkaloids lappaconitine (Synlett.2009,16,2659- 2662) also there is preferable catalytic effect, however, these method reaction time are long, enantioselectivity is not very ideal.And metal In terms of complex, document (Proc.Natl.Acad.Sci.U.S.A.2004,101,5810-5814) reports tartaric acid for the first time The metal complex of derivative chiral ligand and tetravalence Ti coordination；The tartaric acid derivatives and Mg of Feng seminar report in recent years The complex compound of coordination is catalyst (Adv.Synth.Catal.2013,355,1924-1930)；Che report salen ligand with The complex that Fe is formed is that catalyst (Chem.Commun.2014,50,7870-7873) can also obtain some preferable results. But the oxidant of these methods application is generally complicated azepine oxirane.These factors limit above-mentioned two The application of class method.For preparing chiral alpha-hydroxy-beta -one ester compound, it is still desirable to improve more economical preparation side Method.Therefore, the present invention provides one to prepare chiral alpha-hydroxy-beta -one ester compound improved method.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of two-(2- bis (hydroxy-aromatic) ylmethyls) of chiral (1S, 2S)-hexamethylene Amine derivative is that the zirconium complex of ligand is catalyst, and under oxidant effect, catalysis beta-ketoester compounds (III) is asymmetric Hydroxylating, the method for preparing Alpha-hydroxy-beta-ketoester compounds (IV).
Technical scheme is as follows:
A kind of Zr catalyst using chiral two-(2- bis (hydroxy-aromatic) ylmethyl) amine derivative of (1S, 2S)-hexamethylene as ligand Chiral alpha-hydroxy-beta -one ester compound method is prepared, feature preparation process is as follows:
It is catalysis by the zirconium complex that chirality two-(2- bis (hydroxy-aromatic) ylmethyl) amine derivative of (1S, 2S)-hexamethylene is ligand Agent, beta-ketoester compounds and oxidant, which are placed in react in atent solvent, is made chiral alpha-hydroxy-beta -one ester compound；Reaction Temperature is 0~100 DEG C；Catalyst amount is 0.5~50mol% of beta-ketoester compounds；Oxidizer is beta-ketoester 100~2000mol% of compound.
(1S, 2S)-hexamethylene two-(2- bis (hydroxy-aromatic) ylmethyl) amine derivative is the zirconium complex such as following formula of ligand
In this method complex can selected from zirconium alkoxide be complex such as, zirconium iso-propoxide (IV), butanol zirconium (IV), uncle Butanol zirconium (IV) or acetylacetone,2,4-pentanedione zirconium (IV).
Particularly preferred zirconium complex is acetylacetone,2,4-pentanedione zirconium (IV).
Zirconium complex includes the ligand of zirconium and formula II:
Wherein, (1S, 2S)-hexamethylene two-(2- bis (hydroxy-aromatic) ylmethyl) amine is connection chain.
R5, R6It is each independently selected from halogen, NO2, cyano, C2-C8Alkyl, C5-C6Naphthenic base, C2-C8Alkoxy, Buddha's warrior attendant Alkyl, phenyl ring, five yuan of heteroaromatics, hexa-atomic heteroaromatic, 1- naphthalene；N takes 0-4.
Wherein in formula II each phenyl ring have adjacent to be located at-OH functional group R5Or R6Substituent group.
Particularly preferred complex includes the complex of II a ligand of zirconium and formula:
Particularly preferred R5For tert-butyl, R6For 1- naphthalene.
The preparation method of II a ligand of formula can be prepared with universal method known in the art, the method as shown in Scheme1. Note that process is first is that R5And R6Synthetic route when identical.
Process one
Process is second is that R5And R6Asynchronous synthetic route.
Process two
Scheme1. the preparation method of II a ligand of formula
Beta-ketoester compounds such as following formula III, chiral alpha-hydroxy-beta -one ester compound such as following formula IV:
R1For hydrogen atom, halogen, alkyl, alkoxy, naphthenic base；
R2For hydrogen atom, halogen, alkyl, alkoxy, naphthenic base；
R3For hydrogen atom, halogen, alkyl, alkoxy, naphthenic base；
R4For alkyl, naphthenic base, aromatic ring, benzyl；
N takes 1 or 2.
The chiral centre of " * " expression compound.
Wherein oxidants hydrogen peroxide；Alkyl peroxide includes carbamide peroxide, tert-butyl hydroperoxide, hydrogen peroxide Isopropylbenzene, neopentyl hydrogen peroxide；Peroxy acid includes metachloroperbenzoic acid, Peracetic acid.Wherein preferred oxidant is peroxide Change hydrogen isopropylbenzene, tert-butyl hydroperoxide.Optimal oxidant is cumyl hydroperoxide.Oxidizer is beta-ketoester chemical combination 100~2000mol% of object, wherein preferred ratio is 150~500mol%.
The atent solvent includes chloroform, carbon tetrachloride, methylene chloride, bromomethane, methylene bromide, 1,2-, bis- chloroethene The halogenated hydrocarbons such as alkane；The aromatic hydrocarbon such as benzene, toluene, paraxylene, ortho-xylene or mesitylene；N-hexane, normal heptane, hexamethylene, The alkane such as n-dodecane, petroleum ether (60 DEG C~90 DEG C).Preferred solvent is petroleum ether, n-hexane, paraxylene and equal front three Benzene low polar solvent.
Reaction temperature carries out in 0~100 DEG C, and preferably 25 DEG C~60 DEG C.
The invention has the advantages that using (1S, the 2S)-hexamethylene two-(2- being readily synthesized, price is low, property is stable Bis (hydroxy-aromatic) ylmethyl) amine derivative be the zirconium complex of ligand is catalyst, it can effectively prepare chiral alpha-hydroxy-beta -one acid Ester compounds obtain very high yield and good enantioselectivity.Easy to operate, reaction condition is mild, at low cost, is suitble to Commercial scale.
Detailed description of the invention
Fig. 1 is (2S) -6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester chirality HLPC figure.
Fig. 2 is racemic 6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester chirality HLPC Figure.
Specific embodiment
Specific embodiments of the present invention are described in detail below with reference to technical solution.
The preparation of embodiment 1 (1S, 2S) -1,2- bis- ((4,6- diphenyl) phenol -2- methylamino)-hexamethylene (II a of formula, R5, R6For phenyl)
It weighs (1S, 2S) -1,2- cyclohexanediamine 2.28g (20mmol) to be dissolved in 100mL methanol, takes 2- hydroxyl -3,5- bis- Phenyl-benzaldehyde 10.96g (40mmol) is dissolved in 50mLTHF, and after being slowly added drop-wise in system at room temperature, system is added To back flow reaction 3 hours, system turned yellow solution.Then, system is cooled to room temperature, and sodium borohydride 3.08g is added portionwise After (80mmol), react 1 hour at room temperature.50mL water and 100mL methylene chloride are added to system, and liquid separation, water layer is with two Chloromethanes 30mL × 2 is extracted, and merges methylene chloride and water and saturated salt solution 50mL × 3 is used to wash respectively, anhydrous sodium sulfate is dry.It crosses Filter, vacuum rotary steam remove solvent, and remaining solid petrol ether/ethyl acetate=8/1 recrystallization obtains white solid 12.23g yield 97%.1H NMR(400MHz,CDCl3) δ 7.59-7.52 (m, 8H), 7.47 (d, J=2.3Hz, 2H), 7.43- 7.32 (m, 12H), 7.22 (d, J=2.3Hz, 2H), 4.18 (d, J=13.8Hz, 2H), 4.03 (d, J=13.8Hz, 2H), 2.58–2.52(m,2H),2.25–2.18(m,2H),1.76–1.71(m,2H),1.30–1.23(m,4H).13C NMR (126MHz,CDCl3)δ154.41,140.84,138.21,132.45,129.59,129.37,128.72,128.69, 128.13,126.95,126.67,126.57,126.38,123.59,60.04,50.00,30.49,24.19.
Embodiment 2 prepares (1S, 2S) -1,2- two ((4,6- bis- (1- naphthalene)) phenol -2- methylamino)-hexamethylene (formula II a, R5, R6For 1- naphthalene)
It weighs (1S, 2S) -1,2- cyclohexanediamine 1.71g (15mmol) to be dissolved in 100mL methanol, takes 2- hydroxyl -3,5- bis- Phenyl-benzaldehyde 11.22g (30mmol) is dissolved in 50mLTHF, and after being slowly added drop-wise in system at room temperature, system is added To back flow reaction 3 hours, system turned yellow solution.Then, system is cooled to room temperature, and sodium borohydride 2.31g is added portionwise After (60mmol), react 1 hour at room temperature.50mL water and 100mL methylene chloride are added to system, and liquid separation, water layer is with two Chloromethanes 30mL × 2 is extracted, and merges methylene chloride and water and saturated salt solution 50mL × 3 is used to wash respectively, anhydrous sodium sulfate is dry.It crosses Filter, vacuum rotary steam remove solvent, and remaining solid petrol ether/ethyl acetate=10/1 recrystallization obtains white solid 11.84g yield 95%.1H NMR(500MHz,CDCl3) δ 8.05 (d, J=8.2,2H), 7.88 (d, J=8.1Hz, 2H), 7.85–7.71(m,8H),7.53–7.32(m,18H),7.22–7.18(m,2H),4.39–3.90(m,4H),2.68–2.46(m, 2H),2.28–2.13(m,2H),1.75–1.66(m,2H),1.32–1.17(m,4H).13C NMR(126MHz,CDCl3)δ 154.57,139.74,133.89,133.66,133.61,132.74,131.98,131.73,131.48,129.68,128.30, 128.24,127.91,127.69,127.63,127.30,127.05,126.46,126.10,125.99,125.82,125.73, 125.69,125.65,125.46,123.04,60.02,49.89,49.69,30.46,30.21,29.80,24.18.
Embodiment 3 prepares (1S, 2S) -2- ((3,5- di-t-butyl -2- phenol methylene) amino) hexamethylene -1- amine salt Hydrochlorate
It weighs (1S, 2S) -1,2- cyclohexanediamine 5.7g (50mmol) to be dissolved in methanol 100mL, be measured with pipette 4.17mL (50mmol) concentrated hydrochloric acid, is slowly added dropwise in ice bath, continues stirring 30 minutes after being added dropwise to complete.Then, 3,5- are weighed Di-t-butyl -2- hydroxy-benzaldehyde 11.7g (50mmol) is dissolved in 50mLTHF, (is not shorter than 50 in slowly dropwise addition in condition of ice bath Minute), system stops reaction after being warmed to room temperature reaction 35 minutes later.Solvent is removed under reduced pressure, 50mL methanol is added to residue, Decompression filters.Vacuum drying, obtains yellow solid 17.9g, yield 98%.
Embodiment 4 prepares 2- (((1S, 2S) -2- aminocyclohexyl) amine methyl) -4,6- DI-tert-butylphenol compounds
Take (1S, 2S) -2- ((3,5- di-t-butyl -2- phenol methylene) amino) hexamethylene -1- amine hydrochlorate 14.7g (40mmol) is dissolved in 75mL methanol and 8mL glacial acetic acid, be added portionwise under condition of ice bath sodium borohydride 3.04g (80mmol) it Afterwards, system is warmed to room temperature reaction 2 hours.Be added 100mL water and 100mL methylene chloride, liquid separation, water layer with methylene chloride 30mL × 2 extractions, merge dichloromethane layer, are washed respectively with water and saturated salt solution 50mL × 3, and anhydrous sodium sulfate is dry.Filtering, decompression rotation Solvent is evaporated off, remaining solid methylene chloride/methanol=25/1 column chromatography for separation obtains blue solid 13.16g, yield 99%.1H NMR(500MHz,CDCl3) δ 7.21 (d, J=2.4Hz, 1H), 6.89 (d, J=2.4Hz, 1H), 4.07 (d, J= 13.2Hz, 1H), 3.89 (d, J=13.2Hz, 1H), 2.70-2.60 (m, 1H), 2.42-2.33 (m, 1H), 2.23-2.15 (m, 1H),2.06–1.97(m,1H),1.76–1.67(m,2H),1.41(s,9H),1.28(s,9H),1.25–1.10(m,4H).13C NMR(126MHz,CDCl3)δ154.30,140.61,136.03,123.33,122.94,122.89,62.11,54.65, 50.35,34.91,34.82,34.17,31.72,30.59,29.72,24.80,24.60.
Embodiment 5 prepares (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- ((1- naphthalene of 4,6- bis- Base) phenol) -2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene)
It is molten to weigh 2- (((1S, 2S) -2- aminocyclohexyl) amine methyl) -4,6- DI-tert-butylphenol compounds 3.33g (10mmol) In 50mL methanol, weighs 2- hydroxyl -3,5- bis- (1- naphthalene)-benzaldehyde 3.75g (10mmol) and be dissolved in 25mLTHF, in room After being slowly added drop-wise in system under temperature, system is added to back flow reaction 2 hours, system turns yellow solution.Then, system is cold But it to room temperature, is added portionwise after sodium borohydride 0.77g (20mmol), reacts 1 hour at room temperature.50mL water is added to system With 100mL methylene chloride, liquid separation, water layer is extracted with methylene chloride 30mL × 2, is merged methylene chloride and is used water and saturated common salt respectively Water 50mL × 3 are washed, and anhydrous sodium sulfate is dry.Filtering, vacuum rotary steam remove solvent, remaining solid petrol ether/ethyl acetate =5/1 column chromatography for separation obtains violet solid 6.84g, yield 98%.1H NMR(500MHz,CDCl3) δ 8.08 (d, J= 8.2Hz, 1H), 7.90-7.80 (m, 5H), 7.55-7.37 (m, 9H), 7.32-7.28 (m, 1H), 7.19 (t, J=2.9Hz, 1H),6.91–6.80(m,1H),4.27–4.18(m,1H),4.15–4.11(m,1H),4.10–4.04(m,1H),3.88(dd,J =13.3,6.9Hz, 1H), 2.64-2.48 (m, 2H), 2.29-2.17 (m, 2H)), 1.76-1.72 (m, 2H), 1.31 (s, 9H), 1.30–1.25(m,4H),1.23(s,9H).13C NMR(126MHz,CDCl3)δ154.83,154.17,140.74,139.86, 136.41,136.00,133.84,133.61,132.60,132.02,131.73,131.26,129.43,128.23,128.15, 127.95,127.66,127.18,126.99,126.54,126.12,125.91,125.83,125.68,125.53,125.43, 125.38,
The preparation of embodiment 6 (2S) -5-Chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indole-2-carboxylic acid methyl ester (formula III, Middle R1, R3For H, R2For Cl, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle chloro- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester of addition 5- (formula III, wherein R1, R3For H, R2For Cl, R4For Me, 0.0224g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating acquired solution is extremely 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the chloro- 2,3- dihydro -1- of 5- > 99% conversion occurs for oxo -1H- indenes -2- carboxylate methyl ester, generates chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic of 5- Sour methyl esters, yield 98%, and the ee of S- enantiomter are 96%.1H NMR(500MHz,CDCl3) δ 7.74 (d, J=8.3Hz, 1H), 7.50 (s, 1H), 7.43 (d, J=8.2Hz, 1H), 3.97 (s, 1H), 3.75 (s, 3H), 3.71 (d, J=17.5Hz, 1H), 3.24 (d, J=17.5Hz, 1H)
Embodiment 7 prepares (2S) -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1, R2, R3For H, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- amine-(4,6- DI-tert-butylphenol compounds) methyl)-(2- amine-(4,6- bis- (1- naphthalene) phenol) first Base)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).After stirring 30 minutes, with 0.22 μ M membrane filtration, filtrate are spin-dried for solution under reduced pressure, dissolve the residue in petroleum ether 2mL.2,3- is added into this toluene solution Dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1, R2, R3For H, R4For Me, 0.0190g, 0.1mmol) and mistake Hydrogen oxide isopropyl benzene aquatic solution (70%, 0.0326g, 0.15mmol), heating acquired solution is to 50 DEG C, after being kept for 2 hours, solution The 2mL that adds methylene chloride dilution.The generation of quantitative and chiral HPLC display 2,3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester > 99% conversion, generates 2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester, yield 99%, and S- enantiomter Ee be 94%.1H NMR(500MHz,CDCl3) δ 7.81 (dd, J=7.7,1.1Hz, 1H), 7.68 (td, J=7.7,1.2Hz, 1H), 7.50 (dd, J=7.6,1.1Hz, 1H), 7.43 (td, J=7.7,1.2Hz, 1H), 3.75 (s, 3H), 3.74 (d, J= 17.2H, 1H), 3.26 (d, J=17.2Hz, 1H)
The preparation of embodiment 8 bromo- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester of (2S) -5- (formula III, Middle R1, R3For H, R2For Br, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle bromo- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester of addition 5- (formula III, wherein R1, R3For H, R2For Br, R4For Me, 0.0269g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating acquired solution is extremely 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the bromo- 2,3- dihydro -1- of 5- > 99% conversion occurs for oxo -1H- indenes -2- carboxylate methyl ester, generates bromo- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic of 5- Sour methyl esters, yield 97%, and the ee of S- enantiomter are 93%.1H NMR(500MHz,CDCl3)δ7.69(m,1H),7.66 (d, J=8.2Hz, 1H), 7.59 (d, J=8.2Hz, 1H), 3.75 (s, 3H), 3.71 (d, J=17.4Hz, 1H), 3.24 (d, J =17.4Hz, 1H)
The preparation of embodiment 9 bromo- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester of (2S) -6- (formula III, Middle R1, R2For H, R3For Br, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- amine-(4,6- DI-tert-butylphenol compounds) methyl)-(2- amine-(4,6- bis- (1- naphthalene) phenol) first Base)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).After stirring 30 minutes, with 0.22 μ M membrane filtration, filtrate are spin-dried for solution under reduced pressure, dissolve the residue in petroleum ether 2mL.6- is added into this toluene solution Bromo- 2,3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1, R2For H, R3For Br, R4For Me, 0.0269g, 0.1mmol) kept with cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating acquired solution to 50 DEG C After 2 hours, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the bromo- 2,3- dihydro -1- oxo -1H- of 6- > 99% conversion occurs for indenes -2- carboxylate methyl ester, generates bromo- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester of 6-, Yield 88%, and the ee of S- enantiomter is 87%.1H NMR(500MHz,CDCl3) δ 7.93 (d, J=2.0Hz, 1H), 7.78 (dd, J=8.2,2.0Hz, 1H), 7.39 (d, J=8.2Hz, 1H), 3.75 (s, 3H), 3.67 (d, J=17.4Hz, 1H), 3.20 (d, J=17.3Hz, 1H)
The preparation of embodiment 10 bromo- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester of (2S) -4- (formula III, Middle R2, R3For H, R1For Br, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle bromo- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester of addition 4- (formula III, wherein R2, R3For H, R1For Br, R4For Me, 0.0269g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating acquired solution is extremely 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the bromo- 2,3- dihydro -1- of 4- > 99% conversion occurs for oxo -1H- indenes -2- carboxylate methyl ester, generates bromo- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic of 4- Sour methyl esters, yield 97%, and the ee of S- enantiomter are 80%.1H NMR(500MHz,CDCl3) δ 7.85 (dd, J=7.8, 1.0Hz, 1H), 7.76 (dd, J=7.8,0.9Hz, 1H), 7.37 (dt, J=7.7,0.9Hz, 1H), 3.97 (s, 1H), 3.77 (s, 3H), 3.68 (d, J=17.8Hz, 1H), 3.19 (d, J=17.8Hz, 1H)
Embodiment 11 prepares (2S) -6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1, R2For H, R3For-OCH3, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- amine-(4,6- DI-tert-butylphenol compounds) methyl)-(2- amine-(4,6- bis- (1- naphthalene) phenol) first Base)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).After stirring 30 minutes, with 0.22 μ M membrane filtration, filtrate are spin-dried for solution under reduced pressure, dissolve the residue in petroleum ether 2mL.6- first is added into this toluene solution Oxygroup -2,3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1, R2For H, R3For-OCH3, R4For Me, 0.0220g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating acquired solution is extremely 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows 6- methoxyl group -2,3- two > 99% conversion occurs for hydrogen -1- oxo -1H- indenes -2- carboxylate methyl ester, generates 6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo - 1H- indenes -2- carboxylate methyl ester, yield 98%, and the ee of S- enantiomter are 98%.1H NMR(500MHz,CDCl3)δ7.39 (d, J=8.4Hz, 1H), 7.27 (dd, J=8.4,2.6Hz, 1H), 7.22 (d, J=2.6Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.65 (d, J=16.9Hz, 1H), 3.18 (d, J=16.9Hz, 1H)
Attached drawing 1 is (2S) -6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester chirality HLPC Figure, following table is details:
Attached drawing 2 is that racemic 6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester is chiral HLPC figure, following table is details:
Embodiment 12 prepares (2S) -4- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R2, R3For H, R1For-OCH3, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle addition 4- methoxyl group -2,3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R2, R3For H, R1For-OCH3, R4 For Me, 0.0220g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), it is molten to heat gained Liquid to 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows methoxyl group -2 4-, > 99% conversion occurs for 3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester, generates 4- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxygen Generation -1H- indenes -2- carboxylate methyl ester, yield 94%, and the ee of S- enantiomter are 89%.1H NMR(500MHz,CDCl3)δ 7.45-7.36 (m, 2H), 7.11 (dd, J=7.1,1.7Hz, 1H), 3.92 (s, 3H), 3.74 (s, 3H), 3.66 (d, J= 17.7Hz, 1H), 3.12 (d, J=17.7Hz, 1H)
Embodiment 13 prepares (2S) -5,6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1For H, R2, R3For-OCH3, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle addition 5,6- methoxyl group -2,3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1For H, R2, R3For-OCH3, R4For Me, 0.0250g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating gained Solution to 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows 5,6- methoxy > 99% conversion occurs for base -2,3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester, generates 5,6- methoxyl group -2,3- dihydro -2- hydroxyl Base -1- oxo -1H- indenes -2- carboxylate methyl ester, yield 81%, and the ee of S- enantiomter are 84%.1H NMR(500MHz, CDCl3) δ 7.20 (s, 1H), 6.91 (s, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.75 (s, 3H), 3.65 (d, J= 16.9Hz, 1H), 3.17 (d, J=16.9Hz, 1H)
The preparation of embodiment 14 (2S) -6- methyl -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, Wherein R1, R2For H, R3For-CH3, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle addition 6- methyl -2,3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester (formula III, wherein R1, R2For H, R3For-CH3, R4For Me, 0.0204g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heat acquired solution To 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows 6- methyl -2,3- two > 99% conversion occurs for hydrogen -1- oxo -1H- indenes -2- carboxylate methyl ester, generates 6- methyl -2,3- dihydro -2- hydroxyl -1- oxo -1H- Indenes -2- carboxylate methyl ester, yield 99%, and the ee of S- enantiomter are 95%.1H NMR(500MHz,CDCl3)δ7.60(d,J =1.8Hz, 1H), 7.50 (dd, J=7.8,1.8Hz, 1H), 7.38 (dd, J=7.8Hz, 1H), 3.74 (s, 3H), 3.68 (d, J =17.1Hz, 1H), 3.21 (d, J=17.1Hz, 1H), 2.42 (s, 3H)
The preparation of embodiment 15 fluoro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylate methyl ester of (2S) -6- (formula III, Middle R1, R2For H, R3For-F, R4For Me)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle fluoro- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylate methyl ester of addition 6- (formula III, wherein R1, R2For H, R3For-F, R4For Me, 0.0208g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating acquired solution is extremely 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the fluoro- 2,3- dihydro -1- of 6- > 99% conversion occurs for oxo -1H- indenes -2- carboxylate methyl ester, generates fluoro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic of 6- Sour methyl esters, yield 81%, and the ee of S- enantiomter are 94%.1H NMR(500MHz,CDCl3)δ7.52–7.36(m,3H), 3.76 (s, 3H), 3.69 (d, J=17.1Hz, 1H), 3.22 (d J=17.1,1H)
The preparation of embodiment 16 chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid, ethyl ester of (2S) -5- (formula III, Middle R1, R3For H, R2For Cl, R4For ethyl)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle chloro- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylic acid, ethyl ester of addition 5- (formula III, wherein R1, R3For H, R2For Cl, R4For ethyl, 0.0239g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating acquired solution is extremely 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the chloro- 2,3- dihydro -1- of 5- 99% conversion occurs for oxo -1H- indenes -2- carboxylic acid, ethyl ester, generates chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic of 5- Acetoacetic ester, yield 91%, and the ee of S- enantiomter are 94%.1H NMR(500MHz,CDCl3) δ 7.74 (d, J=8.2Hz, 1H), 7.50 (d, J=1.6Hz, 1H), 7.42 (dd, J=8.2,1.6Hz, 1H), 4.22 (q, J=7.2Hz, 2H), 3.99 (s, 1H), 3.69 (d, J=17.4Hz, 1H), 3.23 (d, J=17.4Hz, 1H), 1.20 (t, J=7.2Hz, 3H)
The preparation of embodiment 17 chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid isopropyl of (2S) -5- (formula III, Wherein R1, R3For H, R2For Cl, R4For isopropyl)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle chloro- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylic acid isopropyl of addition 5- (formula III, wherein R1, R3For H, R2For Cl, R4It is different Propyl, 0.0253g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), it is molten to heat gained Liquid to 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the chloro- 2,3- bis- of 5- 96% conversion occurs for hydrogen -1- oxo -1H- indenes -2- carboxylic acid isopropyl, generates chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- of 5- Indenes -2- carboxylic acid isopropyl, yield 82%, and the ee of S- enantiomter are 88%.1H NMR(500MHz,CDCl3)δ7.73(d, J=8.2Hz, 1H), 7.50 (d, J=1.5Hz, 1H), 7.42 (dd, J=8.2,1.7Hz, 1H), 5.08 (hept, J=6.2Hz, 1H), 4.00 (s, 1H), 3.66 (d, J=17.3Hz, 1H), 3.22 (d, J=17.3Hz, 1H), 1.21 (d, J=6.3Hz, 3H), 1.14 (d, J=6.2Hz, 3H)
The preparation of embodiment 18 chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid benzyl ester of (2S) -5- (formula III, Wherein R1, R3For H, R2For Cl, R4For benzyl)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle chloro- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylic acid benzyl ester of addition 5- (formula III, wherein R1, R3For H, R2For Cl, R4For benzyl Base, 0.0301g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heat acquired solution To 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the chloro- 2,3- dihydro-of 5- 95% conversion occurs for 1- oxo -1H- indenes -2- carboxylic acid benzyl ester, generates chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes-of 5- 2- carboxylic acid benzyl ester, yield 85%, and the ee of S- enantiomter are 93%.1H NMR(500MHz,CDCl3) δ 7.73 (d, J= 8.7Hz, 1H), 7.48 (s, 1H), 7.42 (d, J=8.7Hz, 1H), 7.36-7.30 (m, 5H), 7.23-7.14 (m, 3H), 5.29-5.07 (m, 2H), 3.97 (s, 1H), 3.68 (d, J=17.5Hz, 1H), 3.23 (d, J=17.6Hz, 1H)
The preparation of embodiment 19 chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid Buddha's warrior attendant ester of (2S) -5- (formula III, Wherein R1, R3For H, R2For Cl, R4For adamantyl)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle chloro- 2, the 3- dihydro -1- oxo -1H- indenes -2- carboxylic acid Buddha's warrior attendant ester of addition 5- (formula III, wherein R1, R3For H, R2For Cl, R4For gold Rigid base, 0.0345g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), it is molten to heat gained Liquid to 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows the chloro- 2,3- bis- of 5- 96% conversion occurs for hydrogen -1- oxo -1H- indenes -2- carboxylic acid Buddha's warrior attendant ester, generates chloro- 2, the 3- dihydro -2- hydroxyl -1- oxo -1H- of 5- Indenes -2- carboxylic acid Buddha's warrior attendant ester, yield 81%, and the ee of S- enantiomter are 89%.1H NMR(500MHz,CDCl3)δ7.74(d, J=8.2Hz, 1H), 7.52 (s, 1H), 7.42 (d, J=8.2Hz, 1H), 4.03 (s, 1H), 3.68 (d, J=17.2Hz, 1H), 3.28 (d, J=17.2Hz, 1H), 1.96-1.22 (m, 15H)
Embodiment 20 prepares (2S) -5,6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid tert-butyl ester (formula III, wherein R1For H, R2, R3For-OCH3, R4It is t-Bu) chiral zirconium complex by toluene 3mL, in 50 DEG C of stirring second Acyl acetone zirconium (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) -2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).After stirring 30 minutes, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in stone In oily ether 2mL.5,6- methoxyl group -2,3- dihydro -1- oxo -1H- indenes -2- carboxylic acid tert-butyl ester (formula is added into this toluene solution III, wherein R1For H, R2, R3For-OCH3, R4For t-Bu, 0.0292g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heat acquired solution to 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.It is quantitative and Chiral HPLC shows that 98% conversion occurs for 5,6- methoxyl group -2,3- dihydro -1- oxo -1H- indenes -2- carboxylic acid tert-butyl ester, raw At 5,6- methoxyl group -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid tert-butyl ester, yield 95%, and S- enantiomerism The ee of body is 91%.1H NMR(500MHz,CDCl3)δ7.20(s,1H),6.89(s,1H),4.00(s,3H),3.93(s,3H), 3.57 (d, J=16.8Hz, 1H), 3.13 (d, J=16.8Hz, 1H), 1.39 (s, 9H)
The preparation of embodiment 21 (2S) -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid -9- anthracene methyl esters (formula III, Middle R1, R2, R3For H, R4For -9- anthracene methyl)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle addition 2,3- dihydro -1- oxo -1H- indenes -2- carboxylic acid -9- anthracene methyl esters (formula III, wherein R1, R2, R3For H, R4For -9- anthracene first Base, 0.0366g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heat acquired solution To 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows 2,3- dihydro -1- oxygen 95% conversion occurs for generation -1H- indenes -2- carboxylic acid -9- anthracene methyl esters, generates 2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid - 9- anthracene methyl esters, yield 85%, and the ee of S- enantiomter are 82%.1H NMR(500MHz,CDCl3)δ8.49(s,1H), 8.13 (d, J=7.6Hz, 2H), 8.00 (d, J=7.6Hz, 2H), 7.72 (d, J=7.9Hz, 1H), 7.56 (t, J=7.8Hz, 1H), 7.49 (qd, J=7.6,2.4Hz, 4H), 7.36 (t, J=7.9Hz, 1H), 7.29 (d, J=7.9Hz, 1H), 6.38 (d, J =12.6Hz, 1H), 6.01 (d, J=12.5Hz, 1H), 3.92 (s, 1H), 3.50 (d, J=17.0Hz, 1H), 3.12 (d, J= 17.0Hz,1H).
Embodiment 22 prepares (2S) -2,3- dihydro -2- hydroxyl -1- oxo -1H- indenes -2- carboxylic acid -3- ethyl -3- pentyl ester (formula III, wherein R1, R2, R3For H, R4For 3- ethyl -3- amyl)
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle addition 2,3- dihydro -1- oxo -1H- indenes -2- carboxylic acid -3- ethyl -3- pentyl ester (formula III, wherein R1, R2, R3For H, R4For 3- second Base -3- amyl, 0.0274g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heating Acquired solution to 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.Quantitative and chiral HPLC shows 2,3- bis- > 99% conversion occurs for hydrogen -1- oxo -1H- indenes -2- carboxylic acid -3- ethyl -3- pentyl ester, generates 2,3- dihydro -2- hydroxyl -1- oxo - 1H- indenes -2- carboxylic acid -3- ethyl -3- pentyl ester, yield 94%, and the ee of S- enantiomter are 94%.1H NMR(500MHz, CDCl3) δ 7.80 (d, J=7.7,1.2Hz, 1H), 7.65 (td, J=7.4,1.2Hz, 1H), 7.49 (dd, J=7.7,1.2Hz, 1H), 7.42 (td, J=7.4,1.2Hz, 1H), 4.03 (s, 1H), 3.64 (d, J=17.0Hz, 1H), 3.26 (d, J= 17.0Hz, 1H), 1.70 (q, J=7.5Hz, 6H), 0.65 (t, J=7.5Hz, 9H)
Embodiment 23 prepares (1S) -1- hydroxyl -2- oxo-cyclopentane -1- carboxylic acid benzyl ester
Chiral zirconium complex by toluene 3mL, 50 DEG C of stirring acetylacetone,2,4-pentanedione zirconiums (IV) (0.0048g, 0.01mmol) and (1S, 2S)-(1- (4,6- DI-tert-butylphenol compounds) -2- methylamino)-(2- (4,6- bis- (1- naphthalene) phenol) - 2- methylamino)-hexamethylene (formula II a, R5For tert-butyl, R6For 1- naphthalene, 0.0076g, 0.011mmol).Stirring 30 minutes Afterwards, with 0.22 μm of membrane filtration, filtrate is spin-dried for solution under reduced pressure, dissolves the residue in petroleum ether 2mL.To this toluene solution Middle addition 2- oxo-cyclopentane -1- carboxylic acid benzyl ester (0.0218g, 0.1mmol) and cumyl hydroperoxide aqueous solution (70%, 0.0326g, 0.15mmol), heat acquired solution to 50 DEG C, keep 2 hours after, solution add methylene chloride 2mL dilution.It is quantitative and Chiral HPLC shows that 94% conversion occurs for 2- oxo-cyclopentane -1- carboxylic acid benzyl ester, generates 1- hydroxyl -2- oxo ring penta Alkane -1- carboxylic acid benzyl ester, yield 71%, and the ee of S- enantiomter are 90%.1H NMR(500MHz,CDCl3)δ7.42– 7.34 (m, 3H), 7.31 (dd, J=7.7,1.9Hz, 2H), 5.21 (m, 1H), 3.64 (s, 1H), 2.58-2.37 (m, 3H), 2.21–1.99(m,3H)。

Claims (8)

1. a kind of prepare chiral alpha-hydroxy-beta -one ester compound method, which is characterized in that preparation process is as follows:
It is catalyst by the zirconium complex that (1S, 2S)-hexamethylene two-(2- bis (hydroxy-aromatic) ylmethyl) amine derivative is ligand, beta-keto acid Ester compounds and oxidant, which are placed in react in atent solvent, is made chiral alpha-hydroxy-beta -one ester compound；Reaction temperature be 0~ 100℃；Catalyst amount is 0.5~50mol% of beta-ketoester compounds；Oxidizer is beta-ketoester compounds 100~2000mol%；
(1S, 2S)-hexamethylene two-(2- bis (hydroxy-aromatic) ylmethyl) amine derivative is the zirconium complex of ligand, formula I
2. the method according to claim 1, which is characterized in that the zirconium complex is selected from the C of zirconium (IV)1-C4Alkoxide or acetyl Acetone zirconium (IV).
3. the method according to claim 1, wherein the beta-ketoester compounds such as following formula III, chiral alpha- Hydroxy-beta -one ester compound such as following formula IV:
R1For hydrogen atom, halogen, alkyl, alkoxy or naphthenic base；
R2For hydrogen atom, halogen, alkyl, alkoxy or naphthenic base；
R3For hydrogen atom, halogen, alkyl, alkoxy or naphthenic base；
R4For alkyl, naphthenic base, aromatic ring or benzyl；
N takes 1 or 2；
The chiral centre of " * " expression compound.
4. the method according to claim 1, which is characterized in that the oxidant is selected from tert-butyl hydroperoxide, hydrogen peroxide Isopropylbenzene, neopentyl hydrogen peroxide, metachloroperbenzoic acid, hydrogen peroxide, carbamide peroxide or Peracetic acid.
5. the method according to claim 1, which is characterized in that the atent solvent is halogenated hydrocarbons, aromatic hydrocarbon or alkane.
6. method according to claim 5, which is characterized in that the halogenated hydrocarbons is chloroform, carbon tetrachloride, methylene chloride, bromine Methane, methylene bromide or 1,2- dichloroethanes.
7. method according to claim 5, which is characterized in that the aromatic hydrocarbon is benzene, toluene, paraxylene, ortho-xylene Or mesitylene.
8. method according to claim 5, which is characterized in that the alkane is n-hexane, normal heptane, hexamethylene, positive 12 Alkane.
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