CN1807421A - High optical activity chiral phthalide analog compound and synthesis method - Google Patents

High optical activity chiral phthalide analog compound and synthesis method Download PDF

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CN1807421A
CN1807421A CN 200610023621 CN200610023621A CN1807421A CN 1807421 A CN1807421 A CN 1807421A CN 200610023621 CN200610023621 CN 200610023621 CN 200610023621 A CN200610023621 A CN 200610023621A CN 1807421 A CN1807421 A CN 1807421A
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徐明华
林国强
黄凌琳
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention relates to a chirality phthalide compound and its synthesizing process, wherein the compound has a structure disclosed in the specification, wherein R1 is aryl or O- or S-containing 2-7 heteroaryl, the aryl can be phenyl, naphthyl, halogeno benzene, C1-C6 alkoxy substituted phenyl, C1-C8 alkyl substituted phenyl, R2, R3, R4 or R5 is H, halogen, C1-C8 alkyl or C1-C6 alkoxy, or the adjacent R2, R3, R4 or R5 substituent is -C4H4-, * represents chirality, wherein when R2, R3, R4 and R5 are all H, R1 is not phenyl. The compound can be prepared through asymmetric method.

Description

High optical activity chiral phthalide analog compound and synthetic method
Technical field
The present invention relates to the chiral phthalide analog compound and the synthetic method of a series of high-optical-purities.
Background technology
Phthalide is that a class extensively is present in the particularly lactone compound in the plant of nature, much all has physiologically active.In the report in early days, obtain optically pure phthalide analog compound, general method commonly used is after the lactonic ring open loop is obtained acid, splits with chiral reagent, closes and encircles into lactone.Afterwards, for the method for utilizing asymmetric synthesis to obtain chiral phthalide analog compound some reports have been arranged also.As: nineteen eighty-three M.A.Hanagan and L.M.Trefonas have reported that the oxazoline that utilizes chirality comes asymmetric synthesis chiral phthalide (M.A.Hanagan for prothetic group, etc.Tetrahedron 1983,39,1911), afterwards, also there is other group to report to utilize the asymmetric synthesis of the chiral phthalide of chirality prothetic group control successively.H.C.Brown had reported to come asymmetric synthesis of chiral phthalide (H.C.Brown, etc. with the chirality borane reagent in 1996; Tetrahedron Lett.1996,37,2205).In the same year, people such as Masami Sakamoto have reported the method for solid state optics synthesis of chiral phthalide, have described and have utilized the migration of photochemical induction 1,4 phenyl to cause latent chirality to be converted into process (Masami Sakamoto, the etc. of chirality; J.Am.Chem.Soc, 1996,118,8138).Takashi Kitayama in 1998 has reported and has utilized micro-reduction and two kinds of methods of microorganism hydrogenation to come synthesis of chiral phthalide (Takashi Kitayama, etc; Tetrahedron:Asymmetry 1997,8, and 3765).Calendar year 2001 J.F.Carpertier has reported method (J.F.Carpertier, the etc that utilizes the catalytic asymmetric transfer hydrogenation stereoselectivity of ruthenium reagent synthesis of chiral phthalide; Tetrahedron Lett.2001,42,1899).Recently, woods Guoqiang etc. has reported method (Guo-Qiang Lin, the etc that utilizes nickel catalysis asymmetric synthesis chiral phthalide in the presence of chiral reagent; Synlett, 2002,927).Although above-mentioned work sutdy has obtained certain result, the reaction needed multistep that has transforms, and the needs that have also have some reaction times longer with comparatively expensive metal reagent, and the product corresponding selection is not ideal enough, method narrow application range or the like.Therefore, chemists still constantly are being devoted to develop new efficient, easy synthetic method.
Summary of the invention
The purpose of this invention is to provide a kind of new chiral phthalide analog compound.
Another object of the present invention provides the method for a class asymmetric synthesis chiral phthalide analog compound.
Chiral phthalide analog compound of the present invention, it has following structural formula: Can be
Figure A20061002362100052
Or Wherein, R 1For aryl or contain O or five to seven yuan of aromatic heterocyclics of S; Described aryl can be phenyl, naphthyl, halogenophenyl, C 1～C 6The alkoxyl group phenyl, the C that replace 1～C 8The phenyl that replaces of alkyl; R 2, R 3, R 4Or R 5Be H, halogen, C 1～C 8Alkyl or C 1～C 6Alkoxyl group; Perhaps adjacent R 2, R 3, R 4Or R 5Substituting group is-C 4H 4-, R especially 3And R 4For-C 4H 4-.Wherein, work as R 2, R 3, R 4And R 5When being H, R 1Be not equal to phenyl.
Described five yuan to seven yuan aromatic heterocyclics that contain O or S are recommended as furyl or thienyl; Described halogen is F, Cl, Br or I.
The optical purity height of chiral phthalide analog compound of the present invention, the ee value can reach 90-99%.
The method of asymmetric synthesis chiral phthalide analog compound of the present invention is in tetrahydrofuran (THF) (THF), under-78 ℃～room temperature condition, by substrate 2-acyl group benzoic ether, chiral reagent, samarium diodide (SmI 2) and exist or reaction 0.5～24 hour when not having achirality proton source compound, can obtain the chiral phthalide analog compound of high-optical-purity.The mol ratio of described reactant 2-acyl group benzoic ether, chiral reagent, samarium diodide and achirality proton source compound is: 1: 0.05～2: 0.5～5: 0～5.Its reaction expression is as follows:
The structural formula of described 2-acyl group benzoic ether substrate is as follows:
Figure A20061002362100055
The structural formula of described chiral reagent is as follows:
Figure A20061002362100056
Or
The structural formula of described achirality proton source compound is as follows:
Wherein, R 1, R 2, R 3, R 4And R 5As mentioned above; R 6Be C 1～C 6Alkyl; R 7Or R 8Be phenyl, p-methylphenyl, p-methoxyphenyl; R, R ' are H or C 1～C 6Alkyl; Ac, Ph, Ts, Bn represent ethanoyl, phenyl respectively, to Methyl benzenesulfonyl base and benzyl; *Represent chirality.
Described chiral reagent is recommended
Figure A20061002362100064
Can be Or Ph in the formula represents phenyl.
Described achirality proton source compound is recommended
Chiral reagent in the inventive method can also can be catalytic amount for stoichiometry, and when using stoichiometric chiral reagent, reaction does not need to add achirality proton source compound; When using the chiral reagent of catalytic amount, reaction will be added achirality proton source compound.That is to say that reaction can carry out existing or do not exist under the achirality proton source compound situation respectively.When reacting under not having achirality proton source compound situation, the mol ratio of reactant 2-acyl group benzoic ether, chiral reagent, samarium diodide and achirality proton source compound is preferably: 1: 1～1.5: 2～3: 0.When reacting under having achirality proton source compound situation, the mol ratio of reactant 2-acyl group benzoic ether, chiral reagent, samarium diodide and achirality proton source compound is preferably: 1: 0.05～0.3: 2～3: 1～2.
In the method for the invention, temperature of reaction can make speed of response slower when low, and the higher meeting of temperature descends enantioselectivity, and the recommendation response temperature is-78 ℃～-50 ℃.The preferable reaction times of recommending is 2～5 hours.
Below, part of the present invention exist or do not exist the reaction of carrying out under the achirality proton source compound situation to list in table 1 and table 2 for example:
Table 1: the response situation when chiral reagent of interpolation catalytic amount and normal achiral reagent
Sequence number The substrate numbering R 1 R 2 R 3 R 4 R 5 Product ee (%) Productive rate (%)
1 S-1 C 6H 5 H H H H 96 80
2 S-2 4-CH 3-C 6H 4 H H H H 94 81
3 S-3 4-CH 3O-C 6H 4 H H H H 96 82
4 S-4 4-F-C 6H 4 H H H H 97 83
5 S-5 4-Cl-C 6H 4 H H H H 90 83
6 S-6 4-Br-C 6H 4 H H H H 92 85
7 S-7 3，4-(CH 3) 2-C 6H 3 H H H H 97 75
8 S-8 3，4-(CH 3O) 2-C 6H 3 H H H H 97 72
9 S-9 The 2-naphthyl H H H H 95 83
10 S-10 The 2-furans H H H H 96 65
11 S-11 2-thiophene phenol H H H H 97 62
12 S-12 4-Cl-C 6H 4 H Br H H 93 75
13 S-13 4-Br-C 6H 4 H Br H H 97 76
14 S-14 C 6H 5 H OCH 3 H H 95 76
15 S-15 The 2-naphthyl H OCH 3 H H 95 72
16 S-16 C 6H 5 H -C 4H 4- H 92 82
17 S-17 4-CH 3-C 6H 4 H -C 4H 4- H 98 80
18 S-18 C 6H 5 H Cl Cl H 92 75
19 S-19 4-CH 3-C 6H 4 H Cl Cl H 97 76
20 S-20 4-CH 3-C 6H 4 H CH 3 H H 99 83
21 S-21 3，4-(CH 3) 2-C 6H 3 H CH 3 H H 96 82
22 S-22 C 6H 5 CH 3 H H CH 3 97 80
Table 2: add normal chiral reagent response situation when (not having achirality proton source compound)
Sequence number The substrate numbering R 1 R 2 R 3 R 4 R 5 Product ee (%) Productive rate (%)
1 S-1 C 6H 5 H H H H 98 82
2 S-2 4-CH 3-C 6H 4 H H H H 98 88
3 S-3 4-CH 3O-C 6H 4 H H H H 97 85
4 S-4 4-F-C 6H 4 H H H H 99 81
5 S-5 4-Cl-C 6H 4 H H H H 95 86
6 S-6 4-Br-C 6H 4 H H H H 98 83
7 S-7 3，4-(CH 3) 2-C 6H 3 H H H H 97 73
8 S-8 3，4-(CH 3O) 2-C 6H 3 H H H H 99 76
9 S-9 The 2-naphthyl H H H H 97 81
10 S-10 The 2-furans H H H H 91 60
11 S-11 2-thiophene phenol H H H H 93 65
12 S-12 4-Cl-C 6H 4 H Br H H 97 79
13 S-13 4-Br-C 6H 4 H Br H H 94 82
14 S-14 C 6H 5 H OCH 3 H H 94 79
15 S-15 The 2-naphthyl H OCH 3 H H 96 75
16 S-16 C 6H 5 H -C 4H 4- H 94 80
17 S-17 4-CH 3-C 6H 4 H -C 4H 4- H 98 82
18 S-18 C 6H 5 H Cl Cl H 95 80
19 S-19 4-CH 3-C 6H 4 H Cl Cl H 98 81
20 S-20 4-CH 3-C 6H 4 H CH 3 H H 94 83
21 S-21 3，4-(CH 3) 2-C 6H 3 H CH 3 H H 96 80
22 S-22 C 6H 5 CH 3 H H CH 3 97 80
23 S-23 4-CH 3-C 6H 4 CH 3 H H CH 3 97 82
24 S-24 4-CH 3-C 6H 4 CH 3 CH 3 H CH 3 95 75
25 S-25 4-CH 3-C 6H 4 CH 3 CH 3 CH 3 CH 3 95 55
The invention provides a kind of method of utilizing a series of chiral phthalide analog compounds of asymmetric synthesis of samarium diodide inductive chiral reagent participation.Use method of the present invention, can access the chiral phthalide analog compound of high-optical-purity.Wherein, used chiral reagent can also can be catalytic amount for stoichiometry.Under the situation that adds achirality proton source compound, only need add the chiral reagent of catalytic amount, just can obtain the chiral phthalide analog compound of high-optical-purity.The inventive method is easy, and substrate prepares easily, and the reaction times is short, and the productive rate of product and enantioselectivity are all very excellent, are a kind of methods of the phthalide analog compound of synthesis of chiral preferably.
Specific implementation method
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1 chiral reagent
Figure A20061002362100081
Preparation
Will (1S, 2R)-2-amino-1,2-phenylbenzene ethanol [(1S, 2R)-2-amino-1,2-diphenylethanol] (213mg 1mmol) is dissolved in the 20mL acetonitrile, adds 4-Dimethylamino pyridine (4-Dimethylaminopyridine) (10mg) and tertbutyloxycarbonyl two carbonic ethers (Di-tert-butyl dicarbonate) (240mg, 1.1mmol), stirred 10 minutes under the room temperature, concentrate purifying, get white solid 201mg, yield 84%.
1HNMR(300MHz，CD 3COCD 3)：δ5.04(d，1H，J＝8.1Hz)，6.02(d，1H，J＝8.4Hz)，7.03-7.16(m，10H)，7.25(br，1H)ppm
Embodiment 2 chiral reagents Preparation
Will (1R, 2S)-2-amino-1,2-phenylbenzene ethanol [(1R, 2S)-2-amino-1,2-diphenylethanol] (213mg 1mmol) is dissolved in the 20mL acetonitrile, adds 4-Dimethylamino pyridine (4-Dimethylaminopyridine) (10mg) and tertbutyloxycarbonyl two carbonic ethers (Di-tert-butyl dicarbonate) (240mg, 1.1mmol), stirred 10 minutes under the room temperature, concentrate purifying, get white solid 210mg, yield 88%.
1HNMR(300MHz，CD 3COCD 3)：δ5.06(d，1H，J＝8.1Hz)，6.03(d，1H，J＝8.4Hz)，7.04-7.17(m，10H)，7.27(br，1H)ppm
Embodiment 3 chiral reagents
Figure A20061002362100091
Preparation
Working method is with example 1, reaction raw materials be (1S, 2R)-2-amino-1,2-two (p-methylphenyl) ethanol, yield 80%
1HNMR(300MHz，CD 3COCD 3)：δ1.96(s，3H)，2.72(s，3H)，4.98(dd，1H，J1＝7.8Hz，J2＝7.2Hz)，5.24(d，1H，J＝8.1Hz)，6.15(d，1H，J＝7.5Hz)，7.08-7.26(m，8H)ppm
Embodiment 4 chiral reagents
Figure A20061002362100092
Preparation
Working method is with example 1, reaction raw materials be (1S, 2R)-2-amino-1,2-two (p-methoxyphenyl) ethanol, yield 82%
1HNMR(300MHz，CD 3COCD 3)：δ3.75(s，3H)，3.80(s，3H)，4.56(dd，1H，J1＝8.1Hz，J2＝6.9Hz)，5.09(d，1H，J＝8.1Hz)，6.25(d，1H，J＝6.9Hz)，6.83-7.03(m，6H)，7.24-7.28(m，2H)ppm.
Embodiment 5 chiral reagents Preparation
Will (1R, 2S)-1-amino-2-indanol [(1R, 2S)-1-amino-2-indanol] (745mg 5mmol) is dissolved in the 40mL methylene dichloride, add triethylamine (1.4mL, 11mmol) and Tosyl chloride (1.05g 5.5mmol), stirs 5h under the room temperature, the saturated common salt washing, drying concentrates.The gained white solid is dissolved in the 40mL methylene dichloride, add 4-Dimethylamino pyridine (4-Dimethylaminopyridine) (20mg) and diacetyl oxide (0.51mL, 5.5mmol), stirred 10 minutes under the room temperature, concentrate purifying, get white solid 1.55g, yield 90%
1HNMR(300MHz，CDCl 3)：δ1.91(s，3H)，2.46(s，3H)，3.00(d，1H，J＝17.1Hz)，3.23(dd，1H，J1＝5.4Hz，J2＝14.3Hz)，4.95-5.00(m，1H)，5.06-5.09(m，1H)，5.25(d，1H，J＝7.5Hz)，7.16-7.35(m，6H)，7.82(d，2H，J＝8.4Hz)ppm
Embodiment 6 chiral reagents
Figure A20061002362100101
Preparation
Will (1R, 2S)-1-amino-2-indanol [(1R, 2S)-1-amino-2-indanol] (149mg, 1mmol) be dissolved in the 20mL methylene dichloride, add triethylamine (0.32mL, 2.5mmol) and 4-Dimethylamino pyridine (4-Dimethylaminopyridine) (5mg) and diacetyl oxide (0.25mL, 2.5mmol), stirred 30 minutes saturated common salt washing, drying under the room temperature, concentrate, purifying gets white solid 233mg, yield 99%.
1HNMR(300MHz，CDCl 3)：δ2.04(s，3H)，2.11(s，3H)，3.00(d，1H，J＝17.1Hz)，3.23(dd，1H，J1＝5.4Hz，J2＝14.3Hz)，5.53-5.57(m，1H)，5.65-5.70(m，1H)，6.03(d，1H，J＝9.0Hz)，7.22-7.28(m，4H)ppm
Embodiment 7 chiral reagents Preparation
Will (1R, 2S)-1-amino-2-indanol [(1R, 2S)-1-amino-2-indanol] (298mg, 2mmol) be dissolved in the 20mL methylene dichloride, add 1,1 '-carbonyl dimidazoles (1,1 '-carbonyldiimidazole) (648mg 4mmol), stirs 5h under the room temperature, the saturated common salt washing, drying concentrates purifying, get white solid 304mg, yield 87%.
1HNMR(300MHz，CDCl 3)：δ3.36-3.4(m，2H)，5.18(d，1H，J＝7.2Hz)，5.40-5.45(m，1H)，6.65(m，1H)，7.25-7.32(m，4H)ppm
Embodiment 8 chiral reagents Preparation
Will (1R, 2S)-norephedrine [(1R, 2S)-Norephedrine] (302mg, 2mmol) be dissolved in the 20mL ethanol, add 1,5 '-dibromo pentane (0.383mL, 2.5mmol) and salt of wormwood (828mg, 6mmol), reflux 24h, cooling, filter, concentrate purifying, get 329mg, yield 75%.
1HNMR(300MHz，CDCl 3)：δ0.82(d，3H，J＝6.9Hz)，1.39-1.48(m，2H)，1.50-1.63(m，4H)，2.44-2.56(m，4H)，2.65-2.73(m，1H)，3.39-3.48(m，1H)，4.16(br，1H)，7.24-7.40(m，5H)ppm
Embodiment 9 chiral reagents Preparation
Will (1R, 2S)-norephedrine [(1R, 2S)-Norephedrine] (302mg, 2mmol) be dissolved in the 20mL methylene dichloride, and the adding triethylamine (0.32mL, 2.5mmol), 4-Dimethylamino pyridine (4-Dimethylaminopyridine) (5mg) and diacetyl oxide (0.25mL 2.5mmol), stirred under the room temperature 30 minutes, the saturated common salt washing, drying concentrates purifying, get white solid 437mg, yield 93%.
1HNMR(300MHz，CDCl 3)：δ1.61(d，3H，J＝6.9Hz)，2.04(s，3H)，2.08(s，3H)，4.51(d，1H，J＝4.2Hz)，4.82(m，1H)，6.38(d，1H，J＝11.7Hz)，7.14-7.32(m，5H)ppm
Embodiment 10 chiral reagents Preparation
Will (1R, 2R)-1,2-diphenylethyleneglycol [(1R, 2R)-1,2-diphenylethanol-1,2-diol] (1.07g, 5mmol) be dissolved in the 50mL benzene, add phenyl aldehyde (0.613mL, 6mmol) and tosic acid (20mg), reflux is divided water, concentrates, the gained solid is added in the exsiccant three-necked bottle, add 10mL toluene, 0 ℃ adds diisobutyl lithium hydride (Diisobutylaluminum hydride) (1M in toluene down, 4mL, 4mmol), 0 ℃ is stirred 12h down, add the methyl alcohol cancellation, aftertreatment, saturated common salt washing, drying, concentrate, purifying gets 1.00g, productive rate 67%.
1HNMR(300MHz，CDCl 3)：δ4.23(br，1H)，4.50-4.53(m，1H)，4.61(s，2H)，5.12-5.15(m，1H)，7.14-7.39(m，8H)，7.42-7.46(m，7H)ppm
Embodiment 11 chiral reagents
Figure A20061002362100113
Preparation
Will (1S, 2R)-2-amino-1,2-phenylbenzene ethanol [(1S, 2R)-and 2-amino-1,2-diphenylethanol] (213mg 1mmol) is dissolved in the 20mL methylene dichloride, add triethylamine (0.32mL, 2.5mmol), 4-Dimethylamino pyridine (4-Dimethylaminopyridine) (5mg) and diacetyl oxide (0.25mL, 2.5mmol), stirred 30 minutes the saturated common salt washing under the room temperature, drying concentrates purifying, get white solid 276mg, yield 93%.
1HNMR(300MHz，CDCl 3)：δ1.97(s，3H)，2.08(s，3H)，5.10(d，1H，J＝4.2Hz)，5.26(dd，1H，J1＝4.8Hz，J2＝9.0Hz)，5.96(d，1H，J＝8.7Hz)，7.06-7.12(m，4H)，7.26-7.29(m，6H)ppm
Embodiment 12 chiral reagents Preparation
(1S, 2R)-2-amino-1,2-phenylbenzene ethanol [(1S, 2R)-2-amino-1,2-diphenylethanol] (213mg 1mmol) is dissolved in the 20mL methylene dichloride, adds triethylamine (0.12mL, 1.1mmol) and Tosyl chloride (209mg, 1.1mmol), stir 5h under the room temperature, the saturated common salt washing, drying concentrates.The gained white solid is dissolved in the 20mL methylene dichloride, add 4-Dimethylamino pyridine (4-Dimethylaminopyridine) (10mg) and diacetyl oxide (0.08mL, 1.1mmol), stirred 10 minutes under the room temperature, concentrate purifying, get white solid 364mg, yield 89%.
1HNMR(300MHz，CDCl 3)：δ1.19(s，3H)，2.33(s，3H)，4.81(dd，1H，J1＝4.8Hz，J2＝9.3Hz)，5.37(d，1H，J＝8.4Hz)，5.91(d，1H，J＝4.5Hz)，6.87-6.49(m，4H)，7.07-7.26(m，8H)，7.50-7.53(m，2H)ppm
The preparation of embodiment 13 substrate S-1
Figure A20061002362100121
Synthetic:
With Tetra hydro Phthalic anhydride (296mg, 2mmol) be suspended in the 50mL methylene dichloride, and adding 1mL benzene and aluminum trichloride (anhydrous) (665mg, 5mmol), stir under the room temperature and spend the night, in reaction solution impouring 20mL1N hydrochloric acid soln, extract with chloroform 50mL * 3, merge organic layer, use unsaturated carbonate potassium solution 60mL * 3 to extract again, combining water layer, concentrated hydrochloric acid is transferred pH＜2, extracts with chloroform 100mL * 3.The saturated common salt washing, drying concentrates.The gained white solid is dissolved in 20mL N, and dinethylformamide (N, N-dimethylformamide), add cesium fluoride (380mg, 2.5mmol) and iodoethane (0.20mL, 2.5mmol), stir under the room temperature and spend the night,, add ethyl acetate (100mL) dissolving except that after desolvating, the saturated common salt washing, drying concentrates purifying, get white solid 337mg, yield 66%.
1HNMR(300MHz，CDCl 3)：δ1.09(t，3H，J＝7.2Hz)，4.12(q，2H，J＝7.2Hz)，7.36-7.39(m，2H)，7.56-7.66(m，6H)，8.06-8.10(m，1H)ppm
The preparation of embodiment 14 substrate S-2
Figure A20061002362100122
Synthetic:
Working method is with example 13, productive rate 73%.
1HNMR(300MHz，CDCl 3)：δ1.11(t，3H，J＝6.3Hz)，2.67(s，3H)，4.12(q，2H，J＝7.2Hz)，7.13-7.44(m，4H)，7.54-7.60(m，3H)，7.93-7.96(m，1H)ppm
The preparation of embodiment 15 substrate S-3
Figure A20061002362100131
Synthetic:
Working method is with example 13, productive rate 70%.
1HNMR(300MHz，CDCl 3)：δ1.08(t，3H，J＝7.5Hz)，3.86(s，3H)，4.16(q，2H，J＝7.2Hz)，6.90(d，2H，J＝7.2Hz)，7.37(d，1H，J＝7.2Hz)，7.54-7.63(m，3H)，7.75(d，1H，J＝6.9Hz)，8.07(d，1H，J＝7.2Hz)ppm
The preparation of embodiment 16 substrate S-4
Figure A20061002362100132
Synthetic:
Working method is with example 13, productive rate 60%.
1HNMR(300MHz，CDCl 3)：δ1.11(t，3H，J＝7.2Hz)，4.13(q，2H，J＝7.2Hz)，7.08-7.40(m，3H)，7.55-7.82(m，4H)，8.07-8.10(m，1H)ppm
19FNMR(282MHz，CDCl 3)：δ-105.46ppm
The preparation of embodiment 17 substrate S-5
Figure A20061002362100133
Synthetic:
Working method is with example 13, productive rate 61%.
1HNMR(300MHz，CDCl 3)：δ1.11(t，3H，J＝7.2Hz)，4.12(q，2H，J＝7.2Hz)，7.36-7.42(m，3H)，7.59-7.72(m，4H)，8.06-8.10(m，1H)ppm
The preparation of embodiment 18 substrate S-6
Synthetic:
Working method is with example 13, productive rate 60%.
1HNMR(300MHz，CDCl 3)：δ1.11(t，3H，J＝7.2Hz)，4.12(q，2H，J＝7.2Hz)，7.36-7.39(m，1H)，7.56-7.66(m，6H)，8.06-8.10(m，1H)ppm
The preparation of embodiment 19 substrate S-7
Synthetic:
Working method is with example 13, productive rate 74%.
1HNMR(300MHz，CDCl 3)：δ1.19(t，3H，J＝7.5Hz)，2.24(s，3H)，2.26(s，3H)，4.05(q，2H，J＝7.5Hz)，7.12-7.34(m，2H)，7.55-7.65(m，4H)，7.95-7.97(m，1H)ppm
The preparation of embodiment 20 substrate S-8
Figure A20061002362100143
Synthetic:
Working method is with example 13, productive rate 76%.
1HNMR(300MHz，CDCl 3)：δ1.09(t，3H，J＝7.5Hz)，3.89(s，3H)，3.92(s，3H)，4.10(q，2H，J＝7.5Hz)，7.06(s，1H，J＝8.1Hz)，7.37(d，1H，J＝7.5Hz)，7.53-7.61(m，4H)，8.03(d，1H，J＝7.5Hz)ppm
The preparation of embodiment 21 substrate S-9
Synthetic:
Working method is with example 13, productive rate 71%.
1HNMR(300MHz，CDCl 3)：δ1.13(t，3H，J＝7.5Hz)，4.15(q，2H，J＝7.2Hz)，7.23(d，2H，J＝7.8Hz)，7.60-7.64(m，3H)，7.71(d，2H，J＝8.1Hz)，7.87(s，1H)，7.89(d，1H，J＝3.3Hz)，7.99(d，1H，J＝6.0Hz)，8.59(s，1H)ppm
The preparation of embodiment 22 substrate S-10
Synthetic:
Working method is with example 13, productive rate 40%.
1HNMR(300MHz，CDCl 3)：δ1.14(t，3H，J＝7.2Hz)，4.17(q，2H，J＝7.2Hz)，6.53(d，1H，J＝3.9Hz)，6.96(d，1H，J＝3.6Hz)，7.48-7.67(m，3H)，8.02-8.05(m，2H)ppm
The preparation of embodiment 23 substrate S-11
Synthetic:
Working method is with example 13, productive rate 62%.
1HNMR(300MHz，CDCl 3)：δ1.13(t，3H，J＝7.2Hz)，4.16(q，2H，J＝7.2Hz)，7.05-7.09(m，1H)，7.26-7.28(m，1H)，7.47-7.71(m，4H)，8.04-8.07(m，1H)ppm
The preparation of embodiment 24 substrate S-12
Figure A20061002362100161
Synthetic:
Working method is with example 13, productive rate 60%.
1HNMR(300MHz，CDCl 3)：δ1.10(t，3H，J＝6.9Hz)，4.11(q，2H，J＝7.2Hz)，7.41-7.44(m，2H)，7.50-7.7.51(m，1H)，7.67-7.73(m，3H)，7.93-7.96(m，1H)ppm
The preparation of embodiment 25 substrate S-13
Figure A20061002362100162
Synthetic:
Working method is with example 13, productive rate 62%.
1HNMR(300MHz，CDCl 3)：δ1.12(t，3H，J＝7.2Hz)，4.13(q，2H，J＝7.2Hz)，7.41-7.44(m，3H)，7.67-7.73(m，3H)，7.93-7.96(m，1H)ppm
The preparation of embodiment 26 substrate S-14
Synthetic:
Working method is with example 13, productive rate 52%.
1HNMR(300MHz，CDCl 3)：δ1.05(t，3H，J＝7.2Hz)，3.73(s，3H)，4.05(q，2H，J＝6.9Hz)，7.15-7.35(m，4H)，7.64(m，2H)，7.95(m，2H)ppm
The preparation of embodiment 27 substrate S-15
Synthetic:
Working method is with example 13, productive rate 55%.
1HNMR(300MHz，CDCl 3)：δ1.05(t，3H，J＝7.2Hz)，3.73(s，3H)，4.08(q，2H，J＝7.5Hz)，7.15-7.35(m，4H)，7.46(m，2H)，7.64-7.70(m，2H)，7.95(m，2H)ppm
The preparation of embodiment 28 substrate S-16
Figure A20061002362100172
Synthetic:
Working method is with example 13, productive rate 68%.
1HNMR(300MHz，CDCl 3)：δ1.06(t，3H，J＝7.5Hz)，4.12(q，2H，J＝7.5Hz)，7.24(d，2H，J＝7.8Hz)，7.46(s，1H)，7.58-7.65(m，5H)，7.73(d，2H，J＝3.9Hz)，8.14(s，1H)ppm
The preparation of embodiment 29 substrate S-17
Synthetic:
Working method is with example 13, productive rate 70%.
1HNMR(300MHz，CDCl 3)：δ1.13(t，3H，J＝7.2Hz)，2.40(s，3H)，4.15(q，2H，J＝7.2Hz)，7.23(d，2H，J＝7.8Hz)，7.60-7.65(m，4H)，7.71(d，1H，J＝8.1Hz)，7.87(s，1H)，7.88-8.01(m，1H)，8.60(s，1H)ppm
The preparation of embodiment 30 substrate S-18
Synthetic:
Working method is with example 13, productive rate 50%.
1HNMR(300MHz，CDCl 3)：δ1.06(t，3H，J＝7.2Hz)，4.10(q，2H，J＝7.2Hz)，7.43-7.50(m，3H)，7.56-7.61(m，1H)，7.73-7.80(m，2H)，8.15(s，1H)ppm
The preparation of embodiment 31 substrate S-19
Figure A20061002362100182
Synthetic:
Working method is with example 13, productive rate 62%.
1HNMR(300MHz，CDCl 3)：δ1.06(t，3H，J＝7.2Hz)，2.37(s，3H)，4.10(q，2H，J＝7.2Hz)，7.43-7.50(m，4H)，7.73-7.80(m，1H)，8.15(s，1H)ppm
The preparation of embodiment 32 substrate S-20
Synthetic:
Working method is with example 13, productive rate 60%.
1HNMR(300MHz，CDCl 3)：δ1.05(t，3H，J＝7.2Hz)，2.39(s，3H)，2.43(s，3H)，4.05(q，2H，J＝6.9Hz)，7.15-7.35(m，4H)，7.64(d，2H，J＝7.8Hz)，7.95(d，1H，J＝8.1Hz)ppm
The preparation of embodiment 33 substrate S-21
Figure A20061002362100191
Synthetic:
Working method is with example 13, productive rate 63%.
1HNMR(300MHz，CDCl 3)：δ1.07(t，3H，J＝7.8Hz)，2.29(d，6H，J＝5.7Hz)，2.43(s，3H)，4.08(q，2H，J＝7.8Hz)，7.15-7.44(m，4H)，7.59-7.97(m，2H)ppm
The preparation of embodiment 34 substrate S-22
Synthetic:
Working method is with example 13, productive rate 58%.
1HNMR(300MHz，CDCl 3)：δ0.99(t，3H，J＝8.2Hz)，2.41(s，3H)，2.48(s，3H)，4.02(q，2H，J＝8.2Hz)，7.22-7.27(m，4H)，7.66-7.69(m，3H)ppm
The preparation of embodiment 35 substrate S-23
Figure A20061002362100193
Synthetic:
Working method is with example 13, productive rate 61%.
1HNMR(300MHz，CDCl 3)：δ0.99(t，3H，J＝8.4Hz)，2.12(s，3H)，2.41(s，3H)，2.48(s，3H)，3.97(q，2H，J＝8.4Hz)，7.22-7.27(m，4H)，7.66-7.69(m，2H)ppm
The preparation of embodiment 36 substrate S-24
Figure A20061002362100201
Synthetic:
Working method is with example 13, productive rate 55%.
1HNMR(300MHz，CDCl 3)：δ1.12(t，3H，J＝8.1Hz)，2.10(s，6H)，2.35(s，3H)，2.41(s，3H)，3.98(q，2H，J＝8.1Hz)，7.22-7.29(m，2H)，7.66-7.69(m，4H)ppm
The preparation of embodiment 37 substrate S-25
Synthetic:
Working method is with example 13, productive rate 55%.
1HNMR(300MHz，CDCl 3)：δ1.10(t，3H，J＝8.4Hz)，2.18(s，6H)，2.36(s，3H)，2.41(s，3H)，2.43(s，3H)，4.05(q，2H，J＝8.4.Hz)，7.25-7.27(m，2H)，7.66-7.69(m，2H)ppm
The preparation of embodiment 38 methyl esters substrate S-26
Synthetic
With Tetra hydro Phthalic anhydride (592mg, 4mmol) be suspended in the 50mL methylene dichloride, and adding 1mL 1,2-dimethoxy benzene and aluminum trichloride (anhydrous) (1.06g, 8mmol), stir under the room temperature and spend the night, in reaction solution impouring 40mL1N hydrochloric acid soln, extract with chloroform 80mL * 3, merge organic layer, use unsaturated carbonate potassium solution 100mL * 3 to extract again, combining water layer, concentrated hydrochloric acid is transferred pH＜2, extracts with chloroform 100mL * 3.The saturated common salt washing, drying concentrates.The gained white solid is dissolved in 20mLN, and dinethylformamide adds cesium fluoride (760mg, 5mmol) and methyl iodide (0.40mL 5mmol), stirs under the room temperature and spends the night, except that after desolvating, add ethyl acetate (100mL) dissolving, saturated common salt washing, drying, concentrate, purifying gets white solid 744mg, yield 62%.
1HNMR(300MHz，CDCl 3)：δ3.66(s，3H)，3.92(s，3H)，3.95(s，3H)，6.78(d，1H，J＝8.7Hz)，7.08(d，1H，J＝8.4Hz)，7.39(d，1H，J＝7.2Hz)，7.56-7.64(m，3H)，8.05(d，1H，J＝7.5Hz)ppm
The preparation of embodiment 39 chiral phthalides
Synthetic:
In the exsiccant three-necked bottle, (200mg is 1.3mmol) with the 5mL tetrahydrofuran (THF) to add the samarium powder; under the nitrogen protection, add 0.081mL (1.0mmol) methylene iodide, stir under the room temperature after 1 hour; system is cooled to-78 ℃, add keto ester substrate S-1 (127mg, 0.5mmol) and chiral reagent (119.5mg, 5mL tetrahydrofuran solution 0.5mmol) after 30 minutes, make it slowly be warming up to-50 ℃-78 ℃ of following reactions, descend reaction after one hour at-50 ℃ afterwards, aftertreatment, purifying.Productive rate 82%, ee 98%.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 40
Figure A20061002362100213
Synthetic:
Working method is with example 39, and chiral reagent is Aftertreatment, purifying.Productive rate 85%, ee 93%.
1HNMR(300MHz，CDCl 3)：δ6.52(s，1H)，6.99-7.03(m，2H)，7.13-7.41(m，4H)，7.58-7.62(m，2H)，7.81-7.85(m，1H)ppm
Embodiment 41
Figure A20061002362100215
Synthetic:
Working method is with example 39, and chiral reagent is
Figure A20061002362100221
Aftertreatment, purifying.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 42
Synthetic:
Working method is with example 39, and chiral reagent is
Figure A20061002362100223
Aftertreatment, purifying.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 43
Synthetic:
Working method is with example 39, and chiral reagent is
Figure A20061002362100225
Aftertreatment, purifying.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 44
Figure A20061002362100226
Synthetic:
Working method is with example 39, and chiral reagent is Aftertreatment, purifying.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 45
Synthetic:
Working method is with example 39, and chiral reagent is Aftertreatment, purifying.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 46
Figure A20061002362100233
Synthetic:
Working method is with example 39, and chiral reagent is Aftertreatment, purifying.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 47
Figure A20061002362100235
Synthetic:
Working method is with example 39, and chiral reagent is
Figure A20061002362100236
Aftertreatment, purifying.
1HNMR(300MHz，CDCl 3)：δ6.53(s，1H)，6.99-7.02(m，2H)，7.12-7.40(m，4H)，7.58-7.63(m，2H)，7.80-7.85(m，1H)ppm
Embodiment 48
Synthetic:
Working method is with example 39, and substrate is S-2, reacts 3 hours, and aftertreatment is the same, productive rate 88%, and ee 98%.
1HNMR(300MHz，CDCl 3)：δ2.67(s，3H)，6.41(s，1H)，7.12-7.40(m，4H)，7.58-7.63(m，3H)，7.80-7.85(m，1H)ppm
Embodiment 49
Figure A20061002362100242
Synthetic:
Working method is with example 39, and substrate is S-2, and chiral reagent is
Figure A20061002362100243
Reacted 3 hours, aftertreatment is the same, productive rate 82%, and ee 95%.
1HNMR(300MHz，CDCl 3)：δ2.66(s，3H)，6.42(s，1H)，7.12-7.41(m，4H)，7.58-7.63(m，3H)，7.81-7.86(m，1H)ppm
Embodiment 50
Figure A20061002362100244
Synthetic:
Working method is with example 39, and substrate is S-3, reacts 3 hours, and aftertreatment is the same, productive rate 85%, and ee 97%.
1HNMR(300MHz，CDCl 3)：δ3.81(s，3H)，6.38(s，1H)，7.02-7.18(m，4H)，7.32-7.52(m，3H)，7.82-7.88(m，1H)ppm
Embodiment 51
Figure A20061002362100245
Synthetic:
Working method is with example 39, and substrate is S-4, reacts 3 hours, and aftertreatment is the same, productive rate 81%, and ee 99%.
1HNMR(300MHz，CDCl 3)：δ6.39(s，1H)，7.04-7.10(m，2H)，7.23-7.32(m，3H)，7.55-7.70(m，2H)，7.96(d，1H，J＝7.8Hz)ppm
19FNMR(282MHz，CDCl 3)：δ-112.08ppm
Embodiment 52
Synthetic:
Working method is with example 39, and substrate is S-5, reacts 2 hours, and aftertreatment is the same, productive rate 86%, and ee 95%.
1HNMR(300MHz，CDCl 3)：δ6.38(s，1H)，7.20-7.24(m，2H)，7.30-7.38(m，3H)，7.55-7.69(m，2H)，7.96(d，1H，J＝7.8Hz)ppm
Embodiment 53
Synthetic:
Working method is with example 39, and substrate is S-6, reacts 3 hours, and aftertreatment is the same, productive rate 83%, and ee 98%.
1HNMR(300MHz，CDCl 3)：δ6.37(s，1H)，7.15-7.18(m，2H)，7.30-7.34(m，1H)，7.51-7.68(m，4H)，7.96-7.99(m，1H)ppm
Embodiment 54
Synthetic:
Working method is with example 39, and substrate is S-7, reacted 3 hours, and aftertreatment, purifying, productive rate 73%, ee 97%.。
1HNMR(300MHz，CDCl 3)：δ2.24(d，6H，J＝5.4Hz)，6.35(s，1H)，6.99-7.01(m，2H)，7.12-7.34(m，2H)，7.55-7.65(m，2H)，7.95-7.97(m，1H)ppm
Embodiment 55
Figure A20061002362100261
Synthetic:
Working method is with example 39, and substrate is ethyl ester S-8, reacts 3 hours, and aftertreatment is the same, productive rate 76%, and ee 99%.
1HNMR(300MHz，CDCl 3)：δ3.80(s，3H)，3.88(s，3H)，6.37(s，1H)，6.68(s，1H)，6.87(s，2H)，7.32-7.35(m，1H)，7.56-7.67(m，2H)，7.97(d，1H，J＝7.5Hz)ppm
Embodiment 56
Synthetic:
Working method is with example 39, and substrate is methyl esters S-26, reacts 3 hours, and aftertreatment is the same, productive rate 78%, and ee 94%.
1HNMR(300MHz，CDCl 3)：δ3.80(s，3H)，3.88(s，3H)，6.37(s，1H)，6.68(s，1H)，6.87(s，2H)，7.32-7.35(m，1H)，7.56-7.67(m，2H)，7.97(d，1H，J＝7.5Hz)ppm
Embodiment 57
Figure A20061002362100263
Synthetic:
Working method is with example 39, and substrate is S-9, reacts 3 hours, and aftertreatment is the same, productive rate 81%, and ee 97%.
1HNMR(300MHz，CDCl 3)：δ6.56(s，1H)，7.21-7.25(m，1H)，7.34(d，1H，J＝4.2Hz)，7.49-7.65(m，4H)，7.81-7.86(m，4H)，7.99(d，1H，J＝7.2Hz)ppm
Embodiment 58
Synthetic:
Working method is with example 39, and substrate is S-10, reacts 3 hours, and aftertreatment is the same, productive rate 60%, and ee 91%.
1HNMR(300MHz，CDCl 3)：δ6.68(s，1H)，7.01-7.05(m，1H)，7.15-7.16(m，1H)，7.26-7.49(m，2H)，7.58-7.95(m，2H)，7.98-7.99(m，1H)ppm
Embodiment 59
Figure A20061002362100271
Synthetic:
Working method is with example 39, and substrate is S-11, reacts 3 hours, and aftertreatment is the same, productive rate 65%, and ee 93%.
1HNMR(300MHz，CDCl 3)：δ6.68(s，1H)，7.02-7.04(m，1H)，7.14-7.16(m，1H)，7.36-7.39(m，1H)，7.46-7.49(m，1H)，7.71-7.74(m，2H)，7.97(d，1H，J＝7.5Hz)ppm
Embodiment 60
Figure A20061002362100272
Synthetic:
Working method is with example 39, and substrate is S-12, reacts 3 hours, and aftertreatment is the same, productive rate 79%, and ee 97%.
1HNMR(300MHz，CDCl 3)：δ6.34(s，1H)，7.19-7.23(m，2H)，7.36-7.47(m，3H)，7.69-8.09(m，2H)ppm
Embodiment 61
Figure A20061002362100273
Synthetic:
Working method is with example 39, and substrate S-13 reacted 3 hours, and aftertreatment is the same, productive rate 82%, and ee 94%.
1HNMR(300MHz，CDCl 3)：δ6.32(s，1H)，7.13-7.21(m，3H)，7.46-7.55(m，2H)，7.67-8.08(m，2H)ppm
Embodiment 62
Figure A20061002362100274
Synthetic:
Working method is with example 39, and substrate is S-14, reacts 3 hours, and aftertreatment is the same, productive rate 79%, and ee 94%.
1HNMR(300MHz，CDCl 3)：δ3.75(s，3H)，6.52(s，1H)，6.81(m，2H)，7.20-7.35(m，2H)，7.54-7.62(m，3H)，7.89(d，1H，J＝7.5Hz)ppm
Embodiment 63
Synthetic:
Working method is with example 39, and substrate is S-15, reacts 3 hours, and aftertreatment is the same, productive rate 75%, and ee 96%.
1HNMR(300MHz，CDCl 3)：δ3.80(s，3H)，6.56(s，1H)，6.89(m，2H)，7.15-7.19(m，2H)，7.25-7.31(m，2H)，7.51-7.64(m，2H)，7.79-7.85(m，2H)ppm
Embodiment 64
Figure A20061002362100282
Synthetic:
Working method is with example 39, and substrate is S-16, reacts 3 hours, and aftertreatment is the same, productive rate 80%, and ee 94%
1HNMR(300MHz，CDCl 3)：δ6.42(s，1H)，7.21-7.26(m，5H)，7.59-7.64(m，2H)，7.74(s，1H)，7.87-8.05(m，2H)，8.64(s，1H)ppm
Embodiment 65
Figure A20061002362100283
Synthetic:
Working method is with example 39, and substrate is S-17, reacts 3 hours, and aftertreatment is the same, productive rate 82%, and ee 98%
1HNMR(300MHz，CDCl 3)：δ2.36(s，3H)，6.50(s，1H)，7.21-7.26(m，4H)，7.59-7.64(m，2H)，7.74(s，1H)，7.87(d，1H，J＝7.5Hz)，8.05(d，1H，J＝7.6Hz)，8.64(s，1H)ppm
Embodiment 66
Figure A20061002362100291
Synthetic:
Working method is with example 39, and substrate is S-18, reacts 3 hours, and aftertreatment is the same, productive rate 80%, and ee 95%
1HNMR(300MHz，CDCl 3)：δ6.29(s，1H)，7.19(s，2H)，7.34(s，4H)，7.96(s，1H)ppm
Embodiment 67
Synthetic:
Working method is with example 39, and substrate is S-19, reacts 3 hours, and aftertreatment is the same, productive rate 81%, ee98%
1HNMR(300MHz，CDCl 3)：δ2.37(s，3H)，6.32(s，1H)，7.11-7.26(m，4H)，7.41(s，1H)，8.02(s，1H)ppm
Embodiment 68
Synthetic:
Working method is with example 39, and substrate is S-20, reacts 3 hours, and aftertreatment is the same, productive rate 83%, ee94%.
1HNMR(300MHz，CDCl 3)：δ2.37(s，3H)，2.44(s，3H)，6.32(s，1H)，7.10(s，1H)，7.17-7.19(m，4H)，7.33-7.36(m，1H)，7.83(d，1H，J＝8.1Hz)ppm
Embodiment 69
Synthetic:
Working method is with example 39, and substrate is S-21, reacts 3 hours, and aftertreatment is the same, productive rate 80%, ee96%.
1HNMR(300MHz，CDCl 3)：δ2.24(s，3H)，2.27(s，3H)，2.77(s，3H)，6.30(s，1H)，7.00-7.19(m，2H)，7.10-7.16(m，2H)，7.33-7.36(m，1H)，7.83(d，1H，J＝7.5Hz)ppm
Embodiment 70
Figure A20061002362100301
Synthetic:
Working method is with example 39, and substrate is S-22, reacts 3 hours, and aftertreatment is the same, productive rate 80%, ee97%.
1HNMR(300MHz，CDCl 3)：δ2.38(s，3H)，2.73(s，3H)，6.20(s，1H)，7.05-7.08(m，2H)，7.13-7.16(m，3H)，7.22-7.26(m，2H)ppm
Embodiment 71
Figure A20061002362100302
Synthetic:
Working method is with example 39, and substrate is S-23, reacts 3 hours, and aftertreatment is the same, productive rate 82%, ee97%.
1HNMR(300MHz，CDCl 3)：δ1.96(s，3H)，2.34(s，3H)，2.71(s，3H)，6.22(s，1H)，7.05-7.08(m，2H)，7.13-7.16(m，2H)，7.22-7.26(m，2H)ppm
Embodiment 72
Figure A20061002362100303
Synthetic:
Working method is with example 39, and substrate is S-24, reacts 3 hours, and aftertreatment is the same, productive rate 75%, ee95%.
1HNMR(300MHz，CDCl 3)：δ1.85(s，3H)，2.27(s，6H)，2.31(s，3H)，6.25(s，1H)，7.04-7.08(m，1H)，7.16-7.21(m，4H)ppm
Embodiment 73
Figure A20061002362100304
Synthetic:
Working method is with example 39, and substrate is S-25, reacts 3 hours, and aftertreatment is the same, productive rate 55%, ee95%.
1HNMR(300MHz，CDCl 3)：δ1.96(s，3H)，2.21(s，6H)，2.24(s，3H)，2.34(s，6H)，6.25(s，1H)，7.02-7.06(m，2H)，7.11-7.15(m，2H)ppm
Embodiment 74
Synthetic:
In the exsiccant three-necked bottle, (200mg is 1.3mmol) with the 5mL tetrahydrofuran (THF) to add the samarium powder; under the nitrogen protection, add 0.081mL (1.0mmol) methylene iodide, stir under the room temperature after 1 hour; system is cooled to-78 ℃, add reaction substrate S-2 (134mg, 0.5mmol) and chiral reagent (12mg, 0.05mmol) and achirality proton source (71mg, 5mL tetrahydrofuran solution 0.5mmol) after 30 minutes, make it slowly be warming up to-30 ℃-78 ℃ of following reactions, descend reaction after one hour at-30 ℃ afterwards, aftertreatment, and purifying, productive rate 81%, ee 94%.
1HNMR(300MHz，CDCl 3)：δ2.67(s，3H)，6.41(s，1H)，7.12-7.40(m，4H)，7.58-7.63(m，3H)，7.80-7.85(m，1H)ppm
Embodiment 75
Figure A20061002362100314
Synthetic:
Working method is with example 74, and substrate is S-3, reacts 3 hours, and aftertreatment is the same, productive rate 82%, and ee 96%.
1HNMR(300MHz，CDCl 3)：δ3.81(s，3H)，6.38(s，1H)，7.02-7.18(m，4H)，7.32-7.52(m，3H)，7.82-7.88(m，1H)ppm
Embodiment 76
Synthetic:
Working method is with example 74, and substrate is S-4, reacts 3 hours, and aftertreatment is the same, productive rate 83%, and ee 97%.
1HNMR(300MHz，CDCl 3)：δ6.39(s，1H)，7.04-7.10(m，2H)，7.23-7.32(m，3H)，7.55-7.70(m，2H)，7.96(d，1H，J＝7.8Hz)ppm
19FNMR(282MHz，CDCl 3)：δ-112.08ppm
Embodiment 77
Synthetic:
Working method is with example 74, and substrate is S-5, reacts 3 hours, and aftertreatment is the same, productive rate 83%, and ee 90%.
1HNMR(300MHz，CDCl 3)：δ6.38(s，1H)，7.20-7.24(m，2H)，7.30-7.38(m，3H)，7.55-7.69(m，2H)，7.96(d，1H，J＝7.8Hz)ppm
Embodiment 78
Figure A20061002362100322
Synthetic:
Working method is with example 74, and substrate is S-6, reacts 3 hours, and aftertreatment is the same, productive rate 85%, and ee 92%.
1HNMR(300MHz，CDCl 3)：δ6.37(s，1H)，7.15-7.18(m，2H)，7.30-7.34(m，1H)，7.51-7.68(m，4H)，7.96-7.99(m，1H)ppm
Embodiment 79
Synthetic:
Working method is with example 74, and substrate is S-7, reacted 3 hours, and aftertreatment, purifying, productive rate 75%, ee 97%.
1HNMR(300MHz，CDCl 3)：δ2.24(d，6H，J＝5.4Hz)，6.35(s，1H)，6.99-7.01(m，2H)，7.12-7.34(m，2H)，7.55-7.65(m，2H)，7.95-7.97(m，1H)ppm
Embodiment 80
Figure A20061002362100331
Synthetic:
Working method is with example 74, and substrate is S-8, reacts 3 hours, and aftertreatment is the same, productive rate 72%, and ee 97%.
1HNMR(300MHz，CDCl 3)：δ3.80(s，3H)，3.88(s，3H)，6.37(s，1H)，6.68(s，1H)，6.87(s，2H)，7.32-7.35(m，1H)，7.56-7.67(m，2H)，7.97(d，1H，J＝7.5Hz)ppm
Embodiment 81
Figure A20061002362100332
Synthetic:
Working method is with example 74, and substrate is S-9, reacts 3 hours, and aftertreatment is the same, productive rate 83%, and ee 95%.
1HNMR(300MHz，CDCl 3)：δ6.56(s，1H)，7.21-7.25(m，1H)，7.34(d，1H，J＝4.2Hz)，7.49-7.65(m，4H)，7.81-7.86(m，4H)，7.99(d，1H，J＝7.2Hz)ppm
Embodiment 82
Synthetic:
Working method is with example 74, and substrate is S-10, reacts 3 hours, and aftertreatment is the same, productive rate 65%, and ee 96%.
1HNMR(300MHz，CDCl 3)：δ6.68(s，1H)，7.01-7.05(m，1H)，7.15-7.16(m，1H)，7.26-7.49(m，2H)，7.58-7.95(m，2H)，7.98-7.99(m，1H)ppm.

Claims (10)

1. high-optical-purity chiral phthalide analog compound, it has following structure:
Figure A2006100236210002C1
Wherein,
R 1For aryl or contain O or five to seven yuan of aromatic heterocyclics of S; Described aryl can be phenyl, naphthyl, halogenophenyl, C 1～C 6The alkoxyl group phenyl, the C that replace 1～C 8The phenyl that replaces of alkyl; R 2, R 3, R 4Or R 5Be H, halogen, C 1～C 8Alkyl or C 1～C 6Alkoxyl group; Perhaps adjacent R 2, R 3, R 4Or R 5Substituting group is-C 4H 4-; * represent chirality; Wherein, work as R 2, R 3, R 4And R 5When being H, R 1Be not equal to phenyl.
2. a kind of high-optical-purity chiral phthalide analog compound as claimed in claim 1 is characterized in that having following structural formula: Or R wherein 1, R 2, R 3, R 4And R 5According to claim 1.
3. a kind of high-optical-purity chiral phthalide analog compound as claimed in claim 1 is characterized in that having following structural formula:
Figure A2006100236210002C4
Or
Figure A2006100236210002C5
R wherein 1, R 3And R 4According to claim 1.
4. a kind of high-optical-purity chiral phthalide analog compound as claimed in claim 1 is characterized in that five yuan to the seven yuan aromatic heterocyclics of the described O of containing, S are recommended as furan food in one's mouth base or thienyl; Described halogen is F, Cl, Br or I.
5. as according to claim 1,2,3 or 4 tins of a kind of chiral phthalide analog compounds of stating, it is characterized in that the ee value of described chiral phthalide analog compound is 90-99%.
6. the synthetic method of a kind of high-optical-purity chiral phthalide analog compound as claimed in claim 1, it is characterized in that in tetrahydrofuran (THF), under-78 ℃～room temperature condition, by substrate 2-acyl group benzoic ether, chiral reagent, samarium diodide and existence or the time reaction 0.5～24 hour that do not have achirality proton source compound;
The mol ratio of described reactant 2-acyl group benzoic ether, chiral reagent, samarium diodide and achirality proton source compound is: 1: 0.05～2: 0.5～5: 0～5;
The structural formula of described 2-acyl group benzoic ether substrate is as follows:
The structural formula of described chiral reagent is as follows:
Figure A2006100236210003C3
Or
The structural formula of described achirality proton source compound is as follows:
Wherein, R 1, R 2, R 3, R 4And R 5According to claim 1; R 6Be C 1～C 6Alkyl; R 7Or R 8Be phenyl, p-methylphenyl, p-methoxyphenyl; R, R ' are H or C 1～C 6Alkyl; Ac, Ph, Ts, Bn represent ethanoyl, phenyl respectively, to Methyl benzenesulfonyl base and benzyl; * represent chirality.
7. method as claimed in claim 6 is characterized in that described being reflected at-78 ℃～-50 ℃ of temperature condition reactions down, reacts 2～5 hours.
8. method as claimed in claim 6 is characterized in that the mol ratio of described reactant 2-acyl group benzoic ether, chiral reagent, samarium diodide and achirality proton source compound is: 1: 0.05～0.5: 1～5: 0.5～5.
9. method as claimed in claim 6 is characterized in that the mol ratio of described reactant 2-acyl group benzoic ether, chiral reagent, samarium diodide and achirality proton source compound is: 1: 0.5～2: 1～5: 0.
10. method as claimed in claim 6 is characterized in that the structural formula of described chiral reagent is as follows: Or
Figure A2006100236210003C7
Ph in the formula represents phenyl.
CN 200610023621 2006-01-25 2006-01-25 High optical activity chiral phthalide analog compound and synthesis method Withdrawn CN1807421A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010117040A1 (en) * 2009-04-10 2010-10-14 富士フイルム株式会社 Five-membered heterocyclic compound
CN102267977A (en) * 2011-05-06 2011-12-07 中国药科大学 Thio and seleno homologue of 3-substituted benzo [c] furanone, preparation method and medical application thereof
CN102993340A (en) * 2012-12-21 2013-03-27 天津久日化学股份有限公司 Photoinitiator for ultraviolet light curing agent and manufacturing method thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010117040A1 (en) * 2009-04-10 2010-10-14 富士フイルム株式会社 Five-membered heterocyclic compound
CN102267977A (en) * 2011-05-06 2011-12-07 中国药科大学 Thio and seleno homologue of 3-substituted benzo [c] furanone, preparation method and medical application thereof
CN102267977B (en) * 2011-05-06 2014-09-10 中国药科大学 Thio and seleno homologue of 3-substituted benzo [c] furanone, preparation method and medical application thereof
CN102993340A (en) * 2012-12-21 2013-03-27 天津久日化学股份有限公司 Photoinitiator for ultraviolet light curing agent and manufacturing method thereof
CN102993340B (en) * 2012-12-21 2015-09-02 天津久日化学股份有限公司 A kind of light trigger for ultraviolet curable agent and manufacture method thereof

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