CN109320447A - A kind of synthetic method of chirality 3,3- disubstituted indole -2- ketone derivatives - Google Patents
A kind of synthetic method of chirality 3,3- disubstituted indole -2- ketone derivatives Download PDFInfo
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Abstract
The present invention relates to a kind of chiral 3, the synthetic method of 3- disubstituted indole -2- ketone derivatives, the following steps are included: organic micromolecule catalyst chiral camphor sulfohydrazide, organic acid and organic solvent are mixed, after mixing evenly, sequentially add α, beta-unsaturated aldehyde and 3- substituted indole -2- ketone, reaction while stirring is until reaction terminates, it is successively quenched, extracted, obtain crude product, sodium borohydride reduction is added, then silica gel column chromatography purifies up to chiral 3, the 3- disubstituted indole -2- ketone derivatives.Compared with prior art, the present invention is using chiral camphor sulfohydrazide simple and easy to get and organic acid as catalyst, in the presence of an organic, 3- substituted indole -2- ketone and α, beta-unsaturated aldehyde compounds occur Michael addition reaction and form corresponding 3,3 disubstituted indole -2- ketone compounds, reaction condition is mild, environmental-friendly, and reaction reagent is cheap and easy to get, reaction substrate range is wide, and enantioselectivity is high.
Description
Technical field
The present invention relates to organic chemistry medicine intermediate technical fields, and in particular to a kind of chiral 3,3- disubstituted indole-
The synthetic method of 2- ketone derivatives.
Background technique
Asymmetry catalysis is one of field most popular in current organic synthesis, because it is to obtain single chiral product most
Important means and most challenging synthetic method.Asymmetry catalysis mainly includes organocatalysis, metal is organic matches
Three aspects such as body catalysis and biological enzyme.In recent years, organocatalysis becomes asymmetry catalysis with the advantage of itself
In mainstay.
3,3- disubstituted indole -2- ketone derivatives are widely present in many natural products and drug molecule, and are had good
Good bioactivity.Therefore, the synthesis of 3,3- disubstituted indole -2- ketone derivatives is in manyization such as organic synthesis, pharmaceutical synthesis
Field all has great importance.It and is even more organic chemistry for the synthesis of chirality 3,3- disubstituted indole -2- ketone derivatives
One of the hot spot of family's research.Preparation 3,3- of chirality disubstituted indole -2- ketone derivatives are mainly the following method at present:
Mainly include three kinds of methods: (1) aldol condensation occurs for isatin and aldehydes or ketones；(2) 3- with leaving group takes
It is reacted for indol-2-one with nucleopilic reagent；(3) cycloaddition occurs for 3- alkane subunit indol-2-one, forms 3,3- bis- and replaces spirocyclization
Close object.These three methods have in common that indol-2-one is all used as the receptor of necleophilic reaction, and the universality of some substrates is inadequate
Good, some enantioselectivities are not high enough.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of easy to operate, substrates
The synthetic method of wide adaptation range and selective high chiral 3,3- disubstituted indole -2- ketone derivatives.
The purpose of the present invention can be achieved through the following technical solutions: a kind of chirality 3,3- disubstituted indole -2- ketone spreads out
The synthetic method of biology, the structural formula of the chirality 3,3- disubstituted indole -2- ketone derivatives are as follows:
The synthetic method the following steps are included: by organic micromolecule catalyst chiral camphor sulfohydrazide, organic acid and
Organic solvent mixing, after mixing evenly, sequentially adds α, beta-unsaturated aldehyde and 3- substituted indole -2- ketone, reacts while stirring
Until reaction terminates, successively it is quenched, extracted, obtain crude product, sodium borohydride reduction is added, then silica gel column chromatography purifies
Up to chiral 3, the 3- disubstituted indole -2- ketone derivatives, wherein
The structure of the alpha, beta-unsaturated aldehyde be for
The structure of the 3- substituted indole -2- ketone be for
R1Alkyl selected from aryl or C1~C8, R2Alkyl or halogen selected from C1~C2, R3Selected from H, tert-butyl oxygen carbonyl
One of base, acetyl group, benzyloxycarbonyl group or methyl, R4One of alkyl or aryl selected from C1~C5.
Substantially reaction equation of the invention is as follows:
Synthetic method of the invention utilizes various 3- substituted indole -2- ketone and α, and addition reaction occurs for beta-unsaturated aldehyde,
Under the action of chiral catalyst, a series of chiral 3,3- disubstituted indole -2- ketone derivatives are synthesized, are closed in organic synthesis, drug
At etc. many chemical fields all have great importance.The present invention is effectively mentioned using a kind of chiral camphor sulfohydrazide as catalyst
The high enantioselectivity of reaction and the adaptability of reaction substrate.Therefore, present invention addresses three kinds of methods noted earlier
Substrate compounds type is relatively limited to, the relatively low disadvantage of enantioselectivity.
Preferably, the structural formula of the chiral camphor sulfohydrazide is as follows:
Wherein, the R5Selected from C1~C8 alkyl, acyl group, tertiary butyl oxycarbonyl or aryl or benzyl
One of base, it is furthermore preferred that R5Any one in methyl, ethyl or benzyl.The present invention uses chiral camphor sulphonyl
Hydrazine makes it as Lewis-base catalyst due to α-hetero atom effect in self structure, is conducive to form imines with unsaturated aldehyde
Salt, then Michael addition reaction occurs with the 3- substituted indole -2- ketone after acidification, it is effectively formed the hand with high enantioselectivity
Property 3,3- disubstituted indole -2- ketone derivatives.
Preferably, the organic acid is selected from benzoic acid, 2- nitrobenzoic acid, chloroacetic acid, trichloroacetic acid, trifluoro second
Any one in acid, p-methyl benzenesulfonic acid, trifluoromethanesulfonic acid, 3- benzenpropanoic acid or formic acid.It is furthermore preferred that organic acid is selected from three chloroethenes
Acid or trifluoroacetic acid in any one.Organic acid as the additive other than chiral catalyst, be more advantageous to catalyst with not
Saturated aldehyde forms inferior amine salt intermediate, while 3- substituted indole -2- ketone substrate being made to be acidified to form corresponding enol form, and the two is into one
Michael addition reaction occurs for step.
Preferably, the organic solvent is selected from methylene chloride, toluene, tetrahydrofuran, acetonitrile, chloroform, methanol, Isosorbide-5-Nitrae-two
One of six ring of oxygen, ether, dichloroethanes or t-butyl methyl ether, it is furthermore preferred that organic solvent is selected from methylene chloride, dichloro
Any one in ethane or toluene.
Preferably, the chiral camphor sulfohydrazide, acid, 3- substituted indole -2- ketone and α, the molar ratio of beta-unsaturated aldehyde
For (0.1~0.2): (0.1~0.2): 1:(1~3), it is furthermore preferred that chiral camphor sulfohydrazide, acid, 3- substituted indole -2- ketone and
The molar ratio of alpha, beta-unsaturated aldehyde is 0.2:0.2:1:2.
Preferably, the rate of the stirring is 100~2000r/min.
Preferably, the reaction temperature be -10~40 DEG C, the reaction time be 12~for 24 hours, it is furthermore preferred that reaction temperature
For room temperature.
Preferably, described to be quenched using water, extractant used in the extraction is ethyl acetate or methylene chloride,
Crude product is obtained in extract liquor.
Preferably, the sodium borohydride of addition is excessive.
Preferably, the described silica gel column chromatography purifying using the mixed liquor of ethyl acetate and petroleum ether as eluent,
The volume ratio of middle ethyl acetate and petroleum ether is 1:5.
Compared with prior art, the beneficial effects of the present invention are embodied in following several respects:
(1) 3- substituted indole -2- ketone and α, β-insatiable hunger are passed through as catalyst using chiral camphor sulfohydrazide and organic acid
Various 3,3- disubstituted indole -2- ketone compounds are prepared for aldehyde compound reaction, can be used as a kind of important organic centre
Body is applied to the fields such as medicine, pesticide, provides effective method of asymmetric synthesis for synthesis of natural product or drug.
(2) synthetic method provided by the invention, mild condition is environmental-friendly, and process is simple, and reaction reagent is cheap and easy to get,
Reaction substrate wide adaptation range, enantioselectivity is high, has important application value.
Specific embodiment
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
Embodiment 1
It is sequentially added in dry reaction tube catalyst V-a (9.56mg, 0.04mmol), trichloroacetic acid (6.56mg,
0.04mmol), 3- methyl indol -2- ketone I-a (29.4mg, 0.2mmol), trans-2-butene aldehyde II-a (42mg, 0.6mmol),
Toluene (0.4mL), is stirred at room temperature 18h, water quenching is added to go out, and is extracted with dichloromethane 3 times, and saturated common salt washing, organic layer is with anhydrous
Sodium sulphate is dry, after concentration, 0.8mL methanol is added, NaBH is added portionwise under ice bath4(15.2mg, 0.4mmol), reaction
1mL saturated ammonium chloride solution is added in 30min, and ethyl acetate extracts 3 times, saturated sodium-chloride washing, organic layer anhydrous sodium sulfate
Dry, concentration, crude product obtains product 1 through column chromatographic purifying, i.e. IV-a (39.0mg, 89%),1HNMR(400MHz,CDCl3)
δ 8.60 (s, 1H), 7.24-7.14 (m, 2H), 7.02 (t, J=8.0Hz, 1H), 6.91.
(d, J=8.0Hz, 1H), 3.72 (m, 1H), 3.59 (m, 1H), 2.15-2.03 (m, 1H), 1.90-1.82 (m,
2H), 1.42 (s, 3H), 0.86 (d, J=8.0Hz, 3H) .13C NMR (100MHz, CDCl3) δ 183.0,140.7,133.8,
127.7,123.6,122.3,109.6,61.2,51.9,36.9,34.0,21.6,14.2.HP LC analysis condition: Daicel
ChIRALPAK IC column, 254nm, n-hexane/i-PrOH=85/15,1.0ml/min, 12.2min (minor),
15.9min (major), 91%ee.
Take identical reactant, identical operating procedure, respectively with 0.04mmol or less catalyst alternative catalysts V-a
It is reacted, as a result as shown in table 1 below:
1 alternative catalysts of table and reaction result
| Number | Catalyst R5 | Yielda(%) | Dr valueb | Ee valueb(%) |
| Product 2 | CF3Bn | 46 | 5.1/1 | 15 |
| Product 3 | Et | 92 | 10.5/1 | 81 |
| Product 4 | Pentyl | 30 | 2.7/1 | 80 |
| Product 5 | Bn | 70 | 1.5/1 | 81 |
In table 1, subscript a indicates that separation yield, b indicate the diastereo-isomerism analyzed by chiral high performance liquid chromatography
The excessive value of body and enantiomter.
Identical reactant is taken, identical operating procedure is carried out respectively with 0.04mmol or less acid substitution trichloroacetic acid anti-
It answers, as a result as shown in table 2 below:
Table 2 substitutes organic acid and reaction result
In table 2, subscript a indicates that separation yield, b indicate the diastereo-isomerism analyzed by chiral high performance liquid chromatography
The excessive value of body and enantiomter.
Identical reactant is taken, identical operating procedure is reacted with 0.4mL or less solvent substitution toluene respectively, tied
Fruit is as shown in table 3 below:
Table 3 substitutes solvent and reaction result
| Number | Solvent | Yielda(%) | Dr valueb | Ee valueb(%) |
| Product 13 | MeOH | 46 | 7.6/1 | 80 |
| Product 14 | DCM | 67 | 1.7/1 | 91 |
| Product 15 | dioxane | 46 | 1.1/1 | 78 |
| Product 16 | CHCl3 | 64 | 2.5/1 | 89 |
| Product 17 | THF | 41 | 2.1/1 | 84 |
| Product 18 | MeCN | 48 | 6.2/1 | 84 |
| Product 19 | Et2O | 69 | 1.5/1 | 89 |
| Product 20 | TBME | 44 | 1.9/1 | 89 |
| Product 21 | DCE | 57 | 2.0/1 | 91 |
In table three, subscript a indicates separation yield, and b expression is analyzed diastereomeric different by chiral high performance liquid chromatography
The excessive value of structure body and enantiomter.
It can be seen that catalyst V-a, trichloroacetic acid and methylene chloride are that effect is optimal from the result of 1~table of table 3
Condition.
Embodiment 2
Difference from Example 1 is: substrate used replaces trans-2-butene aldehyde to be trans- -2- hexenoic aldehyde II-b
(0.6mmol, 59mg), other reaction conditions and operating procedure are same as Example 1, obtain white solid product IV-b
(33.1mg, 67%),1H NMR (400MHz, CDCl3) δ 8.15 (s, 1H), 7.21 (t, J=8.0Hz, 2H), 7.02 (t, J=
8.0Hz, 1H), 6.89 (d, J=4.0Hz, 1H), 3.70-3.65 (m, 1H), 3.61-3.54 (m, 1H), 1.93-1.89 (m,
2H), 1.60-1.50 (m, 1H), 1.42 (s, 3H), 1.32-1.26 (m, 3H), 1.11-1.04 (m, 1H), 0.81 (t, J=
4.0Hz,3H).13C NMR(100MHz,CDCl3)δ182.9,140.3,134.3,127.7,123.6,122.4,109.6,
62.4,52.0,41.5,33.9,33.6,22.5,21.7,14.4.HPLC analysis condition: Daicel CHIRALPAK IC
Column, 254nm, n-hexane/i-PrOH=85/15,1.0ml/min, 10.4min (minor), 18.8min (major),
82%ee.
Embodiment 3
Difference from Example 1 is: substrate used replaces 3- methyl Indolin-2-one to be 3- benzyl dihydro Yin
Diindyl -2- ketone I-b (0.2mmol, 44.6mg), other reaction conditions and operating procedure are same as Example 1, obtain white solid production
Object IV-d (44.9mg, 76%), 1H NMR (400MHz, CDCl3) δ 7.46 (s, 1H), 7.30 (d, J=8.0Hz, 1H), 7.14-
7.09 (m, 1H), 7.04 (dd, J=8.0,4.0Hz, 1H), 7.02-6.96 (m, 3H), 6.82 (dd, J=8.0,4.0Hz, 2H),
6.60 (d, J=8.0Hz, 1H), 3.79-3.73 (m, 1H), 3.67-3.61 (m, 1H), 3.21 (q, J=12.0Hz, 2H),
2.31-2.20 (m, 1H), 2.02-1.93 (m, 1H), 1.55-1.46 (m, 1H), 0.92 (d, J=8.0Hz, 3H) .13C NMR
(100MHz,CDCl3)δ180.4,141.0,136.1,130.8,129.9,127.8,127.5,126.2,124.4,121.9,
109.1,61.2,58.3,41.4,36.9,34.2,14.4.HPLC analysis condition: Daicel CHIRALPAK ICcolumn,
254nm, n-hexane/i-PrOH=82/18,1.0ml/min, 7.5min (minor), 15.0min (major), 86%ee.
Embodiment 4
Difference from Example 1 is: substrate used replaces 3- methyl Indolin-2-one to be 3- (4- methyl benzyl
Base) Indolin-2-one I-c (0.2mmol, 47.4mg), other reaction conditions and operating procedure are same as Example 1, obtain
White solid product IV-e (49.5mg, 80%),1H NMR (400MHz, CDCl3) δ 8.04 (s, 1H), 7.28 (d, J=
8.0Hz, 1H), 7.16-7.08 (m, 1H), 7.04 (q, J=8.0Hz, 1H), 6.79-6.73 (m, 2H), 6.69-6.62 (m,
3H),3.78–3.70(m,1H),3.66–3.57(m,1H),3.16(s,2H),2.28–2.24(m,1H),2.14(s,3H),
2.01-1.94 (m, 1H), 1.543-1.43 (m, 1H), 0.88 (d, J=8.0Hz, 3H) .13C NMR (101MHz, CDCl3)δ
181.3,141.3,135.6,132.9,130.9,129.7,128.2,127.7,124.4,121.9,109.4,61.0,58.5,
40.9,36.8,34.1,20.9,14.5.HPLC analysis condition: Daicel CHIRALPAK IC column, 254nm, n-
Hexane/i-PrOH=85/15,1.0ml/min, 9.4min (minor), 20.6min (major), 90%ee.
Embodiment 5
Difference from Example 1 is: substrate used replaces 3- methyl Indolin-2-one to be 3- (4- methoxyl group
Benzyl) Indolin-2-one I-d (0.2mmol, 50.6mg), other reaction conditions and operating procedure are same as Example 1, obtain
To white solid product IV-f (52.7mg, 81%),1H NMR (400MHz, CDCl3) δ 7.99 (s, 1H), 7.28 (d, J=
8.0Hz, 1H), 7.16-7.08 (m, 1H), 7.06-7.00 (m, 1H), 6.72 (d, J=8.0Hz, 2H), 6.63 (d, J=
8.0Hz, 1H), 6.52 (d, J=8.0Hz, 2H), 3.77-3.71 (m, 1H), 3.64 (s, 3H), 3.65-3.58 (m, 1H), 3.15
(s, 2H), 2.29-2.21 (m, 1H), 2.02-1.92 (m, 1H), 1.53-1.40 (m, 1H), 0.89 (d, J=8.0Hz, 3H)
.13C NMR(100MHz,CDCl3)δ181.1,157.9,141.2,131.0,130.8,128.1,127.8,124.4,121.9,
112.9,109.4,61.1,58.6,54.9,40.5,36.7,34.2,14.5.HPLC analysis condition: DaicelCHIRALPAK
IC column, 254nm, n-hexane/i-PrOH=70/30,0.8ml/min, 7.4min (minor), 12.2min
(major), 90%ee.
Embodiment 6
Difference from Example 1 is: substrate used replaces 3- methyl Indolin-2-one to be 3- (4- chlorobenzyl)
Indolin-2-one I-e (0.2mmol, 47.4mg), other reaction conditions and operating procedure are same as Example 1, obtain white
Solid product IV-g (47.5mg, 72%),1H NMR (400MHz, CDCl3) δ 8.26 (s, 1H), 7.29 (d, J=8.0Hz,
1H), 7.14 (t, J=8.0Hz, 1H), 7.04 (t, J=8.0Hz, 1H), 6.92 (d, J=8.0Hz, 2H), 6.71 (d, J=
8.0Hz, 2H), 6.66 (d, J=8.0Hz, 1H), 3.77-3.72 (m, 1H), 3.66-3.59 (m, 1H), 3.16 (s, 2H),
2.29-2.22 (m, 1H), 1.98-1.93 (m, 1H), 1.53-1.43 (m, 1H), 0.87 (d, J=8.0Hz, 3H) .13C NMR
(100MHz,CDCl3)δ181.0,141.3,134.6,132.2,131.1,130.5,128.0,127.6,124.3,122.1,
109.6,60.9,58.5,40.7,36.8,34.1,14.4.HPLC analysis condition: Daicel CHIRALPAK IC column,
254nm, n-hexane/i-PrOH=85/15,1.0ml/min, 7.6min (minor), 19.1min (major), 87%ee.
Embodiment 7
Difference from Example 1 is: substrate used replaces 3- methyl Indolin-2-one to be 3- (4- fluoroform
Oxy-benzyl) Indolin-2-one I-f (0.2mmol, 61.5mg), other reaction conditions and operating procedure and 1 phase of embodiment
Together, white solid product IV-h (51.6mg, 68%) is obtained,1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.30(d,J
=8.0Hz, 1H), 7.14 (t, J=8.0Hz, 1H), 7.05 (t, J=8.0Hz, 1H), 6.82 (s, 4H), 6.63 (d, J=
8.0Hz, 1H), 3.79-3.73 (m, 1H), 3.68-3.61 (m, 1H), 3.20 (q, J=12.0Hz, 2H), 2.32-2.21 (m,
1H), 2.04-1.92 (m, 1H), 1.55-1.47 (m, 1H), 0.91 (d, J=8.0Hz, 3H) .13C NMR (100MHz, CDCl3)
δ80.3,147.8,141.1,134.8,131.1,130.4,128.0,124.3,122.1,119.8,109.3,61.0,58.3,
40.7,36.8,34.2,29.6,29.3,14.4.HPLC analysis condition: Daicel CHIRALPAK IC column, 254nm,
N-hexane/i-PrOH=85/15,1.0ml/min, 5.6min (minor), 12.3min (major), 81%ee..
Embodiment 8
Difference from Example 1 is: substrate used replaces 3- methyl Indolin-2-one to be 3- (4- fluoroform
Base benzyl) Indolin-2-one I-g (0.2mmol, 58.3mg), other reaction conditions and operating procedure are same as Example 1,
White solid product IV-i (48.0mg, 66%) is obtained,1H NMR (400MHz, CDCl3) δ .18 (s, 1H), 7.32 (d, J=
8.0Hz, 1H), 7.21 (d, J=8.0Hz, 2H), 7.15 (t, J=4.0Hz, 1H), 7.10-7.02 (m, 1H), 6.89 (d, J=
8.0Hz,2H),6.67–6.65(m,1H),3.80–3.72(m,1H),3.67-3.59(m,1H),3.24(s,2H),2.34–
2.25 (m, 1H), 2.07-1.94 (m, 1H), 1.55-1.45 (m, 1H), 0.87 (d, J=8.0Hz, 3H) .HPLC analysis condition:
DaicelCHIRALPAK IC column, 254nm, n-hexane/i-PrOH=85/15,1.0ml/min, 5.8min
(minor), 13.1min (major), 86%ee.
Embodiment 9
Difference from Example 1 is: substrate used replaces trans-2-butene aldehyde to be trans-cinnamic aldehyde II-d
(0.6mmol, 79.3mg), other reaction conditions and operating procedure are same as Example 1, obtain white solid product IV-i
(36.6mg, 62%),1H NMR (400MHz, CDCl3) δ .09 (s, 1H), 7.23-7.19 (m, 1H), 7.12 (t, J=8.0Hz,
1H), 7.01-6.92 (m, 4H), 6.73 (d, J=8.0Hz, 2H), 6.63 (d, J=8.0Hz, 1H), 3.39-3.34 (m, 1H),
3.26-3.20 (m, 1H), 3.12 (dd, J=12.0,4.0Hz, 1H), 2.26-2.18 (m, 1H), 2.05-1.94 (m, 1H),
1.37(s,3H).13C NMR(100MHz,CDCl3)δ81.9,140.8,139.0,132.9,128.8,128.0,127.7,
126.9,124.1,122.0,109.5,61.0,52.4,49.2,32.4,21.5.HPLC analysis condition: Daicel
CHIRALPAK AS-Hcolumn, 254nm, n-hexane/i-PrOH=85/15,1.0ml/min, 9.5min (major),
14.6min (minor), 54%ee.
Claims (10)
1. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives, the chirality 3,3- disubstituted indole -2- ketone spread out
The structural formula of biology is as follows:It is characterized by:
The synthetic method is the following steps are included: by organic micromolecule catalyst chiral camphor sulfohydrazide, organic acid and organic
Solvent mixing, after mixing evenly, sequentially add α, beta-unsaturated aldehyde and 3- substituted indole -2- ketone, while stirring reaction until
Reaction terminates, and is successively quenched, is extracted, and crude product is obtained, and sodium borohydride reduction is added, then silica gel column chromatography purifies to obtain the final product
Chiral 3, the 3- disubstituted indole -2- ketone derivatives, wherein
The structure of the alpha, beta-unsaturated aldehyde be for
The structure of the 3- substituted indole -2- ketone be for
R1Alkyl selected from aryl or C1~C8, R2Alkyl or halogen selected from C1~C2, R3Selected from H, tertiary butyl oxycarbonyl, second
One of acyl group, benzyloxycarbonyl group or methyl, R4One of alkyl or aryl selected from C1~C5.
2. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
In the structural formula of the chiral camphor sulfohydrazide is as follows:
Wherein, the R5In C1~C8 alkyl, acyl group, tertiary butyl oxycarbonyl or aryl or benzyl
One kind.
3. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
In, the organic acid be selected from benzoic acid, 2- nitrobenzoic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid,
Any one in trifluoromethanesulfonic acid, 3- benzenpropanoic acid or formic acid.
4. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
In, the organic solvent be selected from methylene chloride, toluene, tetrahydrofuran, acetonitrile, chloroform, methanol, Isosorbide-5-Nitrae-dioxane, ether,
One of dichloroethanes or t-butyl methyl ether.
5. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
In the molar ratio of the chiral camphor sulfohydrazide, acid, 3- substituted indole -2- ketone and α, beta-unsaturated aldehyde are (0.1~0.2):
(0.1~0.2): 1:(1~3).
6. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
In the rate of the stirring is 100~2000r/min.
7. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
It is -10~40 DEG C in, the reaction temperature, the reaction time is 12~for 24 hours.
8. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
In described is quenched using water, and extractant used in the extraction is ethyl acetate or methylene chloride, obtains in extract liquor
Crude product.
9. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature exist
In the sodium borohydride of addition is excessive.
10. a kind of synthetic method of chiral 3,3- disubstituted indole -2- ketone derivatives according to claim 1, feature
Be, the described silica gel column chromatography purifying using the mixed liquor of ethyl acetate and petroleum ether as eluent, wherein ethyl acetate
Volume ratio with petroleum ether is 1:5.
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| CN104086535A (en) * | 2014-07-16 | 2014-10-08 | 成都丽凯手性技术有限公司 | 3, 3'-disubstituted 3-pyrrole oxoindole compound and asymmetric synthetic method thereof |
| CN104557665A (en) * | 2015-01-09 | 2015-04-29 | 华东师范大学 | Optically active 3-substituted indole derivatives as well as synthesis method and application thereof |
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| CN104086535A (en) * | 2014-07-16 | 2014-10-08 | 成都丽凯手性技术有限公司 | 3, 3'-disubstituted 3-pyrrole oxoindole compound and asymmetric synthetic method thereof |
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| CN110003134A (en) * | 2019-03-05 | 2019-07-12 | 上海工程技术大学 | Catalyst derived from a kind of chiral camphor sulfohydrazide and its preparation method and application |
| CN110003134B (en) * | 2019-03-05 | 2022-08-26 | 上海工程技术大学 | Chiral camphor sulfonyl hydrazide derived catalyst, preparation method and application thereof |
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