CN109438324A - One kind is containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog - Google Patents
One kind is containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog Download PDFInfo
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- CN109438324A CN109438324A CN201811380513.4A CN201811380513A CN109438324A CN 109438324 A CN109438324 A CN 109438324A CN 201811380513 A CN201811380513 A CN 201811380513A CN 109438324 A CN109438324 A CN 109438324A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention provides one kind containing α derived from trifluoro methyl indole, the preparation method of beta-amino acids analog, the preparation method is that isatin ketimide derivative, 2- ((2 that N-Boc is replaced, 2,2- trifluoroethyls) imino group) diethyl malonate derivative and catalyst be added reaction purification in solvent and obtain.Preparation method raw material provided by the invention is simple and easy to get, and catalyst is environmentally protective, and reaction condition is mild, operation is easy, and synthesis step is few, and product is easy purifies and separates and can obtain high yield and excellent stereoselectivity, simultaneous reactions are easy to amplify, and have very broad application prospect.
Description
Technical field
The invention belongs to technical field of organic synthesis, more particularly, to one kind containing α derived from trifluoro methyl indole, beta-amino
The chiral method for preparing of acid-like substance.
Background technique
Indoles skeleton is widely present in many natural products and bioactivity related compound.Above replace carbon containing four at 3
The Oxoindole skeleton of Stereocenter has always been considered as being " excellent in bioactive natural products and drug large family for a long time
Gesture structure " has many important biology, pharmaceutical properties.In particular, the 3- amino hydroxyindole bracket that chirality 3- replaces is mesh
Preceding key structure is in many drug candidates, such as gastrin/cholecystokinin Type B receptor antagonist AG-041R, anti-malarial agents
The NITD609 and non-peptide pitressin V1b receptor antagonist SSR-149415 of Orally active.In addition, α, beta-amino acids analog by
It proves that there is good bioactivity, is a kind of with activity and the necessary key structure of human body extensively.In this case, to
Ketimide derived from isatin add nucleopilic reagent be trifluoro methyl indole derived from α, beta-amino acids analog provide directly and
Strong approach.
In recent years, fluorine scanning had been widely used for the exploitation of lead drug as conventional method.And fluorine or fluoro-containing group are drawn
Series of active effect can be brought by entering in bioactive molecule.Due to strong electron-withdrawing ability, high electronegativity and small fluorine
Atom introduces the significant changes that trifluoromethyl frequently results in the property of molecule.Therefore exploitation by fluorine incorporation organic compound can
It is pharmaceutical chemical high expectations with method, however usually compared with single fluorination process, it is selectively introducing trifluoromethyl and enters institute
The method for needing position nevertheless suffers from many restrictions.
In view of CF3Introducing and Oxoindole skeleton important meaning, the spiro indole bone containing trifluoromethyl constructed at present
Frame includes: spiral shell [pyrroles -3,2 '-Oxoindoles] compound, spiral shell [3,3 '-oxindole of pyrrolidines -] compound, 3,3 '-pyrroles
Two spiral shell oxindoles compound these three mother nucleus structures of alkyl, and be 3 spiral shell nafoxidine alkyl structures of indoles.However indoles is derivative
α, β-amino acid analogue asymmetric syntheses case is less, and α derived from the indoles containing chiral trifluoromethyl, beta-amino acids
The synthesis of analog has no report, is even more head using quasi-Mannich reaction of the imines polarity reversion to ketimide derived from isatin
Secondary report.
Therefore it develops one kind to efficiently synthesize containing α derived from trifluoro methyl indole, the method for beta-amino acids analog has important
Practical significance.
Summary of the invention
It is an object of that present invention to provide one kind containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
The present invention provides a kind of containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog, the preparation
Method is that isatin ketimide derivative that N-Boc replaces, 2- ((2,2,2- trifluoroethyl) imino group) diethyl malonate spread out
Biology and catalyst are added reaction purification in solvent and obtain.The reaction formula of the preparation method are as follows:
The structural formula for the isatin ketimide derivative that the N-Boc replaces isWherein, R1For hydrogen, alkyl, alkane
Oxygroup, hydroxyl, cyano, amino, nitro, halogen or phenyl;R2For hydrogen, alkyl, alkoxy, phenyl, ester group, acyl group or sulphonyl
Base;
The R1In any one or multiple hydrogen independently by G1Replace;
G1Selected from-OH ,-NH2、-NO2, halogen, halogenated alkyl, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl or C6Virtue
Base;
The R2In any one or multiple hydrogen independently by G2Replace;
G2Selected from-OH ,-NH2、-NO2, halogen, halogenated alkyl, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl or C6Virtue
Base;
2- ((2,2,2- trifluoroethyl) imino group) the diethyl malonate derivant structure is
Wherein R3For hydrogen, alkyl, phenyl, R4Definition and R3It is identical;
The R3In any one or multiple hydrogen independently by G3Replace;
G3Selected from-OH ,-NH2、-NO2, halogen, halogenated alkyl, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl or C6Virtue
Base;
The catalyst is difunctional small organic molecule type catalyst, bronsted alkali or Lewis base type catalyst.
Preferably, R1Selected from hydrogen, C1-C8Alkyl, alkoxy, hydroxyl, cyano, amino, nitro, halogen or substituted-phenyl;R2
Selected from hydrogen, C1-C8Alkyl, alkoxy, substituted-phenyl, ester group, acyl group or sulfonyl;R3Selected from hydrogen, C1-C8Alkyl, benzyl take
For phenyl;
The R1In any one or multiple hydrogen independently by G1Replace;
G1Selected from-OH ,-NH2、-NO2, halogen, C1-6Alkyl or C6Aryl;
The R2In any one or multiple hydrogen independently by G2Replace;
G2Selected from-OH ,-NH2、-NO2, halogen, C1-6Alkyl or C6Aryl;
The R3In any one or multiple hydrogen independently by G3Replace;
G3Selected from-OH ,-NH2、-NO2, halogen, C1-6Alkyl or C6Aryl;
Preferably, R1Selected from hydrogen, C1-C8Alkyl, C1-C6Alkoxy, hydroxyl, cyano, nitro, amino, fluorine, chlorine, bromine, iodine,
Phenyl, benzyl, N, one of N- dimethylamino;
R2Selected from hydrogen, C1-C8Alkyl, phenyl, benzyl, acetyl group, benzoyl, p-toluenesulfonyl, carbamyl, benzyloxy carbonyl
One of base, tert-butoxycarbonyl;
R3Selected from hydrogen, C1-C8One of alkyl, substituted-phenyl, benzyl.
The preferably described catalyst be selected from triethylamine, trimethylamine, 1,8- diazabicylo, 11 carbon -7- alkene,Triethylene diamine, carbon
Sour potassium, sodium carbonate, sodium bicarbonate, cesium carbonate, its structural formula as I-of difunctional organic micromolecule catalyst derived from quinine
XII, the difunctional organic micromolecule catalyst XIII-XV of rosin derivative, other types of difunctional organic micromolecule catalyst
One or more of XVI-XVIII;Above-mentioned difunctional organic micromolecule catalyst structure is as follows:
Wherein difunctional organic micromolecule catalyst can get chiral containing α derived from trifluoro methyl indole, beta-amino acids analog,
Common bronsted alkali or lewis base can get achirality containing α derived from trifluoro methyl indole, beta-amino acids analog.
Preferably, the reaction temperature of the reaction is -78 DEG C -50 DEG C.
Preferably, the Isatine derivatives, 2- ((2,2,2- trifluoroethyl) imino group) diethyl malonate derivative and catalysis
The reaction molar ratio of agent is (1-20): (1-20): 1.
Preferably, the solvent selection methylene chloride, chloroform, 1,2- dichloroethanes, acetonitrile, methanol, ethyl alcohol, n-butanol, isopropyl
One or more of alcohol, ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, trimethylbenzene.
Preferably, the purification is (petroleum ether: ethyl acetate=8: 1) H60 silica gel obtains final product using column chromatography.
Preferably, the reaction time of the reaction is 3-72h.
The present invention has the effect that
Preparation method raw material cheap and simple provided by the invention, catalyst is environmentally protective, and reaction condition is mild, easy to operate, work
Skill route is simple, and product isolates and purifies simply, and target product yield is high, and stereoselectivity is excellent, and reaction amplification is easy.
Specific embodiment
The present invention will be illustrated by the following examples, but not limited in any form to the present invention.As without especially
Illustrate, agents useful for same of the present invention, method and apparatus are the art conventional reagent, method and apparatus.
Unless otherwise noted, agents useful for same and material of the present invention are commercially available.
Embodiment 1:(3R, E) (3- ((tert-butoxycarbonyl) amino) -1- methyl -2- oxoindoline -3- base) -2- ((2,
2,2- trifluoro ethylidene) amino) diethyl malonate structural formula is as follows:
(3R, E) (3- ((tert-butoxycarbonyl) amino) -1- methyl -2- oxoindoline -3- base) -2- ((2,2,2- trifluoros
Ethylidene) amino) diethyl malonate chiral method for preparing:
The methylisatin ketimide 26.0mg (0.10mmol) for taking N-Boc to replace under the conditions of -20 DEG C, 2- ((2,2,2- trifluoro second
Base) imino group) diethyl malonate 38.3mg (0.15mmol) and catalyst V 6.3mg (10mol%) mixing after, take solution
DCE (1.0mL) is added to reaction system and is reacted.Solution is concentrated under reduced pressure after reaction 6h, residue carried out column purification
(H60 silica gel, petroleum ether: ethyl acetate=5: 1 elution), obtains required white solid product (3S, E) (3- ((tert-butoxy carbonyl
Base) amino) -1- methyl -2- oxoindoline -3- base) -2- ((2,2,2- trifluoro ethylidene) amino) diethyl malonate
(47.9mg, yield 93%, > 99%ee).
(c=0.23, CH3OH)
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel IA-H, isopropanol/n-hexane=5/95,1.0ml/min are purple
Outer absorption 254nm.)tminor=9.0min, tmajor=7.9min, enantioselectivity reach > 99%.
Nmr analysis:
1H NMR (400MHz, CDCl3) δ 7.70 (d, J=2.8Hz, 1H), 7.49 (d, J=7.4Hz, 1H), 7.29 (t, J=
7.7Hz, 1H), 6.98 (t, J=7.4Hz, 1H), 6.76 (d, J=7.8Hz, 1H), 6.25 (s, 1H), 4.42-4.32 (m,
2H), 4.08 (d, J=5.5Hz, 2H), 3.21 (s, 3H), 1.33 (t, J=7.1Hz, 3H), 1.22 (s, 9H), 1.12 (t, J=
6.6Hz, 3H);19F NMR (376MHz, CDCl3)δ-72.32(s);13C NMR (101MHz, CDCl3) δ 173.10 (s),
165.25 (s), 163.65 (s), 156.12 (q, J=39.3Hz), 153.55 (s), 145.57 (s), 129.95 (s), 126.85
(s), 125.46 (s), 122.62 (s), 118.75 (q, J=245.7Hz), 107.81 (s), 80.41 (s), 63.68 (s),
The analysis of 63.45 (s), 28.20 (s), 26.53 (s), 13.95 (s), 13.70 (s) high resolution mass spectrums:
HRMS (ESI): m/z [M+H]+calcd.for[C23H28F3N3O7]+: 516.1952, found:516.1964,2.32ppm.
Embodiment 2:(3R, E) (3- ((tert-butoxycarbonyl) amino) -1,5- dimethyl -2- oxoindoline -3- base) -2-
((2,2,2- trifluoro ethylidene) amino) diethyl malonate structural formula is as follows:
(3R, E) (3- ((tert-butoxycarbonyl) amino) -1,5- dimethyl -2- oxoindoline -3- base) -2- ((2,2,2-
Trifluoro ethylidene) amino) diethyl malonate chiral method for preparing:
1, the 5- dimethylisatin ketimide 27.4mg (0.1mmol), 2- ((2,2,2- for taking N-Boc to replace under the conditions of -20 DEG C
Trifluoroethyl) imino group) diethyl malonate 38.3mg (0.1mmol) and catalyst V 6.3mg (10mol%) mixing after, take
Solution D CE (1.0mL) is added to reaction system and is reacted.Solution is concentrated under reduced pressure after reaction 36h, residue carried out column
Purifying (H60 silica gel, petroleum ether: ethyl acetate=5: 1 elution), obtains required white solid product (3S, E) (3- ((tertiary fourth oxygen
Base carbonyl) amino) -1,5- dimethyl -2- oxoindoline -3- base) -2- ((2,2,2- trifluoro ethylidene) amino) malonic acid
Diethylester (46.1mg, yield 87%, > 20: 1 dr and 98%ee).
(c=0.35, CH3OH)
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel IA-H, isopropanol/n-hexane=5/95,1ml/min are ultraviolet
Absorb 254 nm.)tminor=9.9min, tmajor=8.4min, enantioselectivity reach 98%.
Nmr analysis:
1H NMR (400MHz, CDCl3) δ 7.70 (d, J=2.8Hz, 1H), 7.28 (s, 1H), 7.07 (d, J=7.8Hz, 1H),
6.64 (d, J=7.9Hz, 1H), 6.24 (s, 1H), 4.36 (ddq, J=13.9,6.8,3.6Hz, 2H), 4.09 (d, J=
5.2Hz, 2H), 3.18 (s, 3H), 2.27 (s, 3H), 1.32 (t, J=7.1Hz, 3H), 1.22 (s, 9H), 1.15-1.07 (m,
3H);19F NMR (376 MHz, CDCl3)δ-72.31(s);13C NMR (101MHz, CDCl3) δ 172.97 (s), 165.30 (s),
163.69 (s), 156.12 (q, J=39.1Hz), 153.55 (s), 143.14 (s), 131.99 (s), 130.15 (s), 126.78
(s), 126.15 (s), 118.59 (q, J=275.7Hz), 107.52 (s), 80.33 (s), 63.63 (s), 63.42 (s),
28.19 (s), 26.53 (s), 21.31 (s), 13.93 (s), 13.70 (s)
High resolution mass spectrum analysis:
HRMS (ESI): m/z [M+H]+calcd.for[C24H30F3N3O7]+: 530.2109, found:530.2120,2.07ppm.
Embodiment 3:(3R, E) (the fluoro- 2- oxoindoline -3- base of 3- ((tert-butoxycarbonyl) amino) -1- methyl -5-) -2-
((2,2,2- trifluoro ethylidene) amino) diethyl malonate structural formula is as follows:
The isatin ketimide derivative that N-Boc needed for its preparation process replaces is that the fluoro- 1- methylisatin ketone of 5- that N-Boc replaces is sub-
Amine 27.8mg (0.1mmol), other processes are same as Example 2.(3S, E) (3- ((tert-butoxycarbonyl) amino) -1- first
The fluoro- 2- oxoindoline -3- base of base -5-) -2- ((2,2,2- trifluoro ethylidene) amino) diethyl malonate white solid
(50.7mg, yield 95%, 20: 1 dr and > 99%ee of >).
(c=0.43, CH3OH)
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel IA-H, isopropanol/n-hexane=5/95,1.0ml/min are purple
254 nm of outer absorption.)tminor=9.6min, tmajor=8.4min, enantioselectivity reach > 99%.
Nmr analysis:
1H NMR (500MHz, CDCl3) δ 7.73 (s, 1H), 7.29 (d, J=7.5Hz, 1H), 6.99 (t, J=8.4Hz, 1H),
6.74- 6.64 (m, 1H), 6.26 (s, 1H), 4.38 (s, 2H), 4.12 (d, J=0.7Hz, 2H), 3.20 (s, 3H), 1.32 (t,
J=6.4Hz, 3H), 1.25 (s, 9H), 1.16 (s, 3H);19F NMR (471MHz, CDCl3) δ -72.37 (s), -120.42
(s);13C NMR (126MHz, CDCl3) δ 172.90 (s), 164.23 (d, J=207.2Hz), 159.06 (d, J=
240.1Hz), 156.25 (q, J=39.3Hz), 153.46 (s), 141.77 (s), 128.43 (d, J=1.2Hz), 128.38
(d, J=5.2Hz), 118.54 (q, J=275.8 Hz), 116.03 (d, J=23.6Hz), 113.87 (d, J=25.8Hz),
108.15 (d, J=8.0Hz), 80.63 (s), 63.86 (s), 63.61 (s), 28.22 (s), 26.67 (s), 13.94 (s),
13.73(s).
High resolution mass spectrum analysis:
HRMS (ESI): m/z [M+H]+calcd.for[C23H27F4N4O7]+: 534.1858, found:534.1847 ,-
2.06ppm.
Embodiment 4:(3S, E) (3- ((tert-butoxycarbonyl) amino) -1,7- dimethyl -2- oxoindoline -3- base) -2-
((2,2,2- trifluoro ethylidene) amino) diethyl malonate structural formula is as follows:
The isatin ketimide derivative that N-Boc needed for its preparation process replaces is that 1, the 7- dimethylisatin ketone that N-Boc replaces is sub-
27.4 mg of amine (0.1mmol), other processes are same as Example 2.(3S, E) (3- ((tert-butoxycarbonyl) amino) -1,7- bis-
Methyl -2- oxoindoline -3- base) -2- ((2,2,2- trifluoro ethylidene) amino) diethyl malonate white solid
(51.9mg, yield 98%, 20: 1 dr and > 99%ee of >).
(c=0.25, CH3OH)
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel IA-H, isopropanol/n-hexane=5/95,1.0ml/min are purple
254 nm of outer absorption.)tminor=7.2min, tmajor=8.1min, enantioselectivity reach > 99%.
Nmr analysis:
1H NMR (400MHz, CDCl3) δ 7.66 (d, J=2.3Hz, 1H), 7.33 (d, J=7.4Hz, 1H), 7.00 (d, J=
7.7Hz, 1H), 6.85 (t, J=7.6Hz, 1H), 6.28 (s, 1H), 4.42-4.32 (m, 2H), 4.23-4.02 (m, 2H), 3.49
(s, 3H), 2.52 (s, 3H), 1.32 (t, J=7.1Hz, 3H), 1.24 (s, 9H), 1.14 (t, J=6.9Hz, 3H);19F NMR
(376MHz, CDCl3)δ-72.35(s);13C NMR (101MHz, CDCl3) δ 173.93 (s), 165.29 (s), 163.70 (s),
156.10 (q, J=38.5Hz), 153.54 (s), 143.20 (s), 133.75 (s), 127.42 (s), 123.20 (s), 122.52
(s), 119.22 (s), 118.60 (q, J=276.0Hz), 80.34 (s), 63.62 (s), 63.42 (s), 30.12 (s), 28.21
(s), the analysis of 19.27 (s), 13.94 (s), 13.71 (s) high resolution mass spectrums:
HRMS (ESI): m/z [M+H]+calcd.for[C24H30F3N3O7]+: 530.2109, found:530.2114,0.94ppm.
Embodiment 5:(3R, E) (3- ((tert-butoxycarbonyl) amino) -1- benzyl -2- oxoindoline -3- base) -2- ((2,
2,2- trifluoro ethylidene) amino) diethyl malonate structural formula is as follows:
The isatin ketimide derivative that N-Boc needed for its preparation process replaces is the 1- benzyl isatin ketimide that N-Boc replaces
33.6 mg (0.1mmol), other processes are same as Example 2.(3S, E) (3- ((tert-butoxycarbonyl) amino) -1- benzyl -
2- oxoindoline -3- base) (58.0mg is received -2- ((2,2,2- trifluoro ethylidene) amino) diethyl malonate white solid
Rate 98%, 20: 1 dr and > 99%ee of >).
(c=0.42, CH3OH)
High-efficient liquid phase analysis (HPLC): (chiral column Chiralcel IA-H, isopropanol/n-hexane=5/95,1.0ml/min are purple
254 nm of outer absorption.)tminor=30.6min, tmajor=7.6min, enantioselectivity reach > 99%.
Nmr analysis:
1H NMR (400MHz, CDCl3) δ 7.69 (d, J=2.8Hz, 1H), 7.52 (d, J=7.3Hz, 1H), 7.46 (d, J=
7.2Hz, 2H), 7.30 (t, J=7.3Hz, 2H), 7.27-7.22 (m, 1H), 7.16 (td, J=7.7,1.1Hz, 1H), 6.94
(t, J=7.6Hz, 1H), 6.66 (d, J=7.8Hz, 1H), 6.38 (s, 1H), 4.98 (d, J=15.6Hz, 1H), 4.84 (d, J
=15.7Hz, 1H), 4.45-4.35 (m, 2H), 4.14-3.89 (m, 2H), 1.34 (t, J=7.1Hz, 3H), 1.25 (s, 9H),
1.04 (s, 3H);19F NMR (376MHz, CDCl3)δ-72.09(s);13C NMR (101MHz, CDCl3) δ 173.53 (s),
165.32 (s), 163.79 (s), 155.98 (q, J=39.5Hz), 153.59 (s), 144.98 (s), 135.81 (s), 129.79
(s), 128.69 (s), 127.91 (s), 127.58 (s), 126.79 (s), 125.50 (s), 122.64 (s), 118.59 (q, J=
275.7Hz), 108.81 (s), 80.39 (s), 63.69 (s), 63.41 (s), 44.78 (s), 28.22 (s), 13.95 (s),
13.64(s).
High resolution mass spectrum analysis:
HRMS (ESI): m/z [M+H]+calcd.for[C29H32F3N3O7]+: 592.2265, found:592.2280,
2.53ppm.
Claims (9)
1. one kind is containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog, which is characterized in that described
Preparation method is the isatin ketimide derivative for replacing N-Boc, 2- ((2,2,2- trifluoroethyl) imino group) malonic acid diethyl
Ester derivant and catalyst are added reaction purification in solvent and obtain;The reaction formula of the preparation method are as follows:
The structural formula for the isatin ketimide derivative that the N-Boc replacesWherein, R1For hydrogen, alkyl, alcoxyl
Base, hydroxyl, cyano, amino, nitro, halogen or phenyl;R2For hydrogen, alkyl, alkoxy, phenyl, ester group, acyl group or sulfonyl;
The R1In any one or multiple hydrogen independently by G1Replace;
G1Selected from-OH ,-NH2、-NO2, halogen, halogenated alkyl, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl or C6Virtue
Base;
The R2In any one or multiple hydrogen independently by G2Replace;
G2Selected from-OH ,-NH2、-NO2, halogen, halogenated alkyl, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl or C6Virtue
Base;
2- ((2,2,2- trifluoroethyl) imino group) the diethyl malonate derivant structure isWherein R3
For hydrogen, alkyl, phenyl, R4Definition and R3It is identical;
The R3In any one or multiple hydrogen independently by G3Replace;
G3Selected from-OH ,-NH2、-NO2, halogen, halogenated alkyl, C1-6Alkyl, C3-6Naphthenic base, C2-6Alkenyl, C2-6Alkynyl or C6Virtue
Base;
The catalyst is difunctional small organic molecule type catalyst, bronsted alkali or Lewis base type catalyst.
2. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, R1Selected from hydrogen, C1-C8Alkyl, alkoxy, hydroxyl, cyano, amino, nitro, halogen or substituted-phenyl;R2It is selected from
Hydrogen, C1-C8Alkyl, alkoxy, substituted-phenyl, ester group, acyl group or sulfonyl;R3Selected from hydrogen, C1-C8Alkyl, benzyl or substituted benzene
Base;
The R1In any one or multiple hydrogen independently by G1Replace;
G1Selected from-OH ,-NH2、-NO2, halogen, C1-6Alkyl or C6Aryl;
The R2In any one or multiple hydrogen independently by G2Replace;
G2Selected from-OH ,-NH2、-NO2, halogen, C1-6Alkyl or C6Aryl;
The R3In any one or multiple hydrogen independently by G3Replace;
G3Selected from-OH ,-NH2、-NO2, halogen, C1-6Alkyl or C6Aryl.
3. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, R1Selected from hydrogen, C1-C8Alkyl, C1-C6Alkoxy, hydroxyl, cyano, nitro, amino, fluorine, chlorine, bromine, iodine, phenyl,
Benzyl, N, one of N- dimethylamino;
R2Selected from hydrogen, C1-C8Alkyl, phenyl, benzyl, acetyl group, benzoyl, p-toluenesulfonyl, carbamyl, benzyloxy carbonyl
One of base, tert-butoxycarbonyl;
R3Selected from hydrogen, C1-C8One of alkyl, substituted-phenyl, benzyl.
4. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, the catalyst be selected from triethylamine, trimethylamine, 1,8- diazabicylo, 11 carbon -7- alkene, triethylene diamine,
Potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, its structural formula of difunctional organic micromolecule catalyst derived from quinine are such as
I-XII, the difunctional organic micromolecule catalyst XIII-XV of rosin derivative, other types of difunctional organocatalysis
One or more of agent XVI-XVIII;Above-mentioned difunctional organic micromolecule catalyst structure is as follows:
Wherein difunctional organic micromolecule catalyst can get chiral containing α derived from trifluoro methyl indole, beta-amino acids analog,
Common bronsted alkali or lewis base can get achirality containing α derived from trifluoro methyl indole, beta-amino acids analog.
5. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, the reaction temperature of the reaction is -30 DEG C -50 DEG C.
6. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, the Isatine derivatives, 2- ((2,2,2- trifluoroethyl) imino group) diethyl malonate derivative and catalysis
The reaction molar ratio of agent is (1-20): (1-20): 1.
7. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, the solvent selection methylene chloride, chloroform, 1,2- dichloroethanes, acetonitrile, methanol, ethyl alcohol, n-butanol, isopropyl
One or more of alcohol, ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, trimethylbenzene.
8. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, the purification is using column chromatography i.e. H60 silica gel, petroleum ether: ethyl acetate=8: 1, obtain final product.
9. according to claim 1 containing α derived from trifluoro methyl indole, the chiral method for preparing of beta-amino acids analog,
It is characterized in that, the reaction time is 3-72h.
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CN104693092A (en) * | 2015-02-16 | 2015-06-10 | 华东师范大学 | Chiral 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof |
CN105669516A (en) * | 2016-03-09 | 2016-06-15 | 中山大学 | Preparation method of 3,3'-bisindole compounds |
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CN105669516A (en) * | 2016-03-09 | 2016-06-15 | 中山大学 | Preparation method of 3,3'-bisindole compounds |
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---|
JINHUAN SU等: "Asymmetric Synthesis of 2’-Trifluoromethylated Spiro-pyrrolidine-3,3’-oxindoles via Squaramide-Catalyzed Umpolung and 1,3-Dipolar Cycloaddition", 《ADV. SYNTH. CATAL.》 * |
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