CN109678860A - A kind of method of asymmetric synthesis of chirality couroupitine A beta hydroxy acid ester type compound - Google Patents
A kind of method of asymmetric synthesis of chirality couroupitine A beta hydroxy acid ester type compound Download PDFInfo
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- couroupitine
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound, the method is comprised the steps of using tryptamines ketone compounds and malonic acid monoalkyl ester as raw material, in organic solvent, metal directly sufficiently reacts under conditions of being catalyst with chiral ligand, and reaction solution is through isolating and purifying to obtain the chiral couroupitine A beta hydroxy acid ester type compound (natural products Phaitanthrin B medicine series molecule) of the highly-solid selectively after reaction.Its advantages are mainly reflected in: 1, it is easy to operate；2, it is low in cost；3, reaction yield is high；4, there is highly-solid selectively.Therefore present invention basic research value with higher and economic results in society.
Description
Technical field
This application discloses the present invention relates to organic chemistry filed, particularly relate to a kind of chiral couroupitine A beta hydroxy acid esters
Compound (Phaitanthrin B medicine series molecule) method of asymmetric synthesis.
Background technique
Phaitanthrin B is a kind of containing chiral tertiary alcohol structure-biological alkali, is to be extracted from pale reddish brown mun orchid
Tryptanthrin series natural product has good physiological activity.For breast cancer (MCF-7), lung cancer (NCI-H460),
The tumour cells such as central nervous system cancer (SF-268) have good cytotoxicity.Therefore, exploitation is easy to operate, at low cost
Honest and clean, the Phaitanthrin B series compound of high yield highly-solid selectively has master for drug development and basic research
Want meaning.
In existing report, early stage obtain Phaitanthrin B mainly extracted from orchid, process is tedious and
Gained is racemic class compound, is not optically pure single configuration target compound.Its tool is hindered to a certain extent
The research of body pharmaceutical activity.Have recently and the series compound is prepared by the strategy of synthesis, is by Tryptanthrin (tryptamines
Ketone) the β hydroxycarboxylic acid Cephalanthrin A for preparing corresponding construction, so that it is converted into acyl chlorides and is further reacted with methanol,
Preparation synthesis Phaitanthrin B, which needs to undergo addition, acylated, is esterified San Walk, complex steps, reaction system
It is complicated.
Based on this, the simple and convenient method of novel direct construction optical voidness Phaitanthrin B a kind of is developed, it is right
There is very big impetus in drug design in the series compound.It is especially naturally produced for basic theoretical research simultaneously
Object is fully synthetic to provide fine strategy.
Summary of the invention
The technical problem to be solved by the embodiment of the invention is that providing a kind of chiral couroupitine A beta hydroxy acid esters chemical combination
The method of asymmetric synthesis of object.The synthetic method is easy to operate, rational technology, hypotoxicity, reaction condition are mild, reaction yield
Height, has highly-solid selectively at good product quality.
To achieve the above object, the technical scheme is that this method comprises:
Using tryptamines ketone compounds and malonic acid monoalkyl ester as raw material, in organic solvent, with metal and chiral ligand
For catalyst, directly sufficiently reaction under conditions of preference temperature, after completion of the reaction by isolating and purifying to obtain the chiral color
Amine one-3 beta hydroxyl acid esters compound；
The structural formula of the tryptamines ketone compounds and malonic acid monoalkyl ester is
The structural formula of the chiral couroupitine A beta hydroxy acid ester type compound are as follows:
In above-mentioned formula, R1Selected from one of following: hydrogen, fluorine, chlorine, bromine, nitro, alkoxy；R2Selected from one of following: hydrogen, fluorine,
Chlorine, bromine, nitro, alkoxy；R3Selected from one of following: methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, n-pentyl,
Cyclohexyl；
Further, the R1Preferably hydrogen；
Further, the R2Preferably hydrogen；
Further, the R3Preferably methyl.
Organic solvent used is the organic solvent not reacted with reactants and products.
Further setting is that the organic solvent is selected from following one or any several combination: methylene chloride, second
Acetoacetic ester, tetrahydrofuran, acetonitrile, toluene, methanol, chloroform.
It is 1-50 times of raw material that further setting, which is organic solvent quality used,.
It is 1:1-5 that further setting, which is the molar feed ratio of the tryptamines ketone compounds and malonic acid monoalkyl ester,
Preferably 1:2.
Further setting is that metal is selected from following one or any several combination: fluoroform in the catalyst system
Sulfonic acid copper, copper sulphate, copper acetate, palladium acetate, nickel acetate, nickel acetylacetonate, nickel fluoride, nickel chloride, nickel sulfate, acetylacetone,2,4-pentanedione
Zinc.
Further setting is that chiral ligand is selected from following one or any several combination in the catalyst system
Preferably chiral ligand L1；
It is 1wt%-20wt% that further setting, which is the ratio that the amount of the catalyst is tryptamines ketone compounds, preferably
For 10wt%.The reaction time of metal and chiral ligand is 10-120 minutes in catalyst system of the present invention, preferably
30-60 minutes.
Further setting is that the molar ratio of metal and chiral ligand is 1:1-2 in the catalyst system.
In the present invention, reaction temperature be 10-60 DEG C, preferably 15-30 DEG C, the reaction time generally at 3-72 hours, preferably
It is 40-60 hours.
It is of the present invention to isolate and purify using column chromatographic isolation and purification method.Gained reaction solution steams after reaction
Solvent is drying to obtain target product chirality couroupitine A beta hydroxy acid ester type compound (Phaitanthrin through column chromatographic isolation and purification
B class compound).Further, leacheate is methylene chloride and carbinol mixture, and methylene chloride and methanol ratio are 60:1-10:1,
Preferably 40:1-20:1.
It is catalyst tryptamines ketone compounds and third that the present invention, which is for the first time using transition metal nickel salt and chiral ligand,
Decarboxylation aldol addition reaction, synthesis of natural product Phaitanthrin B class compound occur for acid monoethyl ester.Its advantages
It is mainly reflected in: 1, it is easy to operate；2, it is low in cost；3, reaction yield is high；4, there is highly-solid selectively.Therefore the present invention has
Higher basic research value and economic results in society.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with embodiment to the present invention make into
One step it is described in detail.
Preferred embodiment
The present invention specifically recommends the novel method of asymmetric synthesis of the Phaitanthrin B medicine series molecule to press
It is carried out according to following steps: under room temperature, metallic catalyst and chiral ligand being added in reaction kettle and are sufficiently stirred 30-60 points
Then Tryptanthrin and malonic acid monoalkyl ester is added in clock, under conditions of 10-60 DEG C, it is small that stirring makes it react 40-72
When, real-time monitoring reaction process isolates and purifies after completion of the reaction, obtains the chiral Phaitanthrin B system after dry
Column target compound.
Embodiment 1
R1For hydrogen, R2For the general T ryptanthrin (couroupitine A) of hydrogen, R3For the malonic acid monomethyl ester and catalyst of methyl
The mass ratio of the material feed intake for 1.0:2.0:0.1, i.e. substrate couroupitine A 496mg (2mmol), malonic acid monomethyl ester 472mg
(4mmol), four hydration nickel acetate 49.6mg (0.2mmol), chiral ligand L172.6mg (0.22mmol)；Organic solvent is tetrahydro
Furans 10.0g, total dosage are 20 times of substrate couroupitine A.
Under room temperature, metallic catalyst and chiral ligand L1 are added in reaction kettle, after completely dissolution with tetrahydrofuran,
It is sufficiently stirred 30-60 minutes, then couroupitine A and malonic acid monomethyl ester is added into reaction kettle, under conditions of 50 DEG C, stirring makes
It terminates after reacting 12 hours.
It isolates and purifies after completion of the reaction, white solid, as the chiral target compound is obtained after dry
Phaitanthrin B 1a 579.6mg, yield 90%, enantioselectivity are excessively 71%ee, purity 99.6%.
Specific structure are as follows:
Data characterization: Methyl 2- (6-hydroxy-12-oxo-6,12-dihydroindolo [2,1-b]
Quinazolin--6-yl) acetate (1a): Daicel Chiralpak As, hexane/iso-propanol=85/15,
flow rate 1.0mL/min,25℃:tR(major)=9.3min, tR(minor)=14.0min.1H NMR(500MHz,
DMSO) δ 8.44 (d, J=8.0Hz, 1H), 8.33 (d, J=7.8Hz, 1H), 7.90 (t, J=7.6Hz, 1H), 7.82 (d, J=
8.0Hz, 1H), 7.72 (d, J=7.4Hz, 1H), 7.64 (t, J=7.5Hz, 1H), 7.53 (t, J=7.7Hz, 1H), 7.39 (t,
J=7.5Hz, 1H), 6.67 (s, 1H), 3.54-3.45 (m, 2H), 3.32 (s, 3H)13C NMR(126MHz,DMSO)δ
169.36,160.78,158.80,147.02,139.19,134.79,133.22,129.98,127.55,127.47,126.61,
126.44,124.05,121.38,115.98,74.61,51.33,42.63.
Embodiment 2
Substrate couroupitine A 496mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetate 49.6mg
(0.2mmol), chiral ligand L373.5mg (0.22mmol)；Organic solvent is tetrahydrofuran 10.0g, and total dosage is substrate color
20 times of amine ketone.
Remaining obtains target product 1a 560.3mg, yield 87%, enantioselectivity is excessively 45%ee, pure with embodiment 1
Degree is 99.4%.
Embodiment 3
Substrate couroupitine A 496mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetate 49.6mg
(0.2mmol), chiral ligand L586.5mg (0.22mmol)；Organic solvent is tetrahydrofuran 10.0g, and total dosage is substrate color
20 times of amine ketone.
Remaining obtains target product 1a 495.9mg, yield 77%, enantioselectivity is excessively 1%ee, pure with embodiment 1
Degree is 98.9%.
Embodiment 4
Substrate couroupitine A 496mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetate 49.6mg
(0.2mmol), chiral ligand L781.2mg (0.22mmol)；Organic solvent is tetrahydrofuran 10.0g, and total dosage is substrate color
20 times of amine ketone.
Remaining obtains target product 1a 560.3mg, yield 87%, enantioselectivity is excessively 45%ee, pure with embodiment 1
Degree is 99.7%.
Embodiment 5
Substrate couroupitine A 496mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), nickel acetate 35.2mg
(0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 10.0g, and total dosage is substrate
20 times of couroupitine A.
Remaining obtains target product 1a 605.4mg, yield 94%, enantioselectivity is excessively 82%ee, pure with embodiment 1
Degree is 99.8%.
Embodiment 6
Substrate couroupitine A 496mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), nickel acetate 35.2mg
(0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is acetonitrile 10.0g, and total dosage is substrate tryptamines
20 times of ketone.
Under room temperature, metallic catalyst and chiral ligand L1 are added in reaction kettle, after completely dissolution with acetonitrile, stirring
30-60 minutes, then couroupitine A and malonic acid monomethyl ester are added into reaction kettle, under conditions of 15 DEG C, stirring makes it react 12
Terminate after hour.
Remaining obtains target product 1a 334.9mg, yield 52%, enantioselectivity is excessively 96%ee, pure with embodiment 1
Degree is 99.8%.
Embodiment 7
Substrate couroupitine A 496mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), nickel acetate 35.2mg
(0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is acetonitrile 10.0g, and total dosage is substrate tryptamines
20 times of ketone.
Under room temperature, metallic catalyst and chiral ligand L1 are added in reaction kettle, after completely dissolution with acetonitrile, stirring
30-60 minutes, then couroupitine A and malonic acid monomethyl ester are added into reaction kettle, under conditions of 15 DEG C, stirring makes it react 50
Terminate after hour.
Remaining obtains target product 1a 515.2mg, yield 80%, enantioselectivity is excessively 96%ee, pure with embodiment 1
Degree is 99.6%.
Embodiment 8-22
Substrate couroupitine A series compound (2mmol), malonic acid monoalkyl ester (4mmol), nickel acetate 35.2mg
(0.2mmol), chiral ligand L1 are (4) 72.6mg (0.22mmol)；Organic solvent is acetonitrile, and total dosage is substrate couroupitine A
20 times.
Under room temperature, metallic catalyst and chiral ligand (4) are added in reaction kettle, after completely dissolution with acetonitrile, are stirred
It mixes 30-60 minutes, then couroupitine A and malonic acid monomethyl ester is added into reaction kettle, under conditions of 15 DEG C, stirring makes its reaction
Terminate after 50 hours.
Remaining obtains target product 1b-1p. with embodiment 1
The embodiments data of embodiment 7-22 (1a-1p):
Methyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)
Acetate (1a): 80%yield, [α]D 25=-5.42 (c=0.32in MeOH), enantiomeric excess:96%,
(d, J=7.8Hz, 1H), 7.90 (t, J=7.6Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.72 (d, J=7.4Hz, 1H),
7.64 (t, J=7.5Hz, 1H), 7.53 (t, J=7.7Hz, 1H), 7.39 (t, J=7.5Hz, 1H), 6.67 (s, 1H), 3.54-
3.45(m,2H),3.32(s,3H).13C NMR(126MHz,DMSO)δ169.36,160.78,158.80,147.02,139.19,
134.79,133.22,129.98,127.55,127.47,126.61,126.44,124.05,121.38,115.98,74.61,
51.33,42.63.
Methyl 2-(8-fluoro-6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]
quinazolin-6-yl)acetate
(minor)=30.3min.1H NMR (500MHz, DMSO) δ 8.43 (dd, J=8.7,4.6Hz, 1H), 8.32 (d, J=
7.4Hz, 1H), 7.91 (t, J=7.1Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.69-7.62 (m, 2H), 7.38 (td, J=
9.0,2.6Hz, 1H), 6.78 (s, 1H), 3.59 (d, J=16.9Hz, 1H), 3.46 (d, J=16.9Hz, 1H), 3.35 (s,
3H).13C NMR(126MHz,DMSO)δ169.38,161.48,160.66,159.54,158.59,146.92,135.86,
135.80,135.44,134.87,127.58,126.41,121.28,117.51,117.44,116.53,116.34,111.96,
111.76,99.50,74.48,51.43,42.31.
Methyl-2-(8-chloro-6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]
quinazolin-6-yl)acetate
(major)=10.9min, tR(minor)=26.8min.1H NMR (500MHz, DMSO) δ 8.41 (d, J=8.5Hz, 1H),
8.36-8.29 (m, 1H), 7.94-7.89 (m, 1H), 7.87 (d, J=2.1Hz, 1H), 7.82 (d, J=7.9Hz, 1H), 7.65
(t, J=7.2Hz, 1H), 7.61 (dd, J=8.5,2.2Hz, 1H), 6.78 (s, 1H), 3.64 (d, J=17.0Hz, 1H), 3.45
(d, J=17.0Hz, 1H), 3.36 (s, 3H)13C NMR(126MHz,DMSO)δ169.45,160.34,158.67,146.93,
137.95,135.65,134.98,130.74,129.87,127.68,127.62,126.47,124.46,121.22,117.42,
74.46,51.44,42.25.
Methyl-2-(8-bromo-6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]
quinazolin-6-yl)acetate
(major)=14.6min, tR(minor)=35.4min.1H NMR (500MHz, DMSO) δ 8.36 (d, J=8.5Hz, 1H),
8.33-8.30 (m, 1H), 7.99 (d, J=1.9Hz, 1H), 7.93-7.89 (m, 1H), 7.82 (d, J=7.9Hz, 1H), 7.74
(dd, J=8.5,2.0Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 6.75 (s, 1H), 3.64 (d, J=17.0Hz, 1H), 3.44
(d, J=17.0Hz, 1H), 3.36 (s, 3H)13C NMR(126MHz,DMSO)δ169.47,160.22,158.68,146.93,
138.37,135.89,135.00,132.78,127.70,127.63,127.27,126.48,121.22,118.82,117.80,
74.42,51.45,42.22.
Methyl -2-(6-hydroxy-8-iodo-12-oxo-6,12-dihydroindolo[2,1-b]
Quinazolin-6-yl) acetate (1e): 73%
min.1H NMR (500MHz, DMSO) δ 8.31 (d, J=7.8Hz, 1H), 8.22 (d, J=8.4Hz, 1H), 8.11 (d, J=
1.3Hz, 1H), 7.94-7.85 (m, 2H), 7.81 (d, J=7.9Hz, 1H), 7.64 (t, J=7.2Hz, 1H), 6.72 (s, 1H),
3.62 (d, J=17.0Hz, 1H), 3.43 (d, J=17.0Hz, 1H), 3.36 (s, 3H)13C NMR(126MHz,DMSO)δ
169.48,160.07,158.70,146.96,138.88,138.64,135.82,134.96,132.80,127.66,127.62,
126.48,121.24,118.03,74.30,51.44,42.24.
Methyl 2-(6-hydroxy-8-nitro-12-oxo-6,12-dihydroindolo[2,1-b]
Quinazolin-6-yl) acetate (1f): 99%
27.6min.1H NMR (500MHz, DMSO) δ 8.65 (dd, J=12.7,5.4Hz, 2H), 8.48 (dd, J=8.7,2.0Hz,
1H), 8.34 (d, J=7.8Hz, 1H), 7.95 (t, J=7.5Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.68 (t, J=
7.5Hz, 1H), 6.89 (s, 1H), 3.82 (d, J=17.2Hz, 1H), 3.48 (d, J=17.1Hz, 1H), 3.37 (s, 3H)13C
NMR(126MHz,DMSO)δ174.84,165.61,164.17,151.92,150.93,149.13,140.74,140.41,
133.30,133.00,131.93,131.83,126.27,125.17,121.67,79.49,56.77,47.36.
Methyl 2-(9-chloro-6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]
Quinazolin-6-yl) acetate (1g): 89%
19.2min.1H NMR(500MHz,CDCl3) δ 8.30 (s, 1H), 8.21 (d, J=8.1Hz, 1H), 7.77-7.69 (m, 2H),
7.49 (dd, J=11.1,4.9Hz, 2H), 7.22-7.18 (m, 1H), 4.92 (s, 1H), 3.55 (s, 3H), 3.38 (d, J=
16.5Hz, 1H), 3.29 (d, J=16.4Hz, 1H)13C NMR(126MHz,CDCl3)δ170.22,159.49,159.05,
146.86,139.75,136.46,134.78,130.11,127.98,127.73,127.18,126.98,124.53,121.49,
117.50,75.02,52.07,42.62.
Methyl
Hexane/iso-propanol=90/10, flow rate 1.0mL/min, 25 DEG C: tR(major)=16.3min, tR
(minor)=21.1min.1H NMR (500MHz, DMSO) δ 8.59 (d, J=1.2Hz, 1H), 8.32 (d, J=7.7Hz, 1H),
7.92 (t, J=7.2Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.67-7.60 (m, 2H),
6.73 (s, 1H), 3.56 (d, J=16.9Hz, 1H), 3.46 (d, J=16.9Hz, 1H), 3.35 (s, 3H)13C NMR
(126MHz,DMSO)δ169.42,160.36,158.80,146.87,140.28,135.12,132.75,129.38,127.75,
127.65,126.54,126.04,122.26,121.12,118.61,74.39,51.45,42.32.
Methyl 2-(8,9-difluoro-6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]
Quinazolin-6-yl) acetate (1i): 84%yield, [α]D 25=+8.29 (c=0.22in MeOH),
Enantiomeric excess:97%, Daicel Chiralpak AS, hexane/iso-propanol=95/5, flow
rate 1.0mL/min,25℃:tR(minor)=11.4min, tR(major)=16.0min.1H NMR(500MHz,DMSO)δ
8.38 (dd, J=10.6,7.0Hz, 1H), 8.31 (d, J=7.8Hz, 1H), 7.98-7.90 (m, 2H), 7.82 (d, J=
8.0Hz, 1H), 7.66 (t, J=7.5Hz, 1H), 6.80 (s, 1H), 3.60 (d, J=17.0Hz, 1H), 3.45 (d, J=
16.9Hz,1H),3.36(s,3H).13C NMR(126MHz,DMSO)δ169.40,160.30,158.55,146.83,135.14,
130.29,127.82,127.68,126.46,121.05,113.97,113.81,105.97,105.78,74.41,51.48,
42.19.
Ethyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)
Acetate (1j): 81%yield, [α]D 25=-10.82 (c=0.28 in MeOH), enantiomeric excess:
98%, Daicel Chiralpak AS,
7.90 (t, J=7.5Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.72 (d, J=7.4Hz, 1H), 7.64 (t, J=7.4Hz,
1H), 7.54 (t, J=7.7Hz, 1H), 7.40 (t, J=7.4Hz, 1H), 6.68 (s, 1H), 3.68 (dt, J=11.4,5.7Hz,
2H), 3.44 (t, J=11.0Hz, 2H), 0.79 (t, J=7.1Hz, 3H)13C NMR(126MHz,DMSO)δ168.53,
160.77,158.81,147.02,139.13,134.80,133.15,130.00,127.55,127.48,126.61,126.43,
124.09,121.35,115.96,74.72,59.92,43.20,13.43.
Propyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)
Acetate (1k): 78%yield, [α]D 25=-4.62 (c=0.24in MeOH), enantiomeric excess: > 99%,
(d, J=7.0Hz, 1H), 7.93-7.88 (m, 1H), 7.82 (d, J=7.9Hz, 1H), 7.72 (d, J=7.3Hz, 1H), 7.64
(t, J=7.4Hz, 1H), 7.53 (t, J=7.3Hz, 1H), 7.39 (t, J=7.4Hz, 1H), 6.66 (s, 1H), 3.60 (t, J=
6.5Hz 2H), 3.50-3.41 (m, 2H), 1.18 (dd, J=13.9,7.5Hz, 2H), 0.54 (t, J=7.4Hz, 3H)13C
NMR(126MHz,DMSO)δ168.60,160.75,158.80,147.03,139.11,134.80,133.17,129.99,
127.54,127.48,126.62,126.41,124.07,121.36,115.97,74.68,65.46,43.14,21.06,
9.81.
Butyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)
Acetate (1l): 76%yield, [α]D 25=-6.96 (c=0.23 in MeOH), enantiomeric
(500MHz,CDCl3) δ 8.25 (d, J=7.9Hz, 1H), 8.18 (d, J=7.9Hz, 1H), 7.76-7.70 (m, 2H), 7.53
(d, J=7.3Hz, 1H), 7.47 (ddd, J=8.1,5.8,2.5Hz, 1H), 7.18 (dd, J=11.2,4.2Hz, 1H), 7.13
(t, J=7.2Hz, 1H), 5.23 (s, 1H), 3.88-3.78 (m, 2H), 3.47-3.42 (m, 1H), 3.29 (d, J=16.1Hz,
1H), 1.33-1.27 (m, 2H), 1.06 (dd, J=15.2,7.5Hz, 2H), 0.72 (t, J=7.4Hz, 3H)13C NMR
(126MHz,CDCl3)δ169.60,159.83,159.64,147.00,138.96,134.46,131.55,130.56,
127.58,127.45,127.03,123.57,121.69,116.80,75.44,64.93,43.22,30.25,18.86,
13.46.
Pentyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-yl)
Acetate (1m): 77%yield, [α]D 25=-4.68 (c=0.23in MeOH), enantiomeric excess:
=18.0min.1H NMR (500MHz, DMSO) δ 8.44 (d, J=8.0Hz, 1H), 8.33 (d, J=7.9Hz, 1H), 7.90
(dd, J=11.0,4.2Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.72 (d, J=7.4Hz, 1H), 7.63 (t, J=
7.5Hz, 1H), 7.53 (t, J=7.8Hz, 1H), 7.40 (t, J=7.5Hz, 1H), 6.68 (s, 1H), 3.62 (dq, J=10.9,
4.6Hz, 2H), 3.47 (dd, J=35.4,16.1Hz, 2H), 1.11 (td, J=14.2,7.0Hz, 2H), 1.05-0.94 (m,
2H), 0.87-0.79 (m, 2H), 0.64 (t, J=7.3Hz, 3H)13C NMR(126MHz,DMSO)δ168.47,160.73,
158.81,147.05,139.11,134.76,133.14,129.98,127.53,127.43,126.60,126.42,124.05,
121.39,115.98,74.70,63.99,43.23,27.43,27.22,21.52,13.51.
Isopropyl2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-
Yl) acetate (1n): 70%yield, [α]D 25=-9.22 (c=0.10 in MeOH), enantiomeric excess:
97%,
min.1H NMR (500MHz, DMSO) δ 8.44 (d, J=7.9Hz, 1H), 8.36-8.30 (m, 1H), 7.94-7.88 (m, 1H),
7.84 (d, J=7.9Hz, 1H), 7.72 (d, J=7.2Hz, 1H), 7.64 (t, J=7.1Hz, 1H), 7.55 (t, J=7.3Hz,
1H), 7.41 (t, J=7.2Hz, 1H), 6.68 (d, J=9.3Hz, 1H), 4.45 (dt, J=12.4,6.2Hz, 1H), 3.45 (d,
J=15.8Hz, 1H), 3.34 (s, 1H), 0.67 (dd, J=15.1,6.2Hz, 6H)13C NMR(126MHz,DMSO)δ
167.62,160.74,158.84,147.02,139.13,134.82,133.13,129.98,127.53,127.48,126.61,
126.39,124.09,121.30,115.96,74.77,67.22,43.76,20.87,20.69.
Tert-butyl 2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-
Yl) acetate (1o): 70%yield, [α]D 25=-5.11 (c=0.23in MeOH), enantiomeric excess: >
99.99%, Daicel Chiralpak AS,
7.91 (dd, J=11.0,4.0Hz, 1H), 7.84 (d, J=7.9Hz, 1H), 7.70 (d, J=7.4Hz, 1H), 7.64 (t, J=
7.4Hz, 1H), 7.55 (t, J=7.7Hz, 1H), 7.42 (t, J=7.4Hz, 1H), 6.66 (s, 1H), 3.43 (d, J=
15.2Hz, 1H), 3.20 (d, J=15.2Hz, 1H), 0.82 (s, 9H)13C NMR(126MHz,DMSO)δ167.22,160.72,
158.88,147.02,139.09,134.86,133.10,130.00,127.55,127.49,126.64,126.39,124.16,
121.27,115.97,80.15,74.85,44.86,26.82.
Cyclohexyl2-(6-hydroxy-12-oxo-6,12-dihydroindolo[2,1-b]quinazolin-6-
Yl) acet-ate (1p): 79%
(minor)=21.1min.1H NMR(500MHz,CDCl3)δ1H NMR (500MHz, DMSO) δ 8.44 (d, J=8.0Hz, 1H),
8.33 (d, J=7.7Hz, 1H), 7.89 (d, J=7.1Hz, 1H), 7.83 (d, J=7.9Hz, 1H), 7.72 (d, J=7.4Hz,
1H), 7.63 (t, J=7.4Hz, 1H), 7.54 (t, J=7.6Hz, 1H), 7.40 (t, J=7.5Hz, 1H), 6.69 (s, 1H),
4.23 (d, J=8.8Hz, 1H), 3.48 (d, J=15.9Hz, 1H), 3.39 (d, J=15.9Hz, 1H), 1.40-0.67 (m,
11H).13C NMR(126MHz,DMSO)δ167.66,160.72,158.83,147.03,139.13,134.79,133.14,
129.96,127.52,127.46,126.60,126.38,124.05,121.35,115.99,74.73,72.00,43.61,
30.47,30.34,24.54,22.68.
The above disclosure is only the preferred embodiments of the present invention, cannot limit the right model of the present invention with this certainly
It encloses, therefore equivalent changes made in accordance with the claims of the present invention, is still within the scope of the present invention.
Claims (10)
1. a kind of method of asymmetric synthesis of chirality couroupitine A beta hydroxy acid ester type compound, it is characterised in that this method comprises:
Using tryptamines ketone compounds and malonic acid monoalkyl ester as raw material, in organic solvent, matched with metallic compound and chirality
Body is catalyst, directly sufficiently reaction under conditions of preference temperature, after completion of the reaction by isolating and purifying to obtain the chirality
Couroupitine A beta hydroxy acid ester type compound；
The structural formula of the tryptamines ketone compounds and malonic acid monoalkyl ester is
The structural formula of the chiral couroupitine A beta hydroxy acid ester type compound are as follows:
In above-mentioned formula, R1Selected from one of following: hydrogen, fluorine, chlorine, bromine, nitro, alkoxy；R2Selected from one of following: hydrogen, fluorine, chlorine,
Bromine, nitro, alkoxy；R3Selected from one of following: methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, n-pentyl, hexamethylene
Base；
Organic solvent used is the organic solvent not reacted with reactants and products.
2. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: the organic solvent is selected from following one or any several combination: methylene chloride, ethyl acetate, tetrahydro furan
It mutters, acetonitrile, toluene, methanol, chloroform.
3. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: organic solvent quality used is 1-50 times of raw material.
4. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: the molar feed ratio of the tryptamines ketone compounds and malonic acid monoalkyl ester is 1:1-5.
5. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: metallic compound is selected from following one or any several combination in the catalyst system: copper trifluoromethanesulfcomposite,
Copper sulphate, copper acetate, palladium acetate, nickel acetate, nickel acetylacetonate, nickel fluoride, nickel chloride, nickel sulfate, zinc acetylacetonate.
6. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: chiral ligand is selected from following one or any several combination in the catalyst system
7. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: the amount of the catalyst is that the ratio of tryptamines ketone compounds is 1wt%-20wt%.
8. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: the molar ratio of metal and chiral ligand is 1:1-2 in the catalyst system.
9. a kind of method of asymmetric synthesis of chiral couroupitine A beta hydroxy acid ester type compound according to claim 1, special
Sign is: the reaction temperature is 0-60 DEG C, and the reaction time is 3-120 hours.
10. a kind of catalyst for method of asymmetric synthesis described in claim 1, it is characterised in that: the catalyst is with metal
Compound reacts synthesis with chiral ligand, and metallic compound is selected from following one or any several group in the catalyst
Close: copper trifluoromethanesulfcomposite, copper sulphate, copper acetate, palladium acetate, nickel acetate, nickel acetylacetonate, nickel fluoride, nickel chloride, nickel sulfate,
Zinc acetylacetonate；
The chiral ligand is selected from following one or any several combination
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Cited By (2)
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| CN114057785A (en) * | 2021-12-13 | 2022-02-18 | 河南师范大学 | Synthesis method of chiral alpha-difluoromethylsilane compound |
| CN114057785B (en) * | 2021-12-13 | 2023-03-28 | 河南师范大学 | Synthesis method of chiral alpha-difluoromethylsilane compound |
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