CN109608390A - A kind of synthetic method of chirality quaternary carbon pyridines β hydroxyl esters compound - Google Patents
A kind of synthetic method of chirality quaternary carbon pyridines β hydroxyl esters compound Download PDFInfo
- Publication number
- CN109608390A CN109608390A CN201811533989.7A CN201811533989A CN109608390A CN 109608390 A CN109608390 A CN 109608390A CN 201811533989 A CN201811533989 A CN 201811533989A CN 109608390 A CN109608390 A CN 109608390A
- Authority
- CN
- China
- Prior art keywords
- pyridines
- quaternary carbon
- hydroxyl esters
- esters compound
- synthetic method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound, the method is comprised the steps of using pyridine 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 quaternary carbon pyridines β hydroxyl esters compound of the highly-solid selectively after reaction.Its advantages are mainly reflected in: 1, it is easy to operate；2, the novel chiral ligands of the pyridines β hydroxy ester skeleton structure containing quaternary carbon of energy rapid build highly-solid selectively；3, reaction yield is high, and stereoselectivity is good.Therefore the present invention has excellent basis research significance and application prospect.
Description
Technical field
The present invention relates to organic chemistry filed, particularly relate to a kind of chiral quaternary carbon pyridines β hydroxyl esters compound and its
Pass through the novel method of asymmetric synthesis of aldol decarboxylation addition.
Background technique
Nitrogen and hydroxyl oxygen in the chirality β hydroxyl esters compound of pyridines containing quaternary carbon on pyridine have good configurational energy
Power and the close position for being in chiral quaternary carbon, and the group size of quaternary carbon position and the controllable range of ester group are very wide, from
And asymmetric metal catalytic synthesis is used for as a kind of chiral ligand well for such compound and provides good abundant item
Part.
The synthesis of pyridines β hydroxyl esters compound containing quaternary carbon mainly utilizes pyridinone chemical combination in existing report
Object and α halogen ester promote synthesis under the action of equivalent alkali, and condition is relatively violent.Direct asymmetric syntheses chirality contains quaternary carbon
Pyridines β hydroxyl esters compound not yet has been reported that at present.
Therefore, easy to operate, low in cost, the pyridines containing quaternary carbon of the synthesis of chiral of high yield highly-solid selectively are developed
The new method of β hydroxyl esters compound has major significance.
Summary of the invention
The purpose of the invention is to overcome shortcoming and defect of the existing technology, and provide a kind of chiral quaternary carbon pyridine
The synthetic method of class β hydroxyl esters compound.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 includes:
Using pyridine compounds and malonic acid monoalkyl ester as raw material, in organic solvent, with metallic compound and hand
Property ligand be catalyst, decarboxylation aldol addition reaction is carried out, after completion of the reaction by isolating and purifying to obtain the chiral quaternary carbon
Pyridines β hydroxyl esters compound, the structural formula of the chirality quaternary carbon pyridines β hydroxyl esters compound are as follows:
The structural formula of the pyridine compounds are as follows:
The structural formula of the malonic acid monoalkyl ester are as follows:
R1Selected from one of following: hydrogen, fluorine, chlorine, bromine, nitro, alkoxy；R2Selected from one of following: methyl, ethyl, benzyl；
R3Selected from one of following: methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, n-pentyl, cyclohexyl；The R1It is preferred that
For hydrogen；The R2Preferably methyl；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, preferably 20-30 times that further setting, which is solvent for use quality,.
It is 1:1-5 that further setting, which is the molar feed ratio of the pyridine compounds and malonic acid monoalkyl ester,
Preferably 1:2.
Further setting is that metallic compound is selected from following one or any several combination in the catalyst system:
Copper trifluoromethanesulfcomposite, copper acetate, palladium acetate, nickel acetate, nickel acetylacetonate, nickel fluoride, nickel chloride, nickel sulfate, zinc acetylacetonate.
Further setting is that chiral ligand is selected from following one or any several combination in the catalyst system:
It is preferred that are as follows: chiral ligand L1.
It is 1wt%-20wt% that further setting, which is the catalyst and pyridine compounds ratio, preferably
10%.
Further setting is that the molar ratio of metallic compound and chiral ligand is 1:1-2 in the catalyst, preferably
1:1.1.
The reaction time of metal and chiral ligand is 10-120 minutes in catalyst system of the present invention, preferably
30-60 minutes.In the present invention, reaction temperature is 10-60 DEG C, and preferably 15-30 DEG C, the reaction time is excellent generally at 3-72 hours
It is selected as 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 the target product chirality β hydroxyl esters compound of pyridines containing quaternary carbon through column chromatographic isolation and purification.Further,
Leacheate is petroleum ether and ethyl acetate mixture, and petroleum ether and ethyl acetate ratio are 30:1-2:1, preferably 10:1-3:1.
The preferred embodiment of the present invention is chiral ligand (4) the catalytic pyridine ketone for utilizing nickel fluoride and oxazoline skeleton for the first time
Decarboxylation aldol addition reaction, the synthesis of chiral β hydroxyl esters chemical combination of pyridines containing quaternary carbon occur for class compound and malonic acid monomethyl ester
Object.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 high three-dimensional selection
Property.Therefore present invention basic research value with higher 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 chirality pyridines containing the quaternary carbon β hydroxyl esters compound synthesis method according to following step
It is rapid to carry out: under room temperature, metallic catalyst and chiral ligand are added in reaction kettle and are sufficiently stirred 30-60 minutes, then plus
Enter pyridone and malonic acid monoalkyl ester, under conditions of 10-60 DEG C, stirring reacts it 40-72 hours, real-time monitoring reaction
Process isolates and purifies after completion of the reaction, obtains the synthesis of chiral β hydroxyl esters targeted of pyridines containing quaternary carbon after dry
Close object.
Embodiment 1
R1For hydrogen, R2For the 2- acetylpyridine of methyl, R3For the amount of the substance of the malonic acid monomethyl ester and catalyst of methyl
Than feeding intake for 1.0:2.0:0.1, i.e. 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four water
Close nickel acetate 49.6mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g,
Total dosage is 20 times of substrate 2- acetylpyridine.
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 2- acetylpyridine and malonic acid monomethyl ester is added into reaction kettle, under conditions of 25 DEG C,
Stirring terminates after reacting it 12 hours.
It isolates and purifies after completion of the reaction, the target compound chirality β hydroxy ester of pyridines containing quaternary carbon is obtained after dry
1a 296.4mg, yield 76%, enantioselectivity are excessively 56%ee, purity 99.6%.Specific structure are as follows:
Data characterization:
Methyl 3-hydroxy-3-(pyridin-2-yl)butanoate,[α]D 25=-18.21 (C=0.15in
), MeOH Daicel Chiralpak AS, hexane/iso-propanol=95/5, flow rate 1.0mL/min, 25 DEG C:
tR(major)=5.3min, tR(minor)=6.8min.1H NMR(500MHz,CDCl3) δ 8.49 (d, J=4.2Hz, 1H),
7.71 (td, J=7.8,1.7Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.17 (ddd, J=7.3,4.9,0.9Hz, 1H),
4.95 (br, 1H), 3.59 (s, 3H), 3.20 (d, J=15.8Hz, 1H), 2.83 (d, J=15.8Hz, 1H), 1.55 (s, 3H)
.13C NMR(126MHz,CDCl3)δ172.97,164.91,147.91,136.84,121.95,119.29,73.62,51.58,
45.43,29.27.
Embodiment 2
2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetate 49.6mg
(0.2mmol), chiral ligand L3 73.5mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is substrate color
20 times of amine ketone.
Remaining obtains target product 1a 241.8mg, yield 62%, enantioselectivity is excessively 9%ee, pure with embodiment 1
Degree is 99.7%.
Embodiment 3
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetates
49.6mg (0.2mmol), chiral ligand L5 86.5mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is
20 times of substrate 2- acetylpyridine.
Remaining obtains target product 1a 163.8mg, yield 42%, enantioselectivity is excessively 11%ee, pure with embodiment 1
Degree is 99.1%.
Embodiment 4
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetates
49.6mg (0.2mmol), chiral ligand L7 81.2mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is
20 times of substrate 2- acetylpyridine.
Remaining obtains target product 1a 280.8mg, yield 72%, enantioselectivity is excessively 11%ee, pure with embodiment 1
Degree is 99.3%.
Embodiment 5
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetates
49.6mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is
20 times of substrate 2- acetylpyridine.
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 2- acetylpyridine and malonic acid monomethyl ester is added into reaction kettle, under conditions of 25 DEG C,
Stirring terminates after reacting it 24 hours.
Remaining obtains target product 1a 331.5mg, yield 85%, enantioselectivity is excessively 58%ee, pure with embodiment 1
Degree is 99.7%.
Embodiment 6
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetates
49.6mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is toluene 4.8g, and total dosage is substrate
20 times of 2- acetylpyridine.
Remaining obtains target product 1a 206.7mg, yield 53%, enantioselectivity is excessively 5%ee, pure with embodiment 5
Degree is 99.3%.
Embodiment 7
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel acetates
49.6mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is methanol 4.8g, and total dosage is substrate
20 times of 2- acetylpyridine.
Remaining obtains target product 1a 218.4mg, yield 56%, enantioselectivity is excessively 35%ee, pure with embodiment 5
Degree is 99.6%.
Embodiment 8
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), Nickelous nitrate hexahydrate
58.0mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is
20 times of substrate 2- acetylpyridine.
Remaining obtains target product 1a 195.1mg, yield 50%, enantioselectivity is excessively 37%ee, pure with embodiment 5
Degree is 99.2%.
Embodiment 9
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), six perchloric acid hydrate nickel
73.0mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is
20 times of substrate 2- acetylpyridine.
Remaining obtains target product 1a 175.5mg, yield 45%, enantioselectivity is excessively 54%ee, pure with embodiment 5
Degree is 99.5%.
Embodiment 10
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel fluorides
41.2mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is
20 times of substrate 2- acetylpyridine.
Remaining obtains target product 1a 304.2mg, yield 78%, enantioselectivity is excessively 83%ee, pure with embodiment 5
Degree is 99.8%.
Embodiment 11
Substrate 2- acetylpyridine 242mg (2mmol), malonic acid monomethyl ester 472mg (4mmol), four hydration nickel fluorides
41.2mg (0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is
20 times of substrate 2- acetylpyridine.
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 2- acetylpyridine and malonic acid monomethyl ester is added into reaction kettle, under conditions of 10 DEG C,
Stirring terminates after reacting it 48 hours.
Remaining obtains target product 1a 276.9mg, yield 75%, enantioselectivity is excessively 91%ee, pure with embodiment 1
Degree is 99.8%.
Embodiment 12-22
Substrate pyridine compounds (2mmol), malonic acid monoalkyl ester (4mmol), four hydration nickel fluoride 41.2mg
(0.2mmol), chiral ligand L1 72.6mg (0.22mmol)；Organic solvent is tetrahydrofuran 4.8g, and total dosage is substrate 2-
20 times of acetylpyridine.
Remaining obtains target product 1b-1l with embodiment 11.I.e.
| Embodiment | R1 | R2 | R3 | Product | Yield (%) | Ee (%) | Purity (%) |
| 12 | H | Me | Et | 1b | 75 | 92 | 99.2 |
| 13 | H | Me | i-Pr | 1c | 76 | 74 | 99.6 |
| 14 | H | Me | Bn | 1d | 75 | 37 | 99.3 |
| 15 | H | Et | Me | 1e | 75 | 85 | 99.7 |
| 16 | H | Et | Et | 1f | 62 | 85 | 99.2 |
| 17 | H | i-Pr | Et | 1g | 62 | 71 | 98.9 |
| 18 | 4-Me | Me | Me | 1h | 75 | 77 | 99.4 |
| 19 | 4-Me-5-Br | Me | Me | 1i | 62 | 32 | 99.6 |
| 20 | 6-Me | Me | Me | 1j | 62 | 66 | 99.8 |
| 21 | 5-Br | Me | Et | 1k | 60 | 90 | 99.8 |
| 22 | 6-Br | Me | Et | 1l | 60 | 46 | 99.6 |
The embodiments data of embodiment 11-22 (1a-1l):
Methyl 3-hydroxy-3- (pyridin-2-yl) butanoate (1a): 75%yield, [α]D 25=-
18.21 (C=0.15in MeOH),
1H), 4.95 (br, 1H), 3.59 (s, 3H), 3.20 (d, J=15.8Hz, 1H), 2.83 (d, J=15.8Hz, 1H), 1.55 (s,
3H).13C NMR(126MHz,CDCl3)δ172.97,164.91,147.91,136.84,121.95,119.29,73.62,
51.58,45.43,29.27.
Ethyl 3-hydroxy-3- (pyridin-2-yl) butanoate (1b): 75%yield, [α]D 25=-14.40
(C=0.13in MeOH),
Enantiomeric excess:92%, Daicel Chiralpak OJ, hexane/iso-propanol=95/
5,flow rate 1.0mL/min,25℃:tR(minor)=9.5min, tR(major)=11.6min.1H NMR(500MHz,
CDCl3)δ1H NMR(500MHz,CDCl3) δ 8.47 (d, J=4.2Hz, 1H), 7.68 (td, J=7.8,1.5Hz, 1H), 7.60
(d, J=7.9Hz, 1H), 7.14 (dd, J=6.6,5.1Hz, 1H), 4.95 (br, 1H), 4.02 (qd, J=7.1,1.6Hz,
2H), 3.17 (d, J=15.7Hz, 1H), 2.80 (d, J=15.7Hz, 1H), 1.53 (s, 3H), 1.12 (t, J=7.1Hz, 3H)
.13C NMR(126MHz,CDCl3)δ172.49,165.03,147.86,136.76,121.88,119.31,73.69,60.42,
45.71,29.28,14.00.
Isopropyl 3-hydroxy-3- (pyridin-2-yl) butanoate (1c): 76%yield,
Enantiomeric excess:74%,
7.17 (dd, J=6.6,5.5Hz, 1H), 4.97 (s, 1H), 4.90 (dt, J=12.5,6.3Hz, 1H), 3.17 (d, J=
15.6Hz, 1H), 2.78 (d, J=15.6Hz, 1H), 1.55 (s, 3H), 1.15 (d, J=6.3Hz, 3H), 1.07 (d, J=
6.2Hz,3H).
Benzyl 3-hydroxy-3- (pyridin-2-yl) butanoate (1d): 75%yield, enantiomeric
Excess:37%, Daicel
(d, J=7.9Hz, 1H), 7.31 (d, J=6.6Hz, 3H), 7.25-7.19 (m, 2H), 7.15 (dd, J=7.1,5.1Hz, 1H),
5.03 (s, 2H), 4.94 (s, 1H), 3.27 (d, J=15.7Hz, 1H), 2.87 (d, J=15.7Hz, 1H), 1.55 (s, 3H)
Methyl 3-hydroxy-3- (pyridin-2-yl) pentanoate (1e): 75%yield, [α]D 25=-
16.81 (C=0.12in MeOH), enantiomeric excess:85%, Daicel Chiralpak OJ,
7.55 (d, J=8.0Hz, 1H), 7.15 (dd, J=6.6,5.1Hz, 1H), 4.97 (s, 1H), 3.56 (s, 3H), 3.16 (d, J=
15.7Hz, 1H), 2.82 (d, J=15.7Hz, 1H), 1.86 (q, J=7.4Hz, 2H), 0.72 (t, J=7.4Hz, 3H)13CNMR
(126MHz,CDCl3)δ173.01,163.62,147.81,136.54,121.80,120.10,75.91,51.52,44.30,
34.70,7.56.
Ethyl 3-hydroxy-3- (pyridin-2-yl) pentanoate (1f): 62%yield, enantiomeric
Excess:85%, Daicel
(s, 1H), 3.97 (q, J=7.3Hz, 2H), 3.16 (d, J=15.7Hz, 1H), 2.82 (d, J=15.7Hz, 1H), 1.86 (q, J
=7.4Hz, 2H), 1.08 (t, J=7.1Hz, 3H), 0.72 (t, J=7.4Hz, 3H)
Ethyl 3-hydroxy-4-methyl-3- (pyridin-2-yl) pentanoate (1g): 62%yield,
Enantiomeric excess:71%,
7.20-7.12 (m, 1H), 5.00 (s, 1H), 3.97 (q, J=7.3Hz, 2H), 3.22 (d, J=15.8Hz, 1H), 2.86 (d, J
=15.7Hz, 1H), 1.08 (t, J=7.1Hz, 3H), 0.93 (d, J=7.0Hz, 3H), 0.76 (d, J=6.8Hz, 3H)
Methyl 3-hydroxy-3- (4-methylpyridin-2-yl) butanoate (1h): 75%yield,
enantiomeric excess:
=15.7Hz, 1H), 2.38 (s, 3H), 1.54 (s, 3H)
Methyl 3- (5-bromo-4-methylpyridin-2-yl) -3-hydroxybutanoate (1i): 62%
yield,enantiomeric
J=16.3Hz, 1H), 2.79 (d, J=16.3Hz, 1H), 1.50 (s, 3H)
Methyl 3-hydroxy-3- (6-methylpyridin-2-yl) butanoate (1j): 62%yield,
Enantiomeric excess:66%,
3H),1.57(s,3H).
Ethyl 3- (5-bromopyridin-2-yl) -3-hydroxybutanoate (1k): 60%yield,
Enantiomeric excess:91%,
Hz, 1H), 4.99 (s, 1H), 4.05 (q, J=7.1Hz, 2H), 3.18 (d, J=15.7Hz, 1H), 2.80 (d, J=15.7Hz,
1H), 1.54 (s, 3H), 1.16 (t, J=7.1Hz, 3H)
Ethyl 3- (6-bromopyridin-2-yl) -3-hydroxybutanoate (1l): 60%yield,
Enantiomeric excess:46%,
Hz, 1H), 4.99 (s, 1H), 4.05 (q, J=7.1Hz, 2H), 3.18 (d, J=15.7Hz, 1H), 2.80 (d, J=15.7Hz,
1H), 1.54 (s, 3H), 1.16 (t, J=7.1Hz, 3H)
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 synthetic method of chirality quaternary carbon pyridines β hydroxyl esters compound, it is characterised in that this method includes:
Using pyridine compounds and malonic acid monoalkyl ester as raw material, in organic solvent, matched with metallic compound and chirality
Body is catalyst, carries out decarboxylation aldol addition reaction, after completion of the reaction by isolating and purifying to obtain the chiral quaternary carbon pyridine
Class β hydroxyl esters compound, the structural formula of the chirality quaternary carbon pyridines β hydroxyl esters compound are as follows:
The structural formula of the pyridine compounds are as follows:
The structural formula of the malonic acid monoalkyl ester are as follows:
R1Selected from one of following: hydrogen, fluorine, chlorine, bromine, nitro, alkoxy；R2Selected from one of following: methyl, ethyl, benzyl；R3Choosing
From one of following: methyl, ethyl, propyl, isopropyl, normal-butyl, tert-butyl, n-pentyl, cyclohexyl；
Organic solvent used is the organic solvent not reacted with reactants and products.
2. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: the organic solvent is selected from following one or any several combination: methylene chloride, ethyl acetate, tetrahydrofuran, second
Nitrile, toluene, methanol, chloroform.
3. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: solvent for use quality is 1-50 times of raw material.
4. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: the molar feed ratio of the pyridine compounds and malonic acid monoalkyl ester is 1:1-5.
5. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: metallic compound is selected from following one or any several combination: copper trifluoromethanesulfcomposite, acetic acid in the catalyst system
Copper, palladium acetate, nickel acetate, nickel acetylacetonate, nickel fluoride, nickel chloride, nickel sulfate, zinc acetylacetonate.
6. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: chiral ligand is selected from following one or any several combination in the catalyst system:
7. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: the catalyst and pyridine compounds ratio is 1wt%-20wt%.
8. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: the molar ratio of metallic compound and chiral ligand is 1:1-2 in the catalyst.
9. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature exist
In: the temperature of the decarboxylation aldol addition reaction is 0-60 DEG C.
10. a kind of synthetic method of chiral quaternary carbon pyridines β hydroxyl esters compound according to claim 1, feature
Be: the reaction time of the decarboxylation aldol addition reaction is 3-120 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811533989.7A CN109608390B (en) | 2018-12-14 | 2018-12-14 | Synthesis method of chiral quaternary carbon pyridine beta-hydroxy ester compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811533989.7A CN109608390B (en) | 2018-12-14 | 2018-12-14 | Synthesis method of chiral quaternary carbon pyridine beta-hydroxy ester compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109608390A true CN109608390A (en) | 2019-04-12 |
| CN109608390B CN109608390B (en) | 2022-03-25 |
Family
ID=66009221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811533989.7A Active CN109608390B (en) | 2018-12-14 | 2018-12-14 | Synthesis method of chiral quaternary carbon pyridine beta-hydroxy ester compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109608390B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851513A (en) * | 2021-01-23 | 2021-05-28 | 温州大学新材料与产业技术研究院 | Synthetic method of 3-carbonyl 5-hydroxy ester compound |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191664A (en) * | 2018-01-16 | 2018-06-22 | 温州大学 | A kind of beta hydroxy acid class compound and its synthetic method |
-
2018
- 2018-12-14 CN CN201811533989.7A patent/CN109608390B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108191664A (en) * | 2018-01-16 | 2018-06-22 | 温州大学 | A kind of beta hydroxy acid class compound and its synthetic method |
Non-Patent Citations (2)
| Title |
|---|
| AKIO OJIDA ET AL.: "Highly Enantioselective Reformatsky Reaction of Ketones: Chelation-Assisted Enantioface Discrimination", 《ORGANIC LETTERS》 * |
| L. HUCK ET AL.: "Reformatsky and Blaise reactions in flow as a tool for drug discovery. One pot diversity oriented synthesis of valuable intermediates and heterocycles", 《GREEN CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112851513A (en) * | 2021-01-23 | 2021-05-28 | 温州大学新材料与产业技术研究院 | Synthetic method of 3-carbonyl 5-hydroxy ester compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109608390B (en) | 2022-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109942364B (en) | Olefin synthesis method using water as hydrogen source | |
| CN101941927A (en) | Method for analyzing (1R, 2R)-2-amino-1-(4-(methylsulfonyl)-phenyl)-1,3-propylene glycol as intermediate of florfenicol | |
| CN109734600B (en) | Synthesis method of chiral beta-hydroxy acid ester compound | |
| CN111205279B (en) | Polysubstituted benzodihydrofuran heterocyclic compound and preparation method and application thereof | |
| CN106902880A (en) | Application of the mercaptopyrimidine univalent copper complex of 4,6 dimethyl 2 in catalysis ketone or aldehyde hydrogen transfer reaction prepare alcohol | |
| CN109608390A (en) | A kind of synthetic method of chirality quaternary carbon pyridines β hydroxyl esters compound | |
| CN111072642B (en) | Preparation method of 5-succinimide chromone compound | |
| CN108586372B (en) | Synthesis method of 2-aryl oxazoline amide compound | |
| CN109867702B (en) | Binuclear palladium/ruthenium complex and preparation and application thereof | |
| CN113861119B (en) | Method for synthesizing quinoline and quinazoline compounds by cobalt catalysis | |
| CN109180446A (en) | A kind of synthetic method of 2,3- diphenyl -1H- 1-Indanone derivative | |
| WO2022260168A1 (en) | Hydroxy thienoimidazole derivative, vinyl sulfide derivative, n-butylidene sulfide derivative, and production method for saturated straight-chain hydrocarbon-substituted thienoimidazole derivative | |
| CN105646288B (en) | A kind of preparation method of carbamate derivatives | |
| CN111116450B (en) | Axial chiral naphthylamine squaramide organic catalyst, and preparation method and application thereof | |
| CN111229312B (en) | Solvent-free catalyst and preparation method and application thereof | |
| CN106083690A (en) | A kind of preparation method of polysubstituted 3 methylene indolones | |
| CN111039858B (en) | Preparation method of fluazuron | |
| Ren et al. | Arylamine synthesis enabled by a photocatalytic skeletal-editing dehydrogenative aromatization strategy | |
| CN110028448B (en) | Preparation method of 3-hydroxy-2,3-dihydroisoquinoline-1, 4-diketone compound | |
| CN108484602B (en) | Preparation method of polysubstituted azatricyclazine derivative | |
| CN108727179B (en) | Synthetic method of alpha-allyl substituted alpha, beta-unsaturated ketone, ester or nitrile compound | |
| CN113511986A (en) | Preparation method of aryl acetonitrile derivative | |
| CN107029759B (en) | Ruthenium trichloride reacts the application prepared in imines with alcohol compound in catalysis nitrobenzene compounds | |
| CN102786466B (en) | Synthetic method of chiral Salan ligand | |
| CN102050721B (en) | Method for synthesizing phenylacetic acid from benzyl chloride carbonyl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |