CN110283119A - A method of synthesizing complete carbon-based substituted pyridine derivative - Google Patents
A method of synthesizing complete carbon-based substituted pyridine derivative Download PDFInfo
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- CN110283119A CN110283119A CN201810361995.2A CN201810361995A CN110283119A CN 110283119 A CN110283119 A CN 110283119A CN 201810361995 A CN201810361995 A CN 201810361995A CN 110283119 A CN110283119 A CN 110283119A
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- formula
- cumarin
- substituted
- pyridine derivative
- complete carbon
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
The invention discloses a kind of methods for synthesizing complete carbon-based substituted pyridine derivative.This method be by (E) -3- (1- (acetoxyl group imines) ethyl) substituted cumarin reacts with alkynes and prepare substituted pyridines [3,4-c] cumarin, then at room temperature, basic hydrolysis coumarin ring, or furtherOAlkylation, obtains object.The method overcome in the prior art, it is difficult to the shortcomings that preparing complete carbon-based substituted pyridine derivative.Synthetic method disclosed by the invention will play a significant role in the research field of pyridine derivate.
Description
Technical field
The present invention relates to a kind of preparation methods of complete carbon-based substituted pyridine derivative, specifically, be related to it is a kind of (E)-3-
(1- (acetoxyl group imines) ethyl) substituted cumarin reacts with alkynes and prepares substituted pyridines [3,4-c] cumarin, then through water
Solution, acidification or the method that complete carbon-based substituted pyridine derivative is further prepared with halohydrocarbons reaction.
Background technique
Polysubstituted pyridine derivative is the nitrogenous 6-membered heterocyclic compound that generally acknowledged one kind has particularly significant application value.
It is widely existed in the fields such as natural products, medicine, functional material and agriculture chemistry.Especially pyridine self structure
Particularity has it in organic catalysis synthesis, pharmaceutical chemistry and Coordinative Chemistry as compound building block unrivaled
Effect.Therefore, many chemical researchers are dedicated in the study on the synthesis of pyridine compounds, and it is more to create a series of buildings
The effective method of substituted pyridine compound.Although these synthetic methods have weight during pyridine synthesis derivative
Meaning is wanted, but many methods may face some limitations at present, especially all be taken by carbon-based in the position C1-5 of pyridine synthesis ring
There is bigger difficulty in terms of derivative replaced Dai Ji.
Therefore it provides a kind of step is succinct, the complete carbon-based substituted pyridine derivative preparation method of mild condition becomes this hair
The bright technical issues that need to address.
Summary of the invention
The object of the present invention is to provide a kind of preparation sides of the complete carbon-based substituted pyridine derivative of simple process, mild condition
Method.
The present invention complete carbon-based substituted pyridine compounds to be prepared, structural formula is as shown in formula II:
And the method for compound shown in preparation formula II provided by the present invention, it has main steps that: (E) -3- (1- (acetoxyl group
Imines) ethyl) substituted cumarin (structural formula is as shown in formula III) reacted with alkynes (structural formula is as shown in formula IV) preparation replace pyrrole
Pyridine [3,4-c] cumarin (structural formula is shown in formula I), then at room temperature, in the presence of sodium hydroxide, in dimethyl Asia
It is reacted in sulfone a few hours, or halogenated alkane the reaction was continued a few hours is added after reacting a period of time, obtain target shown in Formula II
Product:
Wherein, R1For alkyl, alkoxy, halogen；R2For alkyl, aryl；R3For hydrogen, alkyl；R4Or R5For aryl, alkyl, alcoxyl
Carbonyl.
The room temperature refers to 20 DEG C ~ 30 DEG C.
The invention has the characteristics that the substituted pyridines and cumarin (compound shown in Formulas I) to be easy to get are raw material, through alkaline item
Further O- alkylation, obtains target product (compound shown in Formula II), overcomes existing skill after part hydrolysis, acidification, or hydrolysis
In art, the whole difficulties such as derivative replaced carbon-based substituent group in the position C1-5 of pyridine synthesis ring.
The present invention is described in further details below with reference to specific example.
Specific embodiment
Method therefor is conventional method unless otherwise specified in following implementations.
Embodiment 1, with 4- methyl-1,2- hexichol yl pyridines [3,4-c] cumarin hydrolysis 4- (2- hydroxyphenyl) -2- first
Illustrate operation for base -5,6- diphenyl niacin (for the II-1 compound shown in the formula)；
Into reaction flask, 4- methyl-1,2- hexichol yl pyridines [3,4 are successively added-c] cumarin (0.1 mmol), sodium hydroxide
(0.2 mmol) and DMSO(0.3 mL), 2 h are reacted at room temperature.Water, dilute hydrochloric acid, ethyl acetate are sequentially added into reaction solution
Extraction, silica gel column layer are separated by decantation to product, yield 93%；
Mp209-211oC;1H NMR (400 MHz, DMSO) δ 7.20 (d, J = 6.8 Hz, 5H), 7.00 –
6.96 (m, 5H), 6.89 (d, J = 7.2 Hz, 2H), 6.61 (t, J = 7.2 Hz, 2H), 2.61 (s,
3H);13C NMR (101 MHz, DMSO) δ 169.55, 156.70, 154.66, 152.04, 145.35, 140.82,
138.00, 133.71, 130.91, 130.55, 130.06(2C), 129.35, 127.87(2C), 127.79,
127.51, 126.91, 124.46, 118.27, 115.23, 23.00。
Embodiment 2, with 4- methyl-1,2- hexichol yl pyridines [3,4-c] cumarin hydrolysis 4- (2- ethoxyphenyl) -2-
Illustrate operation for methyl -5,6- diphenyl ethyl nicotinate (for the II-2 compound shown in the formula)；
Into reaction flask, 4- methyl-1,2- hexichol yl pyridines [3,4 are successively added-c] cumarin (0.1 mmol), sodium hydroxide
(0.24 mmol) and DMSO(0.3 mL), 0.5 h is reacted at room temperature.Bromoethane (0.24 mmol) is added into mixture,
The reaction was continued 3 h.Water, dilute hydrochloric acid, ethyl acetate extraction are sequentially added into reaction solution, silica gel column layer is separated by decantation to product, receives
Rate 82%；
Mp154-156oC;1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 5.6 Hz, 2H), 7.17 –
7.10 (m, 4H), 7.00 - 6.76 (m, 7H), 6.61 (d, J = 8.4 Hz, 1H), 4.00 (q, J = 6.9
Hz, 2H), 3.83 (quint, J= 7.5 Hz, 1H), 3.61 (quint, J=7.5 Hz, 1H), 2.72 (s,
3H), 1.20 (t, J = 6.8 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H);13C NMR (101 MHz,
CDCl3) δ 168.45, 157.60, 155.50, 153.57, 145.92, 140.52, 137.60, 133.30,
130.67, 129.95(2C), 129.24, 128.73, 127.64(2C), 127.49, 126.97, 126.51,
126.36, 119.52, 110.87, 63.27, 60.99, 23.18, 14.60, 13.63。
Embodiment 3, with 4- methyl-1,2- hexichol yl pyridines [3,4-c] cumarin hydrolysis 4- (2- butoxyphenyl) -2-
Illustrate operation for methyl -5,6- diphenyl niacin butyl ester (for the II-3 compound shown in the formula)；
Into reaction flask, 4- methyl-1,2- hexichol yl pyridines [3,4 are successively added-c] cumarin (0.1 mmol), sodium hydroxide
(0.24 mmol) and DMSO(0.3 mL), 0.5 h is reacted at room temperature.Bromination of n-butane (0.24 is added into mixture
Mmol), the reaction was continued 3 h.Water, dilute hydrochloric acid, ethyl acetate extraction are sequentially added into reaction solution, silica gel column layer is separated by decantation to production
Object, yield 85%；
Mp101-103oC;1H NMR (400 MHz, CDCl3) δ 7.27 (s, 2H), 7.15 – 7.09 (m, 4H),
7.00 – 6.74 (m, 7H), 6.61 (d, J = 8.4 Hz, 1H), 3.94 (t, J = 6.2 Hz, 2H), 3.73
(q, J = 7.6 Hz, 1H), 3.56 (q, J = 7.5 Hz, 1H), 2.71 (s, 3H), 1.62 – 1.55 (m,
2H), 1.30 – 1.26 (m, 4H), 1.20 – 1.11 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H), 0.80
(t, J = 7.2 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 168.59, 157.49, 155.68, 153.45,
145.83, 140.53, 137.61, 133.32, 130.82, 130.51, 129.93(2C), 129.23, 128.85,
127.64(2C), 127.48, 126.96, 126.53, 126.36, 119.51, 110.95, 67.60, 64.92,
31.08, 30.30, 23.17, 19.15, 18.98, 13.84, 13.66。
Embodiment 4, with (E) -3- (1- (acetoxyl group imines) ethyl) cumarin and two benzyne catalyzed cyclizations, hydrolysis, O-
Alkyl is combined to illustrate operation (shown in formula for 4- (2- ethoxyphenyl) -2- methyl -5,6- diphenyl ethyl nicotinate
For II-2 compound)；
Into reaction tube, be successively added (E) -3- (1- (acetoxyl group imines) ethyl) cumarin (0.3 mmol), two benzynes
(0.36 mmol), [Cp*RhCl2]2(2.5 mol%), sodium acetate (30 mol%) and methanol (1.5 mL), in 50oC lower sealing
React 8h.It is extracted with ethyl acetate, organic phase is evaporated.It is transferred in reaction flask, sodium hydroxide (0.58 mmol) and DMSO is added
(1.0 mL), reacts 0.5 h at room temperature.Bromoethane (0.58 mmol) is added into mixture, the reaction was continued 3 h.Toward reaction
Water, dilute hydrochloric acid, ethyl acetate extraction are sequentially added in liquid, silica gel column layer is separated by decantation to product, yield 78%.
Claims (1)
1. a kind of method of compound shown in preparation formula II, which is characterized in that the method has main steps that: (E)-3-(1-
(acetoxyl group imines) ethyl) substituted cumarin (structural formula is as shown in formula III) reacts with alkynes (structural formula is as shown in formula IV)
Substituted pyridines [3,4-c] cumarin (structural formula is shown in formula I) is prepared, then at room temperature, in the presence of sodium hydroxide,
It is reacted in dimethyl sulfoxide a few hours, or halogenated alkane the reaction was continued a few hours is added after reacting a period of time, obtain formula
Target product shown in II:
Wherein, R1For alkyl, alkoxy, halogen；R2For alkyl, aryl；R3For hydrogen, alkyl.
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| CN201810361995.2A CN110283119A (en) | 2018-04-20 | 2018-04-20 | A method of synthesizing complete carbon-based substituted pyridine derivative |
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| CN201810361995.2A CN110283119A (en) | 2018-04-20 | 2018-04-20 | A method of synthesizing complete carbon-based substituted pyridine derivative |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0297613A2 (en) * | 1987-07-01 | 1989-01-04 | Yamanouchi Pharmaceutical Co. Ltd. | Pyridine derivatives, process for production thereof and pharmaceutical composition containing them |
| DE10348022A1 (en) * | 2003-10-15 | 2005-05-25 | Imtm Gmbh | New dipeptidyl peptidase IV inhibitors for the functional influence of different cells and for the treatment of immunological, inflammatory, neuronal and other diseases |
| WO2014130258A1 (en) * | 2013-02-22 | 2014-08-28 | Bristol-Myers Squibb Company | 5h-chromeno[3,4-c]pyridines as inhibitors of adaptor associated kinase 1 (aak1) |
| WO2015002915A1 (en) * | 2013-07-02 | 2015-01-08 | Bristol-Myers Squibb Company | Tricyclic pyri do-carboxam i d e derivatives as rock inhibitors |
-
2018
- 2018-04-20 CN CN201810361995.2A patent/CN110283119A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0297613A2 (en) * | 1987-07-01 | 1989-01-04 | Yamanouchi Pharmaceutical Co. Ltd. | Pyridine derivatives, process for production thereof and pharmaceutical composition containing them |
| DE10348022A1 (en) * | 2003-10-15 | 2005-05-25 | Imtm Gmbh | New dipeptidyl peptidase IV inhibitors for the functional influence of different cells and for the treatment of immunological, inflammatory, neuronal and other diseases |
| WO2014130258A1 (en) * | 2013-02-22 | 2014-08-28 | Bristol-Myers Squibb Company | 5h-chromeno[3,4-c]pyridines as inhibitors of adaptor associated kinase 1 (aak1) |
| WO2015002915A1 (en) * | 2013-07-02 | 2015-01-08 | Bristol-Myers Squibb Company | Tricyclic pyri do-carboxam i d e derivatives as rock inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| CHRISTINA J.DREYTON等: "《Insights into the mechanism of streptonigrin-induced protein arginine deiminase inactivation》", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| MERCHANT, J. R.: "《An interesting reaction of 4H-1-benzopyrano(3,4-d)oxazol- and isoxazol-4-ones》", 《CURRENT SCIENCE 》 * |
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Application publication date: 20190927 |