CN108658977A - A kind of synthetic method of the bromo- 1,5- naphthyridines -3- formic acid of 7- - Google Patents
A kind of synthetic method of the bromo- 1,5- naphthyridines -3- formic acid of 7- Download PDFInfo
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- CN108658977A CN108658977A CN201810324849.2A CN201810324849A CN108658977A CN 108658977 A CN108658977 A CN 108658977A CN 201810324849 A CN201810324849 A CN 201810324849A CN 108658977 A CN108658977 A CN 108658977A
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- naphthyridines
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
The present invention provides a kind of synthetic method of 3 formic acid of 71,5 naphthyridines of bromine, is that raw material generates 71,5 naphthyridines of bromine, 3 carboxylate methyl ester by reaction with 1,5 naphthyridines, finally hydrolysis generates 71,5 naphthyridines of bromine, 3 formic acid under alkaline condition.The synthetic method of 7 bromine, 1,5 naphthyridines, 3 formic acid according to the present invention provides a kind of synthetic route with 1,5 naphthyridines for raw material, simple with synthetic route, low raw-material cost is simple and easy to get, convenient post-treatment, success rate are high, the advantages that being easy to the synthetic route of amplification.
Description
Technical field
The present invention relates to a kind of synthetic methods of intermediate, are specifically related to a kind of synthesis of the bromo- 1,5- naphthyridines -3- formic acid of 7-
Method.
Background technology
Bromo- 1, the 5- naphthyridines -3- formic acid of 7- is the key intermediate of synthesizing amide derivative, in n,N-Dimethylformamide
In the presence of with benzenesulfonamide derivatives carry out coupling reaction generate amide derivatives.These amides compounds can modify the food in one's mouth
Newborn animal ion channel such as VR1 cationic channels.These toxicity of compound are smaller, there is good absorbability, preferable to dissolve
Degree and the binding affinity with protein.These new discoveries cause these compounds to have therapeutic value, for preventing or improving the food in one's mouth
Many illnesss in newborn animal, such as pain caused by various causes or the cause of disease, such as acute, chronic, inflammatory and nerve pain
Pain pain, toothache and headache (such as migraine, cluster headache and tension headache), so the amide derivatives new to these
Research become one of forward position focus of medical field (US8153651B2).
The bromo- 1,5- naphthyridines -3- formic acid of 7- is an important intermediate, Ke Yitong in organic synthesis and pharmaceutical synthesis
It crosses its reactivity position and synthesizes a series of useful organic molecules and molecule drug candidate, it is in recent years, former for starting with it
It is organic conjunction that material synthesizes some molecules that can modify mammal ion channel with various benzenesulfonamide derivatives by condensation
At one of the hot spot on boundary and pharmaceutical chemistry circle.
The synthesis of existing bromo- 1, the 5- naphthyridines -3- formic acid of 7- has experiment route rare, and post-processing trouble, yield is relatively low,
The shortcomings of being not easy to amplify.
Invention content
In view of this, the technical problem to be solved by the present invention is to overcome the defect of the prior art, a kind of 7- bromo- 1,5- is provided
The synthetic method of naphthyridines -3- formic acid, the synthetic method have synthetic route simple, and low raw-material cost is simple and easy to get, post-processing
Convenient, success rate is high, the advantages that being easy to amplify.
In order to solve the above technical problems, the present invention uses following technical scheme：
Formula VI according to the ... of the embodiment of the present invention：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-,
The method comprising the steps of：
(1) compound of formula I carries out bromo-reaction to form II compound of formula；
(2) II compound of formula is subjected to slotting carbonyl and IV compound of formula is obtained by the reaction；
(3) IV compound of formula progress bromo-reaction is obtained into V compound of formula；
(4) VI compound of the formula of being obtained by the reaction is hydrolyzed in V compound of formula；
Preferably, step (1) further includes step：The compound of Formulas I and bromine simple substance are subjected to bromo-reaction.
Preferably, the reaction dissolvent in step (1) is acetic acid.
Preferably, reaction temperature is 60 DEG C -100 DEG C, reaction time 2h-5h.
Preferably, the reagent in step (2) is carbon monoxide, and reaction dissolvent is n,N-Dimethylformamide, and catalyst is
Palladium bichloride.
Preferably, the reaction temperature in step (2) is 40 DEG C -100 DEG C, reaction time 4h-10h.
Preferably, reaction reagent is N-bromosuccinimide or bromine in step (3), and reaction dissolvent is acetic acid.
Preferably, reaction temperature is 70 DEG C -120 DEG C in step (3), reaction time 5h-8h.
Preferably, the reaction dissolvent in step (4) is highly basic.
Preferably, step (4) reaction temperature is 25 DEG C -70 DEG C, reaction time 3h-8h.
Above-mentioned technical proposal of the present invention has the beneficial effect that：
The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7- according to the ... of the embodiment of the present invention, be successfully realized to close on a large scale
At the method for bromo- 1, the 5- naphthyridines -3- formic acid of 7-, one kind is provided with 1,5- naphthyridines as raw material, synthetic route is simple, cost of material
Cheap, simple and easy to get, convenient post-treatment, success rate is high, is easy to the synthetic route of amplification, 7- can not also be synthesized now by solving
The problem of bromo- 1,5- naphthyridines -3- formic acid.
Description of the drawings
Fig. 1 is synthetic route chart of the present invention.
Specific implementation mode
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
Attached drawing, the technical solution of the embodiment of the present invention is clearly and completely described.Obviously, described embodiment is this hair
Bright a part of the embodiment, instead of all the embodiments.Based on described the embodiment of the present invention, ordinary skill
The every other embodiment that personnel are obtained, shall fall within the protection scope of the present invention.
The synthetic method of the bromo- 1,5- naphthyridines -3- formic acid of 7- according to the ... of the embodiment of the present invention is specifically described below in conjunction with the accompanying drawings.
As shown in Figure 1, according to formula VI provided by the invention：The synthetic method of the bromo- 1,5- naphthyridines -3- formic acid of 7- includes following
Step：
The synthesis of step (1) 3- bromonaphthalene pyridines：
By raw material 1,5- naphthyridines (formula I) carries out bromo-reaction, generates 3- bromonaphthalenes pyridine (formula II)；
Step (2) 1, the synthesis of -3 carboxylate methyl ester of 5- naphthyridines：
3- bromonaphthalenes pyridine (formula II) is carried out to insert carbonyl reaction, generates -3 carboxylate methyl ester (formula IV) of 1,5- naphthyridines；
The synthesis of the bromo- 1,5- naphthyridines -3- carboxylate methyl esters of step (3) 7-：
- 3 carboxylate methyl ester of 1,5- naphthyridines (formula IV) is subjected to bromo-reaction, generates bromo- 1, the 5- naphthyridines -3- carboxylate methyl esters of 7-
(formula V)；
The synthesis of the bromo- 1,5- naphthyridines -3- formic acid of step (4) 7-：
The bromo- 1,5- naphthyridines -3- carboxylate methyl esters (formula V) of 7- are hydrolyzed, the bromo- 1,5- naphthalenes of target compound 7- are obtained by the reaction
Pyridine -3- formic acid.
In other words, the synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7- according to the ... of the embodiment of the present invention is with 1,5- naphthyridines
Raw material obtains 3- bromonaphthalene pyridines by bromo-reaction, carries out inserting -3 carboxylate methyl ester of carbonyl reaction 1,5- of generation naphthyridines, then carries out bromo
Reaction generates bromo- 1, the 5- naphthyridines -3- carboxylate methyl esters of 7-, and finally hydrolysis generates bromo- 1, the 5- naphthyridines -3- formic acid of 7- under alkaline condition
(formula VI).
According to one embodiment of present invention, step (1) further includes step：1,5- naphthyridines and bromine simple substance progress bromo is anti-
It answers.
Further, the reaction dissolvent in step (1) is acetic acid.
Optionally, reaction temperature is 60 DEG C -100 DEG C, reaction time 2h-5h.
In certain specific embodiments of the invention, the reagent in step (2) can be carbon monoxide, and reaction dissolvent can be
N,N-Dimethylformamide, catalyst can be palladium bichloride.
It further spends, the reaction temperature in step (2) is 40 DEG C -100 DEG C, reaction time 4h-10h.
According to one embodiment of present invention, in step (3) reaction reagent can be N-bromosuccinimide or bromine, instead
It can be acetic acid to answer solvent, it should be noted that it is also an option that bromine, but effect does not have N-bromosuccinimide good.
It further spends, reaction temperature is 70 DEG C -120 DEG C in step (3), reaction time 5h-8h.
In certain specific embodiments of the invention, the reaction dissolvent in step (4) can be highly basic, wherein reaction dissolvent
Select highly basic, such as lithium hydroxide, potassium hydroxide etc. can, and the concentration of sodium hydrate aqueous solution can be 10%-40%.
Further, step (4) reaction temperature can be 25 DEG C -70 DEG C, reaction time 3h-8h.
In order to further illustrate the present invention, with reference to specific embodiment 1,5- naphthyridines -3- bromo- to 7- provided by the invention
The synthetic method of formic acid is described in detail.
Embodiment 1
The first step is bromo-reaction, reactant 1,5- naphthyridines and bromine simple substance, and reaction dissolvent is acetic acid, reaction temperature 80
DEG C -90 DEG C, reaction time 3h.
Second step is to insert carbonyl to react, and agents useful for same is carbon monoxide, and reaction dissolvent is n,N-Dimethylformamide, catalyst
For palladium bichloride, reaction temperature is 75 DEG C, reaction time 6h.
Third step is bromo-reaction, and reflection reagent is N-bromosuccinimide, and reaction dissolvent is acetic acid, and reaction temperature is
100 DEG C, reaction time 6h.
4th step is hydrolysis, and reaction dissolvent is 10%NaOH aqueous solutions, and reaction temperature is 60 DEG C, the reaction time 5
Hour.
Embodiment 2
The generation of 3- bromonaphthalene pyridines
1,5- naphthyridines (111.6g, 0.85mol) is dissolved in acetic acid (1000mL), addition sodium acetate (140.9g,
1.72mol), 80 DEG C are heated to, solution of the bromine (153g, 0.96mol) in 150mL is added dropwise thereto, keeps the temperature of reaction solution
The reaction 3h at 85 DEG C is added dropwise at 80 DEG C -90 DEG C in degree.It is then cooled down, reaction solution is spin-dried for, H is added2O (1000mL),
30min is stirred after being transferred to alkalinity with 50% sodium hydrate aqueous solution, is filtered, and filter cake washing is dry.Ethyl acetate is added in crude product
(1600mL) is heated to reflux 3h.It is cooled to room temperature, is filtered, filter cake is washed with ethyl acetate, is dried to obtain 3,7- dibromo naphthyridines.Filter
Liquid is spin-dried for obtaining 3- bromonaphthalene pyridines crude product (84g, white light yellow complexion solid, yield 47%), passes through petroleum ether：Ethyl acetate=20：1
~10：1 column purification obtains pure 3- bromonaphthalenes pyridine (67g, white solid, yield 37%).
Embodiment 3
The generation of -3 carboxylate methyl ester of 1,5- naphthyridines
By 3- bromonaphthalenes pyridine (44.5g, 0.213mol), absolute ethyl alcohol (357mL), n,N-Dimethylformamide (90mL) is mixed
It closes, palladium bichloride (2.65g) is added, triethylamine (32.28g, 0.32mol) is reacted at 75 DEG C with the carbon monoxide of 0.8MPa pressure
6h, reaction solution are spin-dried for, and use petroleum ether：Ethyl acetate=10：1~1：1 cross pillar, obtain -3 carboxylate methyl ester of 1,5- naphthyridines (34g,
White solid, yield 84%).
Embodiment 4
The generation of the bromo- 1,5- naphthyridines -3- carboxylate methyl esters of 7-
By -3 carboxylate methyl ester of 1,5- naphthyridines (17.5g, 93.0mmol), acetic acid (150mL) mixing is warming up to 100 DEG C, in batches
N-bromosuccinimide (17.4g, 97.7mmol) is added, finishes and reacts 6h in 100 DEG C.It is monitored and is reacted by TLC.It is spin-dried for,
1 water (100mL) is added, stirs, filtering, filter cake is washed, and EA is washed, and is dried to obtain bromo- 1, the 5- naphthyridines -3- carboxylate methyl esters of 7-
(22.5g, white solid, yield 92%).
Embodiment 5
The generation of the bromo- 1,5- naphthyridines -3- formic acid of 7-
Bromo- 1, the 5- naphthyridines -3- carboxylate methyl esters (26g, 98mmol) of 7- are dissolved in ethyl alcohol (150mL), 10%NaOH is added
Aqueous solution (260mL) finishes reaction solution and is heated to 60 DEG C of reaction 5h, and rotary evaporation removes ethyl alcohol, with 2M salt acid for adjusting pH to 4-
6, solid is precipitated, filters, is dried to obtain bromo- 1, the 5- naphthyridines -3- formic acid of target product 7- (25g, white solid, yield 99%).
The nuclear magnetic resonance spectroscopy (1HNMR) of the bromo- 1,5- naphthyridines -3- formic acid of target product 7- is as follows：
1HNMR(400MHz,DMSO-d6):8.86(d,2H),9.21(s,1H),9.43(s,1H),13.92(s,1H)。
The above is the preferred embodiment of the present invention, it is noted that for those skilled in the art
For, without departing from the principles of the present invention, it can also make several improvements and retouch, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (10)
1. formula VI：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-,
The method comprising the steps of：
(1) compound of formula I is subjected to bromo-reaction to form II compound of formula；
(2) II compound of formula is subjected to slotting carbonyl and IV compound of formula is obtained by the reaction；
(3) IV compound of formula progress bromo-reaction is obtained into V compound of formula；
(4) VI compound of the formula of being obtained by the reaction is hydrolyzed in V compound of formula；
2. formula VI according to claim 1：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(1) further include step：
The compound of Formulas I and bromine simple substance are subjected to bromo-reaction.
3. formula VI according to claim 2：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(1) reaction dissolvent in is acetic acid.
4. formula VI according to claim 3：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that reaction
Temperature is 60 DEG C -100 DEG C, reaction time 2h-5h.
5. formula VI according to claim 1：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(2) reagent in is carbon monoxide, and reaction dissolvent is n,N-Dimethylformamide, and catalyst is palladium bichloride.
6. formula VI according to claim 5：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(2) reaction temperature in is 40 DEG C -100 DEG C, reaction time 4h-10h.
7. formula VI according to claim 1：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(3) reaction reagent is N-bromosuccinimide or bromine in, and reaction dissolvent is acetic acid.
8. formula VI according to claim 7：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(3) reaction temperature is 70 DEG C -120 DEG C in, reaction time 5h-8h.
9. formula VI according to claim 1：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(4) reaction dissolvent in is highly basic.
10. formula VI according to claim 9：The synthetic method of bromo- 1, the 5- naphthyridines -3- formic acid of 7-, which is characterized in that step
(4) reaction temperature is 25 DEG C -70 DEG C, reaction time 3h-8h.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007133637A2 (en) * | 2006-05-10 | 2007-11-22 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
| CN105143190A (en) * | 2013-03-14 | 2015-12-09 | 达特神经科学(开曼)有限公司 | Substituted naphthyridine and quinoline compounds as MAO inhibitors |
| WO2017023905A1 (en) * | 2015-08-03 | 2017-02-09 | Bristol-Myers Squibb Company | Heterocyclic compounds useful as modulators of tnf alpha |
-
2018
- 2018-04-12 CN CN201810324849.2A patent/CN108658977A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007133637A2 (en) * | 2006-05-10 | 2007-11-22 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
| CN105143190A (en) * | 2013-03-14 | 2015-12-09 | 达特神经科学(开曼)有限公司 | Substituted naphthyridine and quinoline compounds as MAO inhibitors |
| WO2017023905A1 (en) * | 2015-08-03 | 2017-02-09 | Bristol-Myers Squibb Company | Heterocyclic compounds useful as modulators of tnf alpha |
Non-Patent Citations (1)
| Title |
|---|
| WILLIAM W. PAUDLER ET AL.: ""Naphthyridine Chemistry. IX. The Bromination and Amination of the l, X-Naphthyridines"", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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