CN110437226A - A kind of new method constructing drug molecule grains of sand pyrrole denier using DMF and ammonium iodide as four step of cyanylation agent - Google Patents
A kind of new method constructing drug molecule grains of sand pyrrole denier using DMF and ammonium iodide as four step of cyanylation agent Download PDFInfo
- Publication number
- CN110437226A CN110437226A CN201910714717.5A CN201910714717A CN110437226A CN 110437226 A CN110437226 A CN 110437226A CN 201910714717 A CN201910714717 A CN 201910714717A CN 110437226 A CN110437226 A CN 110437226A
- Authority
- CN
- China
- Prior art keywords
- pyrrole
- dmf
- denier
- sand
- ammonium iodide
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses one kind using DMF (N,N-dimethylformamide) and ammonium iodide as the new method of four step of cyanylation agent building drug molecule grains of sand pyrrole denier.This method is with 2- (4- chlorphenyl) imidazoles [1; 2-a] pyridine is as reaction raw materials; drug molecule grains of sand pyrrole denier is constructed through cyanalation reaction, reduction reaction, acylation reaction, four step of methylation reaction using DMF (n,N-Dimethylformamide) and ammonium iodide as cyanylation agent.The method of the present invention synthesizing mean is novel, and reaction condition is mild, and reaction reagent is cheap and easy to get, uses safe and non-toxic DMF (n,N-Dimethylformamide) and ammonium iodide to provide cyanogen source as composite reagent, meets the demand for development of Green Chemistry.
Description
Technical field
The invention belongs to the technical fields such as medicine, material, cell biology, and in particular to one kind with DMF (N, N- diformazan
Base formamide) and ammonium iodide as four step of cyanylation agent building drug molecule grains of sand pyrrole denier new method.
Background technique
Grains of sand pyrrole denier and benzodiazepine compounds seemingly, have calm and antidepressant effect.The chemistry knot of grains of sand pyrrole denier
The architectural difference of structure and benzodiazepine compound is larger, therefore is considered being non-benzodiazepine compound.Grains of sand pyrrole denier has good
Good selectivity plays calm and antidepressant pharmacological action by adjusting the binding site with GABAA.In such research
Under background, we have proposed one kind to construct using DMF (n,N-Dimethylformamide) and ammonium iodide as four step of cyanylation agent
The new method of drug molecule grains of sand pyrrole denier, synthetic route are as follows:
The grains of sand pyrrole denier that the present invention synthesizes, structural formula are as follows:
The invention is husky using DMF (N,N-dimethylformamide) and ammonium iodide as four step of cyanylation agent building drug molecule
Grain pyrrole denier, provides a novel synthetic route for the synthesis of such compound.The invention synthesizing mean is novel, reaction condition
Mildly, reaction reagent is cheap and easy to get, uses safe and non-toxic DMF (n,N-Dimethylformamide) and ammonium iodide as composite reagent
Cyanogen source is provided, the demand for development of Green Chemistry is met.
Summary of the invention
The present invention relates to one kind to construct medicine using DMF (N,N-dimethylformamide) and ammonium iodide as four step of cyanylation agent
The new method of object molecule grains of sand pyrrole denier.This method with 2- (4- chlorphenyl) imidazoles [1,2-a] pyridine as reaction raw materials, with DMF
(N,N-dimethylformamide) and ammonium iodide are as cyanylation agent through through cyanalation reaction, reduction reaction, acylation reaction, first
Four step of glycosylation reaction constructs drug molecule grains of sand pyrrole denier.The method of the present invention synthesizing mean is novel, and reaction condition is mild, reaction reagent
It is cheap and easy to get, use safe and non-toxic DMF (n,N-Dimethylformamide) and ammonium iodide to provide cyanogen source as composite reagent, meets
The demand for development of Green Chemistry.
Technical solution of the present invention is as follows.
One kind constructing the drug molecule grains of sand using DMF (N,N-dimethylformamide) and ammonium iodide as four step of cyanylation agent
The new method of pyrrole denier, synthetic route are as follows:
In the above method, the grains of sand pyrrole denier is by compound 1 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine) through cyano
Four change reaction, reduction reaction, acylation reaction, methylation reaction reaction steps are made；The compound 1 is 2- (4- chlorobenzene
Base) imidazoles [1,2-a] pyridine；Specific step is as follows:
(1) compound 1 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine) is taken to be placed in container, be added promotor, solvent,
Additive, ammonium iodide put on the balloon filled with oxygen gas, are stirred to react 1-48 hours, are cooled to room temperature after reaction,
Balloon is removed, reaction solution filters, and after evaporating solvent under reduced pressure, obtains crude product, obtains (2- (the 4- chlorobenzene of compound 2 through column Chromatographic purification
Base) imidazoles [1,2-a] pyridine -3- nitrile)；
(2) compound 2 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine -3- nitrile) is taken to be placed in container, under nitrogen atmosphere
It is dissolved with tetrahydrofuran solvent, lithium aluminium hydride reduction is gradually added under zero degrees celsius, stirred 3 hours under room temperature after addition.
15% sodium hydrate aqueous solution of reaction solution is neutralized later, mixture is stirred at room temperature 1 hour.TLC (thin-layer chromatography
Method) tracing detection to reaction terminates, and filters, and extraction obtains compound 3 ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine)-
3- methylamine) crude product, realize reduction process；
(3) crude product of compound 3 ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine) -3- methylamine) is taken to be placed in container,
It is dissolved with methylene chloride, triethylamine and 4- diamino-pyridine is then added, n butanoic anhydride is gradually added dropwise under zero degrees celsius, be added dropwise
After place reaction liquid under zero degrees celsius and stir 10 minutes, be then placed in and stir 30 minutes at room temperature again.TLC (thin layer color
Spectrometry) tracing detection to reaction terminates, and filters, and extraction obtains compound 4N- ((2- (4- chlorphenyl) imidazoles [1,2, a] pyrrole
Pyridine) -3- base) methyl) and pentanamide crude product, realize acylation process；
(4) compound 4N- ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine) -3- base) methyl is taken) crude product of pentanamide
Be placed in container, with n,N-Dimethylformamide solvent dissolve, sodium hydride is gradually added under zero degrees celsius, after completion of dropwise addition in
It stirs under room temperature 30 minutes, iodomethane is then added and is stirred a hour under room temperature.TLC (thin-layered chromatography) tracing detection
Terminate to reaction, filter, extraction obtains target product grains of sand pyrrole denier.
In the above method, the reaction vessel of the specific steps (1) is teat glass；The promotor is three nitric hydrates
Copper；The additive is acetic acid；The solvent is DMF (N, N- dimethylformamide).
The amount and (2- (4- chlorphenyl) imidazoles of compound 1 of mantoquita are added in the above method, in the specific steps (1)
[1,2-a] pyridine) molar ratio be 2:1.
The amount and (2- (4- chlorphenyl) imidazoles of compound 1 of additive are added in the above method, in the specific steps (1)
[1,2-a] pyridine) molar ratio be 2:1.
The amount and (2- (4- chlorphenyl) imidazoles of compound 1 of ammonium iodide are added in the above method, in the specific steps (1)
[1,2-a] pyridine) molar ratio be 2:1.
In the above method, the balloon pressure filled with oxygen gas described in the specific steps (1) is 1 atmospheric pressure.
Compared with prior art, present invention has an advantage that this method synthesizing mean is novel, with DMF (N, N- dimethyl
Formamide) and ammonium iodide successfully construct grains of sand pyrrole denier as cyanylation agent, synthesizing mean is novel, and reaction condition is mild, instead
It answers reagent cheap and easy to get, safe and non-toxic DMF (n,N-Dimethylformamide) and ammonium iodide is used to provide cyanogen as composite reagent
Source meets the demand for development of Green Chemistry.
Detailed description of the invention
Fig. 1 is the nuclear-magnetism of compound 2 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine -3- nitrile) obtained in embodiment 1
Resonate hydrogen spectrum；
Fig. 2 is the nuclear-magnetism of compound 2 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine -3- nitrile) obtained in embodiment 1
Resonate carbon spectrum；
Fig. 3 is the nuclear magnetic resonance spectroscopy of grains of sand pyrrole denier obtained in embodiment 4；
Fig. 4 is the carbon-13 nmr spectra of grains of sand pyrrole denier obtained in embodiment 4；
Specific embodiment
The invention is further described below by specific embodiment.
Embodiment 1
0.2 mM of compound 1 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine) is added in the reaction tube of 25mL,
It 0.4 mM of Gerhardite, 0.4 mM of ammonium iodide, 0.4 mM of acetic acid, is added n,N-Dimethylformamide (DMF)
2 milliliters are used as reaction dissolvent, put on the balloon filled with oxygen, stir under 130 degrees Celsius.TLC (thin-layered chromatography) detection is anti-
Reaction solution is cooled to room temperature after answering, removes balloon, is slowly vented unreacted oxygen.Reaction solution filtering, filtrate decompression
Revolving removal solvent, then by column chromatographic isolation and purification, obtain (2- (4- chlorphenyl) imidazoles [1, the 2-a] pyridine -3- of compound 2
Nitrile), the step yield 85%.
Embodiment 2
Compound 2 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine -3- nitrile) 0.5 milli is added in the reaction tube of 25mL
Mole, it is added 2 milliliters of tetrahydrofuran and is used as reaction dissolvent, 2 milli of lithium aluminium hydride reduction is gradually added under nitrogen atmosphere and zero degrees celsius
Mole, it is stirred 3 hours under room temperature after addition.Later by reaction solution in 0.2 milliliter 15% of sodium hydrate aqueous solution
With mixture is stirred at room temperature 1 hour.TLC (thin-layered chromatography) tracing detection to reaction terminates, and filters, and extraction obtains
The crude product of compound 3 ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine) -3- methylamine).
Embodiment 3
It is added in the reaction tube of 25mL compound 3 ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine) -3- methylamine)
Crude product is added 2 milliliters of methylene chloride and is used as reaction dissolvent, 1 mM of triethylamine is added under zero degrees celsius, 4- dimethylamino
0.05 mM of pyridine, and 0.6 mM of n butanoic anhydride is gradually added dropwise under zero degrees celsius.It is placed reaction liquid into after completion of dropwise addition
It is stirred 10 minutes under zero degrees celsius, is then placed in and stirs 30 minutes at room temperature again.TLC (thin-layered chromatography) tracing detection extremely reacts
Terminate, filter, extraction obtains compound 4N- ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine) -3- base) methyl) pentanamide
Crude product.
Embodiment 4
Compound 4N- ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine) -3- base) is added in the reaction tube of 25mL
Methyl) pentanamide crude product, be added n,N-Dimethylformamide as reaction dissolvent, be gradually added 60% under zero degrees celsius
1 mM of sodium hydride, stirring at normal temperature is placed reaction liquid into after completion of dropwise addition 30 minutes, then be added 0.75 mM of iodomethane
And it is stirred 1 hour under room temperature.TLC (thin-layered chromatography) tracing detection to reaction terminates, and filters, and extraction, separating-purifying obtains
Grains of sand pyrrole denier.The gross production rate of four steps is 65%.
Claims (7)
1. a kind of construct drug molecule grains of sand pyrrole using DMF (N,N-dimethylformamide) and ammonium iodide as four step of cyanylation agent
The new method of denier, which is characterized in that synthetic route is as follows:
Specific step is as follows:
(1) it takes compound 1 to be placed in container, promotor, solvent, additive, ammonium iodide is added, puts on the gas filled with oxygen gas
Ball is stirred to react 1-48 hours, is cooled to room temperature after reaction, removes balloon, and reaction solution filters, after evaporating solvent under reduced pressure,
Crude product is obtained, obtains compound 2 through column Chromatographic purification；
(2) it takes compound 2 to be placed in container, is dissolved under nitrogen atmosphere with tetrahydrofuran solvent, gradually added under zero degrees celsius
Enter lithium aluminium hydride reduction, is stirred 3 hours under room temperature after addition, later by reaction solution in 15% sodium hydrate aqueous solution
With mixture is stirred at room temperature 1 hour；TLC (thin-layered chromatography) tracing detection to reaction terminates, and filters, and extraction obtains
The crude product of compound 3 realizes reduction process；
(3) it takes the crude product of compound 3 to be placed in container, is dissolved with methylene chloride, triethylamine and 4- diamino pyrrole is then added
N butanoic anhydride is gradually added dropwise in pyridine under zero degrees celsius, places reaction liquid into after completion of dropwise addition and stirs 10 minutes under zero degrees celsius, so
It is placed in and is stirred 30 minutes at room temperature again afterwards；TLC (thin-layered chromatography) tracing detection to reaction terminates, and filters, and extraction obtains chemical combination
The crude product of object 4 realizes acylation process；
(4) crude product of compound 4 is taken to be placed in container, with n,N-Dimethylformamide solvent dissolve, under zero degrees celsius by
Sodium hydride is gradually added, is stirred under room temperature after completion of dropwise addition 30 minutes, iodomethane is then added and is stirred under room temperature one small
When；TLC (thin-layered chromatography) tracing detection to reaction terminates, and filters, and extraction obtains target product grains of sand pyrrole denier.
2. according to claim 1 a kind of using DMF (N,N-dimethylformamide) and ammonium iodide as cyanylation agent four
The new method of step building drug molecule grains of sand pyrrole denier, which is characterized in that the compound 1 is 2- (4- chlorphenyl) imidazoles [1,2-
A] pyridine, the compound 2 is 2- (4- chlorphenyl) imidazoles [1,2-a] pyridine -3- nitrile, and the compound 3 is (2- (4- chlorobenzene
Base) imidazoles [1,2, a] pyridine) -3- methylamine, the compound 4 is N- ((2- (4- chlorphenyl) imidazoles [1,2, a] pyridine) -3-
Base) methyl) pentanamide, the promotor is Gerhardite, and the additive is acetic acid, and the solvent is DMF (N, N- bis-
Methylformamide).
3. according to claim 1 a kind of using DMF (N,N-dimethylformamide) and ammonium iodide as cyanylation agent four
The new method of step building drug molecule grains of sand pyrrole denier, which is characterized in that the container of the specific steps (1) is teat glass.
4. according to claim 1 a kind of using DMF (N,N-dimethylformamide) and ammonium iodide as cyanylation agent four
The new method of step building drug molecule grains of sand pyrrole denier, which is characterized in that the amount and chemical combination of mantoquita are added in the specific steps (1)
The molar ratio of object 1 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine) is 2:1.
5. according to claim 1 a kind of using DMF (N,N-dimethylformamide) and ammonium iodide as cyanylation agent four
The new method of step building drug molecule grains of sand pyrrole denier, which is characterized in that the amount and change of additive are added in the specific steps (1)
The molar ratio for closing object 1 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine) is 2:1.
6. according to claim 1 a kind of using DMF (N,N-dimethylformamide) and ammonium iodide as cyanylation agent four
The new method of step building drug molecule grains of sand pyrrole denier, which is characterized in that the amount and change of ammonium iodide are added in the specific steps (1)
The molar ratio for closing object 1 (2- (4- chlorphenyl) imidazoles [1,2-a] pyridine) is 2:1.
7. according to claim 1 a kind of using DMF (N,N-dimethylformamide) and ammonium iodide as cyanylation agent four
The new method of step building drug molecule grains of sand pyrrole denier, which is characterized in that filled with oxygen gas described in the specific steps (1)
Balloon pressure is 1 atmospheric pressure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910714717.5A CN110437226A (en) | 2019-08-02 | 2019-08-02 | A kind of new method constructing drug molecule grains of sand pyrrole denier using DMF and ammonium iodide as four step of cyanylation agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910714717.5A CN110437226A (en) | 2019-08-02 | 2019-08-02 | A kind of new method constructing drug molecule grains of sand pyrrole denier using DMF and ammonium iodide as four step of cyanylation agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110437226A true CN110437226A (en) | 2019-11-12 |
Family
ID=68433031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910714717.5A Withdrawn CN110437226A (en) | 2019-08-02 | 2019-08-02 | A kind of new method constructing drug molecule grains of sand pyrrole denier using DMF and ammonium iodide as four step of cyanylation agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110437226A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926811A (en) * | 2015-06-17 | 2015-09-23 | 浙江大学 | Synthetic method for 3-cyano group imidazo [1, 2-a] pyridine compounds and application thereof |
-
2019
- 2019-08-02 CN CN201910714717.5A patent/CN110437226A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926811A (en) * | 2015-06-17 | 2015-09-23 | 浙江大学 | Synthetic method for 3-cyano group imidazo [1, 2-a] pyridine compounds and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| JINHO KIM 等: "Copper-Mediated Selective Cyanation of Indoles and 2-Phenylpyridines with Ammonium Iodide and DMF", 《ORGANIC LETTERS》 * |
| JINHO KIM等: "Copper-Mediated Selective Cyanation of Indoles and 2- Phenylpyridines with Ammonium Iodide and DMF", 《J. AM. CHEM.SOC.》 * |
| QIAODONG WEN等: "Copper-mediated three-component synthesis of 3-cyanoimidazo[1,2-a]pyridines", 《CHEM. COMMUN.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20230257392A1 (en) | Intermediate for synthesizing camptothecin derivative, preparation method therefor, and use thereof | |
| JP4901174B2 (en) | Method for producing 2,2'-bis (trifluoromethyl) -4,4'-diaminobiphenyl | |
| CN107629051B (en) | Method for synthesizing evodiamine by carbonylation reaction three-step method | |
| CN114249711A (en) | Method for preparing nicotine by resolution | |
| CN110437226A (en) | A kind of new method constructing drug molecule grains of sand pyrrole denier using DMF and ammonium iodide as four step of cyanylation agent | |
| CN109053724A (en) | The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity | |
| CN111943854A (en) | Synthetic method of 3, 4-dichloro-2-nitrobenzoic acid | |
| CN110483505A (en) | 2- phenylimidazole [1,2-a] pyridine -3- nitrile replaced using DMF and ammonium iodide as cyanylation agent building | |
| CN110372694A (en) | A kind of new method of 2- phenylimidazole [1,2-a] pyridine -3- aldehyde replaced using DMF as formylation reagent building | |
| CN106518939B (en) | Method for preparing Solithromycin compound | |
| CN108101911A (en) | A kind of synthesis technology of sitagliptin intermediate | |
| CN110372696A (en) | One kind constructing the new method of imidazoles [1,2-a] pyridine -3- aldehyde using DMF as formylation reagent | |
| CN110372697A (en) | Using DMF and ammonium iodide as the new method of cyanylation agent building 2- phenylimidazole [1,2-a] pyridine -3- nitrile | |
| CN110483504A (en) | Using DMF as formylation reagent construct 2-(2- naphthalene) imidazoles [1,2-a] pyridine -3- aldehyde new method | |
| CN110372695A (en) | A kind of new method constructing drug molecule grains of sand pyrrole denier using DMF as three step of formylation reagent | |
| CN110551064B (en) | Preparation method of isavuconazole sulfate and intermediate thereof | |
| CN110483506A (en) | Using DMF as formylation reagent construct 2-(2- thienyl) imidazoles [1,2-a] pyridine -3- aldehyde new method | |
| CN110869381B (en) | Preparation method of steroid derivative FXR agonist | |
| CN110386933A (en) | 2-(2- thienyl is constructed using DMF and ammonium iodide as cyanylation agent) imidazoles [1,2-a] pyridine -3- nitrile | |
| CN110437225A (en) | 2-(2- naphthalene is constructed using DMF and ammonium iodide as cyanylation agent) imidazoles [1,2-a] pyridine -3- nitrile | |
| CN105175352A (en) | Preparation method of nitazoxanide | |
| CN107216360B (en) | A method of preparing rope Citropten | |
| CN109369505A (en) | It is the method that three step of starting material constructs alpha-glucosidase restrainer using imines | |
| CN110437262A (en) | 2- phenyl benzo [d] imidazoles [2,1-b] thiazole -3- nitrile is constructed using DMF and ammonium iodide as cyanylation agent | |
| CN111362889B (en) | Method for synthesizing medical intermediate |
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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20191112 |