CN107311923A - A kind of synthetic method of the methoxypyridine of 3 iodine 5 - Google Patents
A kind of synthetic method of the methoxypyridine of 3 iodine 5 Download PDFInfo
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- CN107311923A CN107311923A CN201710455341.1A CN201710455341A CN107311923A CN 107311923 A CN107311923 A CN 107311923A CN 201710455341 A CN201710455341 A CN 201710455341A CN 107311923 A CN107311923 A CN 107311923A
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- China
- Prior art keywords
- methoxypyridines
- synthetic method
- iodo
- iodine
- methoxypyridine
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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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to a kind of synthetic method of the methoxypyridine of 3 iodine 5.Mainly solve the technical problem of its simplified synthetic method.The technical scheme is that：A kind of synthetic method of the methoxypyridine of 3 iodine 5, it is characterized in that comprising the following steps：Natrium nitrosum reaction is added under the methoxypyridine of 3 amino 5, sulfuric acid solution ice salt bath, diazol is generated；Iodide are added, the diazo of diazol is replaced by iodine anion, reaction solution adjusts pH=8 9 with strong base solution, then ethyl acetate is extracted, and is spin-dried for, crude product passes through chromatography, is obtained target product 1：The methoxypyridine of 3 iodine 5.The methoxypyridine of 3 iodine 5 is mainly as medicine intermediate.
Description
Technical field
The present invention relates to the iodo- 5- methoxypyridines of 3-（CAS：873302-36-4）Synthesis.
Background technology
The iodo- 5- methoxypyridines of 3- are used widely as medicine intermediate.2015, Mao Chen etc. were being answered first
With being reported on The Chemicals using the bromo- 5- methoxypyridines of 3- as raw material, cuprous iodide is utilized as catalyst
The synthetic method of Continuous-Flow technologies.But so far, had no on its synthetic method Jing Guo diazo-reaction
Open report.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of the iodo- 5- methoxypyridines of 3-, mainly solve to simplify its synthesis
The technical problem of method.
The technical scheme is that：A kind of synthetic method of the iodo- 5- methoxypyridines of 3-, it is characterized in that including following step
Suddenly：Natrium nitrosum is added under 3- amino -5- methoxypyridines, sulfuric acid solution ice salt bath and carries out nitrite reaction, diazol is generated；
Iodide are added, the diazo of diazol is replaced by iodine anion, reaction solution adjusts pH=8-9, Ran Houyi with strong base solution alkalization
Acetoacetic ester is extracted, and is spin-dried for, crude product passes through chromatography, is obtained target product 1：The iodo- 5- methoxypyridines of 3-.
Synthetic line is as follows：
。
In above-mentioned reaction, natrium nitrosum, 3- ammonia are added under 3- amino -5- methoxypyridines, 1.6 M sulfuric acid solution ice salt baths
Base -5- methoxypyridines are 5-15 minutes, preferred reaction time with the nitrite reaction time of generation in 1.6 M sulfuric acid solutions
For 10 minutes；Reaction temperature is -10-0 DEG C, and preferable reaction temperature is -5 DEG C；The iodide are KI, diazol and iodate
The nak response time is 10-20 minutes, and preferred reaction time is 15 minutes；Reaction temperature is -10-0 DEG C, and preferable reaction temperature is -5
℃；Reaction solution is alkalized with 2 M sodium hydroxide solutions.
The beneficial effects of the invention are as follows：The method reported is compared, and reaction condition is simple, and target product and raw material are easy
By chromatogram post separation, the target product of high-purity is obtained.
Embodiment
Embodiment 1：
Step 1：
3- amino -5- methoxypyridines are added into three-necked flask（10.0 g, 80.6 mmol）, 1.6 M sulfuric acid solutions（200
mL）；Natrium nitrosum is added at -5 DEG C（6.0 g, 88.6 mmol）.- 5 DEG C of reaction solution is stirred 10 minutes.Iodate is added at -5 DEG C
Potassium（40.0 g, 242 mmol）The aqueous solution（100 mL）, -5 DEG C are stirred 15 minutes.2 M of reaction solution sodium hydroxide solution alkali
Change to pH and be equal to 8-9, add water（100 mL）, ethyl acetate extraction（100 mL x 3）;Organic phase merges, and uses saturation sulfurous
Sour hydrogen sodium solution（100 mL）And saturated aqueous common salt（100 mL）Washing, sodium sulphate is dried, filtering.Filtrate is spin-dried for, crude product
Separated by silica gel column chromatography（Petroleum ether：Ethyl acetate volume ratio=40:1）, obtain white solid, target compound 1
（10.2 g, 43.4 mmol, 48 %）.1H NMR (300 MHz, D2O) 8.38 (d, J = 2.7 Hz, 1H), 8.28
(d, J = 2.7 Hz, 1H), 7.80 (m, 1H), 3.82 (s,3H) ppm；LC-MS (ESI): m/z 236.3 [M+
H]+。
Embodiment 2, step 1：3- amino -5- methoxypyridines are in 1.6 M sulfuric acid solutions and the natrium nitrosum reaction time
For 5 minutes, reaction temperature was 0 DEG C；Diazol and KI reaction time are 10 minutes, and reaction temperature is 0 DEG C, and remaining is with implementation
Example 1.
Embodiment 3, step 1：3- amino -5- methoxypyridines are in 1.6 M sulfuric acid solutions and the natrium nitrosum reaction time
For 15 minutes, reaction temperature was -10 DEG C；Diazol and KI reaction time are 20 minutes, and reaction temperature is -10 DEG C, remaining
Be the same as Example 1.
Claims (6)
1. a kind of synthetic method of the iodo- 5- methoxypyridines of 3-, it is characterized in that including lower step：In ice salt bath, 3- amino-
5- methoxypyridines, sulfuric acid solution add natrium nitrosum and carry out nitrite reaction, generate diazol；Add iodide, diazol
Diazo replaced by iodine anion, reaction solution with strong base solution alkalization adjust pH=8-9, then ethyl acetate extract, be spin-dried for,
Crude product passes through chromatography, obtains target product 1：The iodo- 5- methoxypyridines of 3-；Synthetic line is as follows：
。
2. the synthetic method of the iodo- 5- methoxypyridines of a kind of 3- according to claim 1, it is characterized in that described sulfuric acid
Solution is 1.6 M sulfuric acid solutions.
3. the synthetic method of the iodo- 5- methoxypyridines of a kind of 3- according to claim 1, it is characterized in that the nitrous acid
Reaction time is 5-15 minutes.
4. the synthetic method of the iodo- 5- methoxypyridines of a kind of 3- according to claim 1, it is characterized in that the nitrous acid
Reaction temperature is -10-0 DEG C.
5. a kind of synthetic method of the iodo- 5- methoxypyridines of 3- according to claim 1, it is characterized in that the iodine bear from
The sub- substitution reaction time is 10-20 minutes.
6. the synthetic method of the iodo- 5- methoxypyridines of a kind of 3- according to claim 1, it is characterized in that 2 M of reaction solution
Sodium hydroxide solution alkalizes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710455341.1A CN107311923A (en) | 2017-06-16 | 2017-06-16 | A kind of synthetic method of the methoxypyridine of 3 iodine 5 |
Applications Claiming Priority (1)
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|---|---|---|---|
| CN201710455341.1A CN107311923A (en) | 2017-06-16 | 2017-06-16 | A kind of synthetic method of the methoxypyridine of 3 iodine 5 |
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| Publication Number | Publication Date |
|---|---|
| CN107311923A true CN107311923A (en) | 2017-11-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710455341.1A Withdrawn CN107311923A (en) | 2017-06-16 | 2017-06-16 | A kind of synthetic method of the methoxypyridine of 3 iodine 5 |
Country Status (1)
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016177845A1 (en) * | 2015-05-06 | 2016-11-10 | Astrazeneca Ab | Cyclopropane carboxylic acid derivatives and pharmaceutical uses thereof |
-
2017
- 2017-06-16 CN CN201710455341.1A patent/CN107311923A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016177845A1 (en) * | 2015-05-06 | 2016-11-10 | Astrazeneca Ab | Cyclopropane carboxylic acid derivatives and pharmaceutical uses thereof |
Non-Patent Citations (4)
| Title |
|---|
| ELENA A. KRASNOKUTSKAYA ET AL.: "A New, One-Step, Effective Protocol for the Iodination of Aromatic and Heterocyclic Compounds via Aprotic Diazotization of Amines", 《SYNTHESIS》 * |
| HIDEYUKI KONISHI ET AL.: "Pd-Catalyzed Selective Synthesis of Cyclic Sulfonamides and Sulfinamides Using K2S2O5 as a Sulfur Dioxide Surrogate", 《ORG. LETT.》 * |
| MAO CHEN ET AL.: "Rapid and Efficient Copper-Catalyzed Finkelstein Reaction of (Hetero)Aromatics under Continuous-Flow Conditions", 《ANGEW. CHEM. INT. ED.》 * |
| TAMOTSU TAKAHASHI ET AL.: "Coupling Reaction of Zirconacyclopentadienes with Dihalonaphthalenes and Dihalopyridines: A New Procedure for the Preparation of Substituted Anthracenes, Quinolines, and Isoquinolines", 《J. AM. CHEM. SOC.》 * |
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Application publication date: 20171103 |
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