CN107286084A - A kind of synthetic method of the pyridine carboxylic acid of 2,5,6 trimethoxy 3 - Google Patents
A kind of synthetic method of the pyridine carboxylic acid of 2,5,6 trimethoxy 3 Download PDFInfo
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- CN107286084A CN107286084A CN201710351572.8A CN201710351572A CN107286084A CN 107286084 A CN107286084 A CN 107286084A CN 201710351572 A CN201710351572 A CN 201710351572A CN 107286084 A CN107286084 A CN 107286084A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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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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- 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
- C07D213/69—Two or more oxygen atoms
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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
- C07D213/803—Processes of preparation
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Abstract
The present invention relates to a kind of synthetic method of the pyridine carboxylic acid of 2,5,6 trimethoxy 3.Mainly solve to have no the technical problem of its efficient synthesis now.Synthetic method of the present invention comprises the following steps：The pyridone hydroxyl of 2 chlorine 3 is converted into methoxyl group；Methoxyl group nucleophilic displacement of fluorine chlorine；The bromination of pyridine ring；Methoxy based selective replaces bromine；N-BuLi removes bromine, and carbon dioxide reaction introduces carboxyl and obtains the pyridine carboxylic acid of 2,5,6 trimethoxy 3.In whole building-up process, intermediate and target product need not move through chromatogram post separation, and raw material is cheap, and purifying is simple.
Description
Technical field
The present invention relates to 2,5,6- trimethoxies-acidum nicotinicum（CAS：1364917-20-3）Synthesis.
Background technology
2,5,6- trimethoxies-acidum nicotinicum is used widely as fine chemical material, medicine intermediate.But
So far on the not disclosed report of its synthetic method.
The content of the invention
It is an object of the invention to provide one kind 2, the synthetic method of 5,6- trimethoxies-acidum nicotinicum is mainly solved existing
Having no the technical problem of its efficient synthesis.
The technical scheme is that：The synthetic method of 2,5,6- of one kind trimethoxies-acidum nicotinicum, it is characterized in that bag
Include following steps：The first step, 2- chloro-3-hydroxyl pyridines add iodine first in DMF and after sodium methoxide reaction
Alkane, obtains compound 1, and product is directly used in next step reaction without purification；Second step, compound 1 and sodium methoxide reaction, are stirred
Mix overnight, obtain compound 2；3rd step, at room temperature, compound 2 are changed in the acetic acid solution of sodium acetate and bromine reaction
Compound 3；4th step, compound 3 and sodium methoxide react in DMF, and 2- bromines are taken by methoxy based selective
In generation, obtain compound 4；5th step, at low temperature compound 4 and n-BuLi reacted in tetrahydrofuran, then add solid
Carbon dioxide, room temperature reaction, is acidified through hydrochloric acid, obtains target compound 5, in ethanol recrystallization purifying.
Synthetic line is as follows：
。
In above-mentioned reaction, sodium methoxide, 2- are added under 2- chloro-3-hydroxyls pyridine, DMF ice bath in step 1
Chloro-3-hydroxyl pyridine is in DMF and the sodium methoxide reaction time is 10-30 minutes, and preferred reaction time is 20
Minute；Step 2 reaction temperature is 50-70 DEG C, and preferable reaction temperature is 60 DEG C；Step 4 reaction temperature is 80-100 DEG C, preferably instead
It is 90 DEG C to answer temperature；Low temperature described in step 5 is -70~-90 DEG C, and preferable reaction temperature is -78 DEG C；Reaction solution 1 N hydrochloric acid acid
Change.
The beneficial effects of the invention are as follows：Agents useful for same is cheap, and reaction condition is simple, and target product and intermediate are without chromatogram
Post is purified；Recrystallization can obtain the target product of high-purity in ethanol.
Specific embodiment
Embodiment 1：
Step 1：
2- chloro-3-hydroxyl pyridines are added into three-necked flask（5.0 g, 39.0 mmol）, DMF（60
mL）；Sodium methoxide is added in ice bath（2.30 g, 43 .0 mmol）.Reaction solution is stirred at room temperature 20 minutes.Add in ice bath
Enter iodomethane（8.20 g, 58.0 mmol）, it is stirred at room temperature 40 minutes.Add water（120 mL）, ethyl acetate extraction（100
mL x 3）;Organic phase merges, and uses water（100 mL x 2）And saturated aqueous common salt（100 mL）Washing, sodium sulphate is dried, mistake
Filter.Filtrate is spin-dried for obtaining yellow liquid, compound 1（5.58 g, 39.0 mmol, 100 %）, it is directly used in next step anti-
Should；
Step 2：
Compound 1 is added into three-necked flask（5.58 g, 39.0 mmol）, DMF（60 mL）And first
Sodium alkoxide（6.20 g, 115.0 mmol）；Reaction solution is stirred overnight at 60 DEG C.Reaction solution is cooled to room temperature, adds water（120
mL）, ethyl acetate extraction（80 mL x 3）;Organic phase merges, and uses water（100 mL x 2）And saturated aqueous common salt（100
mL）Washing, sodium sulphate is dried, filtering.Filtrate is spin-dried for obtaining yellow liquid, compound 2（4.0 g, 28.9 mmol, 74
%）.1H NMR (400 MHz, CDCl3) 3.87 (s, 3 H), 4.05 (s, 3 H), 6.84 (m, 1 H), 7.04
(m, 1 H), 7.71 (m, 1 H) ppm；
Step 3：
Compound 2 is added into three-necked flask（20.0 g, 140.0 mmol）, sodium acetate（35.5 g, 430.0 mmol）With
Acetic acid（250 mL）；Add bromine（19.0 mL, 370.0 mmol）, it is stirred at room temperature 2 hours.Reaction solution pours into trash ice（250
g）, pH is neutralized to the sodium hydroxide solution of mass percentage concentration 25% equal to 9；Ethyl acetate is extracted（200 mL x 3）;It is organic
Mutually merge, with the sodium sulfite solution of mass percentage concentration 10%（150 mL）And saturated aqueous common salt（150 mL）Washing, sodium sulphate
Dry, filtering.Filtrate is spin-dried for obtaining white solid, compound 3（25.7 g, 86.5 mmol, 62 %）.1H NMR (400
MHz, CDCl3) 3.87 (d, J = 0.8 Hz, 3 H), 4.00 (d, J = 1.2 Hz, 3 H), 7.21 (d, J
= 0.8 Hz, 1 H) ppm；
Step 4：
Compound 3 is added into three-necked flask（25.7 g, 86.5 mmol）, DMF（200 mL）And first
Sodium alkoxide（14.0 g, 260.0 mmol）；Reaction solution is stirred 1.5 hours at 90 DEG C.Reaction solution is cooled to room temperature, adds water（400
mL）, petroleum ether extraction（300 mL x 3）;Organic phase merges, and uses water（200 mL x 2）And saturated aqueous common salt（200 mL）
Washing, sodium sulphate is dried, filtering.Filtrate is spin-dried for obtaining white solid, compound 4（17.0 g, 69.0 mmol, 79 %）
。1H NMR (300 MHz, DMSO-d6) 3.73 (m, 3 H), 3.85 (m, 6 H), 7.54 (m, 1 H) ppm,；
Step 5：
Compound 4 is added into three-necked flask（10.0 g, 40.0 mmol）, tetrahydrofuran（150 mL）；In -78 DEG C of dropwise additions
The hexane solution of n-BuLi（2.5 M, 16.0 mL, 40.0 mmol）, and stir 30 minutes
Add dry ice（10 g）, reaction solution is stirred at room temperature 30 minutes.Add water（150 mL）, petroleum ether extraction（50 mL x 3）；Water
PH is mutually acidified to 1 N hydrochloric acid equal to 3, ethyl acetate extraction（120 mL x 3）;Organic phase merges, and uses saturated aqueous common salt
（150 mL）Washing, sodium sulphate is dried, filtering.Filtrate is spin-dried for obtaining crude product, in ethanol（In 50 mL）Recrystallization, obtains white
Solid, target compound 5（3.1 g, 14.6 mmol, 36 %）.1H NMR (300 MHz, CDCl3) 3.90 (s, 3
H), 4.10 (s, 3 H), 4.16 (s, 3 H), 7.80 (s, 1 H), 9.20 (br. 1 H) ppm。
Embodiment 2, step 1：2- chloro-3-hydroxyl pyridines are in N,N-dimethylformamide and the sodium methoxide reaction time is 10
Minute, step 2 reaction temperature is 70 DEG C；Step 4 reaction temperature is 100 DEG C；Step 5 reaction temperature is -70 DEG C, and remaining is with implementation
Example 1.
Embodiment 3, step 1：2- chloro-3-hydroxyl pyridines are in N,N-dimethylformamide and the sodium methoxide reaction time is 30
Minute, step 2 reaction temperature is 50 DEG C；Step 4 reaction temperature is 80 DEG C；Step 5 reaction temperature is -90 DEG C, and remaining is with implementation
Example 1.
Claims (7)
1. a kind of synthetic method of 2,5,6- trimethoxies-acidum nicotinicum, it is characterized in that including lower step：The first step, 2-
Chloro-3-hydroxyl pyridine adds iodomethane in DMF and after sodium methoxide reaction, obtains compound 1, product without
Purification is needed, next step reaction is directly used in；Second step, compound 1 and sodium methoxide reaction, are stirred overnight, obtain compound 2；
3rd step, at room temperature, compound 2 obtain compound 3 in the acetic acid solution of sodium acetate and bromine reaction；4th step, compound
3 and sodium methoxide reacted in DMF, 2- bromines are replaced by methoxy based selective, obtain compound 4；5th
Step, compound 4 and n-BuLi react in tetrahydrofuran at low temperature, then add drikold, react at room temperature, warp
Hydrochloric acid is acidified, and obtains target compound 5, in ethanol recrystallization purifying, synthetic line is as follows：
。
2. according to claim 1 a kind of 2, the synthetic method of 5,6- trimethoxies-acidum nicotinicum, it is characterized in that institute
State and add sodium methoxide under the first step, 2- chloro-3-hydroxyls pyridine, DMF ice bath.
3. according to claim 1 a kind of 2, the synthetic method of 5,6- trimethoxies-acidum nicotinicum, it is characterized in that institute
The first step is stated, 2- chloro-3-hydroxyl pyridines are in DMF and the sodium methoxide reaction time is 10-30 minutes.
4. according to claim 1 a kind of 2, the synthetic method of 5,6- trimethoxies-acidum nicotinicum, it is characterized in that the
Two step reaction temperatures are 50-70 DEG C.
5. according to claim 1 a kind of 2, the synthetic method of 5,6- trimethoxies-acidum nicotinicum, it is characterized in that the
Four-step reaction temperature is 80-100 DEG C.
6. according to claim 1 a kind of 2, the synthetic method of 5,6- trimethoxies-acidum nicotinicum, it is characterized in that the
Low temperature described in five steps is -70~-90 DEG C.
7. according to claim 1 a kind of 2, the synthetic method of 5,6- trimethoxies-acidum nicotinicum, it is characterized in that the
Five step reaction solutions are acidified with 1 N hydrochloric acid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013041458A1 (en) * | 2011-09-22 | 2013-03-28 | Msd Oss B.V. | Fsh receptor antagonists |
| WO2014043252A2 (en) * | 2012-09-11 | 2014-03-20 | Rutgers, The State University Of New Jersey | Therapeutic hydroxypyridinones, hydroxypyrimidinones and hydroxypyridazinones |
| WO2015109109A1 (en) * | 2014-01-15 | 2015-07-23 | Forum Pharmaceuticals Inc. | Fused morpholinopyrimidines and methods of use thereof |
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- 2017-05-18 CN CN201710351572.8A patent/CN107286084A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013041458A1 (en) * | 2011-09-22 | 2013-03-28 | Msd Oss B.V. | Fsh receptor antagonists |
| WO2014043252A2 (en) * | 2012-09-11 | 2014-03-20 | Rutgers, The State University Of New Jersey | Therapeutic hydroxypyridinones, hydroxypyrimidinones and hydroxypyridazinones |
| WO2015109109A1 (en) * | 2014-01-15 | 2015-07-23 | Forum Pharmaceuticals Inc. | Fused morpholinopyrimidines and methods of use thereof |
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