CN110407744A - A kind of synthetic method of 1- (4-aminopyridine -2- base) ethyl ketone - Google Patents
A kind of synthetic method of 1- (4-aminopyridine -2- base) ethyl ketone Download PDFInfo
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- CN110407744A CN110407744A CN201910742030.2A CN201910742030A CN110407744A CN 110407744 A CN110407744 A CN 110407744A CN 201910742030 A CN201910742030 A CN 201910742030A CN 110407744 A CN110407744 A CN 110407744A
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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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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Abstract
The invention discloses a kind of synthetic methods of 1- (4-aminopyridine -2- base) ethyl ketone; using the chloro- 4- nitropyridine of 2- as raw material; tributyl (1- ethoxy ethylene) tin is coupled acetyl group, restores nitroso reaction, comprising: by the chloro- 4- nitropyridine of 2-, tributyl (1- ethoxy ethylene) tin and Pd (PPh3)2Cl2It is added in solvent a, in 75~100 DEG C of reaction 3h under argon gas or nitrogen protection, is down to room temperature and pours ice water, EA extraction; it is spin-dried for, dilute hydrochloric acid solution is added, EA is extracted after being stirred overnight at room temperature; purifying, gained compound is added in solvent b, while Pd/C catalyst is added, is passed through H2Reduction, is spin-dried for PE and is beaten to obtain.Synthetic method raw material of the invention is easy to get, reaction condition is mild, and yield is higher, and post-processing and purifying are all easy to operate, can amplify production.
Description
Technical field
The invention belongs to medicine intermediate organic synthesis fields, and in particular to a kind of 1- (4-aminopyridine -2- base) ethyl ketone
Synthetic method.
Background technique
Currently, pyridine compounds and their has been studied for preventing and treating atherosclerosis, it is disease-resistant used also as preparing
The substrate of cytotoxic drug, wherein the synthetic method of 1- (4-aminopyridine -2- base) ethyl ketone is it has been reported that synthetic route such as following formula (1)
It is shown:
Under amido protecting, acetyl group is converted by cyano with methyl grignard reagent, due to using grignard reagent, produces work
And reaction temperature control dry to reaction condition such as solvent water, equipment requires harsh in skill, and reaction yield is low, post-processes work
Skill is cumbersome, and economic benefit and environment influence are bad.
Summary of the invention
For the drawbacks described above for overcoming the prior art, the purpose of the present invention is to provide the 1- of a kind of high income, mild condition
The synthetic method of (4-aminopyridine -2- base) ethyl ketone.
Above-mentioned purpose of the invention is achieved through the following technical solutions:
The synthetic method of 1- (4-aminopyridine -2- base) ethyl ketone, the synthetic route are as follows:
Using if the chloro- 4- nitropyridine of 2- shown in formula (I) is raw material, tributyl (1- ethoxy ethylene) tin is through being coupled acetyl
Base restores nitroso reaction and obtains, comprising steps of
I) by the chloro- 4- nitropyridine of 2-, tributyl (1- ethoxy ethylene) tin and Pd (PPh3)2Cl2It is 1 according to molar ratio:
1~1.5:0.01~0.2 is added in solvent a, in 75~100 DEG C of reaction 3h under the conditions of argon gas or nitrogen protection, is down to room
Temperature pours ice water, and EA extraction is spin-dried for, and the dilute hydrochloric acid solution that concentration is 1~4M is added, and EA is extracted after being stirred overnight at room temperature, purifying
It obtains compound (II)；
II) gained compound (II) is added in solvent b, Pd/C catalyst is added, while being passed through H2Reduction, is spin-dried for PE
Mashing, obtains 1- (4-aminopyridine -2- base) ethyl ketone.
Further, the solvent a is dimethylformamide (DMF) or N-Methyl pyrrolidone (NMP), preferably DMF.
Further, step I) described in reaction temperature be 85 DEG C.
Further, step I) solvent of EA extraction is selected from ethyl acetate (EA), methylene chloride (DCM), ether
(Et2) or one of methyl tertiary butyl ether(MTBE) (MTBE) O.
Further, step I) in, the chloro- 4- nitropyridine of the 2-, tributyl (1- ethoxy ethylene) tin and Pd (PPh3)2Cl2Molar ratio be 1:1.15:0.03.
Further, the solvent b is selected from one of methanol, ethyl alcohol, isopropanol or propyl alcohol.
Further, the H2Pressure is 1~5 standard atmospheric pressure.
Further, the amount containing palladium of the Pd/C catalyst is 5%~10%, and additional amount accounts for the chloro- 4- nitropyridine of the 2-
It is added the 8% of quality.
The present invention is using tributyl (1- ethoxy ethylene) tin in Pd (PPh3)2Cl2Under catalytic condition, by halogen coupling at
Ethoxy ethylene, then acetyl group is converted under the conditions of dilute hydrochloric acid.The reaction condition is mild, to reagent and reaction condition requirement
It is lower, and reaction yield is very high, it can reach 99% yield, then with Pd/C and H2Catalyst reduction nitro yield 89%, it is comprehensive to receive
Rate reduces risk up to 90% or more.
Compared with prior art, beneficial effects of the present invention are as follows:
(1) present invention is two-step reaction, and comprehensive yield is not less than 90%, reduces risk while improving yield.
(2) the raw materials used in the present invention and reagent are easy to get, and reaction condition is mild, post-process and purify easily operated, can put
Mass production.
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of target product 1- (4-aminopyridine -2- base) ethyl ketone.
Specific embodiment
Illustrate technical solution of the present invention below by way of specific embodiment, but the scope of the present invention is not limited thereto.
Embodiment 1
1. by the chloro- 4- nitropyridine of 25g (1eq) 2-, 65g (1.15eq) tributyl (1- ethoxy ethylene) tin and 3g
(0.03eq)Pd(PPh3)2Cl2It is added in 300mlDMF, argon gas protection, 85 DEG C of reaction 3h, is down to room temperature and pours into 1L ice water, EA extraction
It takes, is spin-dried for, 300ml 2M aqueous hydrochloric acid solution is added, whole system is stirred overnight at room temperature, EA extraction, mixes sample and crosses column purification and obtains chemical combination
II 26g of object, yield 99%.
2. 26g compound ii is added in 200ml methanol, 2gPd/C is added, leads to hydrogen reaction overnight；TLC has reacted
Entirely, it is spin-dried for being beaten with PE and filter, obtain 19g target product 1- (4-aminopyridine -2- base) ethyl ketone, yield 89.5%, nuclear-magnetism hydrogen
Spectrum is as shown in Figure 1.
Embodiment 2
1. by the chloro- 4- nitropyridine of 5g (1eq) 2-, 12.5g (1.1eq) tributyl (1- ethoxy ethylene) tin and 0.7g
(0.03eq)Pd(PPh3)2Cl2It being added in 50ml NMP, argon gas protection, 90 DEG C of reaction 3h are down to room temperature and pour into 200ml ice water,
EA extraction, is spin-dried for, and 50ml 2M aqueous hydrochloric acid solution is added, is stirred overnight at room temperature, and EA extraction mixes sample and crosses column, obtain compound 23g, receives
Rate 58%.
2. 3g compound 2 is added in 30ml methanol, 0.3gPd/C is added, leads to hydrogen reaction overnight, TLC, fully reacting,
It is spin-dried for, PE mashing obtains 2.1g 1- (4-aminopyridine -2- base) ethyl ketone, yield 85%.
Comparative example 1
1. by the chloro- 4- nitropyridine of 10g (1eq) 2-, 27.3g (1.2eq) tributyl (1- ethoxy ethylene) tin and 1.5g
(0.02eq)Pd(PPh3)4It is added in 100ml DMF, argon gas protection, 85 DEG C of reaction 3h；It is down to room temperature and pours into 400ml ice water, EA
Extraction, is spin-dried for, and 100ml 2M aqueous hydrochloric acid solution is added, is stirred overnight at room temperature, EA extraction, mixes sample and crosses column purification and obtains compound 27g,
Yield 67%.
2. 7g compound 2 is added in 70ml ethyl alcohol, 0.7gPd/C is added, leads to hydrogen reaction overnight, TLC, fully reacting,
It is spin-dried for, PE mashing obtains 4g 1- (4-aminopyridine -2- base) ethyl ketone, yield 70%.
The above is only a preferred embodiment of the present invention, and the present invention is not limited in the content of embodiment.For in this field
Technical staff for, can have various change and change, made any change in the conception range of technical solution of the present invention
Change and change, within that scope of the present invention.
Claims (9)
- The synthetic method of 1.1- (4-aminopyridine -2- base) ethyl ketone, which is characterized in that the synthetic route is as follows:Using if the chloro- 4- nitropyridine of 2- shown in formula (I) is raw material, tributyl (1- ethoxy ethylene) tin through coupling acetyl group, Nitroso reaction is restored to obtain, comprising steps ofI) by the chloro- 4- nitropyridine of 2-, tributyl (1- ethoxy ethylene) tin and Pd (PPh3)2Cl2According to molar ratio be 1:1~ 1.5:0.01~0.2 is added in solvent a, and 75~100 DEG C are reacted 3h under argon gas or nitrogen protection, is down to room temperature and is poured ice Water, EA extraction, is spin-dried for, and the dilute hydrochloric acid solution that concentration is 1~4M is added, and EA is extracted after being stirred overnight at room temperature, and purifies to obtain compound (Ⅱ)；II) gained compound (II) is added in solvent b, while Pd/C catalyst is added, it is passed through H2Reduction is spin-dried for PE mashing, Obtain 1- (4-aminopyridine -2- base) ethyl ketone.
- 2. synthetic method as described in claim 1, which is characterized in that the solvent a is dimethylformamide (DMF) or N- first Base pyrrolidones (NMP).
- 3. synthetic method as described in claim 1, which is characterized in that step I) in, the reaction temperature is 85 DEG C.
- 4. synthetic method as described in claim 1, which is characterized in that step I) in, the solvent of the EA extraction is selected from acetic acid Ethyl ester (EA), methylene chloride (DCM), ether (Et2) or one of methyl tertiary butyl ether(MTBE) (MTBE) O.
- 5. synthetic method as described in claim 1, which is characterized in that step I) in, the chloro- 4- nitropyridine of the 2-, three fourths Base (1- ethoxy ethylene) tin and Pd (PPh3)2Cl2Molar ratio be 1:1.15:0.03.
- 6. synthetic method as described in claim 1, which is characterized in that the solvent b is selected from methanol, ethyl alcohol, isopropanol or third One of alcohol.
- 7. synthetic method as described in claim 1, which is characterized in that the H2Pressure is 1~5 standard atmospheric pressure.
- 8. synthetic method as described in claim 1, which is characterized in that the amount containing palladium of the Pd/C catalyst is 5%~10%, And additional amount accounts for the chloro- 4- nitropyridine of the 2- and is added the 6%~10% of quality.
- 9. synthetic method as described in claim 1, which is characterized in that the way of purification is to mix sample to cross column or recrystallization.
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Cited By (1)
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