CN113582920B - Synthetic method of 4- (4-pyridyl) morpholine - Google Patents
Synthetic method of 4- (4-pyridyl) morpholine Download PDFInfo
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- CN113582920B CN113582920B CN202110884397.5A CN202110884397A CN113582920B CN 113582920 B CN113582920 B CN 113582920B CN 202110884397 A CN202110884397 A CN 202110884397A CN 113582920 B CN113582920 B CN 113582920B
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- 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
Abstract
The invention discloses a method for synthesizing 4- (4-pyridyl) morpholine, which comprises the following steps: at the temperature of 20-25 ℃, morpholine, 4-chloropyridine hydrochloride and sodium iodide are sequentially added into an organic solvent, the temperature is slowly raised after the addition, and the internal temperature is controlled to be 120-130 ℃ and stirred until the mixture is mature; cooling the obtained reaction liquid to room temperature, adding the reaction liquid into a sodium hydroxide solution, stirring, extracting with ethyl acetate, washing, drying and concentrating to obtain a crude product; adding the obtained crude product into a mixed solvent of acetone and isopropyl ether, heating and refluxing, adding activated carbon, filtering, cooling the filtrate at 10-15 ℃, carrying out suction filtration, and carrying out vacuum drying on the obtained filter cake to obtain the white crystal 4- (4-pyridyl) morpholine. The GC purity of the 4- (4-pyridyl) morpholine prepared by the invention can reach more than 99.9 percent, and the total yield is more than 80 percent.
Description
Technical Field
The invention relates to a process method for synthesizing 4- (4-pyridyl) morpholine, belonging to the technical field of synthesis of development and application of organic medical intermediate process methods.
Background
Piperidine, pyrrole, pyridine and morpholine derivatives are important nitrogen-containing hybrid compounds, which are frequently found in a large number of natural products, active alkaloids, medicaments and agricultural preparations as parent nucleus structures, and in addition, nitrogen-containing heterocyclic compounds are also frequently used as important research objects of synthetic intermediates of bioactive compounds. Based on such important applications of such nitrogen-containing hybrid compounds, the development of methods for preparing piperidine, pyrrole, pyridine and morpholine derivatives is becoming a hot issue in the field of organic synthesis. 4- (4-pyridyl) morpholine is an important fine organic chemical product and a medical organic synthesis intermediate, has wide application, is mainly used for synthesizing important starting materials of pyridine and morpholine derivatives, and can also be applied to the synthesis of new medicines in the medical industry and the development and research of pesticides, new rubber materials and the like. With the continuous development of economy and scientific technology, the market demand of 4- (4-pyridyl) morpholine is increasing year by year. Therefore, it is necessary to develop a process for synthesizing 4- (4-pyridyl) morpholine, which has the advantages of good economic practicability, low cost, high conversion rate and suitability for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a process method for synthesizing 4- (4-pyridyl) morpholine, which has the advantages of low cost, environmental protection, good reaction controllability, high conversion rate and simple equipment and process and is suitable for industrial production.
In order to solve the above problems, the present invention provides a method for synthesizing 4- (4-pyridyl) morpholine, comprising the following steps:
step 1): under the condition of 20-25 ℃, morpholine, 4-chloropyridine hydrochloride and sodium iodide are sequentially added into an organic solvent, the temperature is slowly raised after the morpholine, the 4-chloropyridine hydrochloride and the sodium iodide are added, and the internal temperature is controlled to be 120-130 ℃ to be stirred until the materials are mature;
step 2): cooling the reaction liquid obtained in the step 1) to room temperature, adding the reaction liquid into a sodium hydroxide solution, stirring, extracting with ethyl acetate, washing, drying and concentrating to obtain a crude product;
step 3): adding the crude product obtained in the step 2) into a mixed solvent of acetone and isopropyl ether, heating and refluxing, adding activated carbon, filtering, cooling the filtrate at 10-15 ℃, carrying out suction filtration, and carrying out vacuum drying on the obtained filter cake to obtain the white 4- (4-pyridyl) morpholine crystal.
Preferably, the step 1) is specifically: adding DMF into a container, respectively adding morpholine, 4-chloropyridine hydrochloride and sodium iodide under stirring at the temperature of 20-25 ℃, slowly heating to 120-130 ℃ after the addition, refluxing and stirring for 12 hours, and ripening; the ratio of DMF to 4-chloropyridine hydrochloride is 5-6L/kg, the molar ratio of morpholine to 4-chloropyridine hydrochloride is (1.5-2): 1, the molar ratio of sodium iodide to 4-chloropyridine hydrochloride is 0.1:1. in the process of process optimization, conventional organic solvents such as toluene, tetrahydrofuran, acetonitrile, dichloromethane, ethyl acetate and the like can be used for reaction, the effect is poor, the reaction conversion rate is less than 30%, the product is difficult to purify due to more impurities, but the advantages of high conversion rate, less side reactions, simple post-treatment and the like can be achieved by using DMF with high boiling point as the reaction solvent and sodium iodide as the reaction catalyst.
Preferably, the step 2) is specifically: cooling the reaction liquid after aging in the step 1) to 20-25 ℃, adding the reaction liquid into a sodium hydroxide solution with the mass concentration of 10%, stirring while adding, adding ethyl acetate for multiple times of extraction, combining organic phases, and carrying out saturated sodium chloride washing, magnesium sulfate drying, suction filtration, concentration and vacuum drying treatment on the organic phases in turn to obtain a light yellow solid, namely a target crude product.
Preferably, the step 3) is specifically: adding the crude product obtained in the step 2) into a mixed solvent of acetone and isopropyl ether, heating to 55 ℃, refluxing, adding activated carbon, filtering at 50 ℃ while the mixture is hot, cooling the filtrate to 10-15 ℃, standing for 3h, separating out a large amount of white crystals, performing suction filtration, and performing vacuum drying on the obtained filter cake at 50 ℃ to obtain the white crystal target 4- (4-pyridyl) morpholine.
Through detection, the GC purity of the 4- (4-pyridyl) morpholine content can reach 99.9 percent, and the total yield is more than 80 percent. In the process of purifying the compound, single solvents such as acetone, ethyl acetate, acetonitrile, methanol, tetrahydrofuran, ethers and the like and other mixed solvents are tried, and the purity of the final product cannot reach more than 90%.
More preferably, the volume ratio of acetone to isopropyl ether is 1.
More preferably, the ratio of the mixed solvent of acetone and isopropyl ether to the crude product is 10L/kg.
The invention adopts morpholine and 4-chloropyridine hydrochloride which are cheap and easy to obtain industrially as main raw materials, sodium iodide, DMF, ethyl acetate, acetone, isopropyl ether and other common auxiliary materials, synthesizes a target product crude product by controlling a proper proportion, and performs recrystallization purification by using a mixed solvent to obtain a high-purity product 4- (4-pyridyl) morpholine, wherein the GC purity reaches 99.9%, and the total yield is more than 80%. The method has the advantages of low cost of synthetic raw materials, simple process, environmental friendliness, good reaction controllability, high reaction conversion rate and the like, and is suitable for industrial production.
Compared with the prior art, the invention has the following beneficial effects:
1. the raw materials of morpholine, 4-chloropyridine hydrochloride, sodium iodide, DMF, ethyl acetate, acetone, isopropyl ether and the like which are needed for synthesis are all cheap and easily available and industrialized products, and the synthesis process has mild reaction conditions and convenient operation; the reaction is easy to control, the side reaction is less, and the reaction conversion rate is high; the target product is simple to purify, and the whole process is suitable for industrial production.
2. According to the method, DMF with a high boiling point is used as a reaction solvent, cheap sodium iodide is used as a reaction catalyst, an expensive metal palladium catalyst is not needed, side reactions are reduced by controlling the reaction temperature and the dosage ratio of morpholine and 4-chloropyridine hydrochloride, the conversion rate is improved, and a crude product of 4- (4-pyridyl) morpholine is obtained; purification of the final product, using acetone: and (3) recrystallizing the isopropyl ether (volume ratio is 1.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below.
Examples 1 and 2 provide a process for the synthesis of 4- (4-pyridyl) morpholine. The chemical equation of the synthesis process is as follows:
a process for synthesizing 4- (4-pyridyl) morpholine comprises the following steps:
(1) Preparing a 10L glass reaction kettle, firstly adding 5.0L DMF at the temperature of between 20 and 25 ℃, stirring, and then respectively adding 4-chloropyridine hydrochloride (1.0kg, 6.66mol), morpholine (0.87kg, 10.0mol) and sodium iodide (0.1kg, 0.67mol); after the addition, slowly heating, raising the temperature to 120-130 ℃, and refluxing and stirring for 12 hours to ripen;
(2) After the maturation was completed, the reaction solution was cooled to 20 to 25 ℃ and added to 9L 10wt% NaOH solution, followed by extraction with ethyl acetate (5L × 4), organic phases were combined, washed with saturated sodium chloride (6L × 1), dried over magnesium sulfate (200 g), filtered, and concentrated to dryness in vacuo at 40 ℃ to give 940g of a crude pale yellow target, with a yield of 86%.
(3) Preparing a 10L glass reaction kettle, firstly adding 9.4L of mixed solvent (1.88L of acetone and 7.52L of isopropyl ether), then slowly dripping 940g of target crude product while stirring, and starting heating to raise the temperature after finishing adding; when the internal temperature rises to 50-55 ℃, after the solid is completely dissolved and clarified, adding 50g of activated carbon, continuously refluxing for 1h, slightly cooling to 50 ℃, and filtering while the solution is hot; slowly cooling the filtrate to 10-15 ℃, standing for 3h, separating out a large amount of white crystals, carrying out suction filtration, and carrying out vacuum drying on the filter cake at 50 ℃ for 12h to obtain 900g of a dry product, wherein the yield is 95.7%.
The nuclear magnetic resonance processing data, GC and MP of the prepared compound are detected as follows:
1H-NMR(CDCl 3 ，400MHz，δppm)：δ＝8.28～8.29(2H，dd)，6.63～6.64(2H，dd)，3.80～3.82(4H，m)，3.25～3.26(4H，m)ppm
GC：99.9％
MP：106～107℃
from the above data, it can be seen that the compound obtained above is 4- (4-pyridyl) morpholine, with a total yield of 82%.
Example 2
A process for synthesizing 4- (4-pyridyl) morpholine comprises the following steps:
(1) Preparing a 10L glass reaction kettle, firstly adding 5.0L DMF at the temperature of between 20 and 25 ℃, stirring, and then respectively adding 4-chloropyridine hydrochloride (1.0kg, 6.66mol), morpholine (1.16kg, 13.3mol) and sodium iodide (0.1kg, 0.67mol); after the addition, slowly heating, raising the temperature to 120-130 ℃, and refluxing and stirring for 12 hours to ripen;
(2) After completion of the aging, the reaction solution was cooled to 20 to 25 ℃ and added to 9L 10wt% NaOH solution, followed by extraction with ethyl acetate (5L. Times.4), the organic phases were combined, washed with saturated sodium chloride (6L. Times.1), dried over magnesium sulfate (200 g), filtered, and concentrated to dryness in vacuo at 40 ℃ to give 950g of a pale yellow target crude product, with a yield of 87%.
(3) Preparing a 10L glass reaction kettle, firstly adding 9.5L of mixed solvent (1.9L of acetone and 7.6L of isopropyl ether), then slowly dripping 950g of crude target product while stirring, and starting heating to raise the temperature after the addition is finished; when the internal temperature rises to 50-55 ℃, after the solid is completely dissolved and clarified, adding 50g of activated carbon, continuously refluxing for 1h, slightly cooling to 50 ℃, and filtering while the solution is hot; slowly cooling the filtrate to 10-15 ℃, standing for 3h, separating out a large amount of white crystals, carrying out suction filtration, and carrying out vacuum drying on the filter cake at 50 ℃ for 12h to obtain 905g of a dry product, wherein the yield is 95.3%.
The nuclear magnetic resonance processing data, GC and MP of the prepared compound are detected as follows:
1H-NMR(CDCl 3 ，400MHz，δppm)：δ＝8.28～8.30(2H，dd)，6.64～6.65(2H，dd)，3.81～3.82(4H，m)，3.26～3.28(4H，m)ppm
GC：99.9％
MP：106～107℃
from the above data, it is clear that the compound obtained above is 4- (4-pyridyl) morpholine, and the total yield is 82.5%.
Claims (5)
1. A method for synthesizing 4- (4-pyridyl) morpholine is characterized by comprising the following steps:
step 1): adding DMF into a container, respectively adding morpholine, 4-chloropyridine hydrochloride and sodium iodide under stirring at the temperature of 20-25 ℃, slowly heating to 120-130 ℃ after the addition, refluxing and stirring for 12 hours, and ripening; the ratio of DMF to 4-chloropyridine hydrochloride is 5-6L/kg, the molar ratio of morpholine to 4-chloropyridine hydrochloride is (1.5-2): 1, the molar ratio of sodium iodide to 4-chloropyridine hydrochloride is 0.1:1;
step 2): cooling the reaction liquid obtained in the step 1) to room temperature, adding the reaction liquid into a sodium hydroxide solution, stirring, extracting with ethyl acetate, washing, drying and concentrating to obtain a crude product;
and step 3): adding the crude product obtained in the step 2) into a mixed solvent of acetone and isopropyl ether, heating and refluxing, adding activated carbon, filtering, cooling the filtrate at 10-15 ℃, carrying out suction filtration, and carrying out vacuum drying on the obtained filter cake to obtain the white 4- (4-pyridyl) morpholine crystal.
2. The method for synthesizing 4- (4-pyridyl) morpholine according to claim 1, wherein the step 2) is specifically: cooling the reaction liquid after aging in the step 1) to 20-25 ℃, adding the reaction liquid into a sodium hydroxide solution with the mass concentration of 10%, stirring while adding, adding ethyl acetate for multiple times of extraction, combining organic phases, and carrying out saturated sodium chloride washing, magnesium sulfate drying, suction filtration, concentration and vacuum drying treatment on the organic phases in turn to obtain a light yellow solid, namely a target crude product.
3. The method for synthesizing 4- (4-pyridyl) morpholine according to claim 1, wherein the step 3) is specifically: adding the crude product obtained in the step 2) into a mixed solvent of acetone and isopropyl ether, heating to 55 ℃, refluxing, adding activated carbon, filtering at 50 ℃ when the mixture is hot, cooling the filtrate to 10-15 ℃, standing for 3h to separate out a large amount of white crystals, performing suction filtration, and performing vacuum drying on the obtained filter cake at 50 ℃ to obtain the target product 4- (4-pyridyl) morpholine as white crystals.
4. The method of claim 3, wherein the acetone to isopropyl ether volume ratio is 1.
5. The method for synthesizing 4- (4-pyridyl) morpholine according to claim 3 or 4, wherein the ratio of the mixed solvent of acetone and isopropyl ether to the crude product is 10L/kg.
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