CN109796436B - Method for preparing high-purity (+/-) -trans-4' -carboxycotinine - Google Patents
Method for preparing high-purity (+/-) -trans-4' -carboxycotinine Download PDFInfo
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Abstract
The invention discloses a method for synthesizing high-purity (+/-) -trans-4' -carboxycotinine, which is characterized by reacting an ethanol solution of methylamine with 3-pyridylaldehyde, controlling the temperature to be 25-30 ℃, reacting and curing, and then concentrating a solvent under reduced pressure to obtain an ethylenimine intermediate I; adding the ethylenimine intermediate I into xylene, adding succinic anhydride, and refluxing and ripening; cooling the reaction liquid to room temperature, and then concentrating under reduced pressure to remove xylene; after the concentration is finished, adjusting the pH value of the concentrated solution to 8-9, extracting organic impurities by using dichloromethane, removing an organic phase after layering to obtain a white solid, performing suction filtration, washing with water, leaching with cold ethanol, performing vacuum drying to obtain a target crude product, and performing recrystallization by using ethanol to obtain the high-purity (+/-) -trans-4' -carboxycotinine. The HPLC purity of the high-purity (+/-) -trans-4' -carboxycotinine prepared by the method can reach more than 99 percent, and the total yield is more than 60 percent.
Description
Technical Field
The invention relates to a method for preparing high-purity (+/-) -trans-4' -carboxycotinine, belonging to the technical field of synthesis of research and application of medical intermediates and bioactive molecules.
Background
Pyrrolidone and derivatives thereof are a very important five-membered nitrogen heterocyclic ring molecule and have potential drug and biological activity, so chemists put considerable efforts on the synthesis and research of heterocyclic compounds. The pyrrolidine derivative is a key intermediate for synthesizing quinolone antibacterial drugs, antihypertensive drugs, hypoglycemic drugs and antitumor drugs. The research on the derivatives is more and more focused by synthesizers, and particularly, the catalytic stereoselective synthesis of the multifunctional pyrrolidine derivative becomes a hot spot of research at home and abroad in recent years. The synthesis of five-membered azacyclo molecules is generally to synthesize different nitrogen-containing heterocycles by using eneimine as an active intermediate, and also to synthesize nitrogen-containing heterocycles and derivatives thereof by catalyzing the reaction of air oxidation amination, and has been widely applied in the field of azacyclo in recent years.
The synthesis of (+/-) -trans-4' -carboxycotinine adopts metal catalysis according to related literature reports, but has the defects of difficult separation purity and incapability of obtaining a target product, and is in a technical development stage at present.
Disclosure of Invention
The invention provides a process method for synthesizing high-purity (+/-) -trans-4' -carboxycotinine, which has the advantages of low cost, high yield, simple purification process and convenient operation and is suitable for industrial production.
In order to solve the problems, the invention provides a method for synthesizing high-purity (+/-) -trans-4' -carboxycotinine, which is characterized by comprising the following steps:
step 1): reacting an ethanol solution of methylamine with 3-pyridylaldehyde, controlling the temperature to be 25-30 ℃, reacting and curing, and then concentrating the solvent under reduced pressure to obtain an ethylenimine intermediate I;
step 2): adding the ethylenimine intermediate I obtained in the step 1) into dimethylbenzene, adding succinic anhydride, and refluxing and ripening;
step 3): cooling the reaction liquid obtained in the step 2) to room temperature, and then carrying out reduced pressure concentration to remove xylene; after the concentration is finished, adjusting the pH value of the concentrated solution to 8-9, extracting organic impurities by using dichloromethane, removing an organic phase after layering to obtain a white solid, performing suction filtration, washing with water, leaching with cold ethanol, and performing vacuum drying to obtain a target crude product;
step 4): recrystallizing the crude target product obtained in the step 3) by using ethanol to obtain the high-purity (+/-) -trans-4' -carboxycotinine.
Preferably, the step 1) is specifically: sequentially adding 30-33% by mass of methylamine ethanol solution and 3-pyridylaldehyde into a container, stirring, controlling the internal temperature to be 25-30 ℃, curing for 24 hours, and directly concentrating the reaction solution until no liquid is discharged after the reaction is finished to obtain a transparent oily substance, namely an eneimine intermediate I; wherein the weight ratio of the volume of the methylamine ethanol solution to the 3-pyridylaldehyde is 2-3L/kg.
Preferably, the step 2) is specifically: adding the intermediate I obtained in the step 1) into xylene, adding succinic anhydride, stirring, slowly heating, and curing for 10 hours at the internal temperature of 130-135 ℃; wherein the weight ratio of the volume of the dimethylbenzene to the intermediate I is 3.0-4.0L/kg, and the molar ratio of the intermediate I to the succinic anhydride is 1 (1.0-1.2).
Preferably, the step 3) is specifically: cooling the reaction liquid obtained in the step 2) to room temperature, and then concentrating under reduced pressureRemoving xylene by condensation; after the concentration is finished, NaHCO with the mass concentration of 5 percent is added3Adjusting the pH value of the concentrated solution to 8-9, extracting organic impurities with dichloromethane for three times, layering, discarding the organic phase, and using H for the water phase3PO4Adjusting the pH value to 3-4 to obtain a white solid, performing suction filtration, sequentially washing a filter cake with water and rinsing with cold ethanol for 1 time respectively, and performing vacuum drying to obtain a crude product of the target product.
Preferably, the step 4) is specifically: adding the crude target product obtained in the step 3) into ethanol, heating and refluxing, stirring and dissolving, then slowly cooling to room temperature, standing for 5 hours at the temperature of minus 5-minus 10 ℃, cooling and crystallizing, carrying out suction filtration, leaching cold ethanol once again, and carrying out vacuum drying to obtain the high-purity (+/-) -trans-4' -carboxycotinine; wherein the volume of ethanol used for recrystallization and the weight ratio of the crude product are 8-10L/kg.
The method adopts 3-pyridylaldehyde, 30-33% of methylamine ethanol solution and succinic anhydride which are easily obtained industrially as main raw materials, ethanol, xylene and dichloromethane as low-toxicity organic solvents, and obtains a target product crude product through 2-step synthesis, and the target product crude product is recrystallized and purified to obtain a high-purity product (+/-) -trans-4' -carboxycotinine, wherein the HPLC purity is over 99%, and the total yield is over 60%.
The (+/-) -trans-4' -carboxycotinine synthesized and researched by the invention contains functional group pyrrolidone, belongs to one of pyrrolidone derivatives, and has certain research values of medicines and biological activities. The invention relates to the synthesis of (+/-) -trans-4' -carboxycotinine, namely the synthesis by taking eneimine as an active intermediate, and reports and explains the synthesis research of the compound for the first time.
Compared with the prior art, the invention has the following beneficial effects:
1. the synthetic main raw materials of 3-pyridylaldehyde, 30-33% of methylamine ethanol solution, succinic anhydride and the like adopted by the invention are cheap and easily available and industrial products, the reaction condition is mild, the operation is convenient, the reaction is easy to control, the requirement on reaction equipment is simple, and the whole process is suitable for industrial production;
2. the method synthesizes the (+/-) -trans-4' -carboxycotinine by 2 steps, the reaction temperature and the material adding amount ratio of each step are well controlled, the intermediate I is directly put into the next step for production without purification, the obtained target crude product is recrystallized by ethanol, and a high-purity product is obtained after purification, the HPLC purity reaches more than 99%, and the total yield is more than 60%.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below.
The synthesis method of high-purity (+/-) -trans-4' -carboxycotinine of examples 1 and 2 has the following chemical formula:
example 1
A method for synthesizing high-purity (+/-) -trans-4' -carboxycotinine comprises the following steps:
(1) preparing a 5L glass reaction kettle, sequentially adding 2L of 30-33 wt% methylamine ethanol solution and 3-pyridylaldehyde (1kg, 9.34mol), stirring, controlling the internal temperature to be 25-30 ℃, curing for 24 hours, directly concentrating the reaction solution to obtain 0.95kg of transparent oily substance ethylenimine intermediate I after the reaction is finished, wherein the yield is as follows: 85 percent.
(2) Preparing a 5L glass reaction kettle, sequentially adding 2.7L of dimethylbenzene, an eneimine intermediate I (0.9kg, 7.5mol) and succinic anhydride (0.75kg, 7.5mol), stirring, slowly heating, and curing at an internal temperature of 130-135 ℃ for 10 hours.
(3) After the reaction is finished, cooling the reaction liquid to room temperature, and then carrying out reduced pressure concentration to remove xylene; after the concentration was complete, 4L of 5 wt% NaHCO was added3Adjusting the pH value of the concentrated solution to 8-9, extracting organic impurities with dichloromethane (2L multiplied by 3), extracting for three times, layering, discarding the organic phase, and reusing 500mL of H for the aqueous phase3PO4Adjusting the pH value to 3-4 to obtain a large amount of white solid, performing suction filtration, washing a filter cake with water (1L multiplied by 1), rinsing with cold ethanol (1L multiplied by 1), and performing vacuum drying at 40 ℃ to obtain 1.42kg of a target crude product, wherein the yield is as follows: 86 percent;
(4) preparing a 10L glass reaction kettle, sequentially adding 6.4L of ethanol and a target crude product (0.80kg, 3.63mol), stirring, heating to reflux, filtering while the solution is hot after dissolution, slowly cooling the filtrate to room temperature, standing in a freezer cabinet at the temperature of-5 to-10 ℃ for 5 hours, cooling, crystallizing, filtering, leaching a filter cake with cold ethanol (500mL multiplied by 1), and drying in vacuum at the temperature of 40 ℃ to obtain 0.68kg of high-purity (+/-) -trans-4' -carboxycotinine, wherein the yield is as follows: 85 percent.
The nuclear magnetic resonance processing data and HPLC of the prepared compound are detected as follows:
1H-NMR(CDCl3，400MHz，δppm)：δ＝2.62(3H，s)，2.73～2.89(2H，m)，3.12～3.28(1H，m)，4.91～4.92(1H，m)，7.48～7.50(1H，m)，7.80～7.82(1H，m)，8.53～8.54(2H，m)
HPLC：99.2％
from the above data, the compound obtained above was (±) -trans-4' -carboxycotinine, with a total yield of 62%.
Example 2
A method for synthesizing high-purity (+/-) -trans-4' -carboxycotinine comprises the following steps:
(1) preparing a 5L glass reaction kettle, sequentially adding 3L of 30-33 wt% methylamine ethanol solution and 3-pyridylaldehyde (1kg, 9.34mol), stirring, controlling the internal temperature to be 25-30 ℃, curing for 24 hours, directly concentrating the reaction solution to obtain 0.94kg of transparent oily substance ethylenimine intermediate I after the reaction is finished, wherein the yield is as follows: 84 percent.
(2) Preparing a 5L glass reaction kettle, sequentially adding 3.6L of dimethylbenzene, an eneimine intermediate I (0.9kg, 7.5mol) and succinic anhydride (0.90kg, 9.0mol), stirring, slowly heating, and curing at an internal temperature of 130-135 ℃ for 10 hours.
(3) After the reaction is finished, cooling the reaction liquid to room temperature, and then carrying out reduced pressure concentration to remove xylene; after the concentration was complete, 4L of 5 wt% NaHCO was added3Adjusting the pH value of the concentrated solution to 8-9, extracting organic impurities with dichloromethane (2L multiplied by 3), extracting for three times, layering, discarding the organic phase, and reusing 500mL of H for the aqueous phase3PO4Adjusting the pH value to 3-4 to obtain a large amount of white solid, and performing suction filtrationWashing the filter cake with water (1L multiplied by 1), rinsing with cold ethanol (1L multiplied by 1), and vacuum-drying at 40 ℃ to obtain 1.45kg of a target crude product, wherein the yield is as follows: 88 percent;
(4) preparing a 10L glass reaction kettle, sequentially adding 7.0L of ethanol and a target crude product (0.70kg, 3.18mol), stirring, heating to reflux, filtering while the solution is hot after dissolution, slowly cooling the filtrate to room temperature, standing in a freezer cabinet at the temperature of-5 to-10 ℃ for 5 hours, cooling, crystallizing, filtering, leaching a filter cake with cold ethanol (500mL multiplied by 1), and drying in vacuum at the temperature of 40 ℃ to obtain 0.59kg of high-purity (+/-) -trans-4' -carboxycotinine, wherein the yield is as follows: 84 percent.
The nuclear magnetic resonance processing data and HPLC detection of the prepared compound are as follows:
1H-NMR(CDCl3，400MHz，δppm)：δ＝2.62(3H，s)，2.73～2.89(2H，m)，3.12～3.28(1H，m)，4.90～4.92(1H，m)，7.48～7.51(1H，m)，7.79～7.82(1H，m)，8.52～8.54(2H，m)
HPLC：99.1％
from the above data, the compound obtained above was (±) -trans-4' -carboxycotinine, with a total yield of 62%.
Claims (1)
1. A method for synthesizing high-purity (+/-) -trans-4' -carboxycotinine is characterized by comprising the following steps:
(1) preparing a glass reaction kettle, sequentially adding 2L of 30-33 wt% methylamine ethanol solution and 1kg of 3-pyridylaldehyde, stirring, controlling the internal temperature to be 25-30 ℃ and ripening for 24 hours, directly concentrating the reaction solution to an undistilled solution after the reaction is finished, and obtaining 0.95kg of a transparent oily substance, namely an eneimine intermediate I, wherein the yield is as follows: 85 percent;
(2) preparing a glass reaction kettle, sequentially adding 2.7L of dimethylbenzene, 0.9kg of an ene imine intermediate I and 0.75kg of succinic anhydride, stirring, heating, and controlling the internal temperature at 130-135 ℃ for ripening for 10 hours;
(3) after the reaction is finished, cooling the reaction liquid to room temperature, and then carrying out reduced pressure concentration to remove xylene; after the concentration was complete, 4L of 5 wt% NaHCO was added3Adjusting the pH value of the concentrated solution to 8-9, and extracting with 2L dichloromethane multiplied by 3Extracting organic impurities for three times, layering, discarding organic phase, and reusing aqueous phase with 500mL H3PO4Adjusting the pH value to 3-4 to obtain a large amount of white solid, performing suction filtration, sequentially washing a filter cake with 1L of water, rinsing with 1L of cold ethanol, and performing vacuum drying at 40 ℃ to obtain 1.42kg of a target crude product, wherein the yield is as follows: 86 percent;
(4) preparing a glass reaction kettle, sequentially adding 6.4L of ethanol and 0.80kg of crude target product, stirring, heating to reflux, filtering while hot after dissolution, cooling the filtrate to room temperature, standing in a freezer cabinet at the temperature of-5 to-10 ℃ for 5h, cooling, crystallizing, filtering, leaching a filter cake with 500mL of cold ethanol, and drying in vacuum at 40 ℃ to obtain 0.68kg of high-purity (+/-) -trans-4' -carboxycotinine, wherein the yield is as follows: 85 percent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2477268A1 (en) * | 2002-03-01 | 2003-10-09 | The Board Of Regents Of The University Of Nebraska | Compositions and compounds for use as molecular adjuvant for a nicotine vaccine |
| WO2012061717A1 (en) * | 2010-11-05 | 2012-05-10 | Selecta Biosciences, Inc. | Modified nicotinic compounds and related methods |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2477268A1 (en) * | 2002-03-01 | 2003-10-09 | The Board Of Regents Of The University Of Nebraska | Compositions and compounds for use as molecular adjuvant for a nicotine vaccine |
| WO2012061717A1 (en) * | 2010-11-05 | 2012-05-10 | Selecta Biosciences, Inc. | Modified nicotinic compounds and related methods |
Non-Patent Citations (1)
| Title |
|---|
| Sirimanne, Sarath R.;Maggio, Vincent L.;Patterson, Donald G.,.《Synthesis of (±)-[1,1"-15N2, 2"-13C]-trans-3"-methylnicotine》.《Journal of Labelled Compounds and Radiopharmaceuticals》.1992,第31卷(第3期),163-174. * |
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Application publication date: 20190524 Assignee: ALADDIN REAGENT (SHANGHAI) Co.,Ltd. Assignor: SHANGHAI ALADDIN BIOCHEMICAL TECHNOLOGY Co.,Ltd. Contract record no.: X2021980007922 Denomination of invention: Method for preparing high purity (+-) - trans-4 '- carboxycotinine Granted publication date: 20210713 License type: Common License Record date: 20210818 |