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Lets talk a little bit about morpholine derivatives

2022-10-28 08:55:45

Morpholine and its derivatives are very important compounds, widely used in pesticide, medicine and chemical industry. N-methylmorpholine, n-methylmorpholine oxide and N-(2-amine ethyl) morpholine are several important derivatives of morpholine. N-methylmorpholine manufacturers will briefly discuss the synthesis of the above-mentioned morpholine derivatives and moclobemide.

N-Methylmorpholine (N-methylmorpholine) is an organic intermediate, colorless transparent liquid, with ammonia odor, boiling point 115℃ ~ 117℃, can be miscible with water, ethanol. N-methylmorpholine oxide (MMNO) is a heterocyclic tertiary amine oxide, the molecular formula C5H11NO2, melting point 184.2℃, easily soluble in water, and 1 ~ 4 molecules of water to form crystalline hydrate, the melting point of monohydrate 76.5℃, the melting point of dihemihydrate 40.5℃. Can form a strong hydrogen bond, and can form a strong solvent layer with cellulose, make it into the solvent, generate a viscous cellulose solution, so used in spinning, manufacturing rayon cotton, cellophane, food casings, etc.


N-(2- amine - ethyl) morpholine is an important intermediate of clobemide. Moclobemide is a new generation of monoamine oxidase inhibitors. The synthesis of N-methylmorpholine and N-methylmorpholine oxide was tested by injecting 130g of morpholine (1.50mol) into a 500ml4-mouth bottle. The formaldehyde solution of 146g40%(mass fraction) (1.95mol) and formic acid solution of 92g90%(mass fraction) (1.80mol) were mixed, stirred at 30℃, and then dropped into the formaldehyde-formic acid mixture for about 1h. After dripping, the temperature was raised to 70℃ ~ 80℃, and the reaction was continued for 2h. Quickly add solid NaOH to the reaction solution for stratification. Organic phase was separated for distillation, and 141g of 114℃ ~ 117℃ fraction was collected, which was N-methylmorpholine. The purity of the product was over 99% and the yield was up to 92.4%. The prepared N-methylmorpholine 102g(1.0mol) was put into a 500ml4-mouth bottle. Stir fully at 20℃, slowly drop 30%(mass fraction) of H2O2120g(1.05mol), drop for about 1h, control the temperature at 70℃±2℃, continue to react for 6h. After the reaction, the residual H2O2 was removed by mild heat, and then benzene was added for azeotropic dehydration. Some crystals were precipitated, filtered, recrystallized with acetone, and 89g of light yellow N-methylmorpholine hydrate crystal was obtained. The product yield was about 76%. The synthesis of 1.2N-(2-aminoethyl) morph was put into a 500ml4-mouth bottle with 100g diethylene glycol (0.94mol), stirred fully at room temperature, and slowly added 250gSOCl2(2.10mol). After the drip was finished, continued stirring for 3h, heating up, reflux for 3h. Cool, pour the reactants into cold water, stand and stratify, separate. The organic phase was washed to neutral with saturated sodium carbonate aqueous solution and dried with anhydrous calcium chloride. After treatment, the organic phase was distilled under vacuum pressure. At 5062Pa, 121.5g of distillate with boiling point of 122℃ ~ 124℃ was collected, which was 2,2 '-dichlorodiethyl ether. The yield was 89% and the purity was 99%. Put 36.0g ethylenediamine (0.6mol) into a 250ml4-mouth bottle, stir thoroughly, add 28.6g of 2,2 '-dichlorodiethyl ether (0.2mol), control the temperature below 70℃, drop for about 1h, hold at 60℃ for 2h, cool to 50℃, add 17g of solid sodium hydroxide, cool, and filter. The filtrate was distilled under vacuum pressure. At 8666Pa, 16.9g of the distillate with boiling point of 118℃ ~ 130℃ was collected, which was N-(2-amino-ethyl) morpholine. The yield was 59.3%.

13.0gN-(2-aminoethyl) morpholine (0.1mol) was dissolved in 150g toluene, the control temperature was 0℃ ~ 5℃, stirred fully, and 17.5g p-chlorobenzoyl chloride (0.1mol) was added. After dripping, the powder was kept for 1h at 30℃ ~ 40℃, and the sedimentation was removed at room temperature, and the concentration was reduced to obtain white crystalline powder At the end of 10g, the yield was 37.5%.

Synthesis of N-methylmorpholine and N-methylmorpholine NHO+HCHO+HCOOHNOCH3+CO2+H2O, synthesis route of N-methylmorpholine For the synthesis of N-methylmorpholine, considering the economic reasons, should make full use of morpholine, generally make formaldehyde and formic acid excessive. After analyzing the reaction data of each group, increasing the amount of formaldehyde has a certain effect on improving the yield, while increasing the amount of formic acid has no obvious effect. This reaction is exothermic reaction, reaction temperature is too high, there are side reactions, affect the yield. As for the reaction time, experimental data showed that the yield of N-methylmorpholine could reach more than 90% after 2h reaction, and the product yield was limited after 2h (molar ratio of morpholine, formic acid and formaldehyde was 1.0∶1.2∶1.3; Reaction temperature 75℃).

Reaction time influencing on the yield of N - methyl morpholine h reaction time yield % 170.8291.3391.3491.4591.5692.4 NOCH3 + H2O2NOOCH3 figure 2 N - methyl morpholine oxide synthetic route of the synthesis of N - methyl morpholine oxide reaction is a new ecological oxygen is produced by H2O2 decomposition double freedom The group attacks the lone pair electron on N in the n-methylmorpholine molecule. The influence of the pH value of the reaction system and the concentration of N-methylmorpholine on this reaction was discussed in Table 2(temperature 70℃, reaction time 6h) and Table 3(pH 8, reaction temperature 70℃, reaction time 6h).

The pH of the test was adjusted by a combination of 35%(mass fraction)HCl and 40%(mass fraction)NaOH solution. It can be concluded from the test data that pH value has a great influence on the reaction. Under acidic or strong alkaline conditions (pH value 4, 6, 12, 14), the product content is very low. Under neutral or weak alkaline conditions (pH value 7 ~ 9), the product content of oxidation products reaches more than 80%. This is because the decomposition rate of H2O2 is affected by pH value. The concentration of N-methylmorpholine has little effect on the yield of the product. During the reaction, we tried to add catalyst (FeCl3) to promote the decomposition rate of H2O2, but the yield was almost unchanged. The addition of catalyst makes the reaction liquid appear red and form suspension, which makes the separation of products difficult.

The synthesis of N-methylmorpholine is achieved by oxidation reaction, which is a strong exothermic reaction, resulting in boiling phenomenon due to the formation of hydrogen bonds between the oxide and water. When adding H2O2, the temperature should not be too high, and the heat generated by the reaction can keep the reaction going. If the drip temperature is high, the color of the reaction system will be deepened, and the purity of the product will be affected. For the synthesis of N-(2-amine ethyl) morpholine, 2,2 '-dichlorodiethyl ether should be synthesized first. For this reaction, dichlorosulfoxide is used as chlorination agent, the product yield is high, almost no side reaction occurs, the target product is easy to separate and purify. During vacuum distillation, the conditions for collecting fractions were determined as follows: temperature 122℃ ~ 124℃, pressure 5062Pa. Under these conditions, the yield of 2,2 '-dichlorodiethyl ether reached 89% and the purity of the product reached 99%.

The reaction of dichlorodiethyl ether with ethylenediamine is very complicated. In addition to the formation of the target product N-(2-aminoethyl) morpholine, a series of by-products will be generated. Low concentration of reactants should be conducive to the intramolecular reaction. Therefore, this paper conducted tests on the influencing factors such as the concentration of reactants, molecular ratio and feeding rate, and the test data obtained under the conditions of different reaction temperatures and reaction times are shown in Table 4(reaction temperature is 6) 0℃) and Table 5(reaction temperature 60℃), it is found that the optimum reaction temperature is 60℃, the appropriate time is 2h, the yield can reach 59.3%, but the product purity is not very ideal. Table 5 reaction time on the synthesis of N - (2 - amino ethyl) morpholine, the effects of reaction time h product yield % 0.542. Mr Amine chloride synthesis ONCH2CH2NH2 + ClCOCl HClONCH2CH2NH + COCl in figure 4 In this paper, N-(2-aminoethyl) morpholine and p-chlorobenzoyl chloride were used as raw materials. After nuclear magnetic analysis, the solid product contains a certain amount of impurities, the reason should be the last step of the product purity is low or p-chlorobenzoic acid partial hydrolysis of p-chlorobenzoic acid, resulting in side reactions.


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