CN111018746A - Synthetic method of N-benzyloxycarbonyl-L-threonine amide as intermediate for main ring synthesis of aztreonam - Google Patents
Synthetic method of N-benzyloxycarbonyl-L-threonine amide as intermediate for main ring synthesis of aztreonam Download PDFInfo
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Abstract
The invention provides a synthetic method of an intermediate N-benzyloxycarbonyl-L-threonine amide synthesized by a main ring of aztreonam, which comprises the following steps: 1) adding L-threonine solid and methanol into a reaction kettle, stirring and cooling, then dropwise adding thionyl chloride, heating and refluxing to complete the reaction, and evaporating the solvent to dryness; 2) adding methanol into the reactant obtained in the step 1) for dissolving, heating and pressurizing, introducing liquid ammonia, preserving heat and pressure, evaporating the liquid ammonia after the reaction is finished, and evaporating the solvent to dryness; 3) adding water into the reactant obtained in the step 2) for dissolving, dropwise adding benzyl chloroformate, dropwise adding an acid-binding agent solution to control the pH value of the reaction system at the same time, obtaining an intermediate N-benzyloxycarbonyl-L-threonine amide, and performing filter pressing and drying to obtain a solid.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of an aztreonam main ring synthetic intermediate N-benzyloxycarbonyl-L-threonine amide.
Background
The aztreonam is a monocyclic β lactam antibiotic and has a good treatment effect on gram-negative bacteria infection, the main ring of the aztreonam is an important intermediate for synthesizing the aztreonam, the esterification reaction, the ammonolysis reaction and the amino protection reaction are carried out in the production process of the main ring, L-methyl threonine is easy to decompose or hydrolyze in the esterification reaction process, so that the product yield is low, the ammonolysis reaction speed is low, the time is long, the utilization efficiency of ammonia is low, the treatment cost of a large amount of waste ammonia is high, in the amino protection process, the stirring effect is not ideal due to the generation of solids in the reaction process, the local alkalinity is too strong in the process of dripping sodium hydroxide solution, a large amount of ammonium chloride in an amide water solution is converted into ammonia, the ammonia reacts with benzyl chloroformate to generate byproducts, the raw materials are consumed, the quality and the yield of the product are also influenced.
The synthetic routes reported in US4775670 and US4946838 use L-threonine as raw material, and are subjected to esterification, aminolysis, and amino protection; obtaining N-benzyloxycarbonyl-L-threonine amide;
chinese patents CN104592081A, CN102382026A and CN102925510A all use L-threonine as a raw material, and undergo esterification, aminolysis and amino protection to obtain N-benzyloxycarbonyl-L-threonine amide, but the intermediate procedures are improved and adjusted, and are not described in detail.
The above patents have the following disadvantages: the esterification reaction is only carried over once, and the yield of the esterification reaction is not high and is only about 90 percent; the ammonolysis reaction time is long, the yield is low, and the environmental pollution is serious; the amino protection reaction has high raw material cost and more side reactions, which leads to poor product quality.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthetic method of an intermediate N-benzyloxycarbonyl-L-threonine amide synthesized by a main ring of aztreonam, which has the advantages of high reaction conversion rate, high yield, environmental protection, simple process and lower cost.
The synthetic method of the intermediate N-benzyloxycarbonyl-L-threonine amide for the main ring synthesis of aztreonam comprises the following steps:
1) adding L-threonine solid and methanol into a reaction kettle, stirring and cooling, then dropwise adding thionyl chloride, heating and refluxing to react, and evaporating the solvent to dryness, wherein the molar ratio of L-threonine to thionyl chloride is 1: 0.80-0.90;
2) adding methanol into the reactant obtained in the step 1) for dissolving, heating and pressurizing, introducing liquid ammonia, preserving heat and pressure, evaporating the liquid ammonia after the reaction is finished, and evaporating the solvent to dryness, wherein the mass of the liquid ammonia is 0.75-0.8 time of the mass of the L-threonine solid, and the pressure after pressurization is 2.0-2.5 MPa;
3) adding water into the reactant obtained in the step 2) for dissolving, dropwise adding benzyl chloroformate, dropwise adding an acid-binding agent solution at the same time to control the pH value of the reaction system to 6-7 to obtain an intermediate N-benzyloxycarbonyl-L-threonine amide, and performing filter pressing and drying to obtain a solid, wherein the mass of the benzyl chloroformate is 1.5-1.6 times of that of the L-threonine solid.
Preferably, the pH value is 6.0-7.0.
Preferably, the temperature in the heating and pressurizing is 50-60 ℃.
Preferably, the liquid ammonia distillation is pressure distillation, and the distilled liquid ammonia can be directly used.
Preferably, the step 3) further comprises the step of stirring after adding water to dissolve, wherein the stirring speed is 600-700 r/min.
Preferably, the acid-binding agent comprises more than one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
Preferably, the method also comprises the step of adjusting the pH value of the solution to 8-9 after the acid-binding agent solution is dripped.
The method has the advantages that the consumption of the thionyl chloride is less, the acidic waste gas hydrogen chloride generated by the reaction can also catalyze the esterification reaction, so that the quantity of the thionyl chloride is reduced, the L-threonine can be ensured to react completely, the consumption of the thionyl chloride is reduced, the raw material cost is saved, the generation of the acidic waste gas sulfur dioxide is reduced, and the method is more economic and more environment-friendly.
The ammonolysis reaction adopts pressurized liquid ammonia for reaction, and the liquid ammonia is dissolved in methanol, so that the liquid ammonia is a liquid-liquid single-phase reaction, the traditional gas-liquid two-phase reaction is changed, the utilization rate of raw material ammonia is improved, and meanwhile, the liquid ammonia improves the reaction speed and the reaction conversion rate.
The invention uses potassium carbonate with weaker alkalinity as an optimal acid-binding agent, thereby not only reducing the situation of local over-alkali in the dropping process, reducing the reaction of ammonia gas and benzyl chloroformate and ensuring the product quality and yield, but also changing the potassium salt waste water into potassium fertilizer, being more environment-friendly than sodium salt and having more use value.
The pH value of the reaction system is a main factor influencing the yield, and the amino can form salt when the pH value is too low, so that the reaction is influenced; because ammonium chloride exists in the reaction system, ammonia gas can be liberated due to overhigh pH value, and the ammonia gas and benzyl chloroformate have stronger reaction activity, so that the benzyl chloroformate is consumed, and the yield is influenced.
Compared with the prior art, the invention has the following beneficial effects:
the method has the advantages of simple process operation and short period, reduces the usage amount of the raw material thionyl chloride, increases the utilization rate of liquid ammonia, reduces the generation of three wastes from the source, selects more environment-friendly sylvite, can be repeatedly utilized to prepare a potash fertilizer, reduces the generation of waste water and waste gas, realizes the production of a green process, controls weak acidity in the process of dripping the acid-binding agent, reduces the decomposition of the raw material benzyl chloroformate, reduces byproducts generated by the reaction of ammonia and benzyl chloroformate, has better product quality and higher product yield, and can obtain the product with the purity of more than 97.9 percent, the content of more than 97.7 percent and the total yield of more than 93.1 percent.
Detailed Description
The invention is further described with reference to the following examples:
example 1
Adding 60g of L-threonine solid into a 500mL reaction bottle, adding 240g of methanol, cooling to-5 ℃, dropwise adding 50g of thionyl chloride to obtain a mixed reaction solution, heating for reflux reaction, distilling the methanol until the methanol is not discharged after the reaction is finished to obtain colorless or light yellow viscous oily L-threonine methyl ester, adding 300g of methanol for dissolution, heating to 53 ℃, pressurizing to 2.3MPa, adding 45g of liquid ammonia, preserving heat and maintaining pressure for reaction, after the reaction is finished, distilling the residual liquid ammonia under pressure, directly applying the residual liquid ammonia, distilling the methanol under normal pressure, finally distilling the methanol under negative pressure until the methanol is not discharged to obtain L-threonine amide and ammonium chloride solid, adding 150g of water, stirring for dissolution, cooling, accelerating the stirring speed to 650r/min, dropwise adding 90g of benzyl chloroformate, controlling the pH value to be 6.0 by using a saturated potassium carbonate solution, dropwise adding, adjusting the pH value to be 8.0 by using a potassium hydroxide solution, after the reaction is finished, the mixture is directly subjected to plate-and-frame filter pressing, then is rinsed by water, and the wet product is dried to obtain 120.1g of N-benzyloxycarbonyl-L-threonine amide solid with the purity of 98.3 percent, the content of 97.8 percent and the total yield of 94.5 percent.
Example 2
Adding 60g of L-threonine solid into a 500mL reaction bottle, adding 240g of methanol, cooling to-5 ℃, dropwise adding 52g of thionyl chloride to obtain a mixed reaction solution, heating for reflux reaction, distilling the methanol until the methanol is not discharged after the reaction is finished to obtain colorless or light yellow viscous oily L-threonine methyl ester, adding 300g of methanol for dissolution, heating to 55 ℃, pressurizing to 2.1MPa, adding 47g of recovered liquid ammonia, preserving heat and maintaining pressure for reaction, after the reaction is finished, distilling the residual liquid ammonia under pressure, directly applying the residual liquid ammonia, distilling the methanol under normal pressure, finally distilling the methanol under negative pressure until the methanol is not discharged to obtain L-threonine amide and ammonium chloride solid, adding 150g of water, stirring for dissolution, cooling, accelerating the stirring speed to 680r/min, dropwise adding 92g of benzyl chloroformate, controlling the pH value to be 7.0 by using a saturated sodium carbonate solution, dropwise adding, adjusting the pH value to be 8.0 by using a sodium hydroxide solution, after the reaction, the mixture is directly subjected to plate-and-frame filter pressing, then is rinsed by water, and the wet product is dried to obtain 119.3g of N-benzyloxycarbonyl-L-threonine amide solid with the purity of 98.6 percent, the content of 98.2 percent and the total yield of 93.9 percent.
Example 3
Adding 60g of L-threonine solid into a 500mL reaction bottle, adding 240g of methanol, cooling to-5 ℃, dropwise adding 49g of thionyl chloride to obtain a mixed reaction solution, heating for reflux reaction, distilling the methanol until the methanol is not discharged after the reaction is finished to obtain colorless or light yellow viscous oily L-threonine methyl ester, adding 300g of methanol for dissolution, heating to 58 ℃, pressurizing to 2.5MPa, adding 48g of liquid ammonia, preserving heat and maintaining pressure for reaction, after the reaction is finished, distilling the residual liquid ammonia under pressure, directly applying the residual liquid ammonia, distilling the methanol under normal pressure, finally distilling the methanol under negative pressure until the methanol is not discharged to obtain L-threonine amide and ammonium chloride solid, adding 150g of water, stirring for dissolution, cooling, accelerating the stirring speed to 670r/min, dropwise adding 96g of benzyl chloroformate, controlling the pH value to be 6.0 by using a sodium hydroxide solution, dropwise adding, adjusting the pH value to be 8.0 by using the sodium hydroxide solution, after the reaction is finished, the mixture is directly subjected to plate-and-frame filter pressing, then is rinsed by water, and the wet product is dried to obtain 118.3g of N-benzyloxycarbonyl-L-threonine amide solid with the purity of 97.9 percent, the content of 97.7 percent and the total yield of 93.1 percent.
Example 4
Adding 60g of L-threonine solid into a 500mL reaction bottle, adding 240g of methanol, cooling to-5 ℃, dropwise adding 54g of thionyl chloride to obtain a mixed reaction solution, heating for reflux reaction, distilling the methanol until the methanol is not discharged after the reaction is finished to obtain colorless or light yellow viscous oily L-threonine methyl ester, adding 300g of methanol for dissolution, heating to 50 ℃, pressurizing to 2.1MPa, adding 48g of recovered liquid ammonia, preserving heat and maintaining pressure for reaction, after the reaction is finished, distilling the residual liquid ammonia under pressure, directly applying the residual liquid ammonia, distilling the methanol under normal pressure, finally distilling the methanol under negative pressure until the methanol is not discharged to obtain L-threonine amide and ammonium chloride solid, adding 150g of water, stirring for dissolution, cooling, accelerating the stirring speed to 700r/min, dropwise adding 94g of benzyl chloroformate, simultaneously controlling the pH value to be 6.5 by using a saturated potassium bicarbonate solution, dropwise adding potassium hydroxide solution to adjust the pH value to be 8.0, after the reaction, the mixture is directly subjected to plate-and-frame filter pressing, then is rinsed by water, and the wet product is dried to obtain 119.7g of N-benzyloxycarbonyl-L-threonine amide solid with the purity of 98.8 percent, the content of 98.3 percent and the total yield of 94.2 percent.
Example 5
Adding 60g of L-threonine solid into a 500mL reaction bottle, adding 240g of methanol, cooling to-3 ℃, dropwise adding 54g of thionyl chloride to obtain a mixed reaction solution, heating for reflux reaction, distilling the methanol until the methanol is not discharged after the reaction is finished to obtain colorless or light yellow viscous oily L-threonine methyl ester, adding 300g of methanol for dissolution, heating to 60 ℃, pressurizing to 2.1MPa, adding 45g of recovered liquid ammonia, preserving heat and maintaining pressure for reaction, after the reaction is finished, distilling the residual liquid ammonia under pressure, directly applying the residual liquid ammonia, distilling the methanol under normal pressure, finally distilling the methanol under negative pressure until the methanol is not discharged to obtain L-threonine amide and ammonium chloride solid, adding 150g of water, stirring for dissolution, cooling, accelerating the stirring speed to 600r/min, dropwise adding 94g of benzyl chloroformate, simultaneously controlling the pH value to be 6.5 by using a saturated sodium bicarbonate solution, dropwise adding, adjusting the pH value to be 8.0 by using a sodium hydroxide solution, after the reaction is finished, the mixture is directly subjected to plate-and-frame filter pressing, then is rinsed by water, and the wet product is dried to obtain 118.8g of N-benzyloxycarbonyl-L-threonine amide solid with the purity of 98.5 percent, the content of 98.1 percent and the total yield of 93.5 percent.
Comparative example 1
Adding 60g of L-threonine solid into a 500mL reaction bottle, adding 240g of methanol, cooling to-3 ℃, dropwise adding 60g of thionyl chloride to obtain a mixed reaction solution, heating for reflux reaction, distilling the methanol until the methanol is not discharged after the reaction is finished to obtain colorless or light yellow viscous oily L-threonine methyl ester, adding 300g of methanol for dissolution, heating to 60 ℃, pressurizing to 2.1MPa, adding 45g of recovered liquid ammonia, preserving heat and maintaining pressure for reaction, after the reaction is finished, distilling the residual liquid ammonia under pressure, directly applying the residual liquid ammonia, distilling the methanol under normal pressure, finally distilling the methanol under negative pressure until the methanol is not discharged to obtain L-threonine amide and ammonium chloride solid, adding 150g of water, stirring for dissolution, cooling, accelerating the stirring speed to 600r/min, dropwise adding 94g of benzyl chloroformate, simultaneously controlling the pH value to be 6.5 by using a saturated sodium bicarbonate solution, dropwise adding, adjusting the pH value to be 8.0 by using a sodium hydroxide solution, after the reaction is finished, the mixture is directly subjected to plate-and-frame filter pressing, then is rinsed by water, and the wet product is dried to obtain 117.6g of N-benzyloxycarbonyl-L-threonine amide solid with the purity of 97.6 percent, the content of 97.9 percent and the total yield of 92.5 percent.
Comparative example 2
Adding 60g of L-threonine solid into a 500mL reaction bottle, adding 240g of methanol, cooling to-5 ℃, dropwise adding 50g of thionyl chloride to obtain a mixed reaction solution, heating for reflux reaction, distilling the methanol until the methanol is not discharged after the reaction is finished to obtain colorless or light yellow viscous oily L-threonine methyl ester, adding 300g of methanol for dissolution, heating to 53 ℃, pressurizing to 2.3MPa, continuously introducing ammonia gas, keeping the temperature and maintaining the pressure for reaction, directly applying the reaction solution, distilling the methanol at normal pressure, distilling the methanol at negative pressure until the methanol is not discharged to obtain L-threonine amide and ammonium chloride solid, adding 150g of water, stirring for dissolution, cooling, accelerating the stirring speed to 650r/min, dropwise adding 90g of benzyl chloroformate, simultaneously controlling the pH value to be 6.0 by using a saturated potassium carbonate solution, after the dropwise adding is finished, adjusting the pH value to 8.0 by using a potassium hydroxide solution, after the reaction is finished, the mixture is directly subjected to plate-and-frame filter pressing, then is rinsed by water, and the wet product is dried to obtain 114.5g of N-benzyloxycarbonyl-L-threonine amide solid with the purity of 96.8 percent, the content of 95.1 percent and the total yield of 89.4 percent.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (7)
1. A synthetic method of an intermediate N-benzyloxycarbonyl-L-threonine amide synthesized by a main ring of aztreonam is characterized by comprising the following steps: the method comprises the following steps:
1) adding L-threonine solid and methanol into a reaction kettle, stirring and cooling, then dropwise adding thionyl chloride, heating and refluxing to complete the reaction, and evaporating the solvent to dryness;
2) adding methanol into the reactant obtained in the step 1) for dissolving, heating and pressurizing, introducing liquid ammonia, preserving heat and pressure, evaporating the liquid ammonia after the reaction is finished, and evaporating the solvent to dryness;
3) adding water into the reactant obtained in the step 2) for dissolving, dropwise adding benzyl chloroformate, dropwise adding an acid-binding agent solution to control the pH value of the reaction system at the same time, obtaining an intermediate N-benzyloxycarbonyl-L-threonine amide, performing filter pressing, and drying to obtain a solid;
the molar ratio of the L-threonine to the thionyl chloride is 1: 0.80-0.90, the pressure after pressurization is 2.0-2.5 MPa, the pH value is 6.0-7.0, and the mass of the benzyl chloroformate is 1.5-1.6 times of the mass of the L-threonine solid.
2. The method for synthesizing N-benzyloxycarbonyl-L-threonine amide, which is an intermediate in the main ring synthesis of aztreonam, according to claim 1, characterized in that: the temperature in the heating and pressurizing process is 50-60 ℃.
3. The method for synthesizing an N-benzyloxycarbonyl-L-threonine amide, which is an intermediate in the main ring synthesis of aztreonam, according to claim 1 or 2, characterized in that: the liquid ammonia distillation is pressure distillation.
4. The method for synthesizing an N-benzyloxycarbonyl-L-threonine amide, which is an intermediate in the main ring synthesis of aztreonam, according to claim 1 or 2, characterized in that: and 3) adding water to dissolve the mixture, and stirring the mixture at a speed of 600-700 r/min.
5. The method for synthesizing an N-benzyloxycarbonyl-L-threonine amide, which is an intermediate in the main ring synthesis of aztreonam, according to claim 1 or 2, characterized in that: the acid-binding agent comprises more than one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
6. The method for synthesizing an N-benzyloxycarbonyl-L-threonine amide, which is an intermediate in the main ring synthesis of aztreonam, according to claim 1 or 2, characterized in that: the mass of the liquid ammonia is 0.75-0.8 times of that of the L-threonine solid.
7. The method for synthesizing an N-benzyloxycarbonyl-L-threonine amide, which is an intermediate in the main ring synthesis of aztreonam, according to claim 1 or 2, characterized in that: the method also comprises the step of adjusting the pH value of the solution to 8-9 after the acid-binding agent solution is added.
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