A diamide podomer and a method of synthesis thereof

Abstract

The application relates to the technical field of diacyl podioether synthesis, in particular to a diacyl podioether and a synthesis method thereof. The method takes 1,4-dioxane-2-ketone as a raw material, and an intermediate 2-(2-hydroxyethoxy) amide is obtained by ring-opening reaction of 1,4-dioxane-2-ketone and dialkylamine; then, another intermediate oxygen hetero-substituted amide is generated by oxidizing the hydroxyl group into a carboxyl group; finally, the oxygen hetero-substituted amide and the dialkylamine are condensed to prepare the diacyl podioether, the generation of intermediates such as acyl chloride and diethylene glycol anhydride is avoided, the synthesis route is simple to operate and easy to purify, the total yield is more than 61%, the method meets the increasing industrialization demand of the products, and lays a good foundation for batch production.

Description

Technical Field

[0001] This invention relates to the field of diamide podyl ether synthesis technology, and in particular to a diamide podyl ether and its synthesis method. Background Technology

[0002] Diamide ethers are a class of highly efficient solvents suitable for a wide range of nitric acid concentrations, exhibiting good radiation stability and direct applicability to high-level radioactive waste. Because their molecules contain only C, H, O, and N atoms, the resulting organic wastewater can be directly and completely incinerated, producing non-polluting gaseous substances, aligning with the principles of green environmental protection. Compared to solvents containing P and S atoms, wastewater from diamide ether extraction is easier to treat.

[0003] Currently, the synthetic routes for diamide pod ethers all use diethylene glycol as a raw material, and they are mainly divided into the following three types:

[0004] (1) In the literature Sasaki Y, Choppin G R. Solvent extraction of Eu, Th, U, Np and Am with N, N'-dimethyl-N, N'-dihexyl-3-oxapentanediamide and its analogous coumpounds. Anal Sci, 1996, 12(2):225-230, diethylene glycol and amine are directly condensed in the presence of a condensing agent such as DCC to generate the target product. This method is a one-step condensation process, which has the advantages of simple steps and mild reaction conditions. However, the disadvantage is that the reaction byproduct dicyclohexylurea (DCU) will be mixed in with the product and is difficult to remove completely, affecting its quality and subsequent extraction effect. Moreover, the yield is not ideal (around 20%).

[0005] (2) In the literature Pretsch VE, Ammann D, Osswald HF, et al. Ionophore vom Typ der 3-Oxapentandiamide. Helv Chim Acta, 1980, 63(1): 191-196, diethylene glycol acid is converted into acyl chloride through acyl chloride reaction, and then reacted with amine at low temperature to obtain the target product. This method has a short procedure and the intermediate acyl chloride has good activity, which facilitates the reaction. However, the acyl chloride reaction requires highly corrosive reagents such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene and oxalyl chloride, which requires high corrosion resistance of equipment. Moreover, the use of such reagents puts great pressure on environmental protection, and it is easy to cause air pollution in the factory area due to the escape of some reagents. In addition, because the intermediate acyl chloride has high activity, it is easy to decompose during the heating and distillation separation process, resulting in a low yield.

[0006] (3) In the literature Zhang P, Chen J, Li C, Synthesis of N,N,N',N'-tetra-butyl-3-oxa-pentane-diamide and its analogous compounds Chemical journal on Internet, 2003, 5(7):52, diethylene glycol acid is synthesized into diethylene glycol anhydride using acetic anhydride as a dehydrating agent, then reacted with an amine to generate an oxa-monosubstituted amide, then generated an acyl chloride through an acyl chloride reaction, and finally reacted with an amine to synthesize the target product. In this method, diethylene glycol anhydride is not only expensive but also easily absorbs moisture and deteriorates during storage. At the same time, acetic anhydride is a precursor chemical, and its large-scale use is restricted, making it difficult to promote industrialization.

[0007] Based on the above analysis, the applicant found that existing methods for synthesizing diamide ethers using diethylene glycol as a raw material generally suffer from low yield, difficulty in product purification, and environmental unfriendliness. Summary of the Invention

[0008] In view of this, the purpose of this invention is to propose a diamide ether and its synthesis method to solve the problems of low yield, environmental unfriendliness and high purification difficulty in existing synthesis methods.

[0009] To achieve the above objectives, the present invention provides a method for synthesizing diamide podyl ethers, comprising the following steps:

[0010] in, for alkyl;

[0011] (1) Reaction of 1,4-dioxane-2-one (as shown in Formula I) with an amine in an organic solution yields compound Formula II;

[0012] (2) Compound II is oxidized under the action of an oxidizing agent to obtain compound III;

[0013] (3) Compound III is condensed with an amine under the action of a condensing agent and a base to obtain the diamide ether shown in Formula V.

[0014] As one possible implementation, the amine is a dialkylamine.

[0015] As one possible implementation, the dialkylamine is dioctylamine or di(2-ethylhexyl)amine.

[0016] As one possible implementation, the organic solution in step (1) is one of N,N-dimethylformamide, n-heptane, toluene, benzene and xylene.

[0017] As one possible implementation method, the reaction temperature of step (1) is 80~120℃ and the reaction time is 3~12h.

[0018] As one possible implementation, the oxidant in step (2) further includes an oxidizing agent, wherein the oxidant is a sodium hypochlorite solution with a concentration of 2-10% and 1.2-5 eq, and the oxidizing agent is a mixture of 0.02-0.05 eq Tempo and 0.05-0.15 eq sodium bromide.

[0019] As one possible implementation, the pH of the oxidation reaction in step (2) is 7~9, the reaction temperature is 0~30℃, and the reaction time is 2~8h.

[0020] As one possible implementation, the condensing agent in step (3) is at least one of EDCl, HOBt, HATU, HBTU, TBTU, and PyBOP, and the base is at least one of N,N-diisopropylethylamine, triethylamine, and N-methylmorpholine.

[0021] As one possible implementation method, the condensation reaction time of step (3) is 4~18h.

[0022] In addition, the present invention also provides a diamide podyl ether, which is synthesized using the aforementioned synthesis method.

[0023] The beneficial effects of this invention are as follows: This invention provides a method for synthesizing diamide pod ethers. The method uses 1,4-dioxane-2-one-substituted diethylene glycol acid as a raw material and employs a three-step reaction, avoiding the formation of intermediates such as acyl chlorides and diethylene glycol anhydrides. After obtaining a relatively stable intermediate 2-(2-hydroxyethoxy)amide (compound II) through a ring-opening reaction between 1,4-dioxane-2-one and a dialkylamine, the hydroxyl group is oxidized to a carboxyl group to generate another relatively stable intermediate, an oxamonosubstituted amide (compound III). Finally, the oxamonosubstituted amide and the dialkylamine are condensed to prepare the diamide pod ether. This method eliminates the need for highly corrosive and volatile reagents such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, and oxalyl chloride, avoids the need for distillation purification of the acyl chloride intermediate, and does not involve the use of acetic anhydride.

[0024] This synthetic route is simple to operate and does not involve volatile substances that easily cause air pollution. The intermediates are easy to store and stable, and easy to purify. It does not involve the use of precursor chemicals. The yields of each of the three steps are high, at 100% (if the product is not purified before being added to the next step), 82%, and 74%, respectively, with an overall yield of over 61%. It has high economic value and obvious advantages for industrial scale-up. Attached Figure Description

[0025] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0026] Figure 1 This is a schematic diagram of the existing technology for synthesizing diamide podyl ethers;

[0027] Figure 2 The NMR spectrum of the final product of Example 1 of this invention is shown below.

[0028] Figure 3 This is the proton NMR spectrum of the final product of Example 2 of the present invention. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0030] The definitions are as follows:

[0031] DCC: N,N'-Dicyclohexylcarbodiimide; Tempo: 2,2,6,6-Tetramethylpiperidine-1-oxygen radical; Toluene: Toluene; EDCl: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxyhexafluorophosphate; HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate; TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate; PyBOP: benzotriazol-1-yl-oxy-tripyrrolidinyl phosphate; eq: equivalent.

[0032] In the process of researching methods for synthesizing diamide podyl ethers, the inventors discovered that existing methods for synthesizing diamide podyl ethers mainly use diethylene glycol as a raw material, employing a one-step condensation method, acyl chloride method, or acid anhydride method to prepare diamide podyl ethers. The synthetic route is as follows: Figure 1 As shown, all three synthetic routes suffer from low yields, difficult product purification, and environmental unfriendliness.

[0033] Based on the above problems, this invention provides a diamide podyl ether and its synthesis method to solve the problems of low yield, environmental unfriendliness and high purification difficulty in existing synthesis methods.

[0034] This invention provides a method for synthesizing diamide podyl ether, comprising the following steps:

[0035] in, for alkyl;

[0036] (1) Reaction of 1,4-dioxane-2-one (as shown in Formula I) with an amine in an organic solution yields compound Formula II;

[0037] (2) Compound II is oxidized under the action of an oxidizing agent to obtain compound III;

[0038] (3) Compound III is condensed with an amine under the action of a condensing agent and a base to obtain the diamide ether shown in Formula V.

[0039] Preferably, the amine is a dialkylamine.

[0040] Preferably, the dialkylamine is dioctylamine or di(2-ethylhexyl)amine.

[0041] Preferably, the organic solution in step (1) is one of N,N-dimethylformamide, n-heptane, toluene, benzene and xylene.

[0042] Preferably, the reaction temperature in step (1) is 80~120℃ and the reaction time is 3~12h.

[0043] Preferably, the oxidant in step (2) further includes an oxidizing agent, wherein the oxidant is a sodium hypochlorite solution with a concentration of 2-10% and 1.2-0.5 eq, and the oxidizing agent is a mixture of 0.02-0.05 eq Tempo and 0.05-0.15 eq sodium bromide.

[0044] Preferably, the pH of the oxidation reaction in step (2) is 7-9, the reaction temperature is 0-30℃, and the reaction time is 2-8h.

[0045] Preferably, the condensing agent in step (3) is at least one of EDCl, HOBt, HATU, HBTU, TBTU, and PyBOP, and the base is at least one of N,N-diisopropylethylamine, triethylamine, and N-methylmorpholine.

[0046] Preferably, the condensation reaction time in step (3) is 4 to 18 hours.

[0047] In addition, this invention also provides a diamide pod ether, which is synthesized using the synthesis method described above.

[0048] This method uses 1,4-dioxane-2-one as a raw material, eliminating the need for highly corrosive and volatile reagents such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosgene, and oxalyl chloride. It also eliminates the need for distillation and purification of acyl chloride intermediates and avoids the use of acetic anhydride. The intermediates are easy to store and have stable properties. This method is simple to operate and easy to purify. The yields of each of the three reaction steps are high, at 100% (if the unpurified product is directly added to the next step), 82%, and 74%, respectively, with an overall yield of over 61%. It has high economic value and significant advantages for industrial scale-up.

[0049] Specifically, as an example of Example 1, this Example 1 provides a method for synthesizing a diamide ether, which includes the following steps:

[0050] (1) The 1,4-dioxane-2-one shown in Formula I is reacted with an amine in an organic solution to obtain compound Formula II.

[0051]

[0052] 1,4-dioxane-2-one (5.1 g, 0.050 mmol, 1.0 eq) and dioctylamine (13.3 g, 0.055 mmol, 1.1 eq) as shown in Formula I were added to toluene (30 mL), heated to 105 °C, and reacted for 6 h. After cooling to room temperature, 10 mL of 1 M dilute hydrochloric acid was added to wash away excess amine. The mixture was then separated into liquid and liquid phases. The organic phase after separation was washed with 10 mL of saturated sodium chloride. The mixture was then separated into liquid and liquid phases. The organic phase after separation was concentrated to remove excess solvent. The crude product, a pale yellow oily liquid 2-(2-hydroxyethoxy)amide, was directly used in the next reaction.

[0053] (2) Compound II is oxidized under the action of an oxidizing agent to obtain compound III.

[0054]

[0055] 2-(2-hydroxyethoxy)-N,N-dioctylamide (6.87 g, 0.02 mol, 1.0 eq) was dissolved in dichloromethane (50 mL), and Tempo (62.5 mg, 0.4 mmol, 0.02 eq), 20 mL of 5% sodium bicarbonate, and sodium bromide (206 mg, 2 mmol) were added. The mixture was cooled to 10-15 °C, and then sodium hypochlorite (0.024 mol, 14.4 mL, sodium hypochlorite with an available chlorine content of 10%) was added dropwise using a constant pressure dropping funnel. After the addition was complete, the mixture was stirred at room temperature for 3 h. After the TLC monitoring showed the raw material spot disappearing and other spots exhibiting high polarity, a 1 mol / L hydrochloric acid solution containing 5% potassium iodide was added to adjust the pH to between 3 and 4. The mixture was then separated into liquid and liquid phases. The organic phase was stirred with a 20% sodium thiosulfate solution for 0.5 h, followed by another separation. The organic phase was then washed with saturated sodium chloride and concentrated to dryness. Finally, 30 mL of 3 mol / L hydrochloric acid was added to the dry organic phase solid, and the temperature was raised to 50 °C until the solid was completely dissolved. The temperature was then slowly lowered to between 0 and 10 °C. Filtration was then performed to obtain granular white oxamonosubstituted amides.

[0056] The product mass was measured to be 5.85 g, with a yield of 81.9% (yield = Simultaneously, the product was subjected to proton NMR analysis (using deuterated chloroform as the solvent and 400M NMR detection), and the results were as follows: 1 HNMR (CD3Cl, 400MHz) δ: 4.39 (s, 2H; COCH2O), 4.20 (s, 2H; COCH2O), 3.34 (m, 2H; -NCH2), 3.08 (m, 2H;-NCH2), 1.54(m, 4H;-CH2), 1.27(m, 20H;-CH2), 0.65(m, 6H;-CH3). This conforms to the structure of the target product.

[0057] (3) Compound III is condensed with an amine under the action of a condensing agent and a base to obtain the diamide ether shown in Formula V.

[0058]

[0059] Oxalomonosubstituted amide (3.58 g, 0.01 mol) was dissolved in 25 mL of tetrahydrofuran, followed by the addition of EDCI (2.11 g, 0.011 mol, 1.1 eq) and HOBt (1.49 g, 0.011 mol, 1.1 eq). The mixture was cooled to 0–5 °C under nitrogen protection, and then triethylamine (1.52 g, 0.015 mol, 1.5 eq) was added and stirred for 10 min. Dioctylamine (5.07 g, 0.021 mol, 1.05 eq) was then added, and the mixture was finally heated to room temperature and reacted for 6 h.

[0060] After the reaction was completed, 20 mL of 10% citric acid solution was added, and the mixture was extracted three times with 20 mL of ethyl acetate each time. The extracted organic phases were combined, washed with 20 mL of saturated sodium bicarbonate solution, and then separated. The separated organic phases were washed with saturated sodium chloride solution and separated again. The separated organic phases were concentrated to dryness to obtain a colorless oily substance, 2,2'-oxydi(N,N-dioctylacetamide).

[0061] The product mass was measured to be 4.30 g, with a yield of 74.0%. Simultaneously, proton NMR analysis of the product was performed, and the results were as follows: 1 ¹H NMR (CD₃Cl, 400 MHz) δ: 4.06 (s, 4H; -OCH₂), 3.09–2.96 (2m, 8H; -NCH₂), 1.31–1.06 (m, 48H; -CH₂), 0.65 (m, 12H; -CH₃). The structure conforms to the target product structure as follows: Figure 2 As shown.

[0062] Specifically, as an example of Example 2, the synthesis steps are the same as in Example 1, except that in synthesis step (3), dioctylamine is replaced with di(2-ethylhexyl)amine.

[0063] The granular white oxamonosubstituted amide intermediate produced during the synthesis process weighed 5.93 g, with a yield of 83.1%.

[0064] The final synthesized colorless oily compound, 2,2'-oxydi[N,N-di(2-ethylhexyl)]acetamide, weighed 4.37 g, with a yield of 75.2%. The product was analyzed by 1H NMR spectroscopy, and the results were as follows: 1 ¹H NMR (CD₃Cl, 400 MHz) δ: 4.36 (s, 4H; -OCH₂), 3.40–3.19 (m, 4H; -NCH₂), 3.08–3.03 (m, 4H; -NCH₂), 1.70–1.52 (2m, 4H; -CH), 1.38–1.16 (m, 32H; -CH₂), 0.90–0.81 (m, 24H; -CH₃). The structure conforms to the target product structure as follows: Figure 3 As shown.

[0065] Example 2 shows that replacing the linear dioctylamine with the branched di(2-ethylhexyl)amine increases the steric hindrance of the reactants, while still yielding a product with good yield using the same three-step synthetic route. This demonstrates the universality of using dialkylamines in the synthesis of the present invention.

[0066] Specifically, in Example 3, the synthesis steps are the same as in Example 1, except that HATU is used as a condensing agent in synthesis step (3).

[0067] The final product yield was 70.1%.

[0068] Specifically, in Example 4, the synthesis steps are the same as in Example 1, except that dimethylamine is replaced with di(2-ethylhexyl)amine in synthesis step (3).

[0069] The final product yield was 76.9%.

[0070] Specifically, in Example 5, the synthesis steps are the same as in Example 1, except that in synthesis step (3), didecylamine is replaced with di(2-ethylhexyl)amine.

[0071] The final product yield was 69.5%.

[0072] Specifically, in Example 6, the synthesis steps are the same as in Example 1, except that:

[0073] In step (2), the oxidant was a 2% sodium hypochlorite solution at 1.2 eq, and the oxidizing agent was a mixture of 0.02 eq Tempo and 0.05 eq sodium bromide. The pH of the oxidation reaction was 9, the reaction temperature was 0℃, and the reaction time was 2 h.

[0074] The condensation reaction time in step (3) is 4 hours.

[0075] The final product yield was 61.9%.

[0076] Specifically, in Example 7, the synthesis steps are the same as in Example 1, except that:

[0077] In step (2), the oxidant was a 10% sodium hypochlorite solution (5 eq), and the oxidizing agent was a mixture of 0.05 eq Tempo and 0.15 eq sodium bromide. The pH of the oxidation reaction was 9, the reaction temperature was 30℃, and the reaction time was 8 h.

[0078] The condensation reaction time in step (3) is 18 hours.

[0079] The final product yield was 65.3%.

[0080] The synthesis method used in this invention has relatively mild conditions. Previous synthesis methods used highly reactive intermediates such as acid anhydrides and acyl chlorides, which are not easy to preserve and are prone to deterioration when exposed to water or moisture. However, the intermediates involved in the process route of this invention are relatively stable and easy to preserve. Compared with the yield reported in the literature (more than 20%), the yield of this route can reach more than 60%, which is a significant advantage and is conducive to subsequent industrial scale-up.

[0081] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention (including the claims) is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in the details for the sake of brevity.

[0082] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A method for synthesizing diamide ethers, characterized in that, Includes the following steps: in, for alkyl; (1) Reaction of 1,4-dioxane-2-one (as shown in Formula I) with an amine in an organic solution yields compound Formula II; (2) Compound II is oxidized under the action of an oxidizing agent to obtain compound III; (3) Compound III is condensed with an amine under the action of a condensing agent and a base to obtain the diamide ether shown in Formula V.

2. The synthesis method according to claim 1, characterized in that, The amine is a dialkylamine.

3. The synthesis method according to claim 2, characterized in that, The dialkylamine is dioctylamine or di(2-ethylhexyl)amine.

4. The synthesis method according to claim 1, characterized in that, The organic solution in step (1) is one of N,N-dimethylformamide, n-heptane, toluene, benzene and xylene.

5. The synthesis method according to claim 1, characterized in that, The reaction temperature in step (1) is 80~120℃ and the reaction time is 3~12h.

6. The synthesis method according to claim 1, characterized in that, The oxidant in step (2) also includes an oxidizing agent, wherein the oxidant is a sodium hypochlorite solution with a concentration of 2-10% and 1.2-5 eq, and the oxidizing agent is a mixture of 0.02-0.05 eq Tempo and 0.05-0.15 eq sodium bromide.

7. The synthesis method according to claim 1, characterized in that, The oxidation reaction in step (2) has a pH of 7-9, a reaction temperature of 0-30℃, and a reaction time of 2-8h.

8. The synthesis method according to claim 1, characterized in that, The condensing agent in step (3) is at least one of EDCl, HOBt, HATU, HBTU, TBTU, and PyBOP, and the base is at least one of N,N-diisopropylethylamine, triethylamine, and N-methylmorpholine.

9. The synthesis method according to claim 1, characterized in that, The condensation reaction time in step (3) is 4~18h.

10. A diamide ether, characterized in that, It is synthesized using the synthesis method described in any one of claims 1 to 9.

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