A process for one-pot synthesis of 3',3'-dimer phosphoramidites

Abstract

The application relates to the fields of biological medicine and production process technology, and particularly relates to a one-pot synthesis process of 3', 3' site dimer phosphoramidite; a one-pot synthesis process of 3', 3' site dimer phosphoramidite, the synthesis steps are as follows: a compound shown in formula 1 is reacted with a phosphorus source and an alkali to obtain an intermediate; after the intermediate is reacted with a nucleophilic reagent, extraction is carried out to obtain 3', 3' site dimer phosphoramidite shown in formula 2; the method for synthesizing 3', 3' site dimer phosphoramidite provided by the application greatly improves the yield, simplifies the reaction steps and the post-reaction treatment process, greatly reduces the cost, shortens the reaction time and the production cycle, and can realize large-scale production.

Description

Technical Field

[0001] This application relates to the fields of biomedicine and manufacturing technology, specifically to a one-pot process for synthesizing 3',3'-position diphosphamide. Background Technology

[0002] Research on nucleic acid drugs with therapeutic potential, targeting the functions and mechanisms of action of different types of nucleic acids, has become a hot area in new drug development. Nucleic acid drugs possess significant advantages such as high therapeutic efficiency, low toxicity, strong specificity, and wide applicability, and are expected to become the third largest type of drug after small molecule chemical drugs and antibody drugs, with broad prospects for future development and application.

[0003] Traditional small molecule drugs and antibody drugs mostly exert their effects by binding to target proteins. However, their development is limited by the druggability of the target proteins. According to Nature, of the approximately 20,000 proteins encoded by the human genome, only 3,000 are druggable, and currently only 700 have corresponding drugs developed. Moreover, antibody drugs typically only target cell membrane and extracellular proteins. In contrast, nucleic acid drugs regulate protein expression through genes, exerting regulatory effects on both intracellular and extracellular proteins as well as cell membrane proteins. Furthermore, the action of most nucleic acid drugs is based on the principle of complementary base pairing, making sequence design of nucleic acid drugs relatively easy once the base sequence of the target gene is known.

[0004] In the process of sequence synthesis, after removing the conventional nucleic acid sequence, there will be corresponding modifications and changes at the 5' end. 5' dinucleotide phosphate is a major research direction. This scheme requires the synthesis of the key raw material 3', 3'-diphosphoamide. This substance has a series of problems such as high synthesis difficulty, low yield and high purification difficulty.

[0005] The following problems exist in the synthesis of 3',3'-position dimerphosphonamide in related technologies: (1) p-Nitrophenyl sulfone is required as an activator, which increases the reaction steps. At the same time, the intermediate needs to be purified, which increases the difficulty of scale-up of the reaction. (2) The final product requires purification by chromatography to obtain a qualified product, and cannot be scaled up for production; (3) The separation yield is only 7%, which is too low.

[0006] Therefore, it is urgent to develop a method for synthesizing 3',3'-position diphosphonamide with a simple synthesis process, high yield, low purification difficulty, and the ability to quickly and effectively synthesize large quantities of raw materials. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this application provides a one-pot process for synthesizing 3',3'-position dimerphosphonamide.

[0008] This application provides a one-pot process for synthesizing 3',3'-position dimerphosphonamide, using the following technical solution: A one-pot process for synthesizing 3',3'-position dimerphosphonamide, the synthesis steps of which are as follows:

[0009] in, B is a natural, non-natural, or modified base; preferably, B is cytosine, uracil, thymine, adenine, guanine, or hypoxanthine. Y is acetyl, benzoyl, isobutyryl, dimethylformamide, or hydrogen; X is a hydroxyl group protected by hydrogen, hydroxyl, fluorine, methoxy, methoxyethoxy, azide, propoxy, tert-butyldimethylsilyl or a hydroxyl group protected by triisopropylsilyloxymethyl. R is N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, tetrahydropyrrolyl, methoxy, ethoxy, methylthio, ethylthio, 2-cyanoethoxy, or 2-cyanoethylthio.

[0010] A one-pot synthesis process for 3',3'-position diphosphonium amide is disclosed, comprising the following steps: dissolving the compound shown in Formula 1 in a reaction solvent, adding a phosphorus source and a base to react and obtain an intermediate; dissolving a nucleophile in a reaction solvent, adding it to the intermediate to react, and then extracting to obtain the 3',3'-position diphosphonium amide shown in Formula 2.

[0011] Preferably, the intermediate is prepared by the following steps: after the compound shown in Formula 1 reacts with a base, a phosphorus source is added under an inert atmosphere to react and obtain the intermediate.

[0012] Preferably, the steps for adding a phosphorus source to carry out the reaction are as follows: add the phosphorus source dropwise at -20℃ to 0℃, and after the addition is complete, react at -20℃ to 0℃ for 10 to 30 minutes, and then raise the temperature to 20℃ to 25℃ to react for 2 to 4 hours.

[0013] Preferably, the phosphorus source is phosphorus trichloride.

[0014] Preferably, the base is at least one of triethylamine, diisopropylethylamine, and pyridine.

[0015] Preferably, the steps for adding the nucleophile to carry out the reaction are as follows: add the nucleophile dropwise at -20℃ to 0℃, and after the addition is complete, adjust the temperature to 0℃ to 25℃ and carry out the reaction for 2 to 4 hours.

[0016] Preferably, the nucleophile is at least one of N,N-dimethylamine, N,N-diethylamine, N,N-diisopropylamine, tetrahydropyrrole, methanol, ethanol, methanethiol, ethanethiol, 3-hydroxypropionitrile, or 3-mercaptopropionitrile.

[0017] Preferably, the solvent used for extraction is n-heptane.

[0018] Preferably, the reaction solvent is at least one selected from acetonitrile, ethyl acetate, dichloromethane, acetone, n-heptane, n-hexane, N,N-dimethylformamide, toluene, and tetrahydrofuran.

[0019] Preferably, the molar ratio of the compound shown in Formula 1, the phosphorus source, and the base is 1:(1~1.2):(3~5); the molar ratio of the compound shown in Formula 1 to the nucleophile is 1:(1~3).

[0020] This application discloses a one-pot process for synthesizing 3',3'-position diphosphine, which yields high-purity diphosphine through two consecutive nucleophilic substitution reactions and one-step recrystallization. This process has good substrate compatibility and is suitable for synthesizing various types of diphosphine.

[0021] In one specific feasible implementation, a one-pot process for synthesizing 3',3'-position dimerphosphonamide includes the following synthesis steps: The nucleoside (the compound shown in Formula 1) was dissolved in 10 times its volume of solvent. A base was added, and the reaction solution temperature (internal temperature) was lowered to -20°C under an inert atmosphere. A phosphorus source was then slowly added dropwise, with the temperature controlled to not exceed 0°C. After the addition was complete, the reaction was carried out at -20°C for 10–30 minutes, then the temperature was raised to 20°C–25°C for 2–4 hours. After the reaction was complete, the temperature was lowered to -20°C. A nucleophile was dissolved in the solvent and slowly added dropwise to the reaction system, with the temperature controlled to not exceed 0°C. After the addition was complete, the temperature was adjusted to 0°C–25°C for 2–4 hours. The reaction was confirmed by liquid chromatography, and the white solid was removed by filtration. The mixture was extracted twice with 10 times its volume of n-heptane. The solvent was removed by concentration. The solid was recrystallized with 2 times its volume of n-heptane and filtered to obtain the product 3',3'-diphosphite (the compound shown in Formula 2).

[0022] Preferably, the reaction solvent is at least one selected from acetonitrile, ethyl acetate, dichloromethane, acetone, n-heptane, n-hexane, N,N-dimethylformamide, toluene, and tetrahydrofuran.

[0023] Preferably, the phosphorus source is phosphorus trichloride.

[0024] Preferably, the base is one or both of triethylamine and diisopropylethylamine.

[0025] Preferably, the nucleophile is at least one of N,N-dimethylamine, N,N-diethylamine, N,N-diisopropylamine, tetrahydropyrrole, methanol, ethanol, methanethiol, ethanethiol, 3-hydroxypropionitrile, or 3-mercaptopropionitrile.

[0026] Preferably, the molar ratio of the compound shown in Formula 1, the phosphorus source, and the base is 1:(1~1.2):(3~5); the molar ratio of the compound shown in Formula 1 to the nucleophile is 1:(1~3).

[0027] This application selects phosphorus trichloride as the phosphorus source and triethylamine as the base to synthesize a dimer intermediate under conditions of -20℃ to 0℃. After the reaction proceeds, a nucleophile is added for subsequent reactions. After the reaction, a high-purity product is obtained by extraction. This avoids the use of chromatography for purification and enables large-scale production at the kilogram level or above.

[0028] In summary, this application has the following beneficial effects: This application provides a one-pot process for synthesizing 3',3'-position diphosphamide, which greatly improves the yield, simplifies the reaction steps and post-reaction processing, significantly reduces costs, shortens reaction time and production cycle, and enables large-scale production. Attached Figure Description

[0029] Figure 1 The mass spectrum of N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-(2-methoxy)ethyl adenosine 3',3' position diphosphonamide prepared in Example 1; Figure 2 The hydrogen spectrum of N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-(2-methoxy)ethyl adenosine 3',3' position dimerphosphamide prepared in Example 1; Figure 3 The phosphorus spectrum of the N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-(2-methoxy)ethyl adenosine 3',3' position diphosphonamide prepared in Example 1. Detailed Implementation

[0030] The following embodiments further illustrate the content of this application, but should not be construed as limiting the application. Any modifications or substitutions made to the methods, steps, or conditions of this application without departing from the spirit and substance of this application are within the scope of this application.

[0031] Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art; unless otherwise specified, the reagents used in the embodiments are all commercially available.

[0032] Example 1:

[0033]

[0034] 73.1 g of N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-(2-methoxy)ethyl adenosine was dissolved in 731 mL of acetonitrile solution. 55.6 mL of triethylamine was added. Under nitrogen protection, the reaction solution temperature (internal temperature) was lowered to -20°C, and 9.2 mL of phosphorus trichloride was slowly added dropwise, keeping the temperature below 0°C. After the addition was complete, the reaction was carried out at -20°C for 30 minutes, then the temperature was raised to 25°C and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20°C, and 28 mL of N,N-diisopropylamine was dissolved in 56 mL of acetonitrile. The N,N-diisopropylamine solution was slowly added dropwise to the reaction system, keeping the temperature below 0°C. After the addition was complete, the temperature was raised to 0°C and the reaction was carried out for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and the mixture was extracted twice with 731 mL of n-heptane. The solvent was then removed by concentration. The remaining solid was recrystallized from 146 mL of n-heptane, and filtered to obtain 50.1 g of product, yield 63%, purity 98.0%. Theoretical molecular weight 1590.65 [(MH)] - The mass spectrometry peak was 1590.53 [(MH)]. - ].

[0035] Example 2:

[0036]

[0037] 68.7 g of N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-methyl-adenosine was dissolved in 680 mL of acetonitrile solution. 55.6 mL of triethylamine was added. Under nitrogen protection, the reaction solution temperature (internal temperature) was lowered to -20 °C, and 9.2 mL of phosphorus trichloride was slowly added dropwise, keeping the temperature below 0 °C. After the addition was complete, the reaction was maintained at -20 °C for 30 minutes, then the temperature was raised to room temperature (25 °C) and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20 °C, and 28 mL of N,N-diisopropylamine was dissolved in 56 mL of acetonitrile. The N,N-diisopropylamine solution was slowly added dropwise to the reaction system, keeping the temperature below 0 °C. After the addition was complete, the temperature was raised to 0 °C and the reaction was carried out for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and the mixture was extracted twice with 680 mL of n-heptane. The solvent was then removed by concentration. The remaining solid was recrystallized from 136 mL of n-heptane and filtered to obtain 45.8 g of product, with a yield of 61% and a purity of 98.2%.

[0038] Example 3:

[0039]

[0040] 66.9 g of N-isobutyryl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-methyl-guanosine was dissolved in 669 mL of acetonitrile solution. 55.6 mL of triethylamine was added. Under nitrogen protection, the reaction solution temperature (internal temperature) was lowered to -20 °C, and 9.2 mL of phosphorus trichloride was slowly added dropwise, keeping the temperature below 0 °C. After the addition was complete, the reaction was maintained at -20 °C for 30 minutes, then the temperature was raised to 25 °C and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20 °C, and 28 mL of N,N-diisopropylamine was dissolved in 56 mL of acetonitrile. The N,N-diisopropylamine solution was slowly added dropwise to the reaction system, keeping the temperature below 0 °C. After the addition was complete, the temperature was raised to 25 °C and reacted for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and the mixture was extracted twice with 669 mL of n-heptane. The solvent was then removed by concentration. The remaining solid was recrystallized from 134 mL of n-heptane and filtered to obtain 41.8 g of product, with a yield of 57% and a purity of 98.8%.

[0041] Example 4:

[0042]

[0043] 56 g of 5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-methyluridine was dissolved in 560 mL of dichloromethane solution. 55.6 mL of triethylamine was added. Under nitrogen protection, the reaction solution temperature (internal temperature) was lowered to -20°C, and then 9.2 mL of phosphorus trichloride was slowly added dropwise, keeping the temperature below 0°C. After the addition was complete, the reaction was maintained at -20°C for 30 minutes, then the temperature was raised to 25°C and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20°C, and 28 mL of N,N-diisopropylamine was dissolved in 56 mL of dichloromethane. The N,N-diisopropylamine solution was slowly added dropwise to the reaction system, keeping the temperature below 0°C. After the addition was complete, the temperature was raised to 25°C and reacted for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and the mixture was extracted twice with 560 mL of n-heptane. The solvent was then removed by concentration. The remaining solid was recrystallized from 112 mL of n-heptane and filtered to obtain 38.7 g of product, with a yield of 62% and a purity of 98.0%.

[0044] Example 5:

[0045]

[0046] 60.1 g of N-acetyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-methylcytidine was dissolved in 600 mL of dichloromethane solution. 55.6 mL of triethylamine was added. Under nitrogen protection, the reaction solution temperature (internal temperature) was lowered to -20°C, and then 9.2 mL of phosphorus trichloride was slowly added dropwise, keeping the temperature below 0°C. After the addition was complete, the reaction was maintained at -20°C for 30 minutes, then the temperature was raised to 25°C and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20°C, and 28 mL of N,N-diisopropylamine was dissolved in 56 mL of dichloromethane. The N,N-diisopropylamine solution was slowly added dropwise to the reaction system, keeping the temperature below 0°C. After the addition was complete, the temperature was raised to 25°C and reacted for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and 600 mL of n-heptane was added twice. The solution was then concentrated to remove the solvent. The remaining solid was recrystallized from 120 mL of n-heptane and filtered to obtain 45.9 g of product, with a yield of 69% and a purity of 98.2%.

[0047] Example 6:

[0048] 73.1 g of N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-O-(2-methoxy)ethyl-adenosine was dissolved in 730 mL of acetonitrile solution. 74 mL of triethylamine was added, and the reaction solution temperature (internal temperature) was lowered to -20 °C under nitrogen protection. Then, 9.2 mL of phosphorus trichloride was slowly added dropwise, maintaining the temperature below 0 °C. After the addition was complete, the reaction was maintained at -20 °C for 30 minutes, then the temperature was raised to 25 °C and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20 °C, and 42 mL of N,N-diisopropylamine was dissolved in 28 mL of acetonitrile. The N,N-diisopropylamine solution was slowly added dropwise to the reaction system, maintaining the temperature below 0 °C. After the addition was complete, the temperature was raised to 25 °C and reacted for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and the mixture was extracted twice with 730 mL of n-heptane. The solvent was then removed by concentration. The remaining solid was recrystallized from 146 mL of n-heptane and filtered to obtain 50 g of product, with a yield of 62% and a purity of 98.7%.

[0049] Example 7:

[0050]

[0051] 65.7 g of N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-deoxyadenosine was dissolved in 657 mL of dichloromethane solution. 55.6 mL of triethylamine was added. Under nitrogen protection, the reaction solution temperature (internal temperature) was lowered to -20 °C, and then 9.2 mL of phosphorus trichloride was slowly added dropwise, keeping the temperature below 0 °C. After the addition was complete, the reaction was maintained at -20 °C for 30 minutes, then the temperature was raised to 25 °C and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20 °C, and 14.2 g of 3-hydroxypropionitrile was dissolved in 28 mL of acetonitrile. The 3-hydroxypropionitrile solution was slowly added dropwise to the reaction system, keeping the temperature below 0 °C. After the addition was complete, the temperature was raised to 25 °C and reacted for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and the mixture was extracted twice with 657 mL of isopropyl ether. The solvent was then removed by concentration. The remaining solid was recrystallized with 146 mL of isopropyl ether and filtered to obtain 37.4 g of product, with a yield of 53% and a purity of 98.5%.

[0052] Example 8:

[0053] 67.5 g of N-benzoyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-2'-fluoro-deoxyadenosine was dissolved in 675 mL of dichloromethane solution. 55.6 mL of triethylamine was added. Under nitrogen protection, the reaction solution temperature (internal temperature) was lowered to -20 °C, and 9.2 mL of phosphorus trichloride was slowly added dropwise, keeping the temperature below 0 °C. After the addition was complete, the reaction was maintained at -20 °C for 30 minutes, then the temperature was raised to 25 °C and reacted for 4 hours. After the reaction was complete, the temperature was lowered to -20 °C, and 14.2 g of 3-hydroxypropionitrile was dissolved in 28 mL of acetonitrile. The 3-hydroxypropionitrile solution was slowly added dropwise to the reaction system, keeping the temperature below 0 °C. After the addition was complete, the temperature was raised to 25 °C and reacted for 4 hours. The reaction was confirmed by liquid chromatography. The white solid was removed by filtration, and the mixture was extracted twice with 675 mL of isopropyl ether. The solvent was then removed by concentration. The remaining solid was recrystallized from 146 mL of isopropyl ether and filtered to obtain 48.6 g of product; yield 67%, purity 99.3%.

[0054] Comparative example:

[0055] 201.0 g of diisopropylaminophosphorus dichloride was dissolved in 1000 mL of tetrahydrofuran. Under nitrogen protection, a tetrahydrofuran solution of p-nitrophenol and triethylamine (347.6 g of p-nitrophenol and 417 mL of triethylamine dissolved in 5000 mL of tetrahydrofuran) was slowly added dropwise. After reacting at room temperature (25 °C) for 2 hours, the solvent was removed by rotary evaporation under reduced pressure. The residue was dissolved in dichloromethane / petroleum ether and separated by column chromatography to give 346 g of intermediate 1, with a yield of 85%.

[0056] 163.3 g of 5-methyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-deoxyuridine and 50.2 g of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) were dissolved in 300 mL of anhydrous acetonitrile. Under nitrogen protection, an acetonitrile solution of intermediate 1 (134.4 g of intermediate 1 dissolved in 300 mL of anhydrous acetonitrile) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature (25 °C) for 30 minutes. The solvent was removed by rotary evaporation under reduced pressure. The residue was dissolved in dichloromethane and separated by column chromatography to give 170.6 g of intermediate 2, with a yield of 70%.

[0057] 121.8 g of intermediate 2 and 25.1 g of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) were dissolved in 150 mL of anhydrous acetonitrile. Under nitrogen protection, a solution of 5-methyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-deoxyuridine in acetonitrile (90 g of 5-methyl-5'-O-[bis(4-methoxyphenyl)phenylmethyl]-deoxyuridine dissolved in 150 mL of anhydrous acetonitrile) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature (25 °C) for 30 minutes. The solvent was removed by rotary evaporation under reduced pressure. The residue was dissolved in dichloromethane and separated by column chromatography to give 116.9 g of product, with a yield of 64%. The overall yield of the three steps was 38.1%.

[0058] The present application provides a one-pot process for synthesizing 3',3'-position dimerphosphamide, which significantly improves the yield and simplifies the reaction steps and post-reaction processing compared with the comparative example.

[0059] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A one-pot process for synthesizing 3',3'-position dimerphosphonamide, characterized in that, The synthesis steps are as follows: ； in, B is cytosine, uracil, thymine, adenine, guanine, or hypoxanthine; Y is acetyl, benzoyl, isobutyryl, dimethylformamide, or hydrogen; X is a hydroxyl group protected by hydrogen, hydroxyl, fluorine, methoxy, methoxyethoxy, azide, propyne, tert-butyldimethylsilyl or a hydroxyl group protected by triisopropylsilyloxymethyl. R is N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, 2-cyanoethoxy, or 2-cyanoeththio. Specifically, the synthesis steps are as follows: the compound shown in Formula 1 is dissolved in a reaction solvent, a phosphorus source and a base are added to react and an intermediate is obtained; The nucleophile RH was dissolved in the reaction solvent, added to the intermediate for reaction, and then extracted and recrystallized to obtain the 3',3'-diphosphamide shown in Formula 2. The phosphorus source is phosphorus trichloride; the alkali is triethylamine.

2. The process for one-pot synthesis of 3',3'-position dimerphosphonamide according to claim 1, characterized in that, The preparation steps of the intermediate are as follows: after the compound shown in Formula 1 reacts with a base, a phosphorus source is added under an inert atmosphere to react and obtain the intermediate.

3. The process for one-pot synthesis of 3',3'-position dimerphosphonamide according to claim 2, characterized in that, The steps for adding a phosphorus source to carry out the reaction are as follows: Add the phosphorus source dropwise at -20℃ to 0℃. After the addition is complete, react at -20℃ to 0℃ for 10 to 30 minutes, then raise the temperature to 20℃ to 25℃ and react for 2 to 4 hours.

4. The process for one-pot synthesis of 3',3'-position dimerphosphonamide according to claim 1, characterized in that, The steps for adding a nucleophile to carry out the reaction are as follows: add the nucleophile dropwise at -20℃ to 0℃. After the addition is complete, adjust the temperature to 0℃ to 25℃ and carry out the reaction for 2 to 4 hours.

5. The process for one-pot synthesis of 3',3'-position dimerphosphonamide according to claim 1 or 4, characterized in that: The nucleophile is at least one of N,N-dimethylamine, N,N-diethylamine, N,N-diisopropylamine, 3-hydroxypropionitrile, or 3-mercaptopropionitrile.

6. The process for one-pot synthesis of 3',3'-position dimerphosphonamide according to claim 1, characterized in that: The molar ratio of the compound, phosphorus source, and base shown in Formula 1 is 1:(1~1.2):(3~5); the molar ratio of the compound shown in Formula 1 to the nucleophile is 1:(1~3).

7. The process for one-pot synthesis of 3',3'-position dimerphosphonamide according to claim 1, characterized in that: The reaction solvent is at least one of acetonitrile, dichloromethane, n-heptane, and n-hexane.

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