Method for continuous preparation of iodine azide and application thereof

Abstract

The application provides a method for continuously preparing iodine azide and application thereof, and comprises the following steps: sending an azide reagent and a quaternary ammonium salt phase transfer reagent into a continuous flow reactor to obtain a mixture A, then reacting the mixture A with an iodine reagent entering the continuous flow reactor to obtain iodine azide, and continuously discharging the iodine azide from the continuous flow reactor during the reaction to obtain the iodine azide. The application utilizes the continuous flow reactor to quickly and efficiently prepare the explosive iodine azide. Compared with the existing sodium azide / ICl technology, the application greatly solves the explosion risk caused by the storage and transfer of a large amount of sodium azide, and greatly improves the safety.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and in particular relates to a method for the continuous preparation of iodine azide and its application. Background Technology

[0002] Organic azide compounds exhibit unique properties due to their reactivity, leading to their wide application in the pharmaceutical and materials fields. They are not only valuable synthetic substrates in organic synthesis but also crucial structural units in bioactive molecules, drug molecules, and high-energy materials. For example, zidovudine, a nucleoside reverse transcriptase inhibitor with azido groups assembled in its drug molecule, was the world's first FDA-approved anti-AIDS drug, and its proven efficacy has made it a fundamental component of "cocktail" therapy. Other drugs containing azido groups include the antiviral reagent deoxyuridine, the anti-HIV drug azid ocytidine, the myeloma treatment drug LI-102, the fluorescent probe reagent naringenin, the antibiotic adecillin, the analgesic azidomorphine, and the antiviral drug chloramphenicol azido. Furthermore, in materials science, organic azide compounds are also used as high-energy plasticizers, as compounds in rocket fuel additives, and as polymers in propellant binders.

[0003] Therefore, the study of synthetic methods for organoazides has attracted great interest from organic synthesizers. One method for introducing azide groups into organic molecules is the addition of azide groups to double bonds. The addition of NaN3 / ICl reagents to double bonds introduces iodine atoms simultaneously with the azide group. The latter serves as a good leaving group, preparing for the subsequent introduction of nucleophiles. However, this method requires the on-site handling of large quantities of solid sodium azide, posing an explosion hazard. Furthermore, the prepared iodine azide exhibits high reactivity and poor stability, creating safety risks associated with batch operations.

[0004] Furthermore, patent application CN1809582A discloses a method for preparing 4'-azidonucleotide derivatives, specifically disclosing a process for preparing iodinated azides: a mixture of benzyltriethylammonium chloride and sodium azide is prepared into a slurry in MeCN. Insoluble sodium chloride is removed by filtration, and the filtrate is washed with MeCN. A MeCN solution of benzyltriethylammonium azide is added to a homogeneous mixture of Vc, 4-NMM, and THF, producing a clear solution. Iodine in THF is slowly added while maintaining the internal temperature at 0-5°C. After the addition is complete, the reaction mixture is aged at 5-10°C for approximately 2 hours. This yields (2S,3S,4R,5R)-4-benzoyloxy-2-azido-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-iodomethyl-tetrahydro-furan-3-yl ester. Sodium azide was also used as a raw material, and the safety risks associated with storing and transferring large quantities of sodium azide could not be avoided.

[0005] To overcome this problem, a preliminary attempt was made to develop a continuous flow technique for the continuous preparation of iodine azide, enabling continuous operation of the addition transformation of carbon-carbon double bonds. A literature search revealed no reports of continuous flow techniques for this type of reaction or functional group transformation. Summary of the Invention

[0006] In view of this, the present invention aims to overcome the defects in the prior art and propose a method for continuous preparation of iodine azide and its application.

[0007] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0008] In a first aspect, the present invention provides a method for the continuous preparation of iodine azide, comprising the following steps:

[0009] A mixture A is prepared by feeding the azide reagent and the quaternary ammonium salt phase transfer reagent into a continuous flow reactor. The mixture A is then reacted with the iodine reagent that has entered the continuous flow reactor to obtain iodine azide. The iodine azide is continuously discharged from the continuous flow reactor during the reaction.

[0010] Preferably, the azide reagent is selected from one or more of sodium azide, tributyltin azide, and trimethylsilyl azide, and more preferably trimethylsilyl azide.

[0011] Preferably, the quaternary ammonium salt phase transfer reagent is selected from tetrabutylammonium bisulfate and / or tetrabutylammonium fluoride, more preferably tetrabutylammonium fluoride.

[0012] Preferably, the iodinated reagent is selected from iodine and / or iodosuccinimide, more preferably iodosuccinimide.

[0013] Preferably, the concentration of the azide reagent is 0.1–1 mol / L, more preferably 0.6 mol / L.

[0014] Preferably, the iodinated reagent is dissolved in a solvent to prepare a concentration of 0.1–1 mol / L, more preferably 0.55 mol / L.

[0015] Preferably, the concentration of the quaternary ammonium salt phase transfer reagent is 0.1-1 mol / L, more preferably 0.45 mol / L.

[0016] Preferably, the diluents for the iodinated reagent and the azide reagent are independently selected from one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, and water, with acetonitrile being the most preferred.

[0017] Preferably, the reaction temperature in the continuous flow reactor is controlled at 0-40℃, more preferably 25℃-30℃.

[0018] Preferably, the temperature control method of the continuous flow reactor is water bath temperature control.

[0019] Preferably, the continuous flow reactor is a coil reactor.

[0020] Preferably, the feed rate of the continuous flow reactor is 1-50 mL / min, more preferably 10-20 mL / min.

[0021] Preferably, the residence time of the azide reagent and the quaternary ammonium salt phase transfer reagent in the continuous flow reactor is 10s-1min, more preferably 20s-30s.

[0022] Preferably, the residence time of the mixture A and iodosuccinimide in the continuous flow reactor is 30s-5min, more preferably 1min-2min.

[0023] Secondly, the present invention provides a method for preparing iodoazidated nucleosides, comprising the following steps:

[0024] The iodide azid obtained by the above preparation method is discharged from the continuous flow reactor and reacted with a 6-position double bond nucleoside compound with the structural formula shown in formula (1) to obtain iodoazid nucleoside.

[0025]

[0026] R1 is selected from H, hydroxyl, alkyl, cyano, and halogen, and Base is selected from uracil, thymine, cytosine, guanine, and adenine.

[0027] Preferably, the concentration of the 6-position double-bonded nucleoside compound is 0.1-2 mol / L, more preferably 1 mol / L.

[0028] Preferably, the diluent for the 6-position double-bonded nucleoside compound is one or more selected from dichloromethane, tetrahydrofuran, N,N-dimethylformamide, and acetonitrile, more preferably acetonitrile.

[0029] Preferably, the reaction time of the iodine azide with the 6-position double-bonded nucleoside compound is 1 hr to 6 hr, more preferably 2 hr to 3 hr.

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] (1) The present invention uses substituted unsaturated nucleosides containing double bonds as raw materials to prepare azidosubstituted nucleosides by reacting with iodine azidoides prepared in a continuous manner. The reaction time is short and it has good group compatibility.

[0032] (2) A series of azidated substituted nucleosides can be prepared according to the preparation method of the present invention. Some substrates have high stereoselectivity after scale-up, the process is stable and reproducible, and the amount of azidating reagent used is small, the safety is high and the environment is friendly, providing an efficient synthetic route for the synthesis of various substituted azidated nucleosides.

[0033] (3) This invention utilizes a continuous flow reactor to rapidly and efficiently prepare explosive iodine azide. Compared with the existing technology using sodium azide / ICl, it greatly solves the explosion risk caused by the large-scale storage and transfer of sodium azide, and significantly improves safety. The use of continuous flow technology results in a shorter reaction time, which improves reaction efficiency and is conducive to industrial scale-up production. Compared with the traditional batch reaction, the continuous reaction can be stopped or terminated at any time according to the actual situation, making operation and control during production more convenient. Detailed Implementation

[0034] Unless otherwise defined, the technical terms used in the following embodiments have the same meanings as commonly understood by those skilled in the art to which this invention pertains. Unless otherwise specified, the experimental reagents used in the following embodiments are conventional biochemical reagents; and the experimental methods described are conventional methods.

[0035] To address the shortcomings of existing technologies that require handling large quantities of solid sodium azide on-site, posing an explosion hazard, and where the prepared iodine azide exhibits high reactivity but poor stability, resulting in batch operation safety risks, this invention provides a continuous method for preparing iodine azide, comprising the following steps:

[0036] A mixture A is prepared by feeding the azide reagent and the quaternary ammonium salt phase transfer reagent into a continuous flow reactor. The mixture A is then reacted with the iodine reagent that has entered the continuous flow reactor to obtain iodine azide. The iodine azide is continuously discharged from the continuous flow reactor during the reaction.

[0037] To improve reaction efficiency, in a preferred embodiment of the present invention, the reaction temperature in the continuous flow reactor is controlled at 0-40°C, more preferably 25°C-30°C. Preferably, the temperature control method of the continuous flow reactor is water bath temperature control. In a preferred embodiment of the present invention, the continuous flow reactor is a coil reactor.

[0038] In the above method, the azide reagent is selected from one or more of sodium azide, tributyltin azide, and trimethylsilyl azide, more preferably trimethylsilyl azide.

[0039] In the above method, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, and water, and more preferably acetonitrile.

[0040] In the above method, the quaternary ammonium salt phase transfer reagent is selected from tetrabutylammonium bisulfate, tetrabutylammonium fluoride, and more preferably tetrabutylammonium fluoride.

[0041] In the above method, the iodinated reagent is selected from iodine and / or iodosuccinimide, more preferably iodosuccinimide.

[0042] In the above method, the concentration of the azide reagent is 0.1–1 mol / L, more preferably 0.6 mol / L.

[0043] In the above method, the iodinated reagent is dissolved in a solvent to prepare a concentration of 0.1–1 mol / L, more preferably 0.55 mol / L.

[0044] In the above method, the concentration of tetrabutylammonium fluoride is 0.1-1 mol / L, more preferably 0.45 mol / L.

[0045] In the above method, to reduce the impact of impurities on the reaction process and increase the reaction rate, the reaction system is kept in a stable flow through the coil in the reactor. The feed rate of the continuous flow reactor is 1-50 mL / min, more preferably 10-20 mL / min.

[0046] In the above method, the reaction time of the mixed solution entering the coil reactor is reasonably set according to the different types of reactant raw materials. In a preferred embodiment of the present invention, the residence time of the azide reagent and the quaternary ammonium salt phase transfer reagent in the continuous flow reactor is 10s-1min, more preferably 20s-30s. In a preferred embodiment of the present invention, the residence time of the mixture A and iodosuccinimide in the continuous flow reactor is 30s-5min, more preferably 1min-2min.

[0047] It should be noted that in the continuous reaction process of the present invention, as the raw material mixed solution continuously enters the continuous flow reactor for reaction, the reaction product iodine azide is also continuously discharged from the continuous flow reactor. In order to achieve continuous discharge of iodine azide, the product discharge method in the existing continuous production process can be used, as long as this continuous discharge method has no adverse effect on the performance of the product iodine azide.

[0048] Secondly, the present invention provides a method for preparing iodoazidated nucleosides, comprising the following steps:

[0049] The iodide azid obtained by the above preparation method is discharged from the continuous flow reactor and reacted with a 6-position double bond nucleoside compound with the structural formula shown in formula (1) to obtain iodoazid nucleoside.

[0050]

[0051] R1 is selected from H, hydroxyl, alkyl, cyano, and halogen, and Base is selected from uracil, thymine, cytosine, guanine, and adenine.

[0052] In the above method, the reaction time of the iodine azide with the 6-position double-bonded nucleoside compound is 1 hr to 6 hr, more preferably 2 hr to 3 hr.

[0053] The effects of the present invention will be described in detail below with reference to the embodiments.

[0054] The specifications of the continuous flow reactor in the following examples are as follows: 10mL PTFE coil R1, 1 / 8” diameter, retention time 30s; 30mL PTFE coil R2, 1 / 8” diameter, retention time 1min; two T-type mixers; one constant temperature water bath; three plunger pumps; and three 100mL feed bottles.

[0055] Example 1: Preparation of 5-methyl-1H-pyrrole[2,3-b]pyridine

[0056] The synthesis route is as follows:

[0057]

[0058] The specific synthesis steps are as follows:

[0059] Add acetonitrile solution of trimethylsilyl azide (TMSN3) (0.6 mol / L, 10 mL), tetrabutylammonium fluoride (TBAF) tetrahydrofuran solution (0.45 mol / L, 10 mL), and iodosuccinimide (NIS) acetonitrile solution (0.55 mol / L, 10 mL) to three separate feeding bottles. Add 3C (1.14 g) dissolved in 5 mL of acetonitrile to the reaction flask and start stirring at room temperature. Maintain the external bath temperature of the coil reactor at 25-35℃, pump 100 mL of acetonitrile into the coil, rinse the coil thoroughly, and connect the three feeding bottles to three plunger pumps respectively. Set the influent flow rate to 10 mL / min, and sequentially turn on the TMSN3 pump, TBAF pump, and NIS pump to feed the materials into the coil reactor. The feed solution from the coil reactor outlet was directly fed into the reaction flask. After all the feed solution was pumped into the reactor, the flow rate was kept constant, and the reaction system was displaced with acetonitrile equal to the volume of the coil reactor. After the displacement was complete, the pump and the coil were turned off. The reaction flask was allowed to react at room temperature for 3 hours. For post-treatment, a 5% sodium thiosulfate solution was slowly added to the system with stirring. After stirring for 10 minutes, 50 mL of ethyl acetate was added for extraction twice. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain 1.6 g of a yellow solid, with a yield of 80%.

[0060] The 1H NMR and mass spectrometry data of compound 4c prepared in Example 1 are as follows:

[0061] 1 H NMR (400MHz, d6-DMSO) δ11.59(s,1H),7.60(dd,J=8.1,2.1Hz,1H),6.90(d,J=5.5Hz,1H),6.36(dd,J=13.8,5.2Hz, 1H),5.72(dd,J=8.1,2.2Hz,1H),5.33(dt,J=53.6Hz,1H),4.46(dt,J=22.4Hz,1H),3.78-3.70(m,2H).ESI-MS:m / z 396.16[MH] - .

[0062] Examples 2-7 were prepared using the starting material compound 3c, trimethylsilyl azide and iodosuccinimide as reagents according to the reaction conditions in Table 1.

[0063] Table 1 Reaction conditions of Examples 1-7

[0064]

[0065] The HPLC purity of the reaction solutions in the above embodiments was statistically analyzed, and the results are shown in Table 2.

[0066] Table 2 HPLC purity of reaction solution

[0067] Serial Number HPLC purity Example 1 77.92％ Example 2 36％ Example 3 19.86％ Example 4 37.74％ Example 5 64.16％ Example 6 86.87％ Example 7 59.10％

[0068] Example 8: Preparation of compound 4a

[0069] The synthesis route is as follows:

[0070]

[0071] Compound 4a was synthesized using the same method as compound 4c in Example 1, with a yield of 50.0%.

[0072] The 1H NMR and mass spectrometry data of the prepared compound 4a are as follows:

[0073] 1 H NMR (400MHz, d6-DMSO) δ11.43(s,1H),7.68(d,J=8.1Hz,1H),6.32(t,J=6.7Hz,1H),6.19(d,J=5.2Hz,1H),5.6 8(d,J=8.0Hz,1H),4.56(q,J=5.6Hz,1H),3.68-3.61(m,2H),2.57-2.51(m,1H),2.35-2.28(m,1H).ESI-MS:m / z 378.21[MH] - .

[0074] Example 9: Preparation of compound 4b

[0075] The synthesis route is as follows:

[0076]

[0077] The synthesis method of compound 4b is the same as that of compound 4c in Example 1, with a yield of 60.3%.

[0078] The 1H NMR and mass spectrometry data of the prepared compound 4b are as follows:

[0079] 1 H NMR (400MHz, d6-DMSO) δ11.48(s,1H),7.75(d,J=8.1Hz,1H),6.29(d,J=5.6Hz,1H),6.07(d,J=7.1H z,1H),5.74-5.71(m,2H),4.50-4.45(m,1H),4.27(t,J=5.4Hz,1H),3.64-3.51(m,2H).ESI-MS:m / z 394.26[MH] - .

[0080] Preparation of compound 4d (Example 10)

[0081] The synthesis route is as follows:

[0082]

[0083] The synthesis method of compound 4d is the same as that of compound 4c in Example 1, with a yield of 52.3%.

[0084] The 1H NMR and mass spectrometry data of the prepared compound at 4d are as follows:

[0085] 1 H NMR (400MHz, d6-DMSO) δ11.41(s,1H),7.50(d,J=1.4Hz,1H),6.35(t,J=6.8Hz,1H),6.18(d,J=5.1Hz,1H),4.6 0(q,J=5.5Hz,1H),3.70-3.63(m,2H),2.57-2.52(m,1H),2.34-2.27(m,1H),1.81(d,J=1.2Hz,3H).ESI-MS:m / z 392.36[MH] - .

[0086] Example 11: Preparation of compound 4e

[0087] The synthesis route is as follows:

[0088]

[0089] The synthesis method of compound 4e is the same as that of compound 4c in Example 1, with a yield of 45.1%.

[0090] The 1H NMR and mass spectrometry data of the prepared compound 4e are as follows:

[0091] 1 H NMR(400MHz,d6-DMSO)δ11.34(s,1H),8.17(d,J=7.6Hz,1H),8.00-8.02(m,2H),7.66-7.61(m,1H),7.50-7.54(m,2H),7.39(s,1H ),6.38-6.35(m,1H),6.23(d,J=5.2Hz,1H),4.59(q,J=6.2Hz,1H),3.76-3.66(m,2H),2.59-2.44(m,2H).ESI-MS:m / z481.39[MH] - .

[0092] Comparative Example

[0093] The same raw materials were used as in Example 2, and the reaction was carried out in a conventional batch reactor. The reaction time was 1 hour longer than that of Example 1, and the amount of azide reagent used was 3 times that used in Example 1.

[0094] As can be seen from the above description, the embodiments of the present invention achieve the following technical effects:

[0095] (1) The use of a continuous flow reactor to rapidly and efficiently prepare explosive iodine azide greatly solves the explosion risk caused by the large-scale storage and transfer of sodium azide compared with the existing technology using sodium azide / ICl, and significantly improves safety.

[0096] (2) Using continuous flow technology, the reaction time is shorter, the reaction efficiency is improved, and it is conducive to industrial scale-up production;

[0097] (3) Compared with traditional batch reaction, continuous reaction can be stopped or terminated at any time according to the actual situation, making operation and control during production more convenient.

[0098] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for the continuous production of iodine azide, characterized in that: The method comprises the following steps: The azide reagent and the quaternary ammonium salt phase transfer reagent are respectively fed into a continuous flow reactor to obtain a mixture A, and then the mixture A is reacted with an iodinating reagent fed into the continuous flow reactor to obtain an iodine azide, and the iodine azide is continuously discharged from the continuous flow reactor during the reaction to obtain the iodine azide. The azide reagent is trimethylsilyl azide; the quaternary ammonium salt phase transfer reagent is tetrabutylammonium fluoride; and the iodinating reagent is iodinated succinimide.

2. The method of claim 1, wherein: The concentration of the azide reagent is 0.1-1 mol / L.

3. The method of claim 1, wherein: The concentration of the azide reagent is 0.6 mol / L.

4. The method of claim 1, wherein: The iodinating reagent is dissolved in a solvent to obtain a solution with a concentration of 0.1-1 mol / L.

5. The method of claim 1, wherein: The iodinating reagent is dissolved in a solvent to obtain a solution with a concentration of 0.55 mol / L.

6. The method of claim 1, wherein: The concentration of the quaternary ammonium salt phase transfer reagent is 0.1-1 mol / L.

7. The method of claim 1, wherein: The concentration of the quaternary ammonium salt phase transfer reagent is 0.45 mol / L.

8. The method of claim 1, wherein: The dilution solvent of the iodinating reagent and the azide reagent is independently selected from one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide and acetonitrile.

9. The method of claim 1, wherein: The dilution solvent of the iodinating reagent and the azide reagent is acetonitrile.

10. The method of claim 1, wherein: The reaction temperature in the continuous flow reactor is controlled at 0-40℃.

11. The method of claim 1, wherein: The reaction temperature in the continuous flow reactor is controlled at 25-30℃.

12. The method of claim 1, wherein: The temperature control mode of the continuous flow reactor is water bath temperature control.

13. The method of claim 1, wherein: The continuous flow reactor is a coil reactor.

14. The method of claim 1, wherein: The feeding speed of the continuous flow reactor is 1-50 mL / min.

15. The method of claim 1, wherein: The feeding speed of the continuous flow reactor is 10-20 mL / min.

16. The method of claim 1, wherein: The residence time of the azide reagent and the quaternary ammonium salt phase transfer reagent in the continuous flow reactor is 10 s-1 min.

17. The method of claim 1, wherein: The residence time of the azide reagent and the quaternary ammonium salt phase transfer reagent in the continuous flow reactor is 20 s-30 s.

18. The method of claim 1, wherein: The residence time of the mixture A and the iodinated succinimide in the continuous flow reactor is 30 s-5 min.

19. The method of claim 1, wherein: The residence time of the mixture A and the iodinated succinimide in the continuous flow reactor is 1 min-2 min.

20. A method for preparing iodoazidated nucleosides, characterized in that: The method comprises the following steps: The iodine azide prepared by the method according to any one of claims 1-19 is discharged from the continuous flow reactor and reacted with a 6-position double bond nucleoside compound as shown in formula (1) to obtain an iodine azide nucleoside; wherein R1 is selected from H, hydroxyl, alkyl, cyano and halogen, and Base is selected from uracil, thymine, cytosine, guanine and adenine.

21. The method of claim 20, wherein: The concentration of the 6-position double bond nucleoside compound is 0.1-2 mol / L.

22. The method of claim 20, wherein: The concentration of the 6-position double bond nucleoside compound is 1 mol / L.

23. The method of claim 20, wherein: The dilution solvent of the 6-position double bond nucleoside compound is selected from one or more of dichloromethane, tetrahydrofuran, N,N-dimethylformamide and acetonitrile.

24. The method of claim 20, wherein: The dilution solvent of the 6-position double bond nucleoside compound is acetonitrile.

25. The method of claim 20, wherein: The reaction time of the iodine azide and the 6-position double bond nucleoside compound is 1 hr-6 hr.

26. The method of claim 20, wherein: The reaction time of the iodine azide and the 6-position double bond nucleoside compound is 2 hr-3 hr.

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