阅读说明：本技术 一种高效地合成重氮化合物的方法 (Method for efficiently synthesizing diazo compound ) 是由 严兆华 周怡 于 2021-10-14 设计创作，主要内容包括：本发明公开了一种高效地合成重氮化合物的方法,该方法以带有活性亚甲基的有机物作为原料,以NaN-(3)作为重氮转移的碱辅助试剂,以CH-(2)Cl-(2)作为反应溶剂、1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)作为碱,并通入硫酰氟(SO-(2)F-(2))气体作为促进剂,密封条件下室温搅拌进行反应；反应结束后,经过滤除去1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)和生成的无机盐、Na-(2)SO-(4)进行干燥除水、再过滤得到粗产物,最后经由柱层析分离得到纯品。本发明使用了非常价廉易得的硫酰氟(SO-(2)F-(2))作为反应促进剂,绿色环保的NaN-(3)作为重氮转移的碱辅助试剂,因其能和反应物充分接触,所以反应的产率较高；反应后副产物仅为易除去且无污染的水和无机盐(SO-(4)～(2-)和F～(-)),是一种绿色高效的反应体系,适用于大规模的工业生产。(The invention discloses a method for efficiently synthesizing a diazo compound, which takes an organic matter with active methylene as a raw material and NaN 3 As an alkali auxiliary reagent for diazo transfer, with CH 2 Cl 2 1, 8-diazabicyclo [5.4.0] as reaction solvent]Undec-7-ene (DBU) as a base and introduction of sulfuryl fluoride (SO) 2 F 2 ) Gas is taken as an accelerant, and the mixture is stirred at room temperature under the sealing condition for reaction; after the reaction, the 1, 8-diazabicyclo [5.4.0] ring was removed by filtration]Undec-7-ene (DBU) and the resulting inorganic salt, Na 2 SO 4 Drying to remove water, filtering to obtain crude product, and separating by column chromatography to obtain pure product. The invention usesSulfuryl fluoride (SO) is very cheap and easily available 2 F 2 ) As a reaction promoter, the NaN which is green and environment-friendly 3 As the alkali auxiliary reagent for diazo transfer, the alkali auxiliary reagent can be fully contacted with reactants, so that the yield of the reaction is high; the byproducts after the reaction are only water and inorganic Salt (SO) which are easy to remove and pollution-free 4 2‑ And F ‑ ) Is a green and efficient reaction system and is suitable for large-scale industrial production.)

1. A method for efficiently synthesizing a diazo compound is characterized in that an organic matter with active methylene is used as a raw material, and NaN is used as₃As an alkali auxiliary reagent for diazo transfer, with CH₂Cl₂1, 8-diazabicyclo [5.4.0] as reaction solvent]Undec-7-ene (DBU) as a base and introduction of sulfuryl fluoride (SO)₂F₂) Gas is taken as an accelerant, and the mixture is stirred at room temperature under the sealing condition for reaction; after the reaction, the 1, 8-diazabicyclo [5.4.0] ring was removed by filtration]Undec-7-ene (DBU) and the resulting inorganic salt, Na₂SO₄Drying to remove water, filtering to obtain a crude product, and finally separating by column chromatography to obtain a pure product;

the reaction equation for the process is as follows:

wherein R is an electron-withdrawing group, including cyano, nitro and carbonyl.

2. The method for efficiently synthesizing a diazo compound according to claim 1, characterized in that: the reaction time is 2-4 h; the reaction temperature is in the range of 0-40 ℃.

3. The method for efficiently synthesizing a diazo compound according to claim 1, characterized in that: the organic matter with active methylene and the NaN₃The molar equivalent ratio of (A) to (B) is 1: 1-2.

4. The method for efficiently synthesizing a diazo compound according to claim 1, characterized in that: the molar equivalent ratio of the organic matter with active methylene to the 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) is 1: 1-3.

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a method for efficiently synthesizing a diazo compound under mild conditions with excellent yield and extremely short reaction time.

Background

Diazo compounds are a widely used component in organic synthesis because they can be used as precursors of carbene-based compounds, which undergo a wide variety of chemical transformations with remarkable chemical regio-and stereoselectivity. Diazo groups are also found in natural products and amino acids, exhibiting unique antibacterial and antitumor activities, in particular stable diazo compounds, in which the electron delocalization at the α -carbon is compatible with adjacent functional groups (such as carbonyl and aromatic groups) and with living systems, have a wide potential for use in chemical biology.

Diazo transfer reactions of active methylene compounds, in which sulfonyl azides are used as diazo transfer reagents, are one of the effective methods for the synthesis of stable diazo compounds, and the reactions are usually carried out in the presence of an excess of an organic base, such as triethylamine. However, some sulfonyl azides, such as p-toluyl azide and trifluoromethanesulfonyl azide, are shock sensitive and highly explosive. For safer reagents, chemists have developed many new sulfonyl azides, including formyl azides, dodecylbenzenesulfonyl azides, polystyrene-supported benzenesulfonyl azides, and heteroaryl sulfonyl azides (e.g., benzotriazole-1-sulfonyl azide). Although these novel sulfonyl azides are generally superior to p-toluyl azide in stability, serious concerns arise regarding the safety of their preparation, such as the development of high explosiveness and toxicity. Hydrazine acid and sulfuryl diazide. In order to overcome these problems of sulfonyl azide, therefore, the development of a novel diazo transfer reagent which is safe, efficient and stable is urgently needed. The novel reagents are preferably solids which are stable at room temperature and can be prepared from inexpensive, convenient starting materials. Compared with other azides, sodium azide has good thermal stability and low explosiveness, facilitates the separation of diazo products, and has less harm to the environment and sufficient harm to the environment due to decomposed substances compared with other organic azides.

The sulfuryl fluoride derivative is usually selected in the reaction process of synthesizing the azide, and has the advantages of good promoting effect, low toxicity, good catalytic selectivity, small using amount and high fluorination yield. Wherein, the sulfonyl fluoride gas is more fully contacted with reactants, and the yield is higher. And the sulfuryl fluoride has low price and small harm to the environment.

Disclosure of Invention

In view of the disadvantages and problems of the prior art, the present invention is directed to providing a method for efficiently synthesizing a diazo compound under mild conditions with excellent yield and extremely short reaction time. Compared with the prior art, the azide selected is an inorganic compound, has little influence on the environment and has higher stability compared with other azides. The selected promoter is sulfuryl fluoride (SO)₂F₂) Compared with other gases, the gas has low price and less harm to the environment.

The invention is realized by the following technical scheme:

a process for synthesizing diazo compound with high efficiency features that the organic substance with active methylene group is used as raw material, and NaN₃As an alkali auxiliary reagent for diazo transfer, with CH₂Cl₂1, 8-diazabicyclo [5.4.0] as reaction solvent]Undec-7-ene (DBU) as a base and introduction of sulfuryl fluoride (SO)₂F₂) Gas is taken as an accelerant, and the mixture is stirred at room temperature under the sealing condition for reaction; after the reaction, the 1, 8-diazabicyclo [5.4.0] ring was removed by filtration]Undec-7-ene (DBU) and the resulting inorganic salts, as Na₂SO₄Drying to remove water, filtering to obtain crude product, and separating by column chromatography to obtain pure product.

Preferably, the reaction time is 2-4h, most preferably 3 h; the reaction temperature is in the range of 0-40 deg.C, most preferably 30 deg.C.

Preferably, the organic substance having active methylene groups is reacted with NaN₃The molar equivalent ratio of (A) is 1: 1-2, and the most preferable is 1: 1.2.

Preferably, the molar equivalent ratio of the organic substance with active methylene to the 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) is 1: 1-3, and most preferably 1: 2.

In the present invention, "organic substance having active methylene group" has a meaning generally understood by those skilled in the art, such as pentanedione and derivatives thereof, diethyl malonate and derivatives thereof, ethyl benzoylacetate and derivatives thereof, cyclohexanedione and derivatives thereof, and the like.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention adopts NaN₃Sulfuryl fluoride/alkali/CH₂Cl₂As a reaction system, the raw materials are cheap and easily available, and the reaction cost is reduced; the used solvent and oxidant are green and clean and are environment-friendly; the byproducts after the reaction are only water and inorganic Salt (SO) which are easy to remove and pollution-free₄ ^2-And F^-) The post-treatment cost is reduced; meanwhile, the organic matter with active methylene can efficiently obtain the product.

(2) The method has the advantages of mild reaction conditions, short reaction time, simple operation and reduced energy consumption; has higher substrate conversion rate and selectivity.

Detailed Description

The discovery uses an organic substance with active methylene as a raw material and NaN₃As an alkali auxiliary reagent for diazo transfer, with CH₂Cl₂1, 8-diazabicyclo [5.4.0] as reaction solvent]Undec-7-ene (DBU) as a base and introduction of sulfuryl fluoride (SO)₂F₂) Gas is taken as an accelerant, and the mixture is stirred at room temperature under the sealing condition for reaction; after the reaction, the 1, 8-diazabicyclo [5.4.0] ring was removed by filtration]Undec-7-ene (DBU) and the resulting inorganic salt, Na₂SO₄Drying to remove water, filtering to obtain crude product, and separating by column chromatography to obtain pure product.

In specific implementation, the liquid reaction solvent can adopt toluene, ethyl acetate, water, dichloromethane, tetrahydrofuran, acetonitrile, ethanol and dimethyl sulfoxide, and dichloromethane is specifically used as the reaction solvent in the embodiment of the invention; the base can be sodium hydroxide (NaOH), triethylamine (Et)₃N), potassium carbonate (K)₂CO₃) Sodium acetate (CH)₃COONa), sodium hydride (NaH), 1, 4-diazabicyclo [2.2.2]Octane (DABCO), pyridine, 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU), sodium methoxide (CH)₃ONa), examples of the invention are 1, 4-diazabicyclo [2.2.2]Octane(DABCO), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) and triethylamine are particularly preferred, in particular 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU) is most preferred as the base.

Organic material using organic material having active methylene group as raw material and NaN₃The molar equivalent ratio of (A) to (B) is 1: 1-2; in the examples of the present invention, it is specifically 1: 1.2. The organic substance having an active methylene group as a raw material is reacted with the 1, 8-diazabicyclo [ 5.4.0%]The molar equivalent ratio of undec-7-ene (DBU) is 1: 1-3, specifically 1: 2 in the embodiment of the invention.

In a specific embodiment, the reaction temperature is 0 ℃, 10 ℃, 20 ℃, 30 ℃ and 40 ℃, and in an embodiment of the present invention, 30 ℃ is particularly preferable. The oxidation reaction time is 2-4h, and is particularly optimal at 3h in the embodiment of the invention.

The present invention will be further described with reference to examples without departing from the spirit or essential characteristics thereof.

Example 1: method for synthesizing 2-azidobenzoyl ethyl acetate compound

In a 25 mL two-necked flask was added 4mL of dichloromethane, followed by additional benzoylacetic acid ethyl ester (110mg, 0.5mmol) and additional NaN₃(39mg, 1.2eq.), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) (75uL, 1.0eq.) with SO while using two straight-path piston straight-bend type fittings with a hose to connect the balloon₂F₂The reaction was stirred at room temperature of 30 ℃ for 3h under sealed conditions with gas. After the reaction was completed, the solid was removed by filtration, dried over anhydrous sodium sulfate to remove water and filtered again, and the solvent was concentrated to obtain a crude product, which was finally separated and purified by column chromatography to obtain 34.9mg of a yellow oily liquid with a yield of 88%.

The reaction equation is as follows:

ethyl 2-azidobenzoylacetate:¹H NMR(400MHz，CDCl₃)67.61-7.55(m，2H)，7.49-7.42(m，1H)，7.36(td，J＝7.6，7.2，1.6Hz，2H)，4.18(qd，J＝7.1，1.6Hz，2H)，1.18(td，J＝7.1，1.7Hz，3H).¹³C NMR(101MHz，CDCl₃)δ186.78(d，J＝1.4Hz)，160.91，137.05，132.20，128.31，127.80，76.11，61.55，14.15.

example 2: method for synthesizing 2-azido-1, 3-diphenyl-1, 3-propanedione compound

In a 25 mL two-necked flask was added 4mL of dichloromethane, followed by 1, 3-diphenyl-1, 3-propanedione (112mg, 0.5mmol) and NaN₃(39mg, 1.2eq.), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) (75uL, 1.0eq.) was introduced with sulfonyl fluoride (SO) while connecting a balloon with a hose using two straight-path piston straight-bent type joints at the same time₂F₂) And (3) stirring and reacting for 2-4h at room temperature of 30 ℃ under a sealed condition. After the reaction was completed, the solid was removed by filtration, dried over anhydrous sodium sulfate to remove water and filtered again, the solvent was concentrated to obtain a crude product, and finally, separation and purification by column chromatography were performed to obtain 85mg of a yellow solid with a yield of 72%.

The reaction equation is as follows:

2-azido-1, 3-diphenyl-1, 3-propanedione:¹H NMR(400MHz，CDCl₃)δ7.55(d，J＝7.5Hz，4H)，7.41(t，J＝7.4Hz，2H)，7.29(t，J＝7.6Hz，4H).¹³C NMR(101MHz，CDCl₃)δ186.44，136.94，132.61，128.37，128.31.

example 3: method for synthesizing 2-azido-1, 3-cyclopentanedione compound

In a 25 mL two-necked flask was added 4mL of dichloromethane, followed by cyclohexanedione (56mg, 0.5mmol) and NaN₃(39mg, 1.2eq.), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) (75uL, 1.0eq.) was introduced with sulfonyl fluoride (SO) while connecting a balloon with a hose using two straight-path piston straight-bent type joints at the same time₂F₂) Gas, sealed condition in 3O chamberStirring and reacting for 2-4h at a moderate temperature. After the reaction is finished, the solid is removed by filtration, anhydrous sodium sulfate is used for drying and dewatering, the filtration is carried out again, the solvent is concentrated to obtain a crude product, and finally, the crude product is separated and purified by column chromatography to obtain a yellow solid with the yield of 50mg of 71%.

The reaction equation is as follows:

2-azido-1, 3-cyclopentadione:¹H NMR(400MHz，CDCl₃)δ2.52(t，J＝6.4Hz，4H)，2.00(p，J＝6.5Hz，2H).¹³C NMR(100MHz，CDCl₃)：δ190.5，36.9，18.6.

example 4: method for synthesizing 2-azido cyclopropane malonate compound

In a 25 mL two-necked flask was added 4mL of methylene chloride, followed by malonic acid cyclopropane (112mg, 0.5mmol), NaN3(39mg, 1.2eq.), 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU) (75uL, 1.0eq.) was introduced with sulfonyl fluoride (SO) while connecting a balloon with a hose using two straight-path piston straight-bent type joints at the same time₂F2) And (3) stirring and reacting for 2-4h at room temperature of 30 ℃ under a sealed condition. After the reaction was completed, the solid was removed by filtration, dried over anhydrous sodium sulfate to remove water and filtered again, the solvent was concentrated to obtain a crude product, and finally, separation and purification by column chromatography were carried out to obtain 68mg of a white solid with a yield of 80%.

The reaction equation is as follows:

2-azidocyclopropanemalonate propane diester:¹H NMR(400MHz，CDCl₃)δ1.75(d，J＝1.0Hz，6H).¹³C NMR(101MHz，CDCl₃)δ161.63-156.74(m)，130.10(d，J＝1.6Hz)，108.78-106.01(m)，26.75.

example 5: method for synthesizing 2-azido diethyl malonate compound

In a 25 mL two-necked flask was added 4mL of dichloromethane, followed by diethyl malonate (76uL, 0.5mmol) and NaN₃(39mg, 1.2eq.), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU) (75uL, 1.0eq.) was introduced with sulfonyl fluoride (SO) while connecting a balloon with a hose using two straight-path piston straight-bent type joints at the same time₂F₂) The reaction was carried out under gas, sealed conditions at 30 ℃ and room temperature with stirring thoroughly for 3 h. After the reaction was completed, extraction and filtration were performed to remove solids and organic reagents dissolved in water, drying over anhydrous sodium sulfate to remove water and filtration were performed again, the solvent was concentrated to obtain a crude product, and finally, separation and purification by column chromatography were performed to obtain 70mg of a yellow oily liquid, which was obtained in 74% yield.

The reaction equation is as follows:

2-azidomalonic acid diethyl ester:¹H NMR(400MHz，CDCl₃)δ4.27(qd，J＝7.1，1.2Hz，4H)，1.29(td，J＝7.1，1.2Hz，6H).¹³C NMR(101 MHz，CDCl₃)δ161.04，61.59，14.30.

example 6: method for synthesizing 2-azido acetoacetic acid tert-butyl ester compound

A25 mL two-necked flask was charged with 4mL of methylene chloride, followed by tert-butyl acetoacetate (81uL, 0.5mmol), NaN3(39mg, 1.2eq.), and 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (DBU) (75uL, 1.0eq.) was introduced with sulfonyl fluoride (SO) while connecting a balloon with a hose using two straight-path piston straight-bent type joints at the same time₂F₂) Gas, and stirring and reacting for 3 hours at room temperature of 30 ℃ under the sealed condition. After the reaction was completed, the solid was removed by filtration, dried over anhydrous sodium sulfate to remove water and filtered again, the solvent was concentrated to obtain a crude product, and finally, separation and purification by column chromatography were carried out to obtain 78mg of a yellow liquid with a yield of 84%.

The reaction equation is as follows:

2-azidoacetoacetic acid tert-butyl ester:¹H NMR(400MHz，CDCl₃)：δ2.45(s，3H)，1.53(s，J＝1.4Hz，9H).¹³C NMR(100MHz，CDCl₃)：δ190.60，160.62，83.25，28.33，28.28.

example 7: method for synthesizing 2-azido-1, 3-indandione compound

In a 25 mL two-necked flask was added 4mL of dichloromethane, followed by 1, 3-indandione (73mg, 0.5mmol) and NaN₃(39mg, 1.2eq.), DBU (75uL, 1.0eq.), and sulfonyl fluoride (SO) were introduced into the balloon while connecting the balloon with a hose by using two straight-way piston straight-bent type joints at the same time₂F₂) The reaction was stirred at room temperature of 30 ℃ for 3h under sealed conditions with gas. After the reaction was completed, the solid was removed by filtration, dried over anhydrous sodium sulfate to remove water and filtered again, the solvent was concentrated to obtain a crude product, and finally, separation and purification by column chromatography were carried out to obtain 53mg of a yellow liquid with a yield of 74%.

The reaction equation is as follows:

2-azido-1, 3-indandione:¹H NMR(400MHz，CDCl₃)δ7.83(dd，J＝5.5，3.1Hz，2H)，7.75(dd，J＝5.6，3.1Hz，2H).¹³C NMR(100MHz，CDCl₃)：δ187.42，143.23，140.01，126.80，135.10.

the foregoing merely represents preferred embodiments of the invention, which are described in some detail and detail, and therefore should not be construed as limiting the scope of the invention. It should be noted that, for those skilled in the art, various changes, modifications and substitutions can be made without departing from the spirit of the present invention, and these are all within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.