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Synthesis method of 1-phenylpyrrolidine

A technology of phenylpyrrolidine and synthesis method, applied in the direction of organic chemistry, etc., can solve the problems of complex synthesis of nanoparticles, very harsh reaction temperature requirements, metal cobalt toxicity, etc., achieve the effect of low experimental operation level and broaden the synthesis method

Pending Publication Date: 2022-06-24
HENAN UNIVERSITY
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Problems solved by technology

[0007] 2) the deoxyamination reaction of aniline and cyclic ether: this reaction first needs aniline, cyclobutyl ether, I 2 , NaH 2 PO 2 Add it into a closed reaction tube, react at a temperature of 160°C for 11 hours, and then separate to obtain 1-phenylpyrrolidine. The reaction temperature of 160°C is very strict, and a slight decrease in the temperature will result in a huge increase in yield. decline, and the by-product has HI, which is highly corrosive, and the treatment process is complicated
[0008] 3) C-N cross-coupling reaction of phenylboronic acid and N-heterocyclic compounds: This reaction uses a new type of nanoparticle as a catalyst, and phenylboronic acid, N-heterocyclic compounds, K 3 PO 4 , distilled water and catalyst react at 60°C for a period of time to obtain the target product, but the synthesis of nanoparticles required for this reaction is complicated, and the metal cobalt used in the catalyst is highly toxic, and the operation process is complicated
[0011] In summary, although 1-phenylpyrrolidine is an important intermediate in organic synthesis, so far, the existing synthetic methods are the reaction of primary aromatic amines as raw materials or the reductive amination of dicarbonyl compounds. , but these methods have limitations in the functional tolerance of the substrate, and require high conditions and complicated operations, which are not conducive to industrial production

Method used

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  • Synthesis method of 1-phenylpyrrolidine
  • Synthesis method of 1-phenylpyrrolidine
  • Synthesis method of 1-phenylpyrrolidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The synthesis of the present embodiment 1-phenylpyrrolidine 1 is:

[0036]

[0037]Under nitrogen atmosphere, copper(II) chloride [2 mg, 0.015 mmol], zinc powder (49 mg, 0.75 mmol), solvent DMF (2 mL), nitrobenzene (51 μL, 0.5 mmol), and nitrobenzene (51 μL, 0.5 mmol) were successively added to a dry 25 mL schlenk reaction tube. ), 1,4-butanediylbis(4-methylbenzenesulfonate) (321 μL, 1 mmol). The reaction was carried out on a heater with a rotating speed of 360 rpm and a temperature of 65 °C for 8 hours. The reaction of the raw materials was detected by TLC, and the reaction was stopped. The reaction mixture was extracted several times with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2. phase, and dried over anhydrous magnesium sulfate, the organic phase was concentrated, and separated by column chromatography with the eluent (ethyl acetate / petroleum ether=50 / 1) to obtain 67 mg of a light yellow liquid with a yield of 94%.

[0038] 1 H N...

Embodiment 2

[0040] The synthesis of present embodiment 1-(p-tolyl)pyrrolidine 2 is:

[0041]

[0042] Under nitrogen atmosphere, copper(II) sulfate [4 mg, 0.025 mmol], zinc powder (49 mg, 0.75 mmol), solvent Toluene (0.5 mL), p-nitrotoluene (69 mg, 0.5 mmol), 1,4-butanediylbis(4-methylbenzenesulfonate) (468 μL, 1.5 mmol). The reaction was carried out on a heater with a rotating speed of 200 rpm and a temperature of 50 °C for 8 hours. The reaction of the raw materials was detected by TLC and the reaction was stopped. The reaction mixture was extracted several times with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2. phase, and dried over anhydrous magnesium sulfate, the organic phase was concentrated, and then subjected to column chromatography with the eluent (ethyl acetate / petroleum ether=50 / 1) to obtain 76 mg of a light yellow liquid with a yield of 94%.

[0043] 1 H NMR (400MHz, CDCl 3 )δ7.01(d,2H),6.54(d,2H),3.25(t,4H),2.27(s,3H),2.05–1.94(m,4H). 13 ...

Embodiment 3

[0045] The synthesis of the present embodiment 1-(4-fluorophenyl)pyrrolidine 3 is:

[0046]

[0047] Under a nitrogen atmosphere, to a dry 25 mL schlenk reaction flask were successively added copper(II) oxalate [3.8 mg, 0.025 mmol], zinc powder (49 mg, 0.75 mmol), solvent NMP (2 mL), 4-fluoronitrobenzene ( 70.5 mg, 0.5 mmol), 1,4-butanediylbis(4-methylbenzenesulfonate) (468 μL, 1.5 mmol). The reaction was carried out on a heater with a rotating speed of 150 rpm and a temperature of 80 °C for 8 hours. The reaction of the raw materials was detected by TLC, and the reaction was stopped. The reaction mixture was extracted several times with a mixture of distilled water and ethyl acetate with a volume ratio of 1:2. phase, and dried over anhydrous magnesium sulfate, the organic phase was concentrated, and then subjected to column chromatography with the eluent (ethyl acetate / petroleum ether=50 / 1) to obtain 77.6 mg of a light yellow liquid with a yield of 94%.

[0048] 1 HNMR (4...

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Abstract

The invention belongs to the technical field of preparation of organic synthesis intermediates, and particularly relates to a synthesis method of 1-phenylpyrrolidine. The synthesis method specifically comprises the following steps: in a nitrogen atmosphere, sequentially adding a catalyst Cu (II), zinc powder and an organic solvent into a dry schlenk reaction tube, then adding an aromatic nitro-compound and 1, 4-butanediyl bis (4-methylbenzenesulfonate), reacting at 50-80 DEG C for 8 hours, and after the aromatic nitro-compound is completely converted, carrying out a reaction at 50-80 DEG C for 2-3 hours, so as to obtain the 1, 4-butanediyl bis (4-methylbenzenesulfonate)-1, 4-butanediyl bis (4-methylbenzenesulfonate). Adding a mixed solution of distilled water and ethyl acetate into the reaction solution for extraction, combining organic phases, adding anhydrous magnesium sulfate for drying, concentrating the organic phases at 40 DEG C, and performing column chromatography to obtain the target product 1-phenylpyrrolidine. The method is simple, low in cost and high in yield, 1-phenylpyrrolidine can be synthesized through one-step reaction, and the existing synthesis technology is widened.

Description

technical field [0001] The invention belongs to the technical field of preparation of organic synthesis intermediates, in particular to a class of organic intermediates 1 prepared from aromatic nitro compounds and 1,4-butanediylbis(4-methylbenzenesulfonate) as substrates - The method of phenylpyrrolidine. Background technique [0002] 1-Phenylpyrrolidine is an important organic synthesis intermediate, which is widely used in scientific research, drug synthesis, alkaloid synthesis, chemical production and other fields. It is widely found in natural alkaloids, tropane drug molecules, and new drug lead compounds. At the same time, these compounds are also commonly used synthetic building blocks in drug synthesis, and are often used in the total synthesis of some other natural products with a wide range of biological activities. Therefore, N-aryl-substituted nitrogen heterocycles similar to 1-phenylpyrrolidine have high application value in organic synthesis and pharmaceutical...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/06C07D401/04C07D409/04
CPCC07D207/06C07D401/04C07D409/04
Inventor 曹中艳张致凯程亚敏吴玉锋许英蔡永红赵晓伟
Owner HENAN UNIVERSITY
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