Preparation method of N-phenethyl-4-phenylaminopiperidine

A technology of anilinopiperidine and phenethyl, which is applied in the field of preparation of N-phenethyl-4-anilinylpiperidine, an intermediate of fentanyl, can solve the problem of harsh reaction conditions, high price and poor product quality. Stability and other issues, to achieve the effect of less by-products, low cost, and high product purity

Active Publication Date: 2011-11-23
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AI-Extracted Technical Summary

Problems solved by technology

[0006] In the above method, reagents such as lithium aluminum hydride and sodium triacetoxybor...
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The invention relates to a method for preparing N-phenethyl-4-phenylaminopiperidine. The method comprises the main steps of carrying out hydrogenation and amination on N-phenethyl-4-piperidone (structural formula as shown in a formula (II)) and aniline (structural formula as shown in a formula (III)) in ethanol in the presence of Raney Ni at the temperature of 50-100 DEG C so as to obtain the target product. The method for preparing N-phenethyl-4-phenylaminopiperidine has the advantages of cheap and available raw material, less byproduct, good product purity, high yield, low cost and the like.

Application Domain

Organic chemistry

Technology Topic

AnilinePhotochemistry +5


  • Preparation method of N-phenethyl-4-phenylaminopiperidine
  • Preparation method of N-phenethyl-4-phenylaminopiperidine
  • Preparation method of N-phenethyl-4-phenylaminopiperidine


  • Experimental program(7)

Example Embodiment

[0020] In the preparation method of the present invention, thin layer chromatography (TLC) can be used to judge the end point of the preparation reaction (petroleum ether/ethyl acetate=10:1 (v/v)); and the prepared formula I The crude product of the compound shown can be purified by existing conventional purification methods such as recrystallization.
[0021] The method for preparing N-phenethyl-4-anilinopiperidine of the present invention has a wide range of raw material sources, low cost and easy availability, few by-products, good product purity, high yield and low cost.

Example Embodiment

[0023] Example 1
[0024] Preparation of N-phenethyl-4-piperidone (II):
[0025] After mixing methyl acrylate (688.7g, 8.0mol) and anhydrous methanol (480ml), they were stirred for 30 min. Add dropwise a mixture of β-phenethylamine (2) (387.8g, 3.2mol) and anhydrous methanol (320ml) under an ice bath, control the internal temperature to not exceed 40°C, after the dropwise addition, heat to reflux and react for 8h. After cooling to room temperature, methanol and excess methyl acrylate were recovered under reduced pressure to obtain light yellow oily liquid N,N-bis(β-methoxycarbonylethyl)phenethylamine (III) (926.0g, yield 98.5%).
[0026] 1 H NMR (500MHz, CDCl3) δ: 7.27 (dd, J = 9.29, 5.54 Hz, 2H), 7.18 (t, J = 7.44, 7.44 Hz, 3H), 3.66 (s, 6H), 2.85 (t, J = 7.14, 7.14 Hz, 4H), 2.70 (m, 4H), 2.45 (t, J=7.13, 7.13 Hz, 4H). MS-EI (m/z, %): 293 (M+, 3.5), 189 (95), 146 (100), 91 (10).
[0027] Toluene (300ml) and sodium metal wire (22.08g, 0.96mol) were added to a 3000ml three-necked flask, heated to 110°C, stirred and refluxed for 30min, cooled to 40°C, slowly added dropwise anhydrous methanol (8.0ml), stirred for 15min Add N,N-bis(methoxycarbonylethyl)phenethylamine (III) (235.0g, 0.80mol) dropwise, control the temperature not to exceed 60°C, after the dropwise addition, heat to reflux for 3h. TLC tracked the reaction to complete, cooled to room temperature, the solution solidified to obtain Intermediate 3. Add 25% hydrochloric acid (1200ml), reflux in oil bath for 5h, TLC tracked the reaction to complete, cool to room temperature, stir overnight, separate toluene layer, under ice bath conditions The pH of the water layer was adjusted to 12 with 40% sodium hydroxide, and a large amount of light yellow crystalline solid was precipitated. After cooling, suction filtration, petroleum ether was recrystallized to obtain light yellow crystals of 1-phenethyl-4-piperidone 4 (145g, yield) 89.5%), mp: 54.6-56.2°C.
[0028] 1 HNMR (400MHz) δ: 7.28 (t, 5H), 2.86 (dd, J = 13.81, 7.87 Hz, 6H), 2.75 (m, 2H), 2.50 (t, J = 6.11, 6.11 Hz, 4H). MS-EI (m/z, %): 203 (M+, 2.0), 112 (100), 91 (5).

Example Embodiment

[0029] Example 2
[0030] Preparation of N-phenethyl-4-anilinopiperidine (I):
[0031] Add N-phenethyl-4-piperidone (54g, 0.266mol), aniline (27.54, 0.296mol), glacial acetic acid (3.0ml), dry 3A molecular sieve (75g), anhydrous ethanol into a 2L autoclave (1000ml), 3146 Raney-Ni (20g). After the air in the kettle is driven out with nitrogen, hydrogen gas (pressure 0.4MPa) is introduced and reacted at 60°C for 2h. After cooling down to room temperature, the solid was removed by suction filtration to obtain a pale yellow solution. The ethanol was evaporated under reduced pressure, petroleum ether (20ml) was added, cooling and crystallization, and suction filtration to obtain white crystal I 65.6g, yield 88.1%, mp: 99-101 ℃; content 99.5% (HPLC);
[0032] 1 HNMR (400MHz) δ: 7.27 (m, 2H), 7.19 (dd, J = 7.44, 3.43 Hz, 3H), 7.15 (m, 2H), 6.67 (t, J = 7.30, 7.30 Hz, 1H), 6.58 ( d, J = 7.76 Hz, 2H), 3.65 (m, 1H), 3.30 (s, 1H), 2.94 (d, J = 11.70 Hz, 2H), 2.80 (dd, J = 10.17, 6.31 Hz, 2H), 2.60 (m, 2H), 2.18 (t, J = 10.50, 10.50 Hz, H), 2.07 (d, J = 12.23 Hz, 2H), 1.49 (dt, J = 13.60, 13.56, 3.49 Hz, 2H);
[0033] MS-EI (m/z, %): 280 (M+, 5.0), 189 (90), 146 (100), 91 (8).


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