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
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above method, reagents such as lithium aluminum hydride and sodium triacetoxybor

Method used

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

Examples

Experimental program
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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 fl...

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)...

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Abstract

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.

Description

technical field [0001] The invention belongs to the field of pharmaceutical engineering, and relates to a preparation method of N-phenethyl-4-anilinylpiperidine, a fentanyl intermediate. Background technique [0002] N-phenethyl-4-anilinopiperidine (I) is a key intermediate for the preparation of the opioid analgesic drug fentanyl, and can also be used in the antifungal drug N-benzyl-N-[1-(2-benzene Synthesis of ethyl)-4-piperidinyl]propylthioamides. [0003] The existing preparation method uses N-phenethyl-4-piperidone (II) as a raw material, forms the corresponding imine with aniline (III), and then reduces it with lithium aluminum hydride and sodium borohydride to obtain the target product I (US20100016365; Bioorg.Med.Chem., 2009, 17(14):5044-5053; Chem.Pharm.Bulletin, 1985, 33(5):1826-1835); [0004] Or obtain 1 by reductive amination of N-phenethyl-4-piperidone (II) and aniline (III) through sodium triacetoxyborohydride, with a yield of 62%-88% (US20100016365, US 2006...

Claims

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Application Information

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IPC IPC(8): C07D211/58
Inventor 虞心红聂海艳曾海峰殷昕柴传柯刘连军谌志华邓泽军
Owner EAST CHINA UNIV OF SCI & TECH
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