The preparation method of n-phenethyl-4-anilinopiperidine

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 N-phenethyl-4-piperidone (II) and aniline (III) were reductively aminated with sodium triacetoxyborohydride to obtain 1, with a yield of 62%-88% (US20100016365, US20060...

Examples

preparation example Construction

[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 obtained 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 wide sources of raw materials, cheap and easy to obtain, few by-products, good product purity, high yield and low cost.

Embodiment 1

[0024] The preparation of N-phenethyl-4-piperidone (II):

[0025] Methyl acrylate (688.7g, 8.0mol) and anhydrous methanol (480ml) were mixed and stirred for 30min. A mixture of β-phenylethylamine (2) (387.8g, 3.2mol) and anhydrous methanol (320ml) was added dropwise under ice-cooling, and the internal temperature was controlled not to exceed 40°C. After the addition was complete, the temperature was raised to reflux and stirred for 8 hours. After cooling to room temperature, methanol and excess methyl acrylate were recovered under reduced pressure to obtain N,N-bis(β-methoxycarbonylethyl)phenethylamine (III) (926.0 g, yield 98.5%) as light yellow oily liquid.

[0026] 1 HNMR (500MHz, CDCl3) δ: 7.27(dd, J=9.29, 5.54Hz, 2H), 7.18(t, J=7.44, 7.44Hz, 3H), 3.66(s, 6H), 2.85(t, J=7.14 , 7.14Hz, 4H), 2.70(m, 4H), 2.45(t, J=7.13, 7.13Hz, 4H). MS-EI (m / z, %): 293 (M+, 3.5), 189 (95), 146 (100), 91 (10).

[0027] Add toluene (300ml) and metal sodium wire (22.08g, 0.96mol) into a 300...

Embodiment 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 sieves (75g), absolute ethanol to a 2L autoclave (1000ml), 3146 type Raney-Ni (20g), after purging the air in the kettle with nitrogen, feed hydrogen (pressure 0.4MPa), and react at 60°C for 2h. Cool down to room temperature, remove the solid by suction filtration to obtain a light yellow solution, distill ethanol off under reduced pressure, add petroleum ether (20ml), cool and crystallize, and obtain white crystal I65.6g by suction filtration, 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, 3.43Hz, 3H), 7.15(m, 2H), 6.67(t, J=7.30, 7.30Hz, 1H), 6.58( d, J=7.76Hz, 2H), 3.65(m, 1H), 3.30(s, 1H), 2.94(d, J=11.70Hz, 2H), 2.80(dd, J=10.17, 6.31Hz, 2H), 2.60(m, 2H), 2.18(t, J=10.50, 10.50Hz, H), 2.07(d, J=12.23Hz, 2H), 1.49(dt, J=13.60,...

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 N-phenethyl-4-piperidone (II) and aniline (III) were reductively aminated with sodium triacetoxyborohydride to obtain 1, with a yield of 62%-88% (US20100016365, US20060...

Examples

preparation example Construction

[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 obtained 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 wide sources of raw materials, cheap and easy to obtain, few by-products, good product purity, high yield and low cost.

Embodiment 1

[0024] The preparation of N-phenethyl-4-piperidone (II):

[0025] Methyl acrylate (688.7g, 8.0mol) and anhydrous methanol (480ml) were mixed and stirred for 30min. A mixture of β-phenylethylamine (2) (387.8g, 3.2mol) and anhydrous methanol (320ml) was added dropwise under ice-cooling, and the internal temperature was controlled not to exceed 40°C. After the addition was complete, the temperature was raised to reflux and stirred for 8 hours. After cooling to room temperature, methanol and excess methyl acrylate were recovered under reduced pressure to obtain N,N-bis(β-methoxycarbonylethyl)phenethylamine (III) (926.0 g, yield 98.5%) as light yellow oily liquid.

[0026] 1 HNMR (500MHz, CDCl3) δ: 7.27(dd, J=9.29, 5.54Hz, 2H), 7.18(t, J=7.44, 7.44Hz, 3H), 3.66(s, 6H), 2.85(t, J=7.14 , 7.14Hz, 4H), 2.70(m, 4H), 2.45(t, J=7.13, 7.13Hz, 4H). MS-EI (m / z, %): 293 (M+, 3.5), 189 (95), 146 (100), 91 (10).

[0027] Add toluene (300ml) and metal sodium wire (22.08g, 0.96mol) into a 300...

Embodiment 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 sieves (75g), absolute ethanol to a 2L autoclave (1000ml), 3146 type Raney-Ni (20g), after purging the air in the kettle with nitrogen, feed hydrogen (pressure 0.4MPa), and react at 60°C for 2h. Cool down to room temperature, remove the solid by suction filtration to obtain a light yellow solution, distill ethanol off under reduced pressure, add petroleum ether (20ml), cool and crystallize, and obtain white crystal I65.6g by suction filtration, 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, 3.43Hz, 3H), 7.15(m, 2H), 6.67(t, J=7.30, 7.30Hz, 1H), 6.58( d, J=7.76Hz, 2H), 3.65(m, 1H), 3.30(s, 1H), 2.94(d, J=11.70Hz, 2H), 2.80(dd, J=10.17, 6.31Hz, 2H), 2.60(m, 2H), 2.18(t, J=10.50, 10.50Hz, H), 2.07(d, J=12.23Hz, 2H), 1.49(dt, J=13.60,...

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