CN101812054B - 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazole-5-radial)piperidine-1-radical)propyl)-4-amide derivative and preparation method thereof - Google Patents

Abstract

The present invention relates to 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazol-5-yl)piperidine-1-yl) represented by general formula (I) Base) propyl) 4-amide and derivatives thereof, wherein R ¹ represents -H, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -NO ₂ or -CN ; R ² represents -H, -CH ₃ , -Cl, -NO ₂ or -CN; R ³ represents -CH ₃ or -CF ₃ . The present invention also relates to a preparation method of the compound, which uses substituted aniline and 1-bromo-3 chloropropane as raw materials to synthesize N-chloroalkyl substituted aniline, and reacts the compound with N-acetyl piperidine chloride to prepare intermediate 1-acyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide, and then react with 4-(3-substituted phenyl-1-hydropyrazol-5-yl)piperidine The corresponding 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-hydrogen-pyrazol-5-yl)piperidin-1-yl)propyl)-4 - amides, compounds of the present invention are used in the preparation of HIV-1 inhibitors.

Description

1-Acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazol-5-yl)piperidin-1-yl)propyl)-4-amide derivative substances and their preparation methods

technical field

The present invention relates to 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazol-5-yl)piperidin-1-yl)propyl)-4 - Amide derivatives and methods for their preparation. the

Background technique

AIDS is a major infectious disease that gradually destroys the human immune system and seriously threatens human health and survival. Since it was first discovered in 1981, it has spread rapidly around the world. By the end of 2009, there were 33 million surviving HIV-1 infections worldwide. In 2009, the number of new infections was 2.7 million, and 2 million died. The cumulative global HIV/AIDS is about 70 million people. the

HIV-1 (Human Immunodeficiency Virus-I), which belongs to retroviruses, is a virus that causes AIDS (Acquired Immunodeficiency Syndrome, AIDS). the

HIV-1 targets CD4-positive cell populations such as helper T cells, macrophages, and dendritic cells, etc., and destroys these immunocompetent cells, resulting in immunodeficiency. the

Therefore, drugs that eradicate HIV-1 in the body or inhibit its replication can be effective in treating or preventing AIDS. the

FDA-approved drugs for the treatment of AIDS include the following types: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors Fusion inhibitors, co-receptor inhibitors, and integrase inhibitors. The use of these drugs can effectively prolong the lives of AIDS patients. At present, "Highly Active Antiretroviral Therapy (HAART)", which is widely used in the treatment of AIDS, can delay the onset and significantly reduce the mortality rate. For example, two reverse transcriptase inhibitors (zidovudine and didanosine) have been used in combination clinically, and reverse transcriptase inhibitors (zidovudine and lamivudine) and protease inhibitors ( Nelfinavir) three agents, etc. (See The HIV-1 trial guide: a guide to major studies, trials and acronyms of HIV-1 antiretroviral therapy (1985-2004), Boehringer Ingelheim, 2004). the

However, some currently used drugs can cause side effects such as liver failure, central nervous disturbances such as dizziness. In addition, long-term use will cause problems such as serious drug resistance. Drugs with new targets of action need to be investigated. the

Since the discovery that CCR5 and CXCR4 are key coreceptors for HIV-1 entry into cells (Alkhatib et al., 1996; Choe et al., 1996; Deng et al., 1996; Doranz et al., 1996; Dragic et al., 1996 ; Feng et al., 1996; Oberlin et al., 1996; Zhang et al., 1998), inhibiting HIV-1 entry into cells by preventing the combination of viral envelope glycoprotein gp120 and CCR5 by drugs is a hot topic of research, Maraviroc It is currently the only approved AIDS drug targeting CCR5. Many naturally occurring ligands as CCR5 receptors can prevent HIV-1 from entering cells, including CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) (Cocchi et al., 1995), these chemokines Prevent virus infection by blocking the combination of envelope protein and CCR5 (Alkhatib et al., 1997). Because peptides are not suitable for oral administration and high production costs, small molecule CCR5 inhibitors have become a hot spot in current anti-HIV-1 drug research. Piperidine amide derivatives are small molecule inhibitors against CCR5 (Shinichi et al., 2005), and are a class of HIV-1 inhibitors with good research prospects. the

Piperidine or piperazine compounds used as CCR5 receptor antagonists are described in WO 2003/042177, US09/30518, WO 2006/060919, GB 0301575.7, WO 2007/100739, WO 2000/066559, WO 00/66558, CN 101412692A Disclosed in and CN 1706824A. the

Contents of the invention

The object of the present invention is to provide 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazol-5-yl)piperidin-1-yl)propyl )-4-amide derivatives and methods for their preparation. the

The present invention provides 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazol-5-yl)piperidine-1-yl) represented by formula (I) Base) propyl) -4-amide derivatives and preparation methods thereof. the

Wherein, R ¹ represents -H, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -NO ₂ or -CN;

R ² represents -H, -CH ₃ , -Cl, -NO ₂ or -CN;

R ³ represents -CH ₃ or -CF ₃ .

1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazol-5-yl)piperidin-1-yl)propyl) provided by the present invention - Preparation method of amide derivatives, when R ¹ represents -H, -F, -Cl, -Br, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -NO ₂ or -CN; R ² represents - H, -CH ₃ , -Cl, -NO ₂ or -CN; when R ³ represents -CH ₃ or -CF ₃ , the following steps are included:

a) Representing substituted aniline as initial product with formula (II), and reacting with 1-bromo-3 chloropropane represented by formula (III) under the action of organic solvent and alkali, the substance of compound of formula (II) and formula (III) The amount ratio is 1: 1～2, 60～80 ℃ of temperature of reaction, 1～12 hours of reaction time, obtain the N-chloroalkyl substituted aniline represented by formula (IV);

R ² means the same as above;

b) The compound represented by formula (V) is added to the acid anhydride, the substance ratio of the compound of formula (V) to the acid anhydride is 1:3-5, the reaction temperature is 50-110°C, and the reaction time is 4-6 hours, to obtain N-acetyl pipecolic acid or N-trifluoroacetyl pipecolic acid represented by formula (VI);

R ³ means the same as above;

c) Add 10 mL of thionyl chloride to 0.01 mmol of the compound represented by formula (VI), and remove excess thionyl chloride under reduced pressure after reflux for 4 to 5 hours to obtain its acid chloride (VII). After cooling, add 15 mL of Dichloromethane spare;

R ³ same as above;

N-chloroalkyl substituted aniline (IV) and N-substituted piperidine acid chloride (VII) are reacted under the effect of organic solvent and alkali, and the substance ratio of formula (IV) and formula (VII) compound is 1: 2～4, the reaction temperature is 0 ℃ to room temperature, the reaction time is 8～12 hours, and the 1-acyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide represented by the formula (VIII) is generated ;

R ³ same as above;

D) the substituted benzaldehyde represented by formula (IX) and formula (X) is reacted under the effect of organic solvent and alkali to prepare the 2-benzyl-3-quinuclidinone represented by formula (XI), formula ( The molar ratio of IX) and the compound of formula (X) is 1: 1.5～2, and the temperature of reaction is 60～80 ℃, and the reaction time is 3～4 hours;

R ¹ means the same as above;

e) reacting the (XI) compound with hydrazine hydrate in an organic solvent to obtain the substituted 1-acetyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide represented by the formula (XII), The ratio of formula (XI) and the amount of hydrazine hydrate substance is 1: 2～4, the reaction temperature is 110～180 ℃, and the reaction time is 4-12 hours;

R ¹ same as above;

f) reacting the compound represented by formula (VIII) with the compound represented by formula (XII) under the action of an organic solvent and a base to prepare the compound represented by formula (I). The substance ratio of compound VIII and compound XII is 3:1-3, the reaction temperature is 30-80°C, and the reaction time is 5-24 hours to obtain. Wherein, the groups represented by R ¹ , R ² and R ³ are the same as above.

The organic solvent described in step (a) is halogenated hydrocarbon, aromatic hydrocarbon, ketone or their mixed solvent, preferably chloroform, methylene dichloride, ethylene dichloride, benzene, toluene or acetone; Described alkali is inorganic alkali or An organic base, preferably pyridine, a tertiary amine, sodium bicarbonate or potassium bicarbonate. the

The acid anhydride described in (b) in step (b) is acetic anhydride or trifluoroacetic anhydride. the

The organic solvent described in step (c) is halogenated hydrocarbon, aromatic hydrocarbon, ketone or their mixed solvent, preferably chloroform, methylene dichloride, ethylene dichloride, acetone or toluene; Described base is inorganic base or organic base , preferably a tertiary amine, sodium bicarbonate or potassium bicarbonate. the

The organic solvent described in step (d) is ether, halogenated hydrocarbon, aromatic hydrocarbon, alcohol or their mixed solvent, preferably ethylene glycol, chloroform, methylene chloride, ethanol or toluene. the

The organic solvent described in step (e) is halogenated hydrocarbon, aromatic hydrocarbon, alcohol or their mixed solvent, preferably chloroform, methylene dichloride, ethylene dichloride, ethylene glycol or toluene; Described alkali is inorganic alkali or An organic base, preferably a tertiary amine, potassium hydroxide or potassium bicarbonate. the

The organic solvent described in step (f) is acetonitrile, aromatic hydrocarbon, ketone or their mixed solvents, preferably acetonitrile, methylene dichloride, ethylene dichloride, acetone or toluene; Described base is inorganic base or organic base, preferably Tertiary amine, sodium bicarbonate or potassium bicarbonate. the

1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazol-5-yl)piperidin-1-yl)propyl)- The chemical reaction formula for the synthesis of 4-amide derivatives is:

R ¹ , R ² , R ³ are the same as above.

The method of the invention uses common industrial reagents and conventional production conditions, and the reaction conditions are mild. the

Detailed ways

Example 1

a) Preparation of N-chloropropaneaniline:

At room temperature, add aniline (0.05mol), 1-bromo-3-chloropropane (0.05mol), KI (0.005mol), and 30mL acetonitrile into a three-necked flask, install a reflux condenser, and heat to 80°C under stirring. After reacting for 3 hours, cool to room temperature, filter, and distill off the solvent under reduced pressure. The residue is purified by column chromatography to obtain N-chloropropaneaniline. Yield: 65%. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ7.22-7.17(m, 2H), 6.75-6.71(m, 1H), 6.62-6.59(m, 2H), 3.65(brs, 1H), 3.62- 3.59(m, 2H), 3.28(t, J=6.6Hz, 2H), 2.04-1.98(m, 2H); Electrospray mass spectrometry ESI-MS=169.8[M+H] ⁺

b) Preparation of N-acetyl-4-piperidinecarboxylic acid:

4-piperidinecarboxylic acid (0.05mol, 6.5g) was dissolved in 30mL of acetic anhydride, heated to 110°C, reacted for 4 hours and then concentrated under reduced pressure to obtain yellow solid N-acetyl-4-piperidinecarboxylic acid. the

The pure product is a white solid with a yield of 81% and a melting point of 178-180°C. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ4.41-4.38(m, 1H), 4.31-4.78(m, 1H), 3.21-3.14(m, 1H), 2.91-2.84(m, 1H), 2.61-2.56(m, 1H), 2.12(s, 3H), 2.01-1.96(m, 2H), 1.75-1.66(m, 2H)

c) Preparation of 1-acetyl-N-(3-chloropropyl) N-phenylpiperidine-4-amide:

Dissolve N-acetyl-4-piperidinecarboxylic acid (5mmol, 0.85g) in 10mL of thionyl chloride, reflux for 4 hours and remove excess thionyl chloride under reduced pressure to obtain compound N-acetyl-4 -piperidinecarbonyl chloride, after cooling, add 15mL of dichloromethane for subsequent use. the

Triethylamine (1.2g, 12mmol) was added to a solution of N-chloropropaneaniline (0.33g, 2mmol) in dichloromethane (20mL), and the dichloromethane of N-acetyl-4-piperidinecarbonyl chloride Methane solution was slowly added dropwise to the stirred solution at 0°C, and after 1 hour, the ice bath was removed and stirred at room temperature for 11 hours, then saturated NaHCO ₃ solution (30mL), hydrochloric acid (30mL, 2molL ^-1 ) and saturated Wash with brine (30 mL), separate the organic phase with a separatory funnel, dry over anhydrous sodium sulfate, and distill under reduced pressure to remove the solvent dichloromethane. The residue is separated and purified by column chromatography.

The pure product is a white solid, yield: 75%. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ7.42-7.34(m, 3H), 7.12-7.10(m, 2H), 4.43(d, J=13.2Hz, 1H), 3.76-3.67(m, 3H), 3.46(t, J=6.8Hz, 2H), 2.77-2.74(m, 1H), 2.32-2.24(m, 2H), 1.97(s, 3H), 1.96-1.91(m, 2H), 1.71 -1.56 (m, 4H); mass spectrum ESI-MS=344.9[M+Na] ⁺

d) Preparation of 2-benzyl-3-quinuclidinone:

3-quinolinone hydrochloride (0.8g, 5mmol) was added in the there-necked flask, then 20mL of absolute ethanol was added, and (0.24g, 6mmol) was added to the absolute ethanol solution of 3-quinolinone hydrochloride ) NaOH, stirred and reacted for half an hour, then added dropwise (0.8mL, 8mmol) benzaldehyde, heated to 60°C after the dropwise addition, cooled to room temperature after 3 hours of reaction, added 50mL of water and continued to stir for half an hour, filtered, and used 20mL Washing with water: ethanol at a volume ratio of 1:1 gave a yellow solid with a yield of 90%. the

e) Preparation of 4-(3-phenyl-1-hydropyrazol-5-yl)piperidine:

2-benzyl-3-quinuclidinone (1.2g, 5mmol) was added into a three-necked flask, then ethylene glycol (30mL) was added, KOH (5g) was added to the reaction system, and stirred to completely dissolve KOH, Then add hydrazine hydrate (0.6mL, 80%) into the there-necked flask. After the dropwise addition, heat to 110°C. After reacting for half an hour, heat to reflux. After reacting for 5 hours, cool to room temperature, add 60mL of water, and stir for half an hour , filtered and dried. the

The pure product is a white solid with a melting point of 182-184°C. The yield is 85%. the

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ12.65(brs, 1H), 7.75(d, J=7.6Hz, 2H), 7.38(t, J=7.6Hz, 2H), 7.27(t , J=7.6Hz, 1H), 6.46(s, 1H), 3.00-2.97(m, 2H), 2.73-2.65(m, 1H), 2.60-2.53(m, 2H), 1.86-1.82(m, 2H ), 1.56-1.49 (m, 2H); mass spectrum ESI-MS=227.8[M+Na] ⁺

f) 1-acetyl-N-phenyl-N-(3-(4-(3-phenyl-1-hydrogen-pyrazol-5-yl)piperidin-1-yl)propanyl)-4- Preparation of amides

To compound 1-acetyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide (0.33g, 1mmol) and compound 4-(3-phenyl-1-hydropyrazole) at room temperature Add KI (0.2g) and K ₂ CO ₃ (0.3g) to a solution of -5-yl)piperidine (0.08g, 0.3mmol) in acetonitrile (30mL), heat to 80°C, react for 24 hours and then cool to room temperature, Remove the solvent by distilling under reduced pressure, wash the residue with water (30mL), extract with ethyl acetate (2×30mL), separate the organic phase with a separatory funnel, dry it over anhydrous sodium sulfate, and distill under reduced pressure to remove the solvent ethyl acetate , and the residue was separated and purified by column chromatography.

The pure product is a yellow oil with a yield of 55%. the

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ12.55(br, 1H), 7.74(d, J=7.6Hz, 2H), 7.52-7.48(m, 2H), 7.43-7.32(m, 5H), 7.29-7.25(m, 1H), 6.46(s, 1H), 4.26(d, J=14.4Hz, 1H), 3.68(d, J=14.4Hz, 1H), 3.63(t, J=6.8 Hz, 2H), 2.87(d, J=11.2Hz, 2H), 2.72-2.69(m, 1H), 2.62-2.58(m, 1H), 2.30(t, J=6.8Hz, 3H), 2.26-2.18 (m, 1H), 1.98-1.86(m, 7H), 1.62-1.57(m, 7H), 1.40-1.36(m, 1H); ¹³ CNMR (100MHz, DMSO-d ₆ , ppm) 173.7, 168.4, 142.6 , 130.3, 129.1, 128.7, 128.4, 127.7, 125.4, 99.3, 55.7, 53.4, 47.5, 31.9, 29.2, 28.5, 25.0, 21.6; mass spectrum ESI-MS=514.2[M+H] ⁺

Example 2

a), b), c) steps are the same as in Example 1. the

d) Preparation of 2-(4-chlorobenzyl)-3-quinuclidinone:

3-quinolinone hydrochloride (0.8g, 5mmol) was added in the there-necked flask, then 20mL of absolute ethanol was added, and (0.24g, 6mmol) was added to the absolute ethanol solution of 3-quinolinone hydrochloride ) NaOH, after stirring and reacting for half an hour, add dropwise (1.4g, 10mmol) of 4-chlorobenzaldehyde, heat to reflux after dropwise addition, cool to room temperature after reacting for 4 hours, add 50mL water and continue stirring for half an hour, filter, Wash with 20 mL of water:ethanol at a volume ratio of 1:1 to obtain a yellow solid with a yield of 90%. the

e) Preparation of 4-(3-(4-chlorophenyl)-1-hydropyrazol-5-yl)piperidine:

2-(4-chlorobenzyl)-3-quinuclidinone (1.3g, 5mmol) was added into a three-necked flask, then ethylene glycol (30mL) was added, KOH (5g) was added to the reaction system, and stirred Dissolve KOH completely, then add hydrazine hydrate (0.3mL, 80%) into the three-neck flask, after the dropwise addition, heat to 110°C, react for 2 hours and cool to room temperature, add 60mL of water, stir for half an hour, filter and dry . the

The pure product is a white solid with a melting point of 186-187°C. The yield is 85%. the

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ12.72(br, 1H), 7.74(d, J=8.4Hz, 2H), 7.43(d, J=8.4Hz, 2H), 6.48(s , 1H), 2.99(d, J=12Hz, 2H), 2.73-2.67(m, 1H), 2.59-2.53(m, 2H), 1.83(d, J=14Hz, 2H), 1.55-1.45(m, 2H)

(f) 1-acetyl-N-phenyl-N-(3-(4-(3-(4-chlorophenyl)-1-hydrogen-pyrazol-5-yl)piperidin-1-yl) Preparation of propanyl)-4-amide

To compound 1-acetyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide (0.35g, 1mmol) and compound 4-(3-(4-chlorophenyl)- Add KI (0.2g) and K ₂ CO ₃ (0.3g) to a solution of 1-hydropyrazol-5-yl)piperidine (0.25g, 1mmol) in acetonitrile (30mL), heat to reflux, react for 5 hours and then cool to room temperature, evaporated under reduced pressure to remove the solvent, the residue was washed with water (30mL), extracted with ethyl acetate (2×30mL), separated the organic phase with a separatory funnel, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent ethyl acetate, and the residue was separated and purified by column chromatography.

The pure product is a yellow oil, and the yield is 50%. the

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ7.77(d, J=8.4Hz, 2H), 7.52-7.48(m, 2H), 7.44-7.39(m, 3H), 7.34(d, J=7.6Hz, 2H), 6.50(s, 1H), 4.27(d, J=12.8Hz, 1H), 3.71(d, J=13.2Hz, 1H), 3.63(t, J=7Hz, 2H), 2.91(br, 2H), 2.7-2.64(m, 2H), 2.37-2.17(m, 5H), 1.94(s, 3H), 1.94-1.89(m, 3H), 1.63-1.56(m, 8H); ¹³ CNMR (100MHz, DMSO-d ₆ , ppm) 173.7, 168.3, 142.6, 132.1, 130.3, 129.1, 128.7, 128.4, 127.1, 99.5, 55.5, 53.2, 47.4, 45.4, 31.6, 29.2, 28.5, 21.6; -MS＝548.2[M+H] ⁺

Implementation example 3

a) Preparation of 3-chloro-N-(3-chloropropyl)aniline

Add 1-bromo-3-chloropropane (0.05mol) and KI (0.005mol) to 3-chloroaniline (1g, 0.1mol) in 30mL acetonitrile solution at room temperature, heat to 80°C, react for 12 hours and then cool to room temperature, Filtration, distillation under reduced pressure to remove the solvent, the residue was purified by column chromatography to obtain 3-chloro-N-(3-chloropropyl)aniline, yield: 30%;

b) The steps are the same as in Example 1. the

c) Preparation of 1-acetyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide

Dissolve N-acetyl-4-piperidinecarboxylic acid (5mmol, 0.85g) in 10mL of thionyl chloride, reflux for 4 hours and remove excess thionyl chloride under reduced pressure to obtain compound N-acetyl-4 -piperidinecarbonyl chloride, after cooling, add 15mL of dichloromethane for subsequent use. the

Triethylamine (1.2g, 12mmol) was added to 3-chloro-N-(3-chloropropane) (0.2g, 1mmol) in dichloromethane (20mL) solution, and N-acetyl-4- The dichloromethane solution of piperidinecarbonyl chloride was slowly added dropwise to the stirred solution at 0°C, and after 1 hour, the ice bath was removed and stirred at room temperature for 7 hours, then saturated NaHCO ₃ solution (30 mL), hydrochloric acid (30 mL, 2molL ^-1 ) and saturated saline (30mL) solution, and the organic phase was separated with a separatory funnel, dried over anhydrous sodium sulfate, distilled under reduced pressure to remove the solvent methylene chloride, and the residue was separated and purified by column chromatography to produce Rate: 60%;

¹ H NMR (400MHz, CDCl ₃ , ppm): δ8.30(d, J=8Hz, 1H), 8.08(t, J=2.2Hz, 1H), 7.70(t, J=8Hz, 1H), 7.58- 7.55(m, 1H), 4.52(d, J=13.2Hz, 1H), 3.89-3.85(m, 2H), 3.80(d, J=13.2Hz, 1H), 3.56(t, J=6.4Hz, 2H ), 2.86-2.83(m, 1H), 2.37-2.33(m, 2H), 2.06(s, 3H), 2.05-2.01(m, 2H), 1.72-1.64(m, 4H)

d), e) steps are the same as in Example 1. the

f) 1-acetyl-N-(3-chlorophenyl)-N-(3-(4-(3-phenyl-1-hydrogen-pyrazol-5-yl)piperidin-1-yl)propane The preparation of base)-4-amide

To compound 1-acetyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide (0.36g, 1mmol) and compound 4-(3-phenyl-1-hydropyrazole) at room temperature Add KI (0.2g) and K ₂ CO ₃ (0.3g) to a solution of -5-yl)piperidine (0.23g, 1mmol) in acetonitrile (30mL), heat to reflux, cool to room temperature after 12 hours of reaction, and decompress Distilled to remove the solvent, the residue was washed with water (30mL), extracted with ethyl acetate (2×30mL), separated the organic phase with a separatory funnel, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent ethyl acetate, leaving The product was separated and purified by column chromatography.

The pure product is a yellow oil with a yield of 55%. the

¹ H NMR (400 MHz, CDCl ₃ , ppm): 7.70-7.68 (m, 2H), 7.39-7.35 (m, 4H), 7.31-7.27 (m, 1H), 7.22 (s, 1H), 7.10-7.07 ( m, 1H), 6.34(s, 1H), 4.52(d, J=13.6Hz, 1H), 3.76(d, J=13.6Hz, 1H), 3.74-3.67(m, 2H), 2.95(d, J =11.2Hz, 2H), 2.84(t, J=11.2Hz, 1H), 2.70-2.64(m, 1H), 2.38-2.32(m, 4H), 2.04(s, 3H), 2.03-1.94(m, 4H), 1.80-1.72 (m, 8H); ¹³ CNMR (100MHz, CDCl ₃ , ppm) 173.8, 168.8, 152.2, 149.0, 143.6, 135.4, 132.3, 130.8, 128.7, 128.6, 128.4, 127.8, 126.5, 125.6, 99.5, 55.9, 53.6, 48.1, 45.5, 40.7, 39.5, 34.2, 31.9, 28.8, 28.3, 25.3, 21.3; mass spectrum ESI-MS=548.2[M+H] ⁺

Implementation example 4

a) Preparation of N-(3-chloropropane)-4-methylaniline

Add 1-bromo-3-chloropropane (0.05mol) and KI (0.005mol) to 4-methylaniline (0.05mol) in 30mL acetonitrile solution at room temperature, heat to 30°C, react for 1 hour, cool to room temperature, filter, The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain N-(3-chloropropanyl)-4-methylaniline with a yield of 80%. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ7.07-7.04(m, 2H), 6.63-6.60(m, 2H), 3.69(t, J=3.2Hz, 2H), 3.67(brs, 1H) , 3.35(t, J=6.8Hz, 2H), 3.31(d, J=6Hz, 3H), 2.13-2.06(m, 2H)

b) The preparation method is the same as in Example 1

c) Preparation of 1-acetyl-N-(3-chloropropyl)-N-(4-methylphenyl)piperidine-4-amide

N-acetyl-4-piperidinecarboxylic acid (5mmol, 0.85g) was dissolved in 10mL of thionyl chloride, and after reflux for 5 hours, excess thionyl chloride was removed under reduced pressure to obtain compound N-acetyl-4 -piperidinecarbonyl chloride, after cooling, add 15mL of dichloromethane for subsequent use. the

Triethylamine (1.2g, 12mmol) was added to a solution of N-(3-chloropropyl)-4-methylaniline (0.37g, 2mmol) in dichloromethane (20mL), and N-acetyl- The dichloromethane solution of 4-piperidinecarbonyl chloride was slowly added dropwise to the stirred solution at 0°C, and after 1 hour, the ice bath was removed and stirred overnight, and then saturated _NaHCO3 solution (30mL), hydrochloric acid (30mL, 2molL ^{- 1} ) washed with saturated saline (30mL), separated the organic phase with a separatory funnel, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent dichloromethane, and the residue was separated and purified by column chromatography.

The pure product is a white solid, yield: 75%, melting point: 99-101°C. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ7.22 (d, J=8Hz, 2H), 7.01 (d, J=8Hz, 2H), 4.46 (d, J=13.6Hz, 1H), 3.76- 3.70(m, 3H), 3.49(t, J=6.8Hz, 2H), 2.82-2.75(m, 1H), 2.38(s, 3H), 2.36-2.26(m, 2H), 2.01(s, 3H) , 1.99-1.94(m, 2H), 1.75-1.71(m, 1H), 1.65-1.56(m, 3H)

D), e) step is with embodiment 1

f) 1-acetyl-N-(3-(4-(3-phenyl-1-hydrogen-pyrazol-5-yl)piperidin-1-yl)propanyl)-N-p-methylphenyl Preparation of -4-amides

To compound 1-acetyl-N-(3-chloropropyl)-N-(4-methylphenyl)piperidine-4-amide (0.34g, 1mmol) and compound 4-(3-phenyl -1-hydropyrazol-5-yl)piperidine (0.23g, 1mmol) in acetonitrile (30mL) solution was added KI (0.2g) and K ₂ CO ₃ (0.3g), heated to reflux, reacted for 10 hours Cool to room temperature, remove the solvent by distillation under reduced pressure, wash the residue with water (30mL), extract with ethyl acetate (2×30mL), separate the organic phase with a separatory funnel, dry over anhydrous sodium sulfate, and remove by distillation under reduced pressure The solvent was ethyl acetate, and the residue was separated and purified by column chromatography.

The pure product is a yellow oil, and the yield is 60%. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ7.70-7.68(m, 2H), 7.36(t, J=7.4Hz, 2H), 7.3-7.26(m, 1H), 7.23(d, J= 7.2Hz, 2H), 7.05(d, J=8Hz, 2H), 6.34(s, 1H), 4.51(d, J=13.2Hz, 1H), 3.76-3.66(m, 3H), 3.10(d, J =10.4Hz, 2H), 2.85-2.71(m, 2H), 2.52-2.49(m, 2H), 2.41(s, 3H), 2.40-2.32(m, 2H), 2.04(s, 3H), 2.01- 1.95(m, 4H), 1.88-1.60(m, 8H)

Mass spectrum ESI-MS=528.2[M+H] ⁺

Implementation Example 5

a) The steps are the same as in Example 4. the

b) Preparation of N-trifluoroacetyl-4-piperidinecarboxylic acid:

Dissolve 4-piperidinecarboxylic acid (0.05mol, 6.5g) in 20mL of trifluoroacetic anhydride, heat to 50°C, react for 6 hours and concentrate under reduced pressure to obtain yellow solid N-trifluoroacetyl-4-piperidinecarboxylic acid . the

The pure product is a white solid with a yield of 81% and a melting point of 115-117°C. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ1H NMR (400MHz, CDCl3) 4.33-4.27 (m, 1H), 3.95 (d, J=14Hz, 1H), 3.34-3.27 (m, 1H), 3.15- 3.08(m, 1H), 2.72-2.65(m, 1H), 2.09-2.03(m, 2H), 1.86-1.74(m, 2H).ESI-MS=247.7[M+Na] ⁺ , 223.3[MH] ^-

c) Preparation of 1-trifluoroacetyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide:

N-trifluoroacetyl-4-piperidinecarboxylic acid (1.2g, 5mmol) was dissolved in 10mL of thionyl chloride, and after reflux for 5 hours, the excess thionyl chloride was removed under reduced pressure to obtain the compound N-acetyl -4-piperidinecarbonyl chloride, after cooling, add 15mL of dichloromethane for later use. the

Triethylamine (1.2g, 12mmol) was added to a solution of N-(3-chloropropyl)-4-methylaniline (0.38g, 2mmol) in dichloromethane (20mL), and N-trifluoroacetyl Dichloromethane solution of phenyl-4-piperidinecarbonyl chloride was slowly added dropwise to the stirred solution at 0°C, and after 1 hour, the ice bath was removed and stirred overnight, and then saturated NaHCO ₃ solution (30 mL), hydrochloric acid (30 mL, 2molL ^-1 ) and saturated brine (30mL) solution, the organic phase was separated with a separatory funnel, dried over anhydrous sodium sulfate, dichloromethane was evaporated under reduced pressure to remove the solvent, and the residue was separated and purified by column chromatography.

The pure product is a white solid, yield: 70%. the

d) Preparation of 2-(4-methoxybenzyl)-3-quinuclidinone:

3-quinolinone hydrochloride (0.8g, 5mmol) was added in the there-necked flask, then 20mL of absolute ethanol was added, and (0.24g, 6mmol) was added to the absolute ethanol solution of 3-quinolinone hydrochloride ) NaOH, after stirring and reacting for half an hour, add dropwise (1.4g, 10mmol) of 4-methoxybenzaldehyde, heat to reflux after the dropwise addition, cool to room temperature after reacting for 4 hours, add 50mL water and continue stirring for half an hour, Filter and wash with 20 mL of water:ethanol at a volume ratio of 1:1 to obtain a yellow solid with a yield of 90%. the

e) Preparation of 4-(3-(4-methoxyphenyl)-1-hydropyrazol-5-yl)piperidine:

2-(4-methoxyphenenyl)-3-quinuclidinone (1.3g, 5mmol) was added to a three-necked flask, then ethylene glycol (30mL) was added, and KOH (5g) was added to the reaction system , stirred to completely dissolve KOH, then added hydrazine hydrate (0.6mL, 80%) into the there-necked flask, after the dropwise addition, heated to 110°C, reacted for half an hour, heated to reflux, reacted for 5 hours and cooled to room temperature, Add 60mL of water, stir for half an hour, filter and dry. the

The pure product is a white solid with a melting point of 181-182°C. The yield is 85%. the

¹ H NMR (400MHz, DMSO-d ₆ , ppm): δ12.50(br, 1H), 7.68-7.65(m, 2H), 6.96-6.94(m, 2H), 6.35(s, 1H), 3.77( s, 3H), 3.00-2.97(m, 2H), 2.70-2.64(m, 1H), 2.59-2.52(m, 2H), 1.84-1.81(m, 2H), 1.55-1.45(m, 2H)

f) N-(3-(4-(3-(4-methoxyphenyl)-1 hydrogen-pyrazol-5-yl)piperidin-1-yl)propanyl)-N-p-methylbenzene Preparation of base-1-(2,2,2-trifluoroacetyl)piperidine-4-amide:

To compound 1-trifluoroacetyl-N-(3-chloropropyl)-N-phenylpiperidine-4-amide (0.4g, 1mmol) and compound 4-(3-(4-methoxy KI (0.2g) and K ₂ CO ₃ (0.3g) were added to a solution of phenyl)-1-hydropyrazol-5-yl)piperidine (0.25g, 1mmol) in acetonitrile (30mL), heated to reflux, and reacted After 8 hours, cool to room temperature, distill under reduced pressure to remove the solvent, wash the residue with water (30mL), extract with ethyl acetate (2×30mL), separate the organic phase with a separatory funnel, dry over anhydrous sodium sulfate and reduce pressure Ethyl acetate was evaporated to remove the solvent, and the residue was separated and purified by column chromatography.

The pure product is a yellow oil, and the yield is 60%. the

¹ H NMR (400MHz, CDCl ₃ , ppm): δ7.59 (d, J=8.8Hz, 2H), 7.24 (d, J=8Hz, 2H), 7.10 (d, J=8.4Hz, 2H), 6.89 (d, J=8.8Hz, 2H), 6.25(s, 1H), 4.40(d, J=13.2Hz, 1H), 3.93(d, J=13.2Hz, 1H), 3.81(s, 3H), 3.70 -3.65(m, 2H), 3.27(d, 2H), 2.94-2.83(m, 2H), 2.75-2.72(m, 2H), 2.61-2.43(m, 4H), 2.39(m, 3H), 2.05 -2.01 (m, 3H), 1.93-1.88 (m, 2H), 1.81-1.68 (m, 5H); ¹³ CNMR (100MHz, DMSO-d ₆ , ppm) δ176.3, 174.1, 159.5, 155.3 (q, J=3.5Hz), 151.8, 147.2, 138.9, 138.7, 130.8, 127.8, 126.9, 124, 114.2, 99.1, 55.3, 55.1, 52.5, 47.2, 44.9, 42.7, 38.7, 32.9, 29.8, 28.8, 27.9, 23.7, 22.5, 21.1. ESI-MS = 612.2[M+H] ⁺ , 609.9[MH] ^-

Implementation example 6: the anti-HIV-1 activity evaluation of the compound of the present invention

Determination of anti-HIV-1 activity of compounds involved in the present invention in TZM-B1 cells. First, an appropriate amount of TZM-B1 cells (3×10 ⁴ /mL) were inoculated into a 96-well plate, and the next day, 100 μL of compound solutions of different concentrations and 100 μL of a virus solution with certain virulence were added to the 96-well plate, and each compound was set at 4 For each concentration, three replicate wells were set up, and cultured in a 5% carbon dioxide incubator at 37°C for 40-48 hours. Then the coeruleus was counted by MAGI test method (single-cycle coeruleus test method), the antiviral activity of the compound was analyzed, and the half maximal inhibitory concentration (IC ₅₀ ) of the compound was calculated by the modified Cole method.

Implementation example 7: Cytotoxicity evaluation of the compounds of the present invention

First, an appropriate amount of TZM-B1 cells (3×10 ⁴ /mL) were inoculated into a 96-well plate, and then 100 μL of compound solutions of different concentrations were added into the 96-well plate, with 4 concentrations for each compound and 3 replicates for each concentration. Wells were incubated at 37° C. in a 5% carbon dioxide incubator for 40 to 48 hours; then the cytotoxicity of the compounds was determined with a CCK8 kit. Add 10 μL of CCK8 solution to each well, incubate at 37°C with 5% carbon dioxide for 1 to 4 hours, measure the absorbance with a microplate reader at 450nm/630nm, calculate the cell growth inhibition rate of the compound, and calculate the half cytotoxic concentration of the compound (CC ₅₀ ).

The HIV-1 in vitro anti-HIV inhibitory activity (IC ₅₀ ) and cytotoxicity (CC ₅₀ ) of the compounds of the examples are shown in the table below.

serial number _IC50 (μM) _CC50 (μM) Example 1 6.55 80.50 Example 2 0.025 5.35 Example 3 0.54 10.80 Example 4 5.50 32.66 Example 5 0.08 8.30

Claims (3)

1. 1-ethanoyl-N-phenyl-N-(3-(4-(3-phenyl-1-H-pyrazoles-5-yl) piperidin-1-yl) the propyl group)-4-amide derivatives being represented by following general formula (I)

Wherein, R ¹expression-H ,-F ,-Cl ,-Br ,-CH ₃,-CH ₂cH ₃,-OCH ₃,-NO ₂or-CN;

R ²expression-H ,-CH ₃,-Cl ,-NO ₂or-CN; R ³expression-CH ₃or-CF ₃.

2. the preparation method of 1-ethanoyl-N-phenyl-N-according to claim 1 (3-(4-(3-phenyl-1-H-pyrazoles-5-yl) piperidin-1-yl) propyl group)-4-amide derivatives, is characterized in that comprising the following steps:

(a) the bromo-3-chloropropane of 1-that the substituted aniline representing with formula (II) and formula (III) represent reacts and makes the N-chloro alkyl substituted aniline that formula (IV) represents under organic solvent and alkali effect, compound (II) and the ratio of amount of substance (III) are 1: 1～2,30～80 ℃ of temperature of reaction, 1～12 hour reaction times;

R ²definition is with the definition in claim 1 formula of (1);

(b) compound formula (V) being represented joins reaction in acid anhydrides and makes the N-acylpiperidine acid representing with (VI), formula (V) compound is 1: 3～5 with the amount of substance ratio of acid anhydrides, temperature of reaction is 50～110 ℃, 4～6 hours reaction times;

R ³definition is with the definition in claim 1 formula of (1);

(c) in the compound that formula (VI) represents, add sulfur oxychloride, after refluxing 4～5 hours, decompression removes excessive thionyl chloride, obtains its acyl chlorides (VII), adds methylene dichloride standby after cooling;

N-chloro alkyl substituted aniline (IV) and N-substituted piperidine acyl chlorides (VII) are reacted to 1-acyl group-N-(3-chloropropane base)-N-Phenylpiperidine-4-acid amides that production (VIII) represents under the effect of organic solvent and alkali, the amount of substance ratio of formula (IV) and formula (VII) compound is 1: 2～4, temperature of reaction be 0 ℃ to room temperature, 8～12 hours reaction times;

R ³definition is with the definition in claim 1 formula of (1);

(d) substituted benzaldehyde formula (IX) compound being represented with formula (X) reacts the peaceful cyclic ketones of 2-benzyl thiazolinyl-3-quinoline that the formula of making (XI) represents under the effect of organic solvent and alkali, the amount of substance ratio of formula (IX) and formula (X) compound is 1: 1.5～2, temperature of reaction is 60～80 ℃, 3～4 hours reaction times;

R ¹definition is with the definition in claim 1 formula of (1);

(e) (XI) compound is reacted in organic solvent to the formula of making (XII) compound with hydrazine hydrate, the ratio of formula (XI) and hydrazine hydrate amount of substance is 1: 2～4, and temperature of reaction is 110～180 ℃, reaction times 4-12 hour;

R ¹definition is with the definition in claim 1 formula of (1);

(f) compound that compound formula (VIII) being represented represents with formula (XII) reacts the compound that the formula of making (I) represents under the effect of organic solvent and alkali; Compound (VIII) and compound (XII)

Amount of substance ratio be 3: 1～3, temperature of reaction is 30～80 ℃, 5～24 hours reaction times wherein, R ¹, R ², R ³the group representing is with described in claim 1;

Organic solvent described in step (a) is one of chloroform, methylene dichloride, ethylene dichloride, benzene, toluene or acetone; Described alkali is pyridine, tertiary amine, sodium bicarbonate or saleratus;

Organic solvent described in step (c) is one of chloroform, methylene dichloride, ethylene dichloride, acetone or toluene; Described alkali is tertiary amine, sodium bicarbonate or saleratus;

The described organic solvent of step (d) is one of ethylene glycol, chloroform, methylene dichloride, ethanol or toluene;

Organic solvent described in step (e) is one of chloroform, methylene dichloride, ethylene dichloride, ethylene glycol or toluene;

One of organic solvent acetonitrile, methylene dichloride, ethylene dichloride, acetone or toluene described in step (f); Described alkali is tertiary amine, sodium bicarbonate or saleratus.

3. according to the method for claim 2, it is characterized in that: the acid anhydrides described in step (b) is diacetyl oxide or trifluoroacetic anhydride.