CN109535219A - The piperazine amide derivatives and the preparation method and application thereof of 18 β-enoxolone - Google Patents

The piperazine amide derivatives and the preparation method and application thereof of 18 β-enoxolone Download PDF

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CN109535219A
CN109535219A CN201811582206.4A CN201811582206A CN109535219A CN 109535219 A CN109535219 A CN 109535219A CN 201811582206 A CN201811582206 A CN 201811582206A CN 109535219 A CN109535219 A CN 109535219A
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enoxolone
reaction
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piperazine
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蔡东
孙玉琦
杨殿深
宫益霞
贾云宏
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Jinzhou Medical University
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Abstract

The invention discloses the piperazine amide derivatives of one kind 18 β-enoxolone, have the structure as shown in following formula (III), formula (IV) or formula (V):

Description

The piperazine amide derivatives and the preparation method and application thereof of 18 β-enoxolone
Technical field
The invention belongs to pharmaceutical technology fields, piperazine amide derivatives more particularly, to one kind 18 β-enoxolone and its Preparation method and application.
Background technique
Enoxolone (glycyrrhetinic acid, GA) belongs to pentacyclic triterpenoid, has C=on 11, skeleton O, similar 18-H- oleanane type structure.
Enoxolone structure is there are different optical isomers such as 18 α types, 18 β types, and the drug action of these isomers is simultaneously It is not exactly the same, wherein 18 α-enoxolone drug hepatic targeting, in terms of it is more outstanding compared with 18 β-enoxolone [Beaton J M, Spring F S.J.Chem.Soc., 1955:3126-3129.], but due to 18 αisomers in nature Amount it is few, only account for 3% or so of the natural total amount of enoxolone, therefore the developmental research of enoxolone and its derivative is still with 18 β Based on isomers.18 β-enoxolone also has an extensive pharmacological activity, including the effect of steroids sample, anti-inflammatory anti-allergic effects, Protecting liver and detoxication activity, antitumor action, study of anti-atherogenic effect etc..In recent years, researcher is relatively to enoxolone The modification of system, main purpose are to enhance its anti-inflammatory, anti-oxidant liver protection, anticancer isoreactivity, and reduce or eliminate its false aldosterone Increase disease [Chudzik M, Korzonek-Szlacheta I, Kr ó l W.Molecules, 2015,20 (1): 1610- 1625.].The research and development of 18 β-enoxolone and its derivative have become the research heat of various countries' researcher in recent years One of point.
The preparation method for 18 β of the synthesis-enoxolone piperazine amide derivatives reported at present is mainly by following several:
Sommerwerk etc. [Sommerwerk S, Heller L, Kerzig C, et al.Eur.J.Med.Chem., 2017,127:1-9.] with triterpenes carboxylic acid first with acid anhydrides in the presence of the acid binding agents such as triethylamine, reaction obtains hydroxyl under room temperature The triterpenes carboxylic acid of acetylation, the triterpenes chloride derivative then reacted again with oxalyl chloride, without further purification after directly and Piperazine anhydrous reacts to obtain corresponding piperazine amide derivatives.The method acetylization reaction time is long, is existed using oxalyl chloride and is grasped Control is dangerous, it is difficult to industrialized disadvantage.In addition triterpenes chloride derivative is directly reacted with Piperazine anhydrous, due in piperazine structure Symmetry, bisamide by-product easily generated.Reaction is as follows:
It is 2012, old to gather happiness etc. [old to gather happiness, Li Xueqiang, Li Tiancai waits chemistry journal, 2012,70 (7): 852-858.] Using 18 β-enoxolone as starting material, in EDCl, HOBt, Et3It reacts and is corresponded to anhydrous Piperazine anhydrous under the catalysis of N 18 β-enoxolone piperazine amide derivatives.This method is also commonly present bisamide by-product easily generated, causes yield very low, secondary The difficult disadvantage of product separation.Reaction is as follows:
Guo Chaohui etc. [Guo Chaohui, Li Qian Chinese Pharmacological Bulletin, 1996 (2): 192-192.] reports 18 β-enoxolone Sodium has good inhibiting effect to gram-positive bacteria, and the MIC value to staphylococcus aureus is 1.6 × 10-4It is mol/L, right Alpha streptococcus, beta streptococcus MIC value be 6.3 × 10-4It mol/L, is 1.6 × 10 to the MIC value of Streptococcus mutans- 4It mol/L, is 4.5 × 10 to the MIC value of Bacillus acidi lactici-5mol/L.Krausse etc. [Krausse R, Bielenberg J, Blaschek W, et al.J Antimicrob Chemother, 2004,54 (1): 243-246.] carry out In Vitro Bacteriostasis examination It tests and shows that enoxolone is stronger than the ability that glycyrrhizic acid resists helicobacter pylori, it is not only antibacterial rapid, and also minimal inhibitory concentration is remote Lower than glycyrrhizic acid.
Summary of the invention
The invention solves first technical problem be to provide the piperazine amide derivatives of one kind 18 β-enoxolone.
The invention solves second technical problem be to provide the piperazine amide derivatives of above-mentioned 18 β-enoxolone Preparation method；The preparation method is easy to operate, low in cost, and the product yield in each step is both greater than 90%, is easy to industry Metaplasia produces.
The invention solves third technical problem be to provide the piperazine amide derivatives of above-mentioned 18 β-enoxolone Using.
In order to solve the first technical problem mentioned above, the piperazine amide derivatives of one kind 18 β-enoxolone are invented, are had such as Structure shown in following formula (III), formula (IV) or formula (V):
To solve above-mentioned second technical problem, the piperazine amide of 18 β-enoxolone shown in the above-mentioned formula (III) of the present invention spreads out The preparation method of biology, includes the following steps:
S1, amidation process: in EDCl, HOBt or Et3Under the catalysis of N, 18 β-enoxolone (1) and N-Boc- piperazine exist Reaction is heated in organic solvent, after reaction, slurry is evaporated under reduced pressure to, is poured into water stirring, is filtered, is washed to obtain compound (2)；
S2, esterification: in organic solvent, heating reaction in the presence of base is made for compound (2) and 2- chloroacetic anhydride It obtains compound (III)；
Reaction equation is as follows:
Preferably, in step S1, the organic solvent be ethyl acetate, methylene chloride, chloroform (chloroform), acetonitrile, One or more of N,N-dimethylformamide.
Preferably, in step S1, reaction temperature is 40~100 DEG C；It is highly preferred that reaction temperature is 60~90 DEG C.
Preferably, in step S2, the organic solvent is ethyl acetate, methylene chloride, chloroform, acetonitrile, toluene, diformazan One or more of benzene, ethylbenzene, N,N-dimethylformamide.
Preferably, in step S2, reaction temperature is 80~150 DEG C；It is highly preferred that reaction temperature is 120~130 DEG C.
Preferably, in step S2, the alkali is triethylamine, pyridine, K2CO3、Na2CO3、KHCO3、NaHCO3One of or It is several.
The preparation method of the piperazine amide derivatives of 18 β-enoxolone shown in the above-mentioned formula (IV) of the present invention, including walk as follows It is rapid:
S3, ammoxidation: it in organic solvent by compound (III) and secondary-amine compound, heats in the presence of base Reaction is made compound (IV).
Preferably, in step S3, the organic solvent is ethyl acetate, methanol, dehydrated alcohol, acetone, methylene chloride, chlorine One or more of imitative, acetonitrile.
Preferably, in step S3, the alkali is triethylamine, pyridine, K2CO3、Na2CO3、KHCO3、NaHCO3One of or It is several；
Reaction equation is as follows:
Preferably, in step S3, the R in compound (IV) is one of following structures:
The preparation method of the piperazine amide derivatives of 18 β-enoxolone shown in the above-mentioned formula (V) of the present invention, including walk as follows It is rapid:
S4, decarboxylic reaction: compound (IV) and trifluoroacetic acid are stirred to react in organic solvent, to after reaction, Alkali is added in reaction mixture, filters, solid layer organic solvent washing is evaporated under reduced pressure to 18 β of product-enoxolone piperazine amide Derivative (V), reaction equation is as follows:
Preferably, in step S4, the organic solvent is one or more of ethyl acetate, methylene chloride, chloroform.
Preferably, in step S4, reaction temperature is 0~40 DEG C；It is highly preferred that reaction temperature is 0~10 DEG C.
To solve above-mentioned third technical problem, above-mentioned formula (III) of the invention, (IV), 18 β-enoxolone shown in (V) The application in antibacterial medicines of piperazine amide derivatives.
Preferably, the formula (III), (IV), 18 β-enoxolone shown in (V) piperazine amide derivatives inhibiting large intestine Bacillus (E.coli), pseudomonas aeruginosa (P.aeruginosa), staphylococcus aureus (S.aureus) and bacillus subtilis Application in bacterium (B.subtilis) drug.
Any range documented by the present invention includes any numerical value between end value and end value and end value or end value Between any subrange for being constituted of any number.
Unless otherwise specified, each raw material in the present invention can be obtained by commercially available purchase, equipment used in the present invention The conventional equipment in fields can be used or carried out referring to the prior art of fields.
Compared with prior art, the invention has the following beneficial effects:
Formula (III) of the invention, (IV), 18 β-enoxolone shown in (V) piperazine amide derivatives be brand new Compound, preparation method is also completely new preparation method；The piperazine amide derivatives pair of 18 β-enoxolone of the present invention Escherichia coli (E.coli), pseudomonas aeruginosa (P.aeruginosa), staphylococcus aureus (S.aureus) and withered grass bud Spore bacillus (B.subtilis) all has a strong inhibitory effect.
Specific embodiment
In order to illustrate more clearly of the present invention, below with reference to preferred embodiment, the present invention is described further.Ability Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, this should not be limited with this The protection scope of invention.
Embodiment 1:
S1, amidation process: 4- (3-18 β of beta-hydroxy-11- oxo-olive-12- alkene-30- carbonyl) piperazine-1- carboxylic acid The preparation of the tert-butyl ester (2):
By 18 β-enoxolone (0.47g, 1.0mmol), EDCl (0.23g, 1.2mmol), triethylamine (0.13g, It 1.2mmol) is sequentially added in acetonitrile (20mL) solution with HOBt (0.16g, 1.2mmol), the reaction of mixture return stirring 20min.Then N-Boc- piperazine (0.45g, 2.5mmol) is added in above-mentioned reaction solution, then back flow reaction is for 24 hours.To the end of reacting Vacuum distillation removes remaining solid residues after solvent afterwards, after solid residues are stirred pulp with a small amount of ethyl alcohol, under slowly stirring It pours into the hot water of 10 times of volumes, generates a large amount of solids, filter, wash after solution is cooling, it is dry that compound (2), yield are 94.3%；1H NMR (400MHz, Chloroform-d) δ 5.66 (s, 1H), 3.63-3.52 (m, 4H), 3.39 (t, J= 5.2Hz,4H),3.22-3.18(m,1H),2.79-2.74(m,1H),2.31(s,1H),2.30-2.23(m,1H),1.45(s, 9H),1.34(s,3H),1.20(s,3H),1.11(s,3H),1.10(s,3H),0.98(s,3H),0.79(s,3H),0.78(s, 3H), 0.68 (d, J=11.6Hz, 1H)；13C NMR(101MHz,Chloroform-d)δ200.10,174.13,169.40, 154.53,128.56,80.25,78.75,61.77,54.92,48.08,45.26,43.88,43.82,43.26,39.12, 39.10,37.70,37.06,33.1),32.79,31.75,28.40,28.36,28.07,27.28,27.05,26.69, 26.39,23.14,18.66,17.46,16.36,15.56；HRMS(m/z):[M+H]+calcd.For C39H63N2O5: 639.4737,found:639.4736.
S2, esterification: 4- (3 β-(2- chloroethene acyloxy) -18 β of -11- oxo-olive -12- alkene -30- carbonyl) piperazine The preparation of piperazine -1- carboxylic acid (III):
Water segregator, spherical condensation tube are installed, 2- chloroacetic anhydride (1.37g, 8.0mmol) is added to toluene (20mL) on three-necked bottle 20min is reacted in 130 DEG C of heating in solution, then sequentially adds K2CO3(2.76g, 20.0mmol) and compound (2) (0.64g, 1.0mmol), it is further continued for reaction 1h for 130 DEG C of reaction mixture.Remaining solid is residual after being evaporated under reduced pressure remove solvent after reaction It is remaining, by solid residues it is cooling after, add water (20mL) to stir evenly, generate a large amount of solids, filter, washing, dry compound (III), yield 96.5%；1H NMR (400MHz, Chloroform-d) δ 5.66 (s, 1H), 4.59 (dd, J=11.8, 4.7Hz,1H),4.15–3.97(m,4H),3.65(s,4H),3.52(s,2H),2.85–2.75(m,1H),2.34(s,1H), 2.28 (d, J=12.1Hz, 1H), 1.34 (m, 3H), 1.22 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 0.88 (s, 6H), 0.80(s,3H),0.78(m,1H)；13C NMR(101MHz,chloroform-d)δ199.83,174.27,169.43, 167.13,165.34,128.51,82.99,61.62,54.95,48.06,46.28,45.26,43.93,43.83,43.27, 42.21,41.23,40.65,38.67,38.22,37.67,36.88,33.01,32.68,31.76,28.39,28.00, 27.03,26.65,26.35,23.40,23.11,18.65,17.31,16.60,16.40；HRMS(m/z):[M+H]+ calcd.for C37H56ClN2O6:659.3827,found:659.3873；
S3, ammoxidation: 4- (3 β-(2- morpholino acetoxyl group) -18 β of -11- oxo-olive -12- alkene -30- carbonyl Base) piperazine -1- carboxylic acid (IV a) preparation:
By compound (III) (0.66g, 1.0mmol), morpholine (0.13g, 1.5mmol), K2CO3(0.69g, 5.0mmol) and The I of catalytic amount2It sequentially adds in dehydrated alcohol (15mL), back flow reaction 12h；To be evaporated under reduced pressure removing solvent after reaction Remaining solid residues add water (20mL) to stir evenly after solid residues are stirred pulp with a small amount of ethyl alcohol afterwards, generate a large amount of solid Body filters, washing, dry compound (IV a), yield 91.2%；1H NMR(400MHz,Chloroform-d)δ5.66 (d, J=2.9Hz, 1H), 4.58 (dd, J=11.7,4.3Hz, 1H), 3.70 (t, J=4.5Hz, 4H), 3.60 (s, 8H), 3.26-3.16 (m, 2H), 2.86-2.74 (m, 1H), 2.52 (d, J=5.2Hz, 4H), 2.33 (s, 1H), 2.27 (d, J= 13.2Hz,1H),1.34(s,3H),1.21(s,3H),1.14(s,3H),1.09(s,3H),0.87(s,6H),0.79(s,3H), 0.77(m,1H)；13C NMR(101MHz,Chloroform-d)δ199.84,174.27,169.52,167.71,167.13, 128.48,82.98,66.76,61.62,61.45,54.95,53.44,48.10,45.26,43.91,43.79,43.27, 41.86,41.23,38.66,38.22,37.68,36.87,33.09,32.67,31.76,28.40,28.00,27.04, 26.66,26.36,23.40,23.11,18.64,17.31,16.60,16.40；HRMS(m/z):(M+H+)calcd.for C41H64N3O7:710.4744,found:710.4740；
S4, decarboxylic reaction: 3 β-(2- morpholino acetoxyl group) -18 β of -11- oxo-olive -12- alkene -30- carbonyl piperazine The preparation of piperazine (V a):
Compound (IV a) (0.68g, 1.0mmol) is added to CH2Cl2In (10mL), 0 DEG C of stirring 20min.Then trifluoro The CH of acetic acid (5mL)2Cl2(5mL) solution is slowly added drop-wise in said mixture, is then slowly warmed to room temperature and is stirred for reaction 3h. To use Na after reaction2CO3Saturated solution neutralizes, and filters, solid layer CH2Cl2Washing is depressurized after organic solution is dry and is steamed Evaporate to obtain 18 β of product-enoxolone piperazine amide derivatives (V a), yield 91.7%.1H NMR(400MHz, Chloroform-d) δ 5.70 (t, J=3.2Hz, 1H), 4.60 (dt, J=11.2,4.7Hz, 1H), 3.76 (dt, J=6.7, 3.3Hz, 4H), 3.62 (t, J=5.5Hz, 4H), 3.21 (dd, J=4.5,2.4Hz, 2H), 2.91-2.84 (m, 4H), 2.81 (d, J=13.0Hz, 1H), 2.60 (t, J=5.2Hz, 4H), 2.36 (t, J=3.3Hz, 1H), 2.30 (d, J=13.5Hz, 1H),1.36(s,3H),1.23(s,3H),1.16(s,3H),1.12(s,3H),0.88(s,6H),0.82(s,3H),0.79(s, 1H)；13C NMR(101MHz,cdcl3)δ199.95,173.84,170.01,169.73,128.47,81.03,66.83, 61.65,59.78,54.95,53.30,48.23,46.30,45.28,43.79,43.75,43.28,38.75,38.06, 37.75,36.91,33.40,32.71,31.77,28.43,28.13,27.05,26.71,26.44,23.66,23.11, 18.67,17.37,16.77,16.42；HRMS(m/z):(M+H+)calcd.for C40H64N3O5:666.4846,found: 666.4795.
Embodiment 2:
S1, amidation process: 4- (3-18 β of beta-hydroxy-11- oxo-olive-12- alkene-30- carbonyl) piperazine-1- carboxylic acid The preparation of the tert-butyl ester (2)
18 β-enoxolone (0.47g, 1.0mmol), EDCl (0.23g, 1.2mmol), triethylamine (0.13g, 1.2mmol) CH is sequentially added with HOBt (0.16g, 1.2mmol)2Cl2In (20mL) solution, reaction 20min is stirred at room temperature in mixture.Then N- Boc- piperazine (0.45g, 2.5mmol) is added in above-mentioned reaction solution, then back flow reaction is for 24 hours.After TLC monitoring raw material is totally converted, Only trace compound (2) generates.Vacuum distillation removes remaining solid residues after solvent, and a small amount of ethyl alcohol of solid residues is stirred It after pulp, is poured into the hot water of 10 times of volumes under slowly stirring, generates a large amount of solids, filter, wash after solution is cooling, it is dry It obtains compound (2a), yield 95.8%.HRMS(m/z):[M+H]+calcd.for C36H50N3O4:588.3801,found: 588.3801.
S2, esterification: 4- (3 β-(2- chloroethene acyloxy) -18 β of -11- oxo-olive -12- alkene -30- carbonyl) piperazine The preparation of piperazine -1- carboxylic acid (III)
Compound (2) (0.64g, 1.0mmol), 2- chloroacetic anhydride (1.37g, 8.0mmol) and K2CO3(2.76g, 20.0mmol) it is sequentially added back flow reaction 9h in acetonitrile (20mL) solution.After TLC monitoring raw material is totally converted, only trace Object (III) is closed to generate.Vacuum distillation removes remaining solid residues after solvent, after solid residues cooling, adds water (20mL) stirring equal It is even, a large amount of solids are generated, are filtered, washing, dry compound (III a), yield 98.3%.HRMS(m/z):[M+H]+ calcd.for C38H57Cl2N2O5:691.3645,found:691.3641.
S3, ammoxidation: 4- (3 β-(2- morpholino acetoxyl group) -18 β of -11- oxo-olive -12- alkene -30- carbonyl Base) piperazine -1- carboxylic acid (IV a) preparation
The I of compound (III) (0.66g, 1.0mmol), morpholine (0.13g, 3.0mmol) and catalytic amount2Sequentially add nothing In water-ethanol (15mL), back flow reaction 12h.The remaining solid residues after being evaporated under reduced pressure remove solvent after reaction, by solid After the remaining stirring pulp with a small amount of ethyl alcohol, add water (20mL) to stir evenly, generate a large amount of solids, filter, washing is so dry that change It closes object (IV a), yield 91.1%.
S4, decarboxylic reaction: 3 β-(2- morpholino acetoxyl group) -18 β of -11- oxo-olive -12- alkene -30- carbonyl piperazine The preparation of piperazine (V a)
Compound (IV a) (0.68g, 1.0mmol) is added to CH2Cl2In (10mL), trifluoroacetic acid (5mL) at room temperature CH2Cl2(5mL) solution is slowly added drop-wise in said mixture, is then slowly warmed to room temperature and is stirred for reaction 3h.To the end of reacting After use Na2CO3Saturated solution neutralizes, and filters, solid layer CH2Cl2It washes, is evaporated under reduced pressure to 18 β of product-after organic solution is dry Enoxolone piperazine amide derivatives (V a), yield 92.1%.
Embodiment 3:
S1, amidation process: 4- (3-18 β of beta-hydroxy-11- oxo-olive-12- alkene-30- carbonyl) piperazine-1- carboxylic acid The preparation of the tert-butyl ester (2)
By 18 β-enoxolone (0.47g, 1.0mmol), EDCl (0.23g, 1.2mmol), triethylamine (0.13g, It 1.2mmol) is sequentially added in acetonitrile (20mL) solution with HOBt (0.16g, 1.2mmol), 60 DEG C of mixture are stirred to react 20min.Then N-Boc- piperazine (0.45g, 2.5mmol) is added in above-mentioned reaction solution, then 60 DEG C of reaction 20h.To the end of reacting Vacuum distillation removes remaining solid residues after solvent afterwards, after solid residues are stirred pulp with a small amount of ethyl alcohol, under slowly stirring It pours into the hot water of 10 times of volumes, generates a large amount of solids, filter, wash after solution is cooling, it is dry that white solid, column chromatography divide It is 26.3% that compound (2) yield is obtained from after, and compound (2a) yield is 71.8%.
S2, esterification: 4- (3 β-(2- chloroethene acyloxy) -18 β of -11- oxo-olive -12- alkene -30- carbonyl) piperazine The preparation of piperazine -1- carboxylic acid (III)
By compound (2) (0.64g, 1.0mmol), 2- chloroacetic anhydride (1.37g, 8.0mmol) and K2CO3(2.76g, 20.0mmol) it is sequentially added 80 DEG C of reaction 9h in toluene (20mL) solution.After TLC monitoring raw material is totally converted, only trace Object (III) is closed to generate.Vacuum distillation removes remaining solid residues after solvent, after solid residues cooling, adds water (20mL) stirring equal It is even, a large amount of solids are generated, are filtered, washing, dry compound (III a), yield 97.9%.
(- 18 β of 3 β-(2- (4- carbamyl piperazine -1- base) acetoxyl group) -11- oxo-is neat by S3, ammoxidation: 4- Pier fruit -12- alkene -30- carbonyl) piperazine -1- carboxylic acid (IV b) preparation
Compound (III) (0.66g, 1.0mmol), piperidines -4- formamide (0.19g, 1.5mmol), K2CO3(0.69g, 5.0mmol) and the I of catalytic amount2It sequentially adds in dehydrated alcohol (15mL), back flow reaction 12h.To depressurize steaming after reaction Distillation goes remaining solid residues after solvent to add water (20mL) to stir evenly after solid residues are stirred pulp with a small amount of ethyl alcohol, A large amount of solids are generated, are filtered, washing, dry compound (IV b), yield 93.6%.1H NMR(400MHz, Chloroform-d) δ 5.66 (s, 1H), 5.54 (d, J=16.7Hz, 2H), 4.56 (dd, J=11.7,4.7Hz, 1H), 3.60 (td, J=15.7,14.2,8.0Hz, 4H), 3.40 (d, J=5.2Hz, 4H), 3.23 (d, J=4.3Hz, 2H), 2.99 (s, 1H), 2.83-2.73 (m, 1H), 2.33 (s, 1H), 2.28 (t, J=11.5Hz, 4H), 2.16 (tt, J=11.4,4.0Hz, 1H),1.44(s,9H),1.33(s,3H),1.20(s,3H),1.13(s,3H),1.09(s,3H),0.85(s,6H),0.79(s, 3H),0.77(s,1H)；13C NMR(101MHz,Chloroform-d)δ199.92,177.17,174.12,170.09, 169.55,154.52,128.48,81.07,80.25,61.63,59.47,54.94,52.62,52.51,48.10,45.26, 43.87,43.79,43.27,42.13,38.71,38.04,37.70,36.89,33.16,32.70,31.75,28.71, 28.67,28.40,28.35,28.12,27.04,26.67,26.38,23.66,23.09,18.65,17.35,16.78, 16.39；HRMS(m/z):(M+H+)calcd.for C47H75N4O7:807.5636,found:807.5633.
S4, decarboxylic reaction: 3 β-(2- (4- carbamyl piperazine -1- base) acetoxyl group) -18 β of -11- oxo-olive - The preparation of 12- alkene -30- carbonyl piperazine (V b)
Compound (IV b) (0.81g, 1.0mmol) is added to CH2Cl2In (10mL), 0 DEG C of stirring 20min.Then trifluoro second The CH of sour (5mL)2Cl2(5mL) solution is slowly added drop-wise in said mixture, is then slowly warmed to room temperature and is stirred for reaction 3h.To Na is used after reaction2CO3Saturated solution neutralizes, and filters, solid layer CH2Cl2It washes, is evaporated under reduced pressure to after organic solution is dry 18 β of product-enoxolone piperazine amide derivatives (V b), yield 91.7%.1H NMR(400MHz,Chloroform-d)δ 5.68 (s, 1H), 5.55 (d, J=16.6Hz, 2H), 4.58-4.54 (m, 1H), 3.64-3.56 (m, 4H), 3.40 (d, J= 5.2Hz, 4H), 3.22 (d, J=4.3Hz, 2H), 2.99 (s, 4H), 2.82 (d, J=13.0Hz, 1H), 2.34 (s, 1H), 2.30 (t, J=12.0Hz, 3H), 2.19-2.12 (m, 1H), 1.34 (s, 3H), 1.21 (s, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 0.86(s,6H),0.80(s,3H),0.77(s,1H)；13C NMR(101MHz,Chloroform-d)δ199.93,177.17, 174.00,170.06,169.60,154.54,128.46,81.06,80.30,61.63,59.49,54.94,52.63,52.53, 48.12,45.28,43.88,43.80,43.27,42.13,38.73,38.05,37.72,36.89,33.18,32.72, 31.76,28.72,28.68,28.41,28.12,27.05,26.67,26.40,23.66,23.10,18.66,17.36, 16.78,16.40；HRMS(m/z):(M+H+)calcd.for C42H67N4O5:707.5112,found:707.5108.
Experiment effect measurement:
The Determination of Antibacterial Activity of the piperazine amide derivatives of 18 β-enoxolone
The compounds of this invention as antibacterial and treating tuberculosis inhibitor activity can by many standards biological test or Pharmacology test measurement.
Using MIC (μ g/ml) value of agar dilution measurement experiment compound.
The preparation of antibacterials stoste: being configured to 2mg/mL solution after methanol dissolution, with filtration method degerming.
The preparation of drug containing agar stoste: stoste is diluted to multiple gradient concentrations with dilution method.1ml is taken to be added to respectively It performs in the plate well of internal diameter 90mm of label.It is taken in sterilized 50 DEG C of M-H agar 19ml to plate well again, it is cold after mixed bacterium But.
Inoculation: being inoculated in plate well one by one with inoculator, each inoculum concentration be 1~2 μ L (bacteria containing amount is about 5 × 105CFU/ml).It is inoculated with the growth control plate of not drug containing, finally to check the survival shape for testing strain in whole experiment process State.
Be incubated for: plate is placed in 37 DEG C and is incubated for for 24 hours.
As a result judge: it is the compound to detection strain that bacterium colony grows the lowest concentration of drug being totally constrained completely MIC, single bacterium colony growth are negligible.
The Determination of Antibacterial Activity result of table 1:18 β-enoxolone piperazine amide derivatives
The result shows that the piperazine amide derivatives of 18 β-enoxolone are to Escherichia coli (E.coli), pseudomonas aeruginosa (P.aeruginosa), staphylococcus aureus (S.aureus) and bacillus subtilis (B.subtilis) have stronger suppression Production is used, wherein the b fungistatic effect of III containing carboxyl structure, IV a, IV is best.
Obviously, the above embodiment of the present invention be only to clearly illustrate example of the present invention, and not be pair The restriction of embodiments of the present invention.For those of ordinary skill in the art, may be used also on the basis of the above description To make other variations or changes in different ways.Here all embodiments can not be exhaustive.It is all to belong to this hair The obvious changes or variations that bright technical solution is extended out are still in the scope of protection of the present invention.

Claims (10)

1. the piperazine amide derivatives of one kind 18 β-enoxolone, which is characterized in that have such as following formula (III), formula (IV) or formula (V) structure shown in:
2. the preparation method of the piperazine amide derivatives of 18 β-enoxolone shown in formula (III) as described in claim 1, feature It is, includes the following steps:
S1, amidation process: in EDCl, HOBt or Et3Under the catalysis of N, 18 β-enoxolone (1) and N-Boc- piperazine are organic Reaction is heated in solvent, after reaction, slurry is evaporated under reduced pressure to, is poured into water stirring, is filtered, is washed to obtain compound (2)；
S2, esterification: in organic solvent, heating is reacted in the presence of base, obtainedization for compound (2) and 2- chloroacetic anhydride It closes object (III)；
Reaction equation is as follows:
3. preparation method according to claim 2, it is characterised in that: in step S1, the organic solvent be ethyl acetate, One or more of methylene chloride, chloroform, acetonitrile, N,N-dimethylformamide；
Preferably, in step S1, reaction temperature is 40~100 DEG C；It is highly preferred that reaction temperature is 60~90 DEG C.
4. preparation method according to claim 2, it is characterised in that: in step S2, the organic solvent be ethyl acetate, One or more of methylene chloride, chloroform, acetonitrile, toluene, dimethylbenzene, ethylbenzene, N,N-dimethylformamide；
Preferably, in step S2, reaction temperature is 80~150 DEG C；It is highly preferred that reaction temperature is 120~130 DEG C；
Preferably, in step S2, the alkali is triethylamine, pyridine, K2CO3、Na2CO3、KHCO3、NaHCO3One of or it is several Kind.
5. the preparation method of the piperazine amide derivatives of 18 β-enoxolone shown in formula (IV) as described in claim 1, feature It is, includes the following steps:
S1, amidation process: in EDCl, HOBt or Et3Under the catalysis of N, 18 β-enoxolone (1) and N-Boc- piperazine are organic Reaction is heated in solvent, after reaction, slurry is evaporated under reduced pressure to, is poured into water stirring, is filtered, is washed to obtain compound (2)；
S2, esterification: in organic solvent, heating is reacted in the presence of base, obtainedization for compound (2) and 2- chloroacetic anhydride It closes object (III)；
S3, ammoxidation: in organic solvent by compound (III) and secondary-amine compound, heating is anti-in the presence of base It answers, is made compound (IV)；
Reaction equation is as follows:
6. preparation method according to claim 5, it is characterised in that: in step S3, the organic solvent be ethyl acetate, One or more of methanol, dehydrated alcohol, acetone, methylene chloride, chloroform, acetonitrile；
Preferably, in step S3, the alkali is triethylamine, pyridine, K2CO3、Na2CO3、KHCO3、NaHCO3One of or it is several Kind；
Preferably, in step S3, the R in compound (IV) is one of following structures:
7. the preparation method of the piperazine amide derivatives of 18 β-enoxolone shown in (V) as described in claim 1, feature exist In including the following steps:
S1, amidation process: in EDCl, HOBt or Et3Under the catalysis of N, 18 β-enoxolone (1) and N-Boc- piperazine are organic Reaction is heated in solvent, after reaction, slurry is evaporated under reduced pressure to, is poured into water stirring, is filtered, is washed to obtain compound (2)；
S2, esterification: in organic solvent, heating is reacted in the presence of base, obtainedization for compound (2) and 2- chloroacetic anhydride It closes object (III)；
S3, ammoxidation: in organic solvent by compound (III) and secondary-amine compound, heating is anti-in the presence of base It answers, is made compound (IV)；
S4, decarboxylic reaction: compound (IV) and trifluoroacetic acid are stirred to react in organic solvent, to after reaction, react Alkali is added in mixture, filters, solid layer organic solvent washing is evaporated under reduced pressure to 18 β of product-enoxolone piperazine amide and spreads out Biological (V), reaction equation is as follows:
8. preparation method according to claim 7, it is characterised in that: in step S4, the organic solvent be ethyl acetate, One or more of methylene chloride, chloroform；
Preferably, in step S4, reaction temperature is 0~40 DEG C；It is highly preferred that reaction temperature is 0~10 DEG C.
9. formula (III) as described in claim 1, (IV), 18 β-enoxolone shown in (V) piperazine amide derivatives antibacterial Application in drug.
10. application according to claim 9, it is characterised in that: the formula (III), (IV), 18 β-Radix Glycyrrhizae shown in (V) The piperazine amide derivatives of acid are inhibiting Escherichia coli, pseudomonas aeruginosa, staphylococcus aureus and bacillus subtilis medicine Application in object.
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CN111011374A (en) * 2019-11-12 2020-04-17 中国农业大学 Quaternary ammonium salt glycyrrhetinic acid cationic surfactant and preparation method and application thereof

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Publication number Priority date Publication date Assignee Title
CN110713512A (en) * 2019-10-31 2020-01-21 贵州大学 Isopropanolamine substructure-containing glycyrrhetinic acid piperazine compounds and preparation method and application thereof
CN110713512B (en) * 2019-10-31 2022-09-27 贵州大学 Isopropanolamine substructure-containing glycyrrhetinic acid piperazine compounds and preparation method and application thereof
CN111011374A (en) * 2019-11-12 2020-04-17 中国农业大学 Quaternary ammonium salt glycyrrhetinic acid cationic surfactant and preparation method and application thereof
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