CN102863376B - N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications - Google Patents
N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications Download PDFInfo
- Publication number
- CN102863376B CN102863376B CN201210375803.6A CN201210375803A CN102863376B CN 102863376 B CN102863376 B CN 102863376B CN 201210375803 A CN201210375803 A CN 201210375803A CN 102863376 B CN102863376 B CN 102863376B
- Authority
- CN
- China
- Prior art keywords
- piperidone
- cancer
- methyl
- substituent methyl
- benzal base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 C*(C)CI1C=C*(C=C2CCC2)=CC1 Chemical compound C*(C)CI1C=C*(C=C2CCC2)=CC1 0.000 description 2
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to organic synthesis and field of medicaments, disclose the preparation method of N-substituent methyl-3,5-two replacement benzal base-4-piperidone and efficiently suppress the biological activity of the cell line proliferations such as leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer.By all kinds of substituted methylamine and methyl acrylate, successively through Michael addition, Dieckmann condensation, acidolysis decarboxylation obtains N-substituent methyl-4-piperidone, the target compound N-substituent methyl-3,5-pairs that the latter and substituted benzaldehyde obtain through aldol reaction replaces benzal base-4-piperidone.Target compound optionally can efficiently suppress the cell line proliferations such as leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer, and its activity suppressing above-mentioned cancerous cell line to be bred is all apparently higher than the chemotherapeutics 5-fluor-uracil of routine.
Description
Technical field
The invention belongs to chemical medicine field, be specifically related to N-substituent methyl-3,5-two replacement benzal base-4-piperidone, can be used as the lead compound for the treatment of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer medicine.
Background technology
Cancer is one of disease that in the world today, mortality ratio is the highest, and according to the epidemiology statistics that China issues, China's each department leukemia, Primary Hepatic cancer morbidity account for the 6th and the 8th respectively in various tumour.Leukemia is a class hematopoetic cell malignancies illness, is apt to occur in teenager, and its sickness rate comes first of teenager's tumour, has 4,000,000 leukaemics at present at least, annual newly-increased about 40,000.
Primary hepatocarcinoma is one of modal malignant tumour in the world, and the liver cancer in the whole world more than 50% occurs in China.Although the onset of liver cancer rate in the whole world ranks the 8th in various tumour, its mortality ratio comes the 4th.
Ovarian cancer and mammary cancer are the modal tumor diseases of women, have a strong impact on women's physical and mental health even threat to life.According to statistics, ovarian cancer and breast cancer incidence are only second to cervical cancer and carcinoma of uterine body.
At present, above-mentioned various cancer is still adopted to the method for chemotherapy to treat, chemotherapy only makes patient obtain short-term relief by killing and wounding the cancer cells of hyperproliferation in a large number, but cannot effect a radical cure.Due to chemotherapeutics many shortages specificity used at present, so toxic side effect is very large.More thorny, the cancer cells of most of patients with recurrent usually creates resistance to existing chemotherapeutics.
The common shortcoming of now conventional clinically chemotherapeutics is that selectivity is not strong, has almost identical lethal effect, also have very strong lethal effect, so toxicity is larger to marrow, digestive tube cell and sexual cell to normal cell and tumour cell.
Summary of the invention
The object of the invention is to provide a series of N-substituent methyls-3,5-two replacement benzal base-4-piperidone, and this series compound can be used as the lead compound for the treatment of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer medicine.
Second object of the present invention is, provides N-substituent methyl-3,5-two preparation method replacing benzal base-4-piperidone.
3rd object of the present invention is, two for N-substituent methyl-3,5-benzal base-4-piperidone that replaces is used for system
The medicine of the kinds cancers such as standby treatment leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer, this N-replaces
Methyl-3, the two benzal base-4-piperidone compound that replaces of 5-has the biological activity efficiently suppressing the multiple cancerous cell line propagation such as leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer, and IC50 value is all starkly lower than conventional chemotherapeutic drugs 5 FU 5 fluorouracil (5Fu).
The object of the invention is to be achieved through the following technical solutions:
Provided by the invention have the activity of efficiently killing the multiple cancer cells such as leukemia, ovarian cancer, mammary cancer, liver cancer and esophagus cancer, and the lead compound N-substituent methyl-3,5-pairs of cancer therapy drug replaces the structural formula of benzal base-4-piperidone as shown in the formula (I):
R
1for substituted-phenyl, five-membered ring substituting group or hexa-member heterocycle substituting group; Substituted-phenyl is the one in 4-tolyl, 2-tolyl, 4-p-methoxy-phenyl, 2-p-methoxy-phenyl, 4-bromophenyl, 2-bromophenyl, 3-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, described five-membered ring substituting group is the one in 2-tetrahydrofuran base, 2-furyl, 2-thienyl, the chloro-2-thiazolyl of 5-, and described hexa-member heterocycle is the one in 3-pyridyl, 6-chloro-3-pyridyl base;
R
2for 4-cyano group, 2-cyano group, 3, one in the substituting groups such as 4-dichloro, 2,4-dichloros, 3-nitro, 2-nitro, 3-chlorine, 2-bromine, 3-bromine, 4-bromine, 2-fluorine, 3-fluorine, 4-fluorine, 2-trifluoromethyl, 4-dimethylamino, 2-dimethylamino, 4-hydroxy-3-methoxy.
The invention provides the preparation method of formula (I) compound, comprise the steps:
(1) substituted methylamine of formula (a) structure and methyl acrylate are made two (β-methyl propionate) substituted methylamine of formula (II) N, N-through Michael addition reaction; Substituted methylamine and the methyl acrylate mol ratio of formula (II) structure are 1:2 ~ 1:4, take alcohols as solvent, are preferably methyl alcohol or ethanol, back flow reaction 6 ~ 10 hours; Be specially, under condition of ice bath be added drop-wise to the alcoholic solution containing substituted methylamine containing in methyl acrylate alcoholic solution, control temperature is no more than 50 DEG C; Dropwise rear stirring 20 ~ 60min, back flow reaction 6 ~ 10 hours;
(2) under sodium alkoxide effect, be there is Dieckmann condensation in step (1) product, with acid hydrolysis extraction, water intaking phase back flow reaction 6 ~ 10 hours, regulate pH=8 ~ 9, decarboxylation obtains the N-substituent methyl-4-piperidone of formula (III);
R
1-CH
2NH
2R
1CHN(CH
2CH
2COOCH
3)
2
(a)(II)
(3) the substituted benzaldehyde generation aldol condensation of step (2) product N-substituent methyl-4-piperidone and formula (IV) structure is dewatered,
Obtain N-substituent methyl-3,5-two replacement benzal base-4-piperidone that general formula is (I); The mol ratio of N-substituent methyl-4-piperidone and substituted benzaldehyde is 1:2;
R
1for substituted-phenyl, five-membered ring substituting group or hexa-member heterocycle substituting group;
R
2for the one in 4-cyano group, 2-cyano group, 3,4-dichloros, 2,4-dichloros, 3-nitro, 2-nitro, 3-chlorine, 2-bromine, 3-bromine, 4-bromine, 2-fluorine, 3-fluorine, 4-fluorine, 2-trifluoromethyl, 4-dimethylamino, 2-dimethylamino, 4-hydroxy-3-methoxy.
The reaction formula of above-mentioned preparation process is:
The two benzal base-4-piperidone that replaces of compound N-substituent methyl-3,5-of the present invention can be applied to preparation treatment leukemia, the medicine of the kinds cancers such as ovarian cancer, mammary cancer, liver cancer and esophagus cancer.
Cancer therapy drug lead compound N-substituent methyl-3 provided by the invention, 5-is two replaces benzal base-4-piperidone, there is the efficient biological activity suppressing multiple cancerous cell line propagation, specifically comprise following cancerous cell line: 2 kinds of Leukemia Cell Lines, ovarian cancer HO-8910 clone, breast cancer mcf-7 cell line, SMMC-7721 liver cancer cells system and the esophagus cancer ECA-109 clones such as leukemia K 562 and Jarket clone.This compound can be applied to the medicine that preparation suppresses the cancer cell system propagation such as Leukemia Cell Lines, ovarian cancer cell line, breast cancer cell line, hepatoma cell line and esophageal cancer cell system.
Cancer therapy drug lead compound N-substituent methyl-3, the two benzal base-4-piperidone that replaces of 5-suppresses 2 kinds of Leukemia Cell Lines such as leukemia K 562, ovary HO-8910 clone, breast cancer mcf-7 cell line, the activity of SMMC-7721 liver cancer cells system and esophagus cancer ECA-109 cell line proliferation is all apparently higher than the anticancer chemotherapeutic agent 5-fluor-uracil (IC of routine
50value is all starkly lower than 5 FU 5 fluorouracil), that likely become special efficacy, that toxic side effect is less novel anti-leukemia medicine, has potential practicality.
Embodiment
The example of the two benzal phenylpiperidines-4-ketone cancer therapy drug lead compounds of N-substituent methyl-3,5-of prepared by the present invention just have antitumour activity is:
(Ia) two (4-cyano group benzal base)-4-piperidone of N-(4-methoxy-benzyl)-3,5-;
(Ib) two (3,4-dichloro benzal base)-4-piperidone of N-(4-methoxy-benzyl)-3,5-;
(Ic) two (2,4-dichloro benzal base)-4-piperidone of N-(4-methoxy-benzyl)-3,5-;
(Id) two (3-nitre benzal base)-4-piperidone of N-(2-luorobenzyl)-3,5-;
(Ie) two (2-trifluoromethyl benzal base)-4-piperidone of N-(2-luorobenzyl)-3,5-;
(If) two (4-trifluoromethyl benzal base)-4-piperidone of N-(2-luorobenzyl)-3,5-;
(Ig) N-(2-bromobenzyl)-3,5-two (3-benzyl chloride fork base)-4-piperidone;
(Ih) two (4-dimethylamino benzal base)-4-piperidone of N-(2-bromobenzyl)-3,5-;
(Ii) two (4-hydroxyl-2-methoxyl group benzal base)-4-piperidone of N-(2-bromobenzyl)-3,5-;
(Ij) two (2,4-dichloro benzal base)-4-piperidone of N-(4-luorobenzyl)-3,5-.
Two (4-cyano group benzal the base)-4-piperidone (Ia) of embodiment 1N-(4-methoxy-benzyl)-3,5-
In 0 DEG C of ice-water bath, the methyl acrylate of 0.4mol and 7mL methyl alcohol are added in 100mL there-necked flask, after stirring 30min, slowly drip the methanol mixed solution of 0.1mol4-methoxybenzylamine and 10mL wherein, control rate of addition, system temperature is no more than 50 DEG C (rate of addition about 1 drop/sec).After dropwising, stirred at ambient temperature 30min, continues raised temperature to 65 DEG C, and backflow, thin-layer chromatography (TLC) follows the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation,
Obtain pale yellowish oil liquid intermediate (2a).
Under room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, stirring heating refluxes about 40min, pearl is presented to sodium block, slow dropping 0.1mol intermediate (2a) and 20mL dry toluene mixed solution, drip with dropper the carrying out that 3 anhydrous methanols impel reaction when reacting and just starting.In dropping process, reaction system becomes thick pale yellow shape gradually, need strengthen stirring velocity, after dropwising, is joined in reaction vessel by 40mL dry toluene if needed in batches, and hierarchy of control temperature is 110 DEG C, backflow 6h.
After backflow, be cooled to room temperature, adding 1mL anhydrous methanol and stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is hydrochloric acid soln 40mL × 3 extraction of 25% by mixture massfraction subsequently, collect extraction liquid (aqueous phase), by extraction liquid oil bath backflow 8h, after reaction terminates, after cooling reaction system to room temperature, regulate the pH value of reaction system to alkalescence (about pH=8.5) by NaOH solution under stirring, extract with ethyl acetate 40mL × 3.Combined ethyl acetate layer, carries out drying by 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and distillation substrate is pale yellow oily liquid body N-4-methoxybenzyl-4-piperidone (3a).
Intermediate (3a) (0.005mol) and 4-cyanobenzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ia) with ethyl acetate and sherwood oil recrystallization.
Yield: 76.3%; Yellowsolid, mp139-141 ° of C; 1HNMR (400MHz, CDCl
3); 1HNMR (400MHz, CDCl
3) δ 3.67 (s, 2H), 3.64 (s, 3H), 3.82 (s, 4H), 7.04 (d, J=8.7Hz, 2H), 7.14 (d, J=8.7Hz, 2H), 7.23 (d, J=8.0Hz, 4H), 7.37 (d, J=8.0Hz, 4H), 7.75 (s, 2H) IR (KBr): 3138,2814,1672,1594,1525,1342,1261,1109,1005,854cm
-1; Anal.calcd.forC
29h
23n
3o
2.C%78.18, H%5.20, N%9.43; Found:C%78.16, H%5.19, N%9.45
Two (3,4-dichloro benzal the base)-4-piperidone (Ib) of embodiment 2N-(4-methoxy-benzyl)-3,5-
By method preparation (2b) and (3b) that preparation (2a) is identical with (3a).
Intermediate N 4-methoxybenzyl-4-piperidone (3b) (0.005mol) and 3,4-dichlorobenzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ib) with ethyl acetate and sherwood oil recrystallization.
Yield: 80.2%; Yellowsolid, mp131-133 ° of C;
1hNMR (400MHz, CDCl
3) δ 3.65 (s, 2H), 3.71 (s, 3H); (3.85 s, 4H), 7.02 (d, J=8.7Hz; 2H), 7.13 (d, J=8.7Hz; 2H), 7.24 (d, J=8.0Hz; 4H), 7.36 (d, J=8.0Hz; 2H), 7.71 (s, 2H); IR (KBr): 2805,2745,1667,1615,1575,1480,1260,1185,1085,821cm
-1; Anal.calcd.forC
27h
21cl
4nO
2c%60.81, H%3.97, N%2.63; Found:C%60.72H%3.95, N%2.68
Two (2,4-dichloro benzal the base)-4-piperidone (Ic) of embodiment 3N-(4-methoxy-benzyl)-3,5-
By method preparation (2c) and (3c) that preparation (2a) is identical with (3a).
Intermediate N 4-methoxybenzyl-4-piperidone (3c) (0.005mol) and 3,4-dichlorobenzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ic) with ethyl acetate and sherwood oil recrystallization.
Yield: 73.7%; Yellowsolid, mp183-185 ° of C;
1hNMR (400MHz, CDCl
3) δ 3.62 (s, 2H), 3.75 (s, 3H); (3.82 s, 4H), 7.03 (d, J=8.7Hz; 2H), 7.12 (d, J=8.7Hz; 2H), 7.22 (d, J=8.0Hz; 2H), 7.28 (d, J=8.0Hz; 4H), 7.73 (s, 2H); ; IR (KBr): 2805,2743,1664,1603,1574,1487,1262,1185,1094,821cm
-1; Anal.calcd.forC
27h
21cl
4nO
2c%60.81, H%3.97, N%2.63; Found:C%60.72H%3.95, N%2.68
Two (3-nitre benzal the base)-4-piperidone (Id) of embodiment 4N-(2-luorobenzyl)-3,5-
In 0 DEG C of ice-water bath, the methyl acrylate of 0.4mol and 7mL methyl alcohol are added in 100mL there-necked flask, after stirring 30min, slowly drip the methanol mixed solution of 0.1mol2-flunamine and 10mL wherein, control rate of addition, system temperature is no more than 50 DEG C (about 1 drops/sec).After dropwising, stirred at ambient temperature 30min, continues raised temperature to 65 DEG C, and backflow, thin-layer chromatography (TLC) follows the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation, obtain pale yellowish oil liquid intermediate (2d).
Under room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, stirring heating refluxes about 40min, pearl is presented to sodium block, slow dropping 0.1mol intermediate (2d) and 20mL dry toluene mixed solution, drip with dropper the carrying out that 3 anhydrous methanols impel reaction when reacting and just starting.In dropping process, reaction system becomes thick pale yellow shape gradually, need strengthen stirring velocity, after dropwising, is joined in reaction vessel by 40mL dry toluene if needed in batches, and hierarchy of control temperature is 110 DEG C, backflow 6h.
After backflow, be cooled to room temperature, adding 1mL anhydrous methanol and stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is hydrochloric acid soln 40mL × 3 extraction of 25% by mixture massfraction subsequently, collect extraction liquid (aqueous phase), by extraction liquid oil bath backflow 8h, after reaction terminates, after cooling reaction system to room temperature, regulate the pH value of reaction system to alkalescence (about pH=8.5) by NaOH solution under stirring, extract with ethyl acetate 40mL × 3.Combined ethyl acetate layer, carries out drying by 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and distillation substrate is pale yellow oily liquid body N-2-luorobenzyl-4-piperidone (3d).
Intermediate (3d) (0.005mol) and 3-nitrobenzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Id) with ethyl acetate and sherwood oil recrystallization.
Yield: 75.2%; Yellowsolid, mp129-131 ° of C;
1hNMR (400MHz, CDCl
3) 3.65 (s, 2H), 3.85 (s, 4H), 7.05 (d, J=7.8Hz; 2H), 7.14 (d, J=7.9Hz, 2H), 7.55 (d, J=8.6Hz; 4H), 7.87 (s, 2H), 8.18 (d, J=8.6Hz, 4H); IR (KBr): 2824,1603,1487,1456,1264,11802,1096,1004,819cm
-1; Anal.calcd.forC
26h
20fN
3o
5c%65.96, H%4.26, N%8.88; Found:C%65.82H%4.17, N%8.78.
Two (2-trifluoromethyl benzal the base)-4-piperidone (Ie) of embodiment 5N-(2-luorobenzyl)-3,5-
By method preparation (2e) and (3e) that preparation (2d) is identical with (3d).
Intermediate N 2-luorobenzyl-4-piperidone (3e) (0.005mol) and 2-trifluoromethylated benzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ie) with ethyl acetate and sherwood oil recrystallization.
Yield: 87.7%; Yellowsolid, mp121-123 ° of C;
1hNMR (400MHz, CDCl
3) δ 3.63 (s, 2H), 3.87 (s, 4H), 7.05 (d, J=7.8Hz; 2H), 7.16 (d, J=7.9Hz, 2H), 7.55 (d, J=8.6Hz; 4H), 7.92 (s, 2H), 8.24 (d, J=8.6Hz, 4H); IR (KBr): 3127,2983,1679,1615,1506,1267,1224,1193,996,763cm
-1; Anal.calcd.forC
28h
20f
7nOC%64.74, H%3.88, N%2.70; Found:C%64.72H%3.97, N%2.78.
Two (4-trifluoromethyl benzal the base)-4-piperidone (If) of embodiment 6N-(2-luorobenzyl)-3,5-
By method preparation (2f) and (3f) that preparation (2d) is identical with (3d).
Intermediate N 2-luorobenzyl-4-piperidone (3f) (0.005mol) and 4-trifluoromethylated benzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (If) with ethyl acetate and sherwood oil recrystallization.
Yield: 76.6%; Yellowsolid, mp143-145 ° of C;
1hNMR (400MHz, CDCl
3) δ 3.67 (s, 2H), 3.84 (s, 4H), 7.05 (d, J=7.8Hz; 2H), 7.21 (d, J=7.9Hz, 2H), 7.51 (d, J=8.6Hz; 4H), 7.94 (s, 2H), 8.21 (d, J=8.6Hz, 4H); IR (KBr): 3124,2996,1665,1615,1504,1267,1221,1193,997,763cm
-1; Anal.calcd.forC
28h
20f
7nOC%64.74, H%3.88, N%2.70; Found:C%64.72H%3.97, N%2.78.
Embodiment 7N-(2-bromobenzyl)-3,5-two (3-benzyl chloride fork base)-4-piperidone (Ig)
In 0 DEG C of ice-water bath, the methyl acrylate of 0.4mol and 7mL methyl alcohol are added in 100mL there-necked flask, after stirring 30min, slowly drip the methanol mixed solution of 0.1mol2-bretylium and 10mL wherein, control rate of addition, system temperature is no more than 50 DEG C (about 1 drops/sec).After dropwising, stirred at ambient temperature 30min, continues raised temperature to 65 DEG C, and backflow, thin-layer chromatography (TLC) follows the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation, obtain pale yellowish oil liquid intermediate (2g).
Under room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, stirring heating refluxes about 40min, pearl is presented to sodium block, slow dropping 0.1mol intermediate (2g) and 20mL dry toluene mixed solution, drip with dropper the carrying out that 3 anhydrous methanols impel reaction when reacting and just starting.In dropping process, reaction system becomes thick pale yellow shape gradually, need strengthen stirring velocity, after dropwising, is joined in reaction vessel by 40mL dry toluene if needed in batches, and hierarchy of control temperature is 110 DEG C, backflow 6h.
After backflow, be cooled to room temperature, adding 1mL anhydrous methanol and stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is hydrochloric acid soln 40mL × 3 extraction of 25% by mixture massfraction subsequently, collect extraction liquid (aqueous phase), by extraction liquid oil bath backflow 8h, after reaction terminates, after cooling reaction system to room temperature, regulate the pH value of reaction system to alkalescence (about pH=8.5) by NaOH solution under stirring, extract with ethyl acetate 40mL × 3.Combined ethyl acetate layer, carries out drying by 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and distillation substrate is pale yellow oily liquid body N-2-bromobenzyl-4-piperidone (3g).
Intermediate (3g) (0.005mol) and 3-chlorobenzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ig) with ethyl acetate and sherwood oil recrystallization.
Yield: 85.1%; Yellowsolid, mp172-175 ° of C;
1hNMR (400MHz, CDCl
3) δ 3.66 (s, 2H), 3.78 (s, 4H), 7.14 (d, J=8.4Hz, 2H), 7.23-7.24 (m, 2H), 7.26-7.37 (m, 8H), 7.73 (s, 2H); ; IR (KBr): 2825,1606,1486,1455,1263,1181,1096,1001,817cm
-1; Anal.calcd.forC
26h
20brCl2NOC%60.84, H%3.93, N%2.73; Found:C%60.78H%3.97, N%2.78.
Two (4-dimethylamino benzal the base)-4-piperidone (Ih) of embodiment 8N-(2-bromobenzyl)-3,5-
By method preparation (2h) and (3h) that preparation (2g) is identical with (3g).
Intermediate N/-2-bromobenzyl-4-piperidone (3h) (0.005mol) and 4-dimethylaminobenzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ih) with ethyl acetate and sherwood oil recrystallization.
Yield: 67.4%; Yellowsolid, mp109-111 ° of C;
1hNMR (400MHz, CDCl
3) δ δ 2.85(s, 12H), 3.63 (s, 2H), 3.78 (s, 4H), 7.14 (d, J=8.4Hz, 2H), 7.22-7.24 (m, 2H), 7.25-7.37 (m, 8H), 7.75 (s, 2H); ; IR (KBr): 2821,1604,1489,1455,1265,1254,1181,1093,1002,817cm
-1; Anal.calcd.forC
30h
32brN
3oC%67.92, H%6.08, N%7.92; Found:C%67.82H%5.97, N%7.78.
Two (4-hydroxyl-2-methoxyl group benzal the base)-4-piperidone (Ii) of embodiment 9N-(2-bromobenzyl)-3,5-
By method preparation (2i) and (3i) that preparation (2g) is identical with (3g).
Intermediate N 2-bromobenzyl-4-piperidone (3i) (0.005mol) and 4-hydroxyl-2-methoxybenzaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ii) with ethyl acetate and sherwood oil recrystallization.
Yield: 66.3%; Yellowsolid, mp167-169 ° of C;
1hNMR (400MHz, CDCl
3) δ 3.62 (s, 2H), 3.83 (s, 4H); 3.92 (s, 6H), 5.03 (s, 2H); (7.05 d, J=7.8Hz, 2H), 7.14 (d; J=7.9Hz, 2H), 7.26 (d, J=8.3Hz; 2H), 7.44 (d, J=8.4Hz; 4H), 7.81 (s, 2H); ; IR (KBr): 3125,2995,1668,1615,1507,1269,1223,1195,997,764cm
-1; Anal.calcd.forC
28h
26brNO
5c%62.69, H%4.89, N%2.61; Found:C%62.72H%4.97, N%2.68.
Two (2,4-dichloro benzal the base)-4-piperidone (Ii) of embodiment 10N-(4-luorobenzyl)-3,5-
In 0 DEG C of ice-water bath, the methyl acrylate of 0.4mol and 7mL methyl alcohol are added in 100mL there-necked flask, after stirring 30min, slowly drip the methanol mixed solution of 0.1mol4-flunamine and 10mL wherein, control rate of addition, system temperature is no more than 50 DEG C (about 1 drops/sec).After dropwising, stirred at ambient temperature 30min, continues raised temperature to 65 DEG C, and backflow, thin-layer chromatography (TLC) follows the tracks of reaction process.After reacting about 8h, stopped reaction, methyl alcohol and unreacted methyl acrylate are reclaimed in underpressure distillation, obtain pale yellowish oil liquid intermediate (2j).
Under room temperature, 15mL dry toluene and 0.1mol sodium Metal 99.5 (being cut into bulk) are added in the there-necked flask of 250mL drying, stirring heating refluxes about 40min, pearl is presented to sodium block, slow dropping 0.1mol intermediate (2j) and 20mL dry toluene mixed solution, drip with dropper the carrying out that 3 anhydrous methanols impel reaction when reacting and just starting.In dropping process, reaction system becomes thick pale yellow shape gradually, need strengthen stirring velocity, after dropwising, is joined in reaction vessel by 40mL dry toluene if needed in batches, and hierarchy of control temperature is 110 DEG C, backflow 6h.
After backflow, be cooled to room temperature, adding 1mL anhydrous methanol and stir 1h, to remove the complete sodium Metal 99.5 of unreacted, is hydrochloric acid soln 40mL × 3 extraction of 25% by mixture massfraction subsequently, collect extraction liquid (aqueous phase), by extraction liquid oil bath backflow 8h, after reaction terminates, after cooling reaction system to room temperature, regulate the pH value of reaction system to alkalescence (about pH=8.5) by NaOH solution under stirring, extract with ethyl acetate 40mL × 3.Combined ethyl acetate layer, carries out drying by 10g anhydrous sodium sulphate to it, and ethyl acetate is reclaimed in underpressure distillation, and distillation substrate is pale yellow oily liquid body N-4-luorobenzyl-4-piperidone (3j).
Intermediate (3j) (0.005mol) and 2,4 dichloro benzene formaldehyde (0.01mmol) is added, 15mL dehydrated alcohol and 10% (massfraction) sodium hydroxide 1mL in the round-bottomed flask of 50mL.Room temperature (15 ~ 25 DEG C) stirs 1h, has solid to separate out, suction filtration, then uses absolute ethanol washing product, or namely obtain target compound (Ij) with ethyl acetate and sherwood oil recrystallization.
Yield: 74.7%; Yellowsolid, mp119-121 ° of C;
1hNMR (400MHz, CDCl
3) δ 3.63 (s, 2H), 3.79 (s, 4H), 7.13 (d, J=8.4Hz, 2H), 7.21-7.24 (m, 2H), 7.26-7.37 (m, 6H), 7.76 (s, 2H); IR (KBr): 2827,1603,1487,1455,1265,1263,1182,1094,1002,815cm
-1; Anal.calcd.forC
26h
18cl
4fNOC%59.91, H%3.48, N%2.69; Found:C%60.12H%3.57, N%2.78.
Embodiment 11 compound (I) suppresses leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system propagation IC
50test.
1. test medicament and equipment
Experimental drug and reagent: from produced compounds (I), dissolve with DMSO, adding distil water is assigned to desired concn (DMSO concentration≤1 ‰), sterilizing 4 DEG C preservation.MTT (Methyl thiazoly tetrazolium assay) reagent available from Sigma.Leukemia K562 cell, Jarket, ovarian cancer HO-8910, mammary cancer MCF-7, liver cancer SMMC-7721 and esophagus cancer ECA-109 clone are purchased from Shanghai Chinese Academy of Sciences cell bank.10%SDS reagent (Sino-AmericanBiotechnology product), with RPMI-1640 (GiBCo company of the U.S.) nutrient solution containing 20% calf serum (FBS), other reagent is all commercially available analytical pure.At 37 DEG C, 5%CO
2, saturated humidity incubator in carry out Secondary Culture, when cell is in logarithmic phase for experiment.
Plant and instrument: Bechtop, clean <3.5 grain/L (>0.5 μm of grit), the clean treating plant company limited in upper sea; CO
2cell culture incubator, Thermo company FormaScientific, Inc; Inverted microscope, Japanese Olympus (OLYMPUS) company, model C KX41; Enzyme-linked immunosorbent assay instrument, Bio-RADModel680; 96 holes are dull and stereotyped, Costar company of the U.S.; SK2200H type ultrasonic cleaner, Shanghai High Kudos Science Instrument Co., Ltd..
2. test method
Experiment is carried out in 96 orifice plates, collects logarithmic phase cell, and adjustment concentration of cell suspension, divides in 96 orifice plates, 1 × 10
4/ hole, every hole cumulative volume 100 μ L, often organizes 8 multiple holes, arranges medicine color comparator hole (not containing cell) and the culture hole containing cell and different concns medicine, after cultivating 44h respectively, in each hole, add MTT (5mg/mL, 10 μ L), continue to cultivate 4h, add 10%SDS100 μ L termination reaction again, 37 DEG C are spent the night, by the absorbancy OD value of each hole of enzyme linked immunosorbent detection at 570nm, by following formulae discovery survival rate: survival rate (%)=OD administration/OD contrast × 100%; And according to the survival rate of each concentration, adopt LOGIT method to calculate 50% inhibition concentration (IC
50).
3. result investigation
The IC of 2 kinds of leukemia, ovarian cancer, mammary cancer, liver cancer and the esophageal cancer cell system propagation such as N-replacement-3,5-two benzal phenylpiperidines-4-ketone (I) suppression leukemia K 562s is determined with mtt assay
50value, IC
50value is in table 1.
Table 1 Compound I a ~ Ij suppresses the IC of 2 kinds of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system propagation
50value
4. conclusion: table 1 be depicted as Compound I a ~ Ij in vitro cell levels suppress the IC of people 2 kinds of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system propagation
50.From table 1 data, Compound I a ~ Ij suppresses the IC of above-mentioned 2 kinds of leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer cell system propagation
50value is all starkly lower than conventional chemotherapeutic drugs 5 FU 5 fluorouracil (5Fu).
Claims (7)
1.N-substituent methyl-3,5-is two replaces benzal base-4-piperidone, and it is characterized in that, structure is such as formula shown in (I):
In formula: R
1for 4-p-methoxy-phenyl, R
2for 4-cyano group, 3,4-dichloros or 2,4-dichloro; Or,
R
1for 2-fluorophenyl, R
2for 3-nitro, 2-trifluoromethyl or 4-trifluoromethyl; Or,
R
1for 2-bromophenyl, R
2for 3-chlorine, 4-dimethylamino; Or,
R
1for 4-fluorophenyl, R
2it is 2,4-dichloro.
2. the two preparation method replacing benzal base-4-piperidone of N-substituent methyl-3,5-described in claim 1, is characterized in that, comprise the steps:
(1) substituted methylamine of formula (a) structure and methyl acrylate are made two (β-methyl propionate) substituted methylamine of formula (II) N, N-through Michael addition reaction;
(2) under sodium alkoxide effect, be there is Dieckmann condensation in two to step (1) product N, N-(β-methyl propionate) substituted methylamine, obtain the N-substituent methyl-4-piperidone of formula (III) with acid hydrolysis decarboxylation;
(3) the substituted benzaldehyde generation aldol condensation of step (2) product N-substituent methyl-4-piperidone and formula (IV) structure is dewatered,
Obtain N-substituent methyl-3,5-two replacement benzal base-4-piperidone that general formula is (I);
Wherein, R
1and R
2definition as claimed in claim 1.
3. N-substituent methyl-3 described in claim 2, the two preparation method replacing benzal base-4-piperidone of 5-, it is characterized in that, in step (1), the substituted methylamine of formula (II) structure and methyl acrylate mol ratio are 1:2 ~ 1:4, with methyl alcohol or ethanol for solvent, back flow reaction 6 ~ 10 hours.
4. the two preparation method replacing benzal base-4-piperidone of N-substituent methyl-3,5-described in claim 2, it is characterized in that, in step (3), N-substituent methyl-4-piperidone and substituted benzaldehyde mol ratio are 1:2.
5. N-substituent methyl-3,5-described in claim 1 is two replaces the application of benzal base-4-piperidone in preparation treatment leukemia, ovarian cancer, mammary cancer, liver cancer and esophageal cancer medicine.
6. the two benzal base-4-piperidone that replaces of N-substituent methyl-3,5-described in claim 1 is for the preparation of the medicine suppressing Leukemia Cell Lines, ovarian cancer cell line, breast cancer cell line, hepatoma cell line and esophageal cancer cell system propagation.
7. the two benzal base-4-piperidone that replace of N-substituent methyl-3,5-described in claim 1 are for the preparation of the medicine suppressing K562 leukemic cells system, leukemia Jarket clone, ovarian cancer HO-8910 clone, breast cancer mcf-7 cell line, SMMC-7721 liver cancer cells system and esophagus cancer ECA-109 cell line proliferation.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210375803.6A CN102863376B (en) | 2012-09-27 | 2012-09-27 | N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210375803.6A CN102863376B (en) | 2012-09-27 | 2012-09-27 | N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102863376A CN102863376A (en) | 2013-01-09 |
CN102863376B true CN102863376B (en) | 2015-12-16 |
Family
ID=47442540
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210375803.6A Expired - Fee Related CN102863376B (en) | 2012-09-27 | 2012-09-27 | N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102863376B (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104262240B (en) * | 2014-07-31 | 2016-04-20 | 滨州医学院 | For antineoplastic 3,5-diphenylmethylene-4-derivative of piperidone and preparation method thereof |
CN104592098B (en) * | 2015-01-31 | 2017-08-25 | 滨州医学院 | For antineoplastic piperidones of 3,5 2 aryl methylene of N methyl 4 and its quaternary ammonium salt derivative |
CN105037252B (en) * | 2015-05-21 | 2018-05-04 | 温州医科大学 | N- substitutions -3,5- two (2- (trifluoromethyl) benzal) piperidin-4-one-derivative and preparation method and application |
US9655913B2 (en) * | 2015-06-23 | 2017-05-23 | Hong Kong Baptist University | Anti-esophageal cancer compound and method of use thereof |
CN105503709B (en) * | 2015-12-10 | 2019-06-14 | 中国广州分析测试中心 | Bis- (aryl methylene) -1- substitution -4- piperidones series compounds of 3,5- and its in the application for preparing anti esophageal cancer drug |
US9486444B1 (en) | 2016-03-21 | 2016-11-08 | King Saud University | Anti-cancer compound |
CN108976122B (en) * | 2018-09-13 | 2021-01-12 | 南通纺织丝绸产业技术研究院 | Method for producing 1, 3-dicarbonyl compounds based on metal hydride/palladium compound systems |
CN109053446B (en) * | 2018-09-13 | 2021-01-01 | 苏州大学张家港工业技术研究院 | Application of metal hydride/palladium compound system in preparation of 1, 3-dicarbonyl compound by series reaction of electron-deficient alkene compound |
WO2020056564A1 (en) * | 2018-09-17 | 2020-03-26 | 南通纺织丝绸产业技术研究院 | Method for preparing 1,3-dicarbonyl compound based on metal hydride/palladium compound system |
CN114276330B (en) * | 2021-11-04 | 2023-04-18 | 华中师范大学 | Piperidone compound and preparation method and application thereof |
-
2012
- 2012-09-27 CN CN201210375803.6A patent/CN102863376B/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
N-取代-3,5-双苄叉基-哌啶-4-酮的合成及其抗癌活性的测定;单振国 等;《应用化学》;20120229;第29卷(第2期);144-148 * |
Also Published As
Publication number | Publication date |
---|---|
CN102863376A (en) | 2013-01-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102863376B (en) | N-substituent methyl-3,5-is two replaces benzal base-4-piperidone and Synthesis and applications | |
He et al. | 1, 2, 3-Triazole-containing derivatives of rupestonic acid: click-chemical synthesis and antiviral activities against influenza viruses | |
Renko et al. | Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols: A versatile access to restricted isocombretastatin A-4 analogues as antitumor agents | |
CN109705017B (en) | Application of chalcone indole derivative in preparation of antitumor drugs | |
CN106674136A (en) | Anti-tumor pyrimidine compounds and preparation method thereof | |
CN112707833B (en) | Histone deacetylase inhibitor and preparation and application thereof | |
CN101973935B (en) | Preparation method and application of N-substituted-3,5-dibenzal piperidine-4-one | |
CN101591280B (en) | Retinoids with effect of induction of differentiation of tumors and pharmaceutical composition as well as application thereof | |
CN104523664A (en) | Curcumin antineoplastic drug and application thereof | |
CN104016957A (en) | 7-methyl-3-geranyl flavone and 7-methyl-3-isopentene group flavone as well as preparation method and application thereof | |
CN104130176A (en) | 1,5-disubstituted indolone derivative and application thereof | |
CN103102331B (en) | Pharmaceutical application of chalcone compound containing piperazine ring | |
CN104725372B (en) | Tetracyclic indole alkaloid derivative as well as preparation method and application thereof | |
CN110922415A (en) | Synthesis and application of novel anti-tumor active compound | |
CN104016898A (en) | 3,4-disubstituted pyrrole compound as well as preparation method and application thereof | |
CN104163772A (en) | Substituted diaryl ester compound, and preparation method and application thereof | |
CN100503539C (en) | Diphenylethene compound with anti-tumor activity and preparing method | |
CN101497608B (en) | HIV protease inhibitor derivative, preparation thereof and use in antineoplastic medicament preparation | |
CN102952129B (en) | Tetrahydropyridodihyderivative,none derivative,none and its preparation method and application | |
CN104592203A (en) | 2-amino-4-tetrahydroindazole substituted benzamide compounds and application of compound in preparing anti-tumor drugs | |
CN102285993B (en) | Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof | |
CN104974135B (en) | Targeting DNA has the Sai-Mi-Xi-Bu derivative containing benzene-naphthalene diimide structure of antitumor activity, pharmaceutical composition and its preparation method and application | |
CN102276605B (en) | Dihydro-pyrazolo hexahydropyridine derivative, preparation method and application thereof | |
CN110526854A (en) | A kind of ɑ, alpha, beta-unsaturated ketone derivative, preparation method and the purposes as drug | |
CN102382111B (en) | Sulfo-tetrahydro-pyridino-dihydro-pyrimidone derivative, preparation method for same and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151216 Termination date: 20180927 |
|
CF01 | Termination of patent right due to non-payment of annual fee |