CN103772471B - A kind of estradiol-4-aminomethyl-pyridine conjugate and synthetic method thereof and application - Google Patents
A kind of estradiol-4-aminomethyl-pyridine conjugate and synthetic method thereof and application Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 168
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 77
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- 238000006243 chemical reaction Methods 0.000 claims description 66
- 229940126214 compound 3 Drugs 0.000 claims description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000003960 organic solvent Substances 0.000 claims description 53
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- 238000001035 drying Methods 0.000 claims description 48
- 229940125904 compound 1 Drugs 0.000 claims description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 36
- 229940125782 compound 2 Drugs 0.000 claims description 35
- 239000000706 filtrate Substances 0.000 claims description 35
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- 238000003786 synthesis reaction Methods 0.000 claims description 28
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 238000010898 silica gel chromatography Methods 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
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Abstract
The invention discloses a kind of estradiol-4-aminomethyl-pyridine conjugate and 3-hydroxyl-17 β-[6-(4-pyridine-methylamino-)-hexyl-oxygen]-1,3,5 (10)-triolefin-female steroids, and its synthetic method and application.Applicant found through experiments, and it is active that this estradiol-4-aminomethyl-pyridine conjugate has excellent Inhibit proliferaton to cell tumour strains such as HepG-2, BGC-823, A549, MCF-7 and PC-3.The structural formula of above-mentioned estradiol-4-aminomethyl-pyridine conjugate is shown below.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an estradiol-4-aminomethyl pyridine conjugate, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra, and a synthesis method and application thereof.
Background
The existing anticancer drugs have the following defects: while inhibiting the growth of tumor cells, the proliferation of normal cells is also severely inhibited, resulting in the inability of patients to take continuous medication (Curr Opin Chem Biol,2009,13(3): 256-fold 262.), each of which is often taken at the maximum dose and later undergoes a lengthy recovery period, whereas the recovery of tumor cells and tissues is much faster than normal cells and tissues, which severely affects the therapeutic effect of the drugs (bioconjugate Chem,2005,16(4), 803-fold 811; bioconjugate Chem,2006,17(5), 1226-fold 1232.). Therefore, the targeted drugs are receiving more and more attention and are one of the research hotspots for tumor biotherapy (wai xu hua, et al, folate receptor mediated anti-tumor targeting advances to the prodrug research, china new drugs journal, 2012, 21 (22), 2647-2653.). The estrogen receptor exists in cytoplasm and nucleus of human or other mammals having induction organs (breast, uterus, vagina, ovary, etc.) for estrogen stimulation, can be specifically combined with estradiol, and has strong affinity. Studies have found that anti-tumor estradiol derivatives designed with estradiol as a lead compound have selective toxic effects on estrogen-dependent breast, ovarian and prostate cancer cells (J Am Chem Soc 2002,124, (9), 1862-1863; J. Inorg. biochem.,2009,103, 256-261). The design of the compounds is based on the theory of receptor, and the medicine with estradiol as carrier is combined with high-expression estrogen receptor in tumor tissue under the induction of estradiol to reach the effect of targeting tumor cells. Meanwhile, the estrogen receptor is highly expressed in tumor tissues of certain non-estrogen target organs, such as liver cancer, gastric cancer, lung cancer and the like, and the estrogen receptor and sex hormone are considered to be related to the occurrence, development and prognosis of the tumors (the journal of Chinese tumor prevention and treatment, 2012, 19 (3), 235-240; the modern tumor medicine, 2012, 20 (11), 2438-2442; the journal of Chinese tumor prevention and treatment, 2010, 17(5), 326-329; the journal of practical liver disease, 2007, 10 (2), 92-93; the university report of third military science, 1995, 17 (2), 181-183; the medical review, 2009, 15 (3), 342-345; the Hebei medicine, 2002, 24 (1), 63-64). In recent years, many studies using estradiol as a lead compound of antitumor drugs have been reported (Bioorg Med Chem Lett.2004.14: 3829-3833; Steroids.2008.73: 1077-1089; Eur J Med chem.2012.48: 385-390), but no report on 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra has been found so far.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel estradiol-4-aminomethyl pyridine conjugate, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra, and a synthetic method and application thereof.
The chemical name of the estradiol-4-aminomethyl pyridine conjugate, namely the compound 1, is 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra, and the structural formula is shown as the following formula:
the first method for synthesizing the estradiol-4-aminomethyl pyridine conjugate specifically comprises the following steps:
1) synthesis of intermediate compound 3:
dissolving a compound 2 serving as a raw material by using an organic solvent, adding sodium hydride and 1, 6-dibromohexane, reacting completely, diluting a reaction solution by using water, extracting by using ethyl acetate, washing, drying, and performing silica gel column chromatography on obtained residues, wherein the volume ratio of the sodium hydride to the 1, 6-dibromohexane is 60-80: eluting with mixed solvent of petroleum ether and ethyl acetate of 1 to obtain compound 3; wherein:
the compound 2 is 17 beta-hydroxy-3- (benzyl) oxy-1, 3,5(10) -triene-estra, and the molar ratio of the compound 2 to sodium hydride to 1, 6-dibromohexane is 1: 5-15: 3-10;
2) synthesis of intermediate compound 4:
placing the compound 3 in a round-bottom flask, dissolving the compound in an organic solvent, adding ammonium formate and a palladium-carbon catalyst, reacting completely, carrying out suction filtration on a reaction solution, carrying out rotary drying on a filtrate, diluting the filtrate with water, extracting with ethyl acetate, washing, drying, and carrying out silica gel column chromatography on the obtained residue, wherein the volume ratio of the components is 8-15: eluting with mixed solvent of petroleum ether and ethyl acetate of 1 to obtain compound 4; wherein:
the molar ratio of the compound 3 to the ammonium formate is 1: 2-8, wherein the weight ratio of the compound 3 to the palladium carbon catalyst is 1: 0.01 to 0.1;
3) synthesis of target product compound 1:
placing the compound 4 in a round-bottom flask, dissolving the compound in an organic solvent, adding 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide, reacting completely, diluting a reaction solution with water, extracting with ethyl acetate, washing, drying, and performing silica gel column chromatography on an obtained residue, wherein the volume ratio of the mixture is 12-30: 1, eluting with a mixed solvent consisting of dichloromethane and methanol to obtain a target product compound 1, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra; wherein:
the tetrabutylammonium halide is tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium iodide or tetrabutylammonium bromide;
the mol ratio of the compound 4, 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide is 1: 1-5: 0.5-3: 0.05-0.3.
The synthesis method comprises the following steps:
in step 1), the organic solvent used for dissolving the compound 2 may be N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), pyridine, dioxane, acetone, benzene or other organic solvents capable of dissolving the compound 2; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 2 is dissolved in 0.5 to 5mL of an organic solvent. In the mixed solvent for elution, the volume ratio of petroleum ether to ethyl acetate is preferably 65-75: 1. in the step, in order to improve the yield of the compound 3, the compound 2 is dissolved by an organic solvent, then sodium hydride is added for 30-120 min, and then 1, 6-dibromohexane is added until the reaction is complete; the addition of sodium hydride is generally carried out at temperatures below 0 ℃.
In the step 2), the organic solvent used for dissolving the compound 3 may be methanol, ethanol, ethyl acetate, ethyl formate, tetrahydrofuran, acetone or other organic solvents capable of dissolving the compound 3; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 3 is dissolved in 0.5 to 5mL of an organic solvent. The concentration of the palladium carbon catalyst is preferably 5-15% (weight percent of palladium content), and the weight ratio of the compound 3 to the palladium carbon catalyst is the weight ratio of the compound 3 to the palladium carbon catalyst of 5-15%. In the step, in the mixed solvent for elution, the volume ratio of petroleum ether to ethyl acetate is preferably 10-15: 1.
in the step 3), the organic solvent used for dissolving the compound 4 may be N, N-dimethylformamide, tetrahydrofuran, pyridine, dioxane, acetone, benzene, ethyl acetate, ethyl formate or other organic solvents capable of dissolving the compound 4; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 4 is dissolved in 0.5 to 5mL of an organic solvent. In the mixed solvent for elution, the volume ratio of dichloromethane to methanol is preferably 15-25: 1. in this step, potassium carbonate may be replaced with potassium hydroxide, sodium hydroxide or sodium carbonate (in the same ratio as that of potassium carbonate), and the target compound 1 may be obtained as well.
In each step, the reaction is carried out at 90 ℃ or lower, preferably at 20 to 90 ℃, and more preferably at 20 to 80 ℃. Whether the reaction in each step is complete or not can be detected by adopting thin layer chromatography tracking, and under the limited condition, the reaction in the step 1) needs about 10-20 hours until the reaction is complete; in the step 2), the reaction takes about 10 to 20 hours to complete; in the step 3), the stirring reaction is carried out for about 80-100 hours until the reaction is completed.
In the above steps, washing is usually performed with saturated brine, and drying is usually performed with anhydrous sodium sulfate or anhydrous magnesium sulfate.
In the above synthesis method, compound 4 can be synthesized from compound 3 by another method, that is, the following step 2a) can be used instead of step 2), wherein step 2a) is as follows:
2a) synthesis of intermediate compound 4:
dissolving the compound 3 with an organic solvent, adding a palladium-carbon catalyst, carrying out normal-temperature normal-pressure hydrogenation, carrying out suction filtration on a reaction solution, and spin-drying a filtrate to obtain a compound 4; wherein the weight ratio of the compound 3 to the palladium-carbon catalyst is 1: 0.01 to 0.1.
In the step 2a), the organic solvent used for dissolving the compound 3 may also be other organic solvents capable of dissolving the compound 3, such as methanol, ethanol, ethyl acetate, ethyl formate, tetrahydrofuran, acetone, or the like; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 3 is dissolved in 0.5 to 5mL of an organic solvent. The concentration of the palladium carbon catalyst is preferably 5-15% (weight percent of palladium content), and the weight ratio of the compound 3 to the palladium carbon catalyst is the weight ratio of the compound 3 to the palladium carbon catalyst of 5-15%. The normal-temperature and normal-pressure hydrogenation time is generally 10-15 h (the time is short, the reaction is incomplete, the yield is low, and the time is long, so that the number of byproducts is increased).
The estradiol-4-aminomethyl pyridine conjugate can also be synthesized by adopting a second method which specifically comprises the following steps:
i) Synthesis of intermediate Compound 3:
dissolving a compound 2 serving as a raw material by using an organic solvent, adding sodium hydride and 1, 6-dibromohexane, reacting completely, diluting a reaction solution by using water, extracting by using ethyl acetate, washing, drying, and performing silica gel column chromatography on obtained residues, wherein the volume ratio of the sodium hydride to the 1, 6-dibromohexane is 60-80: eluting with mixed solvent of petroleum ether and ethyl acetate of 1 to obtain compound 3; wherein:
the compound 2 is 17 beta-hydroxy-3- (benzyl) oxy-1, 3,5(10) -triene-estra, and the molar ratio of the compound 2 to sodium hydride to 1, 6-dibromohexane is 1: 5-15: 3-10;
II) Synthesis of intermediate Compound 5:
placing the compound 3 in a round-bottom flask, dissolving the compound in an organic solvent, adding 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide, reacting completely, diluting a reaction solution with water, extracting with ethyl acetate, washing, drying, and performing silica gel column chromatography on an obtained residue, wherein the volume ratio of the mixture is 12-30: 1, eluting with a mixed solvent consisting of dichloromethane and methanol to obtain a compound 5; wherein:
the tetrabutylammonium halide is tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium iodide or tetrabutylammonium bromide;
the mol ratio of the compound 3, 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide is 1: 1-5: 0.5-3: 0.05-0.3.
III) Synthesis of the target product Compound 1:
placing the compound 5 in a round-bottom flask, dissolving the compound with an organic solvent, adding ammonium formate and a palladium-carbon catalyst, reacting completely, carrying out suction filtration on a reaction solution, carrying out rotary drying on a filtrate, diluting with water, extracting with ethyl acetate, washing, drying, and carrying out silica gel column chromatography on an obtained residue, wherein the volume ratio of the components is 12-30: 1, eluting with a mixed solvent consisting of dichloromethane and methanol to obtain a target product compound 1, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra; wherein:
the molar ratio of the compound 5 to ammonium formate is 1: 2-8, wherein the weight ratio of the compound 5 to the palladium carbon catalyst is 1: 0.01 to 0.1.
In the second synthesis method:
in the step I), the organic solvent used for dissolving the compound 2 can be N, N-dimethylformamide, tetrahydrofuran, pyridine, dioxane, acetone, benzene or other organic solvents capable of dissolving the compound 2; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 2 is dissolved in 0.5 to 5mL of an organic solvent. In the mixed solvent for elution, the volume ratio of petroleum ether to ethyl acetate is preferably 65-75: 1. in the step, in order to improve the yield of the compound 3, the compound 2 is dissolved by an organic solvent, then sodium hydride is added for 30-120 min, and then 1, 6-dibromohexane is added until the reaction is complete; the addition of sodium hydride is generally carried out at temperatures below 0 ℃.
In the step II), the organic solvent used for dissolving the compound 3 can be N, N-dimethylformamide, tetrahydrofuran, pyridine, dioxane, acetone, benzene, ethyl acetate, ethyl formate or other organic solvents capable of dissolving the compound 3; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 3 is dissolved in 0.5 to 5mL of an organic solvent. In the mixed solvent for elution, the volume ratio of dichloromethane to methanol is preferably 15-25: 1. in this step, potassium carbonate is replaced with potassium hydroxide, sodium hydroxide or sodium carbonate (in the same ratio as that of potassium carbonate), and compound 5 can be synthesized as well.
In step III), the organic solvent used for dissolving the compound 5 can be methanol, ethanol, ethyl acetate, ethyl formate, tetrahydrofuran, acetone or other organic solvents capable of dissolving the compound 5; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 5 is dissolved in 0.5 to 5mL of an organic solvent. In the step, in the mixed solvent for elution, the volume ratio of dichloromethane to methanol is preferably 15-25: 1.
in each step of the second synthesis method, the reaction is carried out at 90 ℃ or lower, preferably at 20 to 90 ℃, and more preferably at 40 to 80 ℃. Whether the reaction in each step is complete or not can be detected by adopting thin layer chromatography tracking, and under the limited condition, the reaction in the step I) needs about 10-20 hours until the reaction is complete; in the step II), the reaction is carried out for about 10 to 20 hours until the reaction is complete; in the step III), the stirring reaction is carried out for about 80-100 hours until the reaction is completed.
In the above steps, washing is usually performed with saturated brine, and drying is usually performed with anhydrous sodium sulfate or anhydrous magnesium sulfate.
In the second synthesis method described above, compound 1 can also be synthesized from compound 5 by another method, i.e., step iiia) is used instead of step iii), said step iiia) is as follows:
dissolving the compound 5 in an organic solvent, adding a palladium carbon catalyst, carrying out normal-temperature normal-pressure hydrogenation, carrying out suction filtration on a reaction solution, and spin-drying a filtrate to obtain a target product compound 1, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estrane.
In the step IIIa), the organic solvent used for dissolving the compound 5 can be methanol, ethanol, ethyl acetate, ethyl formate, tetrahydrofuran, acetone or other organic solvents capable of dissolving the compound 5; the amount of the compound is enough to dissolve the substance participating in the reaction, and usually, 1mmol of the compound 5 is dissolved in 0.5 to 5mL of an organic solvent. The concentration of the palladium carbon catalyst is 5-15% (weight percent of palladium content). The normal-temperature and normal-pressure hydrogenation time is generally 10-15 h (the time is short, the reaction is incomplete, the yield is low, and the time is long, so that the byproducts are increased).
The invention also comprises the application of the estradiol-4-aminomethyl pyridine conjugate in preparing antitumor drugs.
The present invention also includes an antitumor agent prepared with the estradiol-4-aminomethylpyridine conjugate of claim 1 as an active ingredient.
In the first synthesis method and the second synthesis method, the round-bottom flask is preferably a round-bottom flask with a calcium chloride drying tube; the compound 2 can be synthesized by the prior art from estradiol serving as the most basic raw material (see J.Med.chem.,2001,44(1), 110-:
placing estradiol in a round-bottom flask with a calcium chloride drying tube, dissolving with an organic solvent, adding benzyl chloride or benzyl bromide and NaOH, reacting completely, carrying out suction filtration on a reaction solution, pouring a filtrate into ice water, separating out a white solid, separating, and drying to obtain a compound 2. The mole ratio of estradiol, benzyl chloride or benzyl bromide and NaOH is (1: 1.5-3: 1.8-5, the organic solvent used for dissolving estradiol can be N, N-dimethylformamide, tetrahydrofuran, pyridine, dioxane, acetone or benzene or other organic solvents capable of dissolving estradiol, the dosage of the organic solvent can be the amount capable of dissolving substances participating in the reaction, normally, 1mmol of estradiol is dissolved by 0.5-5 mL of organic solvent, and the dosage of ice water is calculated by the dosage of estradiol, and normally, 1mmol of estradiol is dissolved by 50-200 g of ice water.
Compared with the prior art, the invention provides a novel estradiol-4-aminomethyl pyridine conjugate, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra, and a synthesis method and application thereof. The applicant finds that the estradiol-4-aminomethyl pyridine conjugate has excellent proliferation inhibiting activity on cell tumor strains such as HepG-2, BGC-823, A549, MCF-7, PC-3 and the like.
Detailed Description
The present invention is further illustrated by the following specific examples, but the present invention is not limited to these examples.
Example 1
1) Synthesis of Compound 2:
estradiol (1.000g,3.67mmol) is put in CaCl2In a dry tube round-bottom flask, DMF (8.0mL) was added to dissolve benzyl chloride (0.7mL,6.08mmol) and NaOH (0.265g,6.63mmol) to react at room temperature for 12 h; the reaction mixture was filtered with suction, the residue was washed with DMF, the filtrates were combined, the filtrate was poured into ice water to precipitate a white solid, and the white solid was separated and dried to obtain 21.251 g of the compound (white solid, yield 94%).
The compound 2 is subjected to nuclear magnetic resonance hydrogen spectrum detection, and the spectrum data are as follows:
1H NMR(500MHz,CDCl3)0.78(s,3H,H-18),1.15-2.32(m,13H,3×CH,5×CH2),2.86(m,2H,H-6),3.73(t,1H,J=8.4Hz,H-17),5.03(s,2H,PhCH20),6.72(d,1H,J=2.2Hz,H-4),6.78(dd,1H,J=2.5,8.5Hz,H-2),7.21(d,1H,J=8.6Hz,H-1),7.32-7.44(m,5H,Ar-H).
accordingly, it was confirmed that the above compound 2 was 17 β -hydroxy-3- (benzyl) oxy-1, 3,5(10) -triene-estra, and the structural formula thereof was shown by the structural formula denoted by the reference numeral 2 in the following synthetic route.
2) Synthesis of Compound 3:
compound 2(1.109g,3.06mmol) was dissolved in DMF (5.0mL), NaH (0.734g,30.58mmol) was added at 0 ℃ to react for 30min, and 1, 6-dibromohexane (2.4mL,15.60mmol) was added at 0 ℃ to react at room temperature for 12 h. Diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography, and purifying with petroleum ether: ethyl acetate =70:1 (vol.%) in a mixed solvent, and the solvent was evaporated from the eluent to dryness to give 31.116 g (pale yellow oil, 69% yield).
The compound 3 is subjected to nuclear magnetic resonance hydrogen spectrum detection, and the spectrum data are as follows:
1H NMR(500MHz,CDCl3)0.82(s,3H,H-18),1.15-2.30(m,21H,3×CH,9×CH2),2.86(m,2H,H-6),3.38(t,1H,J=8.4Hz,H-17),3.41-3.51(m,4H,OCH2,CH2Br),5.04(s,2H,PhCH20),6.72(d,1H,J=2.0Hz,H-4),6.78(dd,1H,J=2.3,8.5Hz,H-2),7.21(d,1H,J=8.6Hz,H-1),7.32-7.44(m,5H,Ar-H).
thus, it was confirmed that Compound 3 was 17. beta. - (6-bromohexyl) oxy-3- (benzyl) oxy-1, 3,5(10) -triene-estra, and the structural formula thereof was shown by the structural formula denoted by the reference numeral 3 in the following synthetic route.
3) Synthesis of Compound 4:
taking compound 3(2.064g,3.93mmol) and placing in CaCl2In a dry-tube round-bottom flask, with CH3OH (5.0mL) was dissolved, ammonium formate (0.743g,11.78mmol) and 10% Pd/C (0.04g) were added, and the reaction was carried out at 80 ℃ for 12 hours; reaction liquid is filtered, and CH is used for filter residue3OH washing, combining filtrates, carrying out rotary drying on the filtrate under reduced pressure, adding water to dilute the residue, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, and separating the obtained residue by silica gel column chromatography, wherein the weight ratio of petroleum ether: ethyl acetate =12:1 (vol%) and the solvent was evaporated off from the eluent to afford 41.028 g (pale yellow oil, yield 60%).
The compound 4 is subjected to nuclear magnetic resonance hydrogen spectrum detection, and the spectrum data are as follows:
1H NMR(500MHz,CDCl3)0.78(s,3H,H-18),1.16-2.27(m,21H,3×CH,9×CH2),2.81(m,2H,H-6),3.37(t,1H,J=8.4Hz,H-17),3.40-3.52(m,4H,CH2Br,OCH2),4.72(brs,1H,3-OH),6.55(d,1H,J=2.4Hz,H-4),6.63(dd,1H,J=2.5,8.3Hz,H-2),7.15(d,1H,J=8.4Hz,H-1).
thus, it was confirmed that the compound 4 was 3-hydroxy-17 β - (6-bromohexyl) oxy-1, 3,5(10) -triene-estra, and the structural formula thereof was shown by the structural formula given by the reference numeral 4 in the following synthetic route.
4) Synthesis of Compound 1:
taking compound 4(1.321g,3.03mmol) and placing in CaCl2In a dry-tube round-bottom flask, THF (6.0mL) was dissolved, and 4-aminomethylpyridine (0.35mL,3.64mmol), K, was added2CO3(1.256g,2.17mmol) and tetrabutylammonium bromide (0.090g,0.30mmol) at 60 ℃ for 96 h; diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography with dichloromethane: methanol =20:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 10.685 g (yellow solid, yield 49%).
The compound 1 is subjected to nuclear magnetic resonance hydrogen spectrum detection, and the spectrum data are as follows:
1H NMR(500MHz,CDCl3)0.78(s,3H,H-18),1.13-2.28(m,21H,3×CH,9×CH2),2.64(t,2H,J=7.2Hz,CH2N),2.86(m,2H,H-6),3.37(t,1H,J=8.4Hz,H-17),3.42-3.50(m,2H,OCH2),3.81(s,2H,NCH2-Pyridyl),5.03(s,2H,Ar-CH2),6.71(d,1H,J=2.5Hz,H-4),6.77(dd,1H,J=2.7,8.5Hz,H-2),7.12(d,1H,J=8.6Hz,H-1),7.27(d,2H,J=5.1Hz,Pyridyl-H),8.55(d,2H,J=5.8Hz,Pyridyl-H).
thus, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra, and the structural formula thereof was shown by the structural formula 1 in the following synthetic route.
The synthetic route of the whole method is as follows:
example 2
Example 1 is repeated, except that step 3) is replaced by the following step 3a), said step 3a) being as follows:
3a) synthesis of Compound 4:
dissolve Compound 3(2.500g,4.76mmol) in CH3Adding 10% Pd/C (0.05g) into OH (5.0mL), and hydrogenating at room temperature and normal pressure for 12 h; suction filtering the reaction liquid, and using CH for filter residue3OH was washed, the filtrates were combined, and the resulting filtrate was spin-dried under reduced pressure to give 41.346 g of compound (pale yellow oil, yield 65%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 4 gave the same spectral data as in example 1, and therefore, it was confirmed that the compound 4 was 3-hydroxy-17 β - (6-bromohexyl) oxy-1, 3,5(10) -triene-estra.
Example 3
1) Synthesis of Compound 2:
estradiol (1.000g,3.67mmol) is put in CaCl2Dissolving pyridine (15.0mL) in a round-bottom flask of a drying tube, adding benzyl chloride and NaOH (the molar ratio of the estradiol to the benzyl chloride to the NaOH is 1: 3: 4), and reacting for 8 hours at 40 ℃; the reaction mixture was filtered with suction, the residue was washed with pyridine, the filtrates were combined, the filtrate was poured into ice water to precipitate a white solid, and the white solid was separated and dried to obtain 21.304 g of the compound (white solid, yield 98%).
2) Synthesis of Compound 3:
compound 2(1.109g,3.06mmol) was dissolved in THF (5.0mL), NaH was added at 0 ℃ for 90min, and after reaction, 1, 6-dibromohexane (the molar ratio of compound 2, NaH and 1, 6-dibromohexane was 1: 15: 3) was added at 0 ℃ for reaction at room temperature for 15 h. Diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography, and purifying with petroleum ether: ethyl acetate =60:1 (vol.%) and the solvent was evaporated from the eluent to dryness to give 30.965 g (pale yellow oil, 60% yield).
3) Synthesis of Compound 4:
taking compound 3(2.064g,3.93mmol) and placing in CaCl2Dissolving in ethanol (5.0mL) in a round-bottom flask of a drying tube, adding ammonium formate and 15% Pd/C (wherein the molar ratio of the compound 3 to the ammonium formate is 1: 6, and the weight ratio of the compound 3 to the 15% Pd/C is 1: 0.1), and reacting at 60 ℃ for 9 hours; filtering the reaction solution, washing filter residues with ethanol, combining the filtrates, carrying out vacuum spin-drying on the filtrates, diluting the residue with water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and separating the obtained residue by silica gel column chromatography with petroleum ether: ethyl acetate =15:1 (vol%) and the solvent was evaporated off from the eluent to afford 41.368 g (pale yellow oil, yield 80%).
4) Synthesis of Compound 1:
taking compound 4(1.321g,3.03mmol) and placing in CaCl2Dissolving with THF (6.0mL) in a round-bottom flask of a drying tube, adding 4-aminomethyl pyridine, potassium hydroxide and tetrabutylammonium chloride (the molar ratio of the compound 4 to the 4-aminomethyl pyridine to the potassium hydroxide to the tetrabutylammonium chloride is 1: 5: 3: 0.05), and reacting at 50 ℃ for 96 hours; diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography with dichloromethane: methanol =12:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 10.730 g (yellow solid, yield 52%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
Example 4
1) Synthesis of Compound 2:
the same as in example 3.
2) Synthesis of Compound 3:
example 3 was repeated except that:
the molar ratio of the compound 2, NaH and 1, 6-dibromohexane is 1: 5: 10, reacting for 12 hours at 30 ℃; eluting with petroleum ether: ethyl acetate =80:1 (volume ratio) of mixed solvent elution. The solvent was evaporated from the eluate to dryness to give 30.659 g of compound (pale yellow oil, yield 41%).
3) Synthesis of Compound 4:
example 3 was repeated except that:
15% Pd/C was replaced by 10% Pd/C and the molar ratio of compound 3 and ammonium formate was 1: compound 3 and 10% Pd/C in a weight ratio of 1: 0.01; petroleum ether was used for elution: ethyl acetate =10:1 (volume ratio) of the mixed solvent. The solvent was evaporated from the eluate to dryness to give 40.889 g of compound (pale yellow oil, yield 52%).
4) Synthesis of Compound 1:
example 3 was repeated except that:
sodium hydroxide was used instead of potassium hydroxide, tetrabutylammonium iodide was used instead of tetrabutylammonium chloride, and the molar ratio of compound 4, 4-aminomethylpyridine, sodium hydroxide and tetrabutylammonium iodide was 1: 3: 2: reacting at 0.3 ℃ for 48 hours; diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography with dichloromethane: methanol =30:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 10.842 g (yellow solid, yield 60%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
Example 5
1) Synthesis of Compound 2:
the same as in example 3.
2) Synthesis of Compound 3:
example 3 was repeated except that:
the molar ratio of the compound 2, NaH and 1, 6-dibromohexane is 1: 6: 5, reacting for 7 hours at 70 ℃; eluting with petroleum ether: ethyl acetate =65:1 (volume ratio). The solvent was evaporated from the eluate to dryness to give 31.302 g of compound (pale yellow oil, yield 81%).
3) Synthesis of Compound 4:
dissolving the compound 3(2.500g,4.76mmol) in ethyl acetate (5.0mL), adding 15% Pd/C (0.2g), and hydrogenating at room temperature and normal pressure for 6 h; the reaction mixture was filtered with suction, the residue was washed with ethyl acetate, the filtrates were combined, and the resulting filtrate was spin-dried under reduced pressure to give 41.471 g of compound (pale yellow oil, yield 71%).
4) Synthesis of Compound 1:
example 3 was repeated except that:
sodium carbonate is used for replacing potassium hydroxide, tetrabutylammonium bromide is used for replacing tetrabutylammonium chloride, and the molar ratio of the compound 4, 4-aminomethyl pyridine to the sodium carbonate to the tetrabutylammonium bromide is 1: 1: 0.5: reacting at 0.2 and 60 ℃ for 95 h; diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography with dichloromethane: methanol =22:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 10.491 g (yellow solid, yield 35%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
Example 6
I) Synthesis of Compound 2:
the same as in example 1.
II) Synthesis of Compound 3:
the same as in example 1.
III) Synthesis of Compound 5:
taking compound 3(0.900g,1.71mmol), placing in CaCl2In a dry-tube round-bottom flask, THF (6.0mL) was dissolved, and 4-aminomethylpyridine (0.21mL,2.15mmol), K, was added2CO3(0.169g,1.23mmol) and tetrabutylammonium bromide (0.055g,0.171mmol) at 60 ℃ for 72 h; diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography with dichloromethane: methanol =20:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 50.454 g (yellow solid, yield 48%).
The compound 5 is subjected to nuclear magnetic resonance hydrogen spectrum detection, and the spectrum data are as follows:
1H NMR(500MHz,CDCl3)0.78(s,3H,H-18),1.13-2.25(m,21H,3×CH,9×CH2),2.67(t,2H,J=7.3Hz,CH2N),2.77(m,2H,H-6),3.35(t,1H,J=8.4Hz,H-17),3.39-3.50(m,2H,OCH2),3.85(s,2H,NCH2-Pyridyl),6.56(d,1H,J=2.0Hz,H-4),6.64(dd,1H,J=2.0,8.4Hz,H-2),7.12(d,1H,J=8.4Hz,H-1),7.32(d,2H,J=5.3Hz,Pyridyl-H),7.32-7.44(m,5H,Ar-H),8.55(d,2H,J=5.3Hz,Pyridyl-H).
thus, it was confirmed that the compound 5 was 17 β - [6- (4-pyridine-methylamino) -hexyl-oxy ] -3- (benzyl) oxy-1, 3,5(10) -triene-estra, the structural formula of which is shown by the structural formula 5 in the following synthetic route.
IV) Synthesis of Compound 1:
taking compound 5(0.150g,0.27mmol) and placing in the presence of CaCl2In a dry-tube round-bottom flask, with CH3OH (2.0mL) is dissolved, ammonium formate (0.031g,0.81mmol) and 10% Pd/C (0.003g) are added, and reaction is carried out at 80 ℃ for 12 h; suction filtering the reaction liquid, and using CH for filter residue3OH washing, combining filtrates, carrying out rotary drying on the filtrates under reduced pressure, adding water to dilute the residue, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, and separating the obtained residue by silica gel column chromatography, wherein the ratio of dichloromethane: methanol =20:1 (vol) and the solvent was evaporated off from the eluent to afford compound 10.078 g (yellow solid, 62% yield).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
In this example, the synthetic route for compound 1 from compound 3 is as follows:
example 7
Example 6 is repeated, except that step IV) is replaced by the following step IVa) as follows:
iva) synthesis of compound 1:
dissolve Compound 5(0.150g,0.27mmol) in CH3Adding 10% Pd/C (0.003g) into OH (2.0mL), and hydrogenating at room temperature and normal pressure for 12 h; suction filtering the reaction liquid, and using CH for filter residue3OH washing, combining filtrates, and spin-drying the filtrate under reduced pressure gave 10.083 g of compound (yellow solid, yield 66%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
Example 8
I) Synthesis of Compound 2:
estradiol (1.000g,3.67mmol) is put in CaCl2Dissolving the mixture in a round-bottom flask of a drying tube by using benzene (15.0mL), adding benzyl bromide and NaOH (the molar ratio of the estradiol to the benzyl bromide to the NaOH is 1: 3: 2), and reacting at room temperature for 6 hours; the reaction mixture was filtered with suction, the residue was washed with pyridine, the filtrates were combined, the filtrate was poured into ice water to precipitate a white solid, and the white solid was separated and dried to obtain 21.264 g of the compound (white solid, yield 95%).
II) Synthesis of Compound 3:
compound 2(1.109g,3.06mmol) was dissolved in dioxane (10.0mL), NaH was added at 0 ℃ for 50min, and after reaction, 1, 6-dibromohexane (molar ratio of compound 2, NaH and 1, 6-dibromohexane was 1: 8: 6) was added at 0 ℃ for reaction at room temperature for 11 h. Diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, separating the obtained residue by silica gel column chromatography, and purifying with petroleum ether: ethyl acetate =75:1 (vol.%) and the solvent was evaporated from the eluent to dryness to give 31.077 g (pale yellow oil, 67% yield).
III) Synthesis of Compound 5:
taking compound 3(0.900g,1.71mmol), placing in CaCl2Dissolving the mixture in acetone (4.0mL) in a round-bottom flask of a drying tube, adding 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium iodide (the molar ratio of the compound 3, the 4-aminomethyl pyridine, the potassium carbonate and the tetrabutylammonium iodide is 1: 2: 3: 0.3), and reacting at 50 ℃ for 38 hours; diluting the reaction solution with water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and separating the residue by silica gel column chromatographyThe reaction is carried out in a reaction condition of dichloromethane: methanol =12:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 50.587 g (yellow solid, yield 62%).
IV) Synthesis of Compound 1:
dissolving compound 5(0.150g,0.27mmol) in acetone (1.2mL), adding 15% Pd/C (0.015g), and hydrogenating at room temperature and normal pressure for 12 h; the reaction solution was filtered with suction, the residue was washed with acetone, the filtrates were combined, and the filtrate was spin-dried under reduced pressure to obtain 10.094 g of the compound (yellow solid, yield 75%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
Example 9
I) Synthesis of Compound 2:
the same as in example 8.
II) Synthesis of Compound 3:
example 8 was repeated except that:
the molar ratio of the compound 2, NaH and 1, 6-dibromohexane is 1: 12: 10, 40? h; eluting with petroleum ether: ethyl acetate =70:1 (volume ratio). The solvent was evaporated from the eluate to dryness to give 31.158 g of compound (pale yellow oil, yield 72%).
III) Synthesis of Compound 5:
example 8 was repeated except that:
potassium carbonate was used instead of sodium carbonate, tetrabutylammonium fluoride was used instead of tetrabutylammonium iodide, and the molar ratio of compound 3, 4-aminomethylpyridine, potassium carbonate and tetrabutylammonium fluoride was 1: 3: 3: 0.05; elution was performed with dichloromethane: methanol =30:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 50.445 g of compound (yellow solid, yield 47%).
IV) Synthesis of Compound 1:
dissolving compound 5(0.150g,0.27mmol) in acetone (1.2mL), adding 5% Pd/C (0.0075g), and hydrogenating at room temperature and normal pressure for 18 h; the reaction solution was filtered with suction, the residue was washed with acetone, the filtrates were combined, and the filtrate was spin-dried under reduced pressure to obtain 10.074 g of the compound (yellow solid, yield 59%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
Example 10
I) Synthesis of Compound 2:
the same as in example 8.
II) Synthesis of Compound 3:
example 8 was repeated except that:
the molar ratio of the compound 2, NaH and 1, 6-dibromohexane is 1: 5: reacting for 9 hours at the temperature of 3 and 35 ℃; eluting with petroleum ether: ethyl acetate =65:1 (volume ratio). The solvent was evaporated from the eluate to dryness to give 31.045 g of compound (pale yellow oil, yield 65%).
III) Synthesis of Compound 5:
example 8 was repeated except that:
sodium hydroxide was used instead of sodium carbonate, tetrabutylammonium iodide was used instead of tetrabutylammonium iodide, and the molar ratio of compound 3, 4-aminomethylpyridine, sodium hydroxide and tetrabutylammonium chloride was 1: 5: 0.5: 0.2; elution was performed with dichloromethane: methanol =25:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 50.312 g (yellow solid, yield 33%).
IV) Synthesis of Compound 1:
compound 5(0.150g,0.27mmol) was dissolved in THF (1.0mL), ammonium formate (0.034g,0.54mmol) and 5% Pd/C (0.012g) were added and reacted at 45 ℃ for 12 h; filtering the reaction solution, washing filter residues with THF, combining filtrates, carrying out vacuum spin-drying on the filtrate, diluting the residue with water, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and separating the obtained residue by silica gel column chromatography with dichloromethane: methanol =30:1 (volume ratio) and the solvent was evaporated off from the eluent to obtain 10.048 g of compound (yellow solid, yield 38%).
The nuclear magnetic resonance hydrogen spectrum detection of the obtained compound 1 was carried out, and the obtained spectral data were the same as those of example 1, and therefore, it was confirmed that the compound 1 was 3-hydroxy-17 β - [6- (4-pyridin-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
To fully illustrate the utility of 3-hydroxy-17 β - [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra in the pharmaceutical industry, applicants conducted in vitro anti-tumor activity experiments on a variety of tumor strains using compound 1 prepared in example 1, namely 3-hydroxy-17 β - [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra.
The in vitro antitumor activity of the compound 1 prepared in example 1, i.e., 3-hydroxy-17 β - [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra, was determined by a conventional tetramethylazole blue colorimetric method, and selected cell lines were HepG-2 (human hepatoma cell line), BGC-823 (gastric cancer cell line), a549 (human lung cancer cell line), MCF-7 (breast cancer cell line), and PC-3 (prostate cancer cell line), respectively. The positive control drug is 5-fluorouracil.
All cell lines were cultured in 1640 medium containing 10% fetal bovine serum at 37 ℃ with 5% CO2The cells are cultured in the cell culture box until the cells reach the logarithmic growth phase. After the tested compound to be tested is dissolved with DMSO, the test compound is prepared into working solution with the concentration of 100 mu mol/L, 50 mu mol/L, 10 mu mol/L, 5 mu mol/L, 1 mu mol/L and 0.1 mu mol/L, and the working solution is storedStored in a refrigerator at 4 ℃ for testing the IC of the test compounds on selected tumor cell lines50The value is used.
Taking a bottle of cells in an exponential growth phase, adding 0.25% trypsin digestion solution, digesting to make adherent cells fall off, counting 2-4 × 104 cells/mL, and preparing a cell suspension; inoculating the cell suspension on a 96-well plate at 180 μ L/well, and placing in constant temperature CO2Culturing in an incubator for 24 hours; changing the solution, adding the tested compound, 20 mu L/hole, and culturing for 72 hours; adding MTT into a 96-well plate, and reacting for 4 hours in an incubator at 20 mu L/well; the supernatant was aspirated, DMSO was added at 150. mu.L/well, and shaken on a shaker for 5 minutes; the absorbance of each well was measured at a wavelength of 570nm using an enzyme-linked immunosorbent assay, and the cell inhibition ratio (% cell inhibition ratio = (negative control OD value-test substance OD value)/negative control OD value × 100%) was calculated, and the results are shown in table 1 below.
Table 1: data (IC) for in vitro antitumor cell proliferation Activity of Compound 1 and control drugs50,μmol/L）：
| HepG-2 | BGC-823 | A549 | MCF-7 | PC-3 | |
| Compound 1 | 2.85 | 18.74 | 15.22 | 16.54 | 9.14 |
| 5-Fluorouracil | 55.74 | 8.82 | 68.16 | 21.47 | 12.23 |
As can be seen from Table 1, the compound 1 has far higher inhibitory effect on tested tumor cells than 5-fluorouracil, has better potential medicinal value and is expected to be used for preparing various antitumor drugs.
Claims (10)
1. An estradiol-4-aminomethylpyridine conjugate, wherein: the chemical name of the compound is: 3-hydroxy-17 β - [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra having the formula:
2. a method of synthesizing the estradiol-4-aminomethylpyridine conjugate of claim 1, comprising the steps of:
1) synthesis of intermediate compound 3:
dissolving a compound 2 serving as a raw material by using an organic solvent, adding sodium hydride and 1, 6-dibromohexane, reacting completely, diluting a reaction solution by using water, extracting by using ethyl acetate, washing, drying, and performing silica gel column chromatography on obtained residues, wherein the volume ratio of the sodium hydride to the 1, 6-dibromohexane is 60-80: eluting with mixed solvent of petroleum ether and ethyl acetate of 1 to obtain compound 3; wherein:
the compound 2 is 17 beta-hydroxy-3- (benzyl) oxy-1, 3,5(10) -triene-estra, and the molar ratio of the compound 2 to sodium hydride to 1, 6-dibromohexane is 1: 5-15: 3-10;
2) synthesis of intermediate compound 4:
placing the compound 3 in a round-bottom flask, dissolving the compound in an organic solvent, adding ammonium formate and a palladium-carbon catalyst, reacting completely, carrying out suction filtration on a reaction solution, carrying out rotary drying on a filtrate, diluting the filtrate with water, extracting with ethyl acetate, washing, drying, and carrying out silica gel column chromatography on the obtained residue, wherein the volume ratio of the components is 8-15: eluting with mixed solvent of petroleum ether and ethyl acetate of 1 to obtain compound 4; wherein:
the molar ratio of the compound 3 to the ammonium formate is 1: 2-8, wherein the weight ratio of the compound 3 to the palladium carbon catalyst is 1: 0.01 to 0.1;
3) synthesis of target product compound 1:
placing the compound 4 in a round-bottom flask, dissolving the compound in an organic solvent, adding 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide, reacting completely, diluting a reaction solution with water, extracting with ethyl acetate, washing, drying, and performing silica gel column chromatography on an obtained residue, wherein the volume ratio of the mixture is 12-30: 1, eluting with a mixed solvent consisting of dichloromethane and methanol to obtain a target product compound 1, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra; wherein:
the tetrabutylammonium halide is tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium iodide or tetrabutylammonium bromide;
the mol ratio of the compound 4, 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide is 1: 1-5: 0.5-3: 0.05-0.3.
3. The method of synthesizing an estradiol-4-aminomethylpyridine conjugate of claim 2, wherein: in step 3), potassium carbonate is replaced by potassium hydroxide, sodium hydroxide or sodium carbonate.
4. The method of synthesizing an estradiol-4-aminomethylpyridine conjugate of claim 2, wherein:
in the step 1), the organic solvent used for dissolving the compound 2 is N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), pyridine, dioxane, acetone or benzene;
in the step 2), the organic solvent for dissolving the compound 3 is methanol, ethanol, ethyl acetate, ethyl formate, tetrahydrofuran or acetone;
in the step 3), the organic solvent used for dissolving the compound 4 is N, N-dimethylformamide, tetrahydrofuran, pyridine, dioxane, acetone, benzene, ethyl acetate or ethyl formate.
5. The method of synthesizing an estradiol-4-aminomethylpyridine conjugate according to any one of claims 2 to 4, wherein: replacing step 2) with step 2a), said step 2a) being as follows:
2a) synthesis of intermediate compound 4:
dissolving the compound 3 with an organic solvent, adding a palladium-carbon catalyst, carrying out normal-temperature normal-pressure hydrogenation, carrying out suction filtration on a reaction solution, and spin-drying a filtrate to obtain a compound 4; wherein,
the weight ratio of the compound 3 to the palladium-carbon catalyst is 1: 0.01 to 0.1.
6. A method of synthesizing the estradiol-4-aminomethylpyridine conjugate of claim 1, comprising the steps of:
i) Synthesis of intermediate Compound 3:
dissolving a compound 2 serving as a raw material by using an organic solvent, adding sodium hydride and 1, 6-dibromohexane, reacting completely, diluting a reaction solution by using water, extracting by using ethyl acetate, washing, drying, and performing silica gel column chromatography on obtained residues, wherein the volume ratio of the sodium hydride to the 1, 6-dibromohexane is 60-80: eluting with mixed solvent of petroleum ether and ethyl acetate of 1 to obtain compound 3; wherein:
the compound 2 is 17 beta-hydroxy-3- (benzyl) oxy-1, 3,5(10) -triene-estra, and the molar ratio of the compound 2 to sodium hydride to 1, 6-dibromohexane is 1: 5-15: 3-10;
II) Synthesis of intermediate Compound 5:
placing the compound 3 in a round-bottom flask, dissolving the compound in an organic solvent, adding 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide, reacting completely, diluting a reaction solution with water, extracting with ethyl acetate, washing, drying, and performing silica gel column chromatography on an obtained residue, wherein the volume ratio of the mixture is 12-30: 1, eluting with a mixed solvent consisting of dichloromethane and methanol to obtain a compound 5; wherein:
the tetrabutylammonium halide is tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium iodide or tetrabutylammonium bromide;
the mol ratio of the compound 3, 4-aminomethyl pyridine, potassium carbonate and tetrabutylammonium halide is 1: 1-5: 0.5-3: 0.05-0.3;
III) Synthesis of the target product Compound 1:
placing the compound 5 in a round-bottom flask, dissolving the compound with an organic solvent, adding ammonium formate and a palladium-carbon catalyst, reacting completely, carrying out suction filtration on a reaction solution, carrying out rotary drying on a filtrate, diluting with water, extracting with ethyl acetate, washing, drying, and carrying out silica gel column chromatography on an obtained residue, wherein the volume ratio of the components is 12-30: 1, eluting with a mixed solvent consisting of dichloromethane and methanol to obtain a target product compound 1, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estra; wherein:
the molar ratio of the compound 5 to ammonium formate is 1: 2-8, wherein the weight ratio of the compound 3 to the palladium carbon catalyst is 1: 0.01 to 0.1.
7. The method of synthesizing an estradiol-4-aminomethylpyridine conjugate of claim 6, wherein:
in the step I), the organic solvent for dissolving the compound 2 is N, N-Dimethylformamide (DMF), Tetrahydrofuran (THF), pyridine, dioxane, acetone or benzene;
in the step II), the organic solvent for dissolving the compound 3 is N, N-dimethylformamide, tetrahydrofuran, pyridine, dioxane, acetone, benzene, ethyl acetate or ethyl formate;
in the step III), the organic solvent used for dissolving the compound 5 is methanol, ethanol, ethyl acetate, ethyl formate, tetrahydrofuran or acetone;
in step II), potassium carbonate is replaced by potassium hydroxide, sodium hydroxide or sodium carbonate.
8. The method of synthesizing an estradiol-4-aminomethylpyridine conjugate according to claim 6 or 7, wherein: replacing step III) with step IIIa), said step IIIa) being as follows:
dissolving the compound 5 with an organic solvent, adding a palladium-carbon catalyst, carrying out normal-pressure hydrogenation, carrying out suction filtration on a reaction solution, and spin-drying a filtrate to obtain a target product compound 1, namely 3-hydroxy-17 beta- [6- (4-pyridine-methylamino) -hexyl-oxy ] -1,3,5(10) -triene-estrane; wherein,
the weight ratio of the compound 3 to the palladium-carbon catalyst is 1: 0.01 to 0.1.
9. Use of the estradiol-4-aminomethylpyridine conjugate of claim 1 in the preparation of a medicament for inhibiting a HepG-2 cell line and/or a BGC-823 cell line and/or a549 cell line and/or a MCF-7 cell line and/or a PC-3 cell line.
10. An antitumor agent comprising the estradiol-4-aminomethylpyridine conjugate according to claim 1 as an active ingredient.
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