CN107236016B - A kind of steroidal purine nucleoside analogs of the triazole containing 1,2,3- and its preparation method and application - Google Patents

A kind of steroidal purine nucleoside analogs of the triazole containing 1,2,3- and its preparation method and application Download PDF

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CN107236016B
CN107236016B CN201710574673.1A CN201710574673A CN107236016B CN 107236016 B CN107236016 B CN 107236016B CN 201710574673 A CN201710574673 A CN 201710574673A CN 107236016 B CN107236016 B CN 107236016B
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CN107236016A (en
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黄利华
吴增辉
赵建伟
徐洪德
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Zhengzhou University
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Abstract

The invention belongs to field of pharmaceutical chemistry technology, are related to a kind of steroidal purine nucleoside analogs and its preparation method and application for containing 1,2,3- triazoles.The steroidal purine nucleoside analogs have following general formula:

Description

A kind of steroidal purine nucleoside analogs of the triazole containing 1,2,3- and preparation method thereof and Using
Technical field
The invention belongs to field of pharmaceutical chemistry technology, are related to a kind of nucleoside analog, and in particular to one kind contains 1,2,3- tri- Steroidal purine nucleoside analogs of nitrogen azoles and its preparation method and application.
Background technique
Recent decades, the linear ascendant trend of cancer morbidity, it is strong that cancer has become serious harm human life at present Health, the major class disease for restricting socio-economic development, therefore, scientific research institution, various countries and drugmaker have been devoted to develop treatment Effect is good, Small side effects anticancer drugs.Nucleosides is a kind of highly important large biological molecule, by ribose and base two parts group At, considerable effect is played in cell activities, it is outstanding to adjusting of the structure of cell, metabolism, energy and function etc. Its is important.Nucleoside analog is a kind of nucleoside compound by modification and transformation, such as iodoxuridine (IDU), Zidovudine, Ah former times Luo Wei etc. participates in the metabolism of virus although structure is similar with natural nucleus glycoside, these nucleoside analogs cannot but be known by virus Not, to the DNA of viral interference, inhibit the synthesis of protein, or the transcription of nucleic acid is influenced, therefore reaches treatment tumour With antiviral effect.Now, people have developed a large amount of nucleoside medicine, but due to the side effect and virus to human body Diversity, the reasons such as drug resistance, synthesize new nucleoside analog and to existing nucleoside medicine be chemically modified still by To extensive concern.
Since 1,2,3- triazole has highly stable characteristic in physiological conditions, therefore, obtained in field of medicinal chemistry To extensive use, multiple biological activities are shown, such as anticancer, antimycotic, antiviral.It will be different using 1,2,3- triazole Drug effect molecule links together, and forms new drug molecule, is greatly enriched the type of compound, is hot spot in recent years. Steroid derivatives are a kind of important compounds, have the function of anti-inflammatory, antiallergy, adjust metabolism, antitumor etc., in recent years Come, the application in field of medicaments constantly expands.Steroid backbone is connected by 1,2,3- triazole with base, is formed a kind of new Grain husk, the compound with anticancer activity, have no document report at present.
Summary of the invention
The object of the present invention is to provide steroidal purine nucleoside analogs of a kind of triazole containing 1,2,3- and preparation method thereof And application.
The invention adopts the following technical scheme:
The steroidal purine nucleoside analogs for containing 1,2,3- triazoles, which is characterized in that there is following general formula:
Wherein, the R is chlorine atom, hydrogen atom or fluorine atom；The R2It is
The method of steroidal purine nucleoside analogs of the preparation containing 1,2,3- triazoles, which comprises the following steps:
(1) 1a (- 55 alpha-androsterone-17-one of 3 beta-hydroxy) or 1b (4- aza-5 alpha-androstane-synthesis of compound 2a, 2b: are taken 3,17- diketone) be dissolved in methanol, add bromide reagent, flow back, be stirred to react, reaction terminates, post-process compound 2a or 2b；
(2) synthesis of compound 4a: compound 2a is dissolved in acetone, subsequent ice-water bath condition agitation and dropping Jones examination Agent continues stirring and stops reaction, post-processes to obtain compound 4a after being added dropwise；
(3) synthesis of compound 3a, 3b, 5a: compound 2a or 2b or 4a are dissolved in n,N-Dimethylformamide, added Reaction is then stirred at room temperature in sodium azide, and reaction terminates, and post-processes to obtain compound 3a or 3b or 5a；
(4) synthesis of compound 7a, 7b, 7c: base is dissolved in n,N-Dimethylformamide, 3- propargyl bromide, carbonic acid is added Reaction is stirred at room temperature in potassium, post-treated to obtain compound 7a or 7b or 7c；
(5) synthesis of the steroidal purine nucleoside analogs of compound triazole containing 1,2,3-: by compound 7a or 7b or 7c It being dissolved in 3a or 3b or 5a in the mixed solution of tetrahydrofuran and water, adds catalyst, reaction is stirred at room temperature, reaction terminates, Post-process the triazole containing 1,2,3- steroidal purine nucleoside analogs.
1a (- 55 alpha-androsterone-17-one of 3 beta-hydroxy) or 1b (4- aza-5 alpha-androstane -3,17- diketone) and bromine in step (1) Change reagent molar ratio is 1:2.0-4.0, and every gram of -5 5 alpha-androsterone-17-one of 3 beta-hydroxy or 4- aza-5 alpha-androstane -3,17- diketone make With methanol 20-30mL；
Every gram of 2a compound uses Jones reagent 1.5-2.0ml in step (2), and every gram of 2a compound uses acetone 20- 30mL；
In step (3) molar ratio of compound 2a or 2b or 4a and sodium azide be 1:2.0-3.0, every g of compound 2a or 2b or 4a uses N,N-dimethylformamide 15-25mL；
6a or 6b or 6c and 3- propargyl bromide in step (4), potassium carbonate molar ratio be 1:1.0-1.5:1.5-2.0, every gram Compound 6a or 6b or 6c uses N,N-dimethylformamide 20-35mL；
7a or 7b or 7c and 3a or 3b or 5a molar ratio are 1:1.0-1.5,7a or 7b or 7c and catalyst in step (5) Molar ratio is 1:0.2-0.4, and tetrahydrofuran/water volume ratio is 1/0.8-1.0, and every g of compound 7a or 7b or 7c uses tetrahydro furan It mutters and water 40-60mL.
Bromide reagent in the step (1) is copper bromide or bromine；Base is 2,6- dichloropurine, 6- in step (4) The fluoro- 6- chlorine of chloropurine, 2- is fast；Catalyst is CuI, Cu in step (5)2O、CuSO4/NaAsc(1/3-6)。
The last handling process of the step (1) is vacuum distillation, extraction, organic phase drying, the post-processing of the step (2) Process is vacuum distillation, extraction, organic phase drying, and the last handling process of the step (3) is plus elutriation goes out, filters, drying, institute The last handling process of step (4) is stated as vacuum distillation, extraction, organic phase drying, column chromatography, the post-processing of the step (5) Journey is vacuum distillation, extraction, organic phase drying, column chromatography.
The synthetic route of the steroidal purine nucleoside analogs of the triazole containing 1,2,3- is as follows:
The steroidal purine nucleoside analogs of the triazole of the present invention containing 1,2,3- are to various tumor cell strains such as prostate The cell strains such as cancer, gastric cancer have significant inhibiting effect, can be used in preparing anti-tumor drug, have potential medicinal application valence Value, the kind new medicine to develop one's own intellectual property are had laid a good foundation.
The invention has the advantages that with -5 5 alpha-androsterone-17-one of 3 beta-hydroxy or 4- aza-5 alpha-androstane -3,17- diketone for raw material, warp Bromination, oxidation, Azide, cycloaddition reaction are made, and preparation method is simple, mild condition, and object total recovery is up to 75% or more. Steroid backbone is connected by gained compound by 1,2,3- triazole with base, forms a kind of novel, chemical combination with anticancer activity Object has Prostatic cancer cell lines (PC-3), gastric carcinoma cells (MGC-803), human esophagus cancer cell (EC-109) preferable Activity enriches the type of steroidal nucleoside analog, provides lead compound for further research anticancer drug.
Specific embodiment
It is as follows for embodiment for the present invention is better described:
Embodiment 1
Preparing R shown in general formula is chlorine atom, R2It isThat is compound 8a (16 β-(4- ((2,6- dichloropurine -9- Base) methyl) -1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) preparation.
Step 1: the synthesis of compound 2a (bromo- -5 5 alpha-androsterone-17-one of 3 beta-hydroxy of 16 α -)
It takes compound 1a (5g, 17.2mmol) in 250mL flask, methanol (100mL) stirring and dissolving is added, is then added Copper bromide (11.5g, 51.6mmol) stirs lower back flow reaction 12h reaction；After completion of the reaction, most of alcohol is removed under reduced pressure first Then water (150ml) is added in class organic solvent, extracted with methylene chloride (100mL × 3), merges organic phase and uses unsaturated carbonate Hydrogen sodium solution washs (20mL × 3), then uses saturated common salt water washing (20mL × 3), anhydrous Na2SO4It is dry, it finally depressurizes dense Contract to obtain white solid, obtains white solid (6.2g, 16.8mmol) after dry, yield 97%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ4.53(d,1H-16),3.61(m, 1H-3),0.90(s,3H),0.83(s,3H).13C NMR(151 MHz,Chloroform-d)δ213.48,71.07,54.27, 47.96,47.82,46.40,44.78,38.02,36.87,35.66,34.33,34.10,32.37,31.41,30.75, 28.26,20.41,14.22,12.28.。
Step 2: the synthesis of compound 4a (16 α-bromo- 5 α-androstane -3,17- diketone)
Acetone (120ml) stirring and dissolving, ice water is added in 250mL flask in Weigh Compound 2a (6.2g, 16.8mmol) Bath is lower to be added dropwise Jones reagent (9.4mL, 18.5mmol), and after being added dropwise, 1h is stirred under ice bath, after having reacted, 1ml ethyl alcohol is added dropwise Excessive Jones reagent is neutralized, stops reaction, removes most of organic solvent under reduced pressure first, water (150ml) then is added, with two Chloromethanes (100mL × 3) extraction merges organic phase and washs (20mL × 3) with saturated sodium bicarbonate solution, then with saturation food Salt water washing (20mL × 3), anhydrous Na2SO4It is dry, be finally concentrated under reduced pressure to obtain white solid, it is dry after white solid (6.1g, 16.6mmol), yield 98%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ4.54(d,1H-16),1.04(s, 3H),0.93(s,3H).13C NMR(151 MHz,Chloroform-d)δ213.12,211.27,53.69,47.79,47.75, 46.47,46.22,44.51,38.31,38.01,35.81,34.22,34.09,32.29,30.39,28.47,20.60, 14.21,11.44.。
Step 3: the synthesis of compound 5a (- 5 α of 16 β-nitrine-androstane -3,17- diketone)
Weigh Compound 4a (6.1g, 16.6mmol) is dissolved in n,N-Dimethylformamide (100mL), and Azide is added Sodium (3.25g, 50mmol), is stirred at room temperature 20min, pours into a large amount of ice water, and (20mL × 3) are washed with water in filtering, white filter cake, It is dry, obtain compound 5a white solid (5.2g, 15.8mmol), yield 95%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ3.74(t,1H-16),1.04(s, 3H),0.95(s,3H).13C NMR(151 MHz,Chloroform-d)δ214.98,211.24,63.10,53.95,47.12, 46.70,46.52,44.50,38.35,38.00,35.87,34.26,31.61,30.62,28.89,28.47,20.46, 14.19,11.45.。
Step 4: the synthesis of compound 7a (the chloro- 9- propargyl -9- hydrogen purine of 2,6- bis-)
In round-bottomed flask, 6a (2,6- bis- chloro- 9- hydrogen purine) (5g, 26.4mmol) and N, N- dimethyl formyl is added Amine (100mL) adds 3- propargyl bromide (3.77g, 31.7mmol), potassium carbonate (5.52g, 40mmol) is stirred overnight at room temperature.Instead Water (200mL) is added after answering, is extracted with ethyl acetate (100mL × 4), saturated sodium bicarbonate solution washs (20mL × 3), Then saturated common salt water washing (20mL × 3) are used, anhydrous Na2SO4It is dry, it is finally concentrated under reduced pressure, column chromatographs to obtain product 7a (4.25g, 18.75mmol), yield 71%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ8.35(s,1H),5.06(d, 2H),2.63(t,1H).13C NMR(151 MHz,Chloroform-d)δ153.28,152.55,152.04,144.88, 130.77,76.39,74.57,33.91.。
Step 5: compound 8a (16 β-(4- ((2,6- dichloropurine -9- base) methyl) -1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) preparation
Weigh Compound 5a (1g, 3mmol) and 7a (0.68g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water In the mixed solution of (25ml), then add cupric sulfate pentahydrate (37.5mg, 0.15mmol), sodium ascorbate (120mg, 5h 0.6mmol) is stirred at room temperature.After completion of the reaction, it removes most of organic solvent under reduced pressure first, water (50ml) then is added, use Methylene chloride (50mL × 3) extraction, merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4It is dry, column layer White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8a (16 β-(4- ((2,6- dichloropurine -9- base) methyl) -1,2,3- Triazole -1- base) -5 α-androstane -3,17- diketone) (1.38g, 2.5mmol), yield 83%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ8.37(s,1H),7.86(s, 1H),5.61–5.49(m,2H),4.69(dd,1H-16),1.09(d,7H).13C NMR(151 MHz,Chloroform-d)δ 211.19,210.73,153.04,152.83,151.92,145.87,140.64,130.72,124.09,64.94,53.94, 47.78,47.05,46.52,44.47,39.03,38.35,38.00,35.90,34.16,31.78,30.69,29.29, 28.40,20.49,14.65,11.50.。
Embodiment 2
Preparing R shown in general formula is hydrogen atom, R2It isThat is compound 8b (16 β-(4- ((6-chloropurine -9- base) first Base) -1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) and preparation.
Step 1: the synthesis of compound 7b (the chloro- 9- propargyl -9- hydrogen purine of 6-)
In round-bottomed flask, 6b (the chloro- 9- hydrogen purine of 6-) (5g, 32.5mmol) and n,N-Dimethylformamide is added (100mL) adds 3- propargyl bromide (4.64g, 39mmol), potassium carbonate (6.8g, 49.3mmol) is stirred overnight at room temperature.Reaction knot Water (200mL) is added after beam, is extracted with ethyl acetate (100mL × 4), saturated sodium bicarbonate solution washs (20mL × 3), then With saturated common salt water washing (20mL × 3), anhydrous Na2SO4It is dry, be finally concentrated under reduced pressure, column chromatograph product 7b (3.9g, 20.3mmol), yield 62.5%.
The analysis data of product are as follows:1H NMR(400 MHz,Chloroform-d)δ8.79(s,1H),8.36(s, 1H),5.09(d,2H),2.61(t,1H).13C NMR(100.6 MHz,Chloroform-d)δ152.24,151.29, 144.29,131.62,75.96,75.00,33.70.。
Step 2: compound 8b (16 β-(4- ((6-chloropurine -9- base) methyl) -1,2,3- triazole -1- base) -5 α-hero Steroid -3,17- diketone) preparation
Weigh Compound 5a (1g, 3mmol) and 7b (0.58g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water In the mixed solution of (25ml), then add cupric sulfate pentahydrate (50mg, 0.20mmol), sodium ascorbate (160mg, 4h 0.8mmol) is stirred at room temperature.After completion of the reaction, it removes most of organic solvent under reduced pressure first, water (50ml) then is added, use Methylene chloride (50mL × 3) extraction, merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4It is dry, column layer White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8b (16 β-(4- ((6-chloropurine -9- base) methyl) -1,2,3- tri- nitrogen Azoles -1- base) -5 α-androstane -3,17- diketone) (1.28g, 2.45mmol), yield 81.7%.
The analysis data of product are as follows:1H NMR(400 MHz,Chloroform-d)δ8.77(s,1H),8.36(s, 1H),7.83(s,1H),5.68–5.49(m,2H),4.66(dd,1H-16),1.08(d,7H).13C NMR(100.6 MHz, Chloroform-d)δ211.22,210.79,152.05,151.52,151.18,145.17,140.12,131.54,123.98, 64.87,53.92,47.77,47.03,46.52,44.46,38.97,38.35,38.00,35.89,34.14,31.76, 30.68,29.20,28.39,20.48,14.63,11.49.。
Embodiment 3
Preparing R shown in general formula is fluorine atom, R2It isThat is compound 8c (16 β-(4- ((the fluoro- 6-chloropurine-of 2- 9- yl) methyl) -1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) preparation.
Step 1: the synthesis of compound 7c (the chloro- 9- propargyl -9- hydrogen purine of the fluoro- 6- of 2-)
In round-bottomed flask, 6c (the chloro- 9- hydrogen purine of the fluoro- 6- of 2-) (5g, 29mmol) and n,N-Dimethylformamide is added (100mL) adds 3- propargyl bromide (4.2g, 35.3mmol), potassium carbonate (6.0g, 43.5mmol) is stirred overnight at room temperature.Reaction After be added water (250mL), with ethyl acetate (100mL × 4) extract, saturated sodium bicarbonate solution wash (15mL × 3), so Saturated common salt water washing (15mL × 3) are used afterwards, anhydrous Na2SO4It is dry, be finally concentrated under reduced pressure, column chromatograph product 7c (3.75g, 17.9mmol), yield 62%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ8.33(s,1H),5.02(d, 2H),2.62(t,1H).13C NMR(100.6 MHz,Chloroform-d)δ158.50,156.30,153.1,144.89, 130.30,76.30,74.54,33.86.。
Step 2: compound 8c (16 β-(4- ((the fluoro- 6-chloropurine -9- base of 2-) methyl) -1,2,3- triazole -1- base) - 5 α-androstane -3,17- diketone) preparation
Weigh Compound 5a (1g, 3mmol) and 7c (0.63g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water In the mixed solution of (25ml), then add cupric sulfate pentahydrate (37.5mg, 0.15mmol), sodium ascorbate (160mg, 4h 0.8mmol) is stirred at room temperature.After completion of the reaction, it removes most of organic solvent under reduced pressure first, water (50ml) then is added, use Methylene chloride (50mL × 3) extraction, merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4It is dry, column layer White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8c (16 β-(4- ((the fluoro- 6-chloropurine -9- base of 2-) methyl) -1,2,3- Triazole -1- base) -5 α-androstane -3,17- diketone) (1.23g, 2.28mmol), yield 76%.
The analysis data of product are as follows:1H NMR(400 MHz,Chloroform-d)δ8.35(s,1H),7.86(s, 1H),5.51(m,2H),4.68(dd,1H-16),1.10(s,3H),1.07(s,3H).13C NMR(100.6 MHz, Chloroform-d)δ211.23,210.76,158.40,156.22,153.08,145.88,140.60,130.23,124.09, 64.92,53.92,47.77,47.03,46.51,44.47,39.03,38.34,38.00,35.90,34.14,31.76, 30.68,29.27,28.39,20.48,14.63,11.49.。
Embodiment 4
Preparing R shown in general formula is chlorine atom, R2It isThat is compound 8d (16 β-(4- ((2,6- dichloropurine- 9- yl) methyl) -1,2,3- triazole -1- base) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) preparation.
Step 1: the synthesis of compound 3a (- 5 α of 16 β-nitrine-androstane -3,17- diketone)
Weigh Compound 2a (5g, 13.5mmol) is dissolved in n,N-Dimethylformamide (80mL), and sodium azide is added (2.6g, 40mmol), is stirred at room temperature 20min, pours into a large amount of ice water, and (15mL × 3) are washed with water in filtering, white filter cake, does It is dry, obtain compound 5a white solid (4.2g, 12.7mmol), yield 94%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ3.72(t,1H-16),3.60(m, 1H-3),0.92(s,3H),0.83(s,3H).13C NMR(151 MHz,Chloroform-d)δ215.32,71.07,63.18, 54.52,47.19,46.87,44.80,38.01,36.88,35.71,34.35,31.70,31.39,30.99,28.89, 28.26,20.27,14.19,12.29.。
Step 2: compound 8d (16 β-(4- ((2,6- dichloropurine -9- base) methyl) -1,2,3- triazole -1- base) -3 - 55 alpha-androsterone-17-one of beta-hydroxy) preparation
Weigh Compound 3a (500mg, 1.51mmol) and 7a (0.34g, 1.51mmol), is dissolved in tetrahydrofuran (15ml) In the mixed solution of water (15ml), then add cupric sulfate pentahydrate (25mg, 0.10mmol), sodium ascorbate (80mg, 5h 0.4mmol) is stirred at room temperature.After completion of the reaction, it removes most of organic solvent under reduced pressure first, water (30ml) then is added, use Methylene chloride (30mL × 3) extraction, merges organic phase saturated common salt water washing (6mL × 3), anhydrous Na2SO4It is dry, column chromatography White solid is obtained, ethyl alcohol recrystallization obtains compound 8d (16 β-(4- ((2,6- dichloropurine -9- base) methyl) -1,2,3- tri- Nitrogen azoles -1- base) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) (0.66g, 1.18mmol), yield 78%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ8.35(s,1H),7.83(s, 1H),5.62–5.45(m,2H),4.67(t,1H-16),3.61(m,1H),2.66(m,1H),2.39(m,1H),1.07(s, 3H),0.86(s,3H).13C NMR(151 MHz,Chloroform-d)δ210.99,153.06,152.80,151.96, 145.82,140.59,130.73,123.92,71.06,65.02,54.54,47.87,47.26,44.82,39.04,38.00, 36.90,35.76,34.28,31.89,31.40,31.07,29.34,28.21,20.31,14.66,12.33.。
Embodiment 5
Preparing R shown in general formula is hydrogen atom, R2It isThat is compound 8e (16 β-(4- ((6-chloropurine -9- base) Methyl) -1,2,3- triazole -1- base) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) and preparation.
Compound 8e (- 5 α of 16 β-(4- ((6-chloropurine -9- base) methyl) -1,2,3- triazole -1- base) -3 beta-hydroxy - Androstane -17- ketone) preparation
Weigh Compound 3a (500mg, 1.51mmol) and 7b (0.29g, 1.51mmol), is dissolved in tetrahydrofuran (15ml) In the mixed solution of water (15ml), then adds cuprous iodide (57mg, 0.3mmol) and 5h is stirred at room temperature.After completion of the reaction, It removes most of organic solvent under reduced pressure first, water (30ml) then is added, extracted with methylene chloride (30mL × 3), merged organic Saturated common salt water washing (6mL × 3) mutually are used, anhydrous Na2SO4Dry, column chromatographs to obtain white solid, and ethyl alcohol recrystallization obtains chemical combination Object 8e (- 55 alpha-androsterone-17-one of 16 β-(4- ((6-chloropurine -9- base) methyl) -1,2,3- triazole -1- base) -3 beta-hydroxy) (0.59g, 1.12mmol), yield 74.5%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ8.77(s,1H),8.36(s, 1H),7.82(s,1H),5.58(t,2H),4.69–4.61(m,1H-16),3.60(m,1H),2.65(m,1H),2.39(m, 1H),1.06(s,3H),0.86(s,3H).13C NMR(151 MHz,Chloroform-d)δ211.07,152.03,151.52, 151.19,145.19,141.09,131.55,123.86,71.02,64.97,54.52,47.85,47.23,44.81,38.97, 37.99,36.89,35.75,34.26,31.87,31.39,31.05,29.27,28.20,20.30,14.64,12.32.。
Embodiment 6
Preparing R shown in general formula is fluorine atom, R2It isThat is compound 8f (16 β-(4- ((the fluoro- 6-chloropurine-of 2- 9- yl) methyl) -1,2,3- triazole -1- base) -5 5 alpha-androsterone-17-one of -3 beta-hydroxy) preparation.
Compound 8f (16 β-(4- ((the fluoro- 6-chloropurine -9- base of 2-) methyl) -1,2,3- triazole -1- base) -3 β-hydroxyl - 55 alpha-androsterone-17-one of base) preparation
Weigh Compound 3a (500mg, 1.51mmol) and 7c (0.32g, 1.51mmol), is dissolved in tetrahydrofuran (15ml) In the mixed solution of water (15ml), then adds cuprous oxide (43mg, 0.3mmol) and 5h is stirred at room temperature.After completion of the reaction, It removes most of organic solvent under reduced pressure first, water (30ml) then is added, extracted with methylene chloride (30mL × 3), merged organic Saturated common salt water washing (8mL × 3) mutually are used, anhydrous Na2SO4Dry, column chromatographs to obtain white solid, and ethyl alcohol recrystallization obtains chemical combination Object 8f (16 β-(4- ((the fluoro- 6-chloropurine-9- base of 2-) methyl)-1,2,3- triazole-1- base)-3-5 α of beta-hydroxy-androstane-17- Ketone) (0.65g, 1.2mmol), yield 79.5%.
The analysis data of product are as follows:1H NMR(600 MHz,DMSO-d6)δ8.80(s,1H),8.22(s,1H),5.57 (s,2H),5.23(t,1H-16),4.43(s,1H),3.34(m,1H),3.32(s,2H),2.06(m,1H),0.99(s,3H), 0.79(s,3H).13C NMR(151 MHz,DMSO-d6)δ212.53,157.46,156.04,152.55,148.81,141.62, 130.36,125.23,69.70,64.81,54.38,47.46,46.26,44.83,39.43,38.56,36.99,35.82, 34.09,31.84,31.79,31.12,30.14,28.54,20.42,14.76,12.52.。
Embodiment 7
Preparing R shown in general formula is chlorine atom, R2It isThat is compound 8g (- 16 β of 4- azepine-(4- ((2,6- dichloro Purine -9- base) methyl) -1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) preparation.
Step 1: the synthesis of compound 2b (- 16 α of 4- azepine-bromo- 5 α-androstane -3,17- diketone)
It takes compound 1b (5g, 17.3mmol) in 250mL flask, methanol (120mL) stirring and dissolving is added, is then added Copper bromide (11.6g, 52mmol) stirs lower back flow reaction 12h reaction；After completion of the reaction, most of alcohols is removed under reduced pressure first Then water (200ml) is added in organic solvent, extracted with methylene chloride (150mL × 3), merges organic phase and with unsaturated carbonate hydrogen Sodium solution washs (20mL × 3), then uses saturated common salt water washing (20mL × 3), anhydrous Na2SO4It is dry, finally it is concentrated under reduced pressure White solid is obtained, obtains white solid (5.7g, 15.5mmol) after dry, yield 90%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ6.08(s,1H-4NH),4.54 (d,1H-16),3.15–3.04(m,1H),0.93(t,7H).13C NMR(151 MHz,Chloroform-d)δ212.74, 172.01,60.48,51.22,47.84,47.52,46.02,35.86,34.02,33.92,33.37,32.14,28.32, 26.94,20.34,14.25,11.34.。
Step 2: the synthesis of compound 3b (- 16 β of 4- azepine--5 α of nitrine-androstane -3,17- diketone)
Weigh Compound 2b (5.7g, 15.5mmol) is dissolved in n,N-Dimethylformamide (80mL), and Azide is added Sodium (3.25g, 50mmol), is stirred at room temperature 20min, pours into a large amount of ice water, and (20mL × 3) are washed with water in filtering, white filter cake, It is dry, obtain compound 5a white solid (4.9g, 14.85mmol), yield 96%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ6.24(s,1H-4NH),3.74 (t,1H-16),3.08(d,1H),0.94(d,6H),13C NMR(151 MHz,Chloroform-d)δ214.63,172.05, 62.98,60.53,51.44,47.23,46.43,35.93,33.97,33.29,31.45,28.83,28.53,28.48, 27.01,20.20,14.24,11.36.。
Step 3: compound 8g (- 16 β of 4- azepine-(4- ((2,6- dichloropurine -9- base) methyl) -1,2,3- triazole - 1- yl) -5 α-androstane -3,17- diketone) preparation
Weigh Compound 3b (1g, 3mmol) and 7a (0.68g, 3mmol), is dissolved in tetrahydrofuran (30ml) and water In the mixed solution of (30ml), then add cupric sulfate pentahydrate (37.5mg, 0.15mmol), sodium ascorbate (120mg, 5h 0.6mmol) is stirred at room temperature.After completion of the reaction, it removes most of organic solvent under reduced pressure first, water (50ml) then is added, use Methylene chloride (50mL × 3) extraction, merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4It is dry, column layer White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8g (- 16 β of 4- azepine-(4- ((2,6- dichloropurine -9- base) methyl) - 1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) (1.4g, 2.52mmol), yield 84%.
The analysis data of product are as follows:1H NMR(600 MHz,DMSO-d6)δ8.83(s,1H),8.22(s,1H),7.29 (s,1H),5.60(s,2H),5.25(t,1H-16),3.32(s,1H),2.99(d,1H),1.02(s,4H),0.83(s,3H) .13C NMR(151 MHz,DMSO-d6)δ212.33,170.59,153.74,151.62,150.22,148.87,141.67, 130.88,125.21,64.77,60.13,51.17,47.56,45.81,39.47,35.66,33.62,33.29,31.66, 30.10,28.91,28.67,26.54,20.34,14.81,11.54.。
Embodiment 8
Preparing R shown in general formula is hydrogen atom, R2It isThat is ((((6- chlorine is fast by 4- by -16 β of 4- azepine-by compound 8h Purine -9- base) methyl) -1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) preparation.
Compound 8h (- 16 β of 4- azepine-(4- ((6-chloropurine -9- base) methyl) -1,2,3- triazole -1- base) -5 α-hero Steroid -3,17- diketone) preparation
Weigh Compound 3b (1g, 3mmol) and 7b (0.57g, 3mmol), is dissolved in tetrahydrofuran (30ml) and water In the mixed solution of (30ml), then add cupric sulfate pentahydrate (50mg, 0.2mmolmmol), sodium ascorbate (120mg, 5h 0.6mmol) is stirred at room temperature.After completion of the reaction, it removes most of organic solvent under reduced pressure first, water (50ml) then is added, use Methylene chloride (50mL × 3) extraction, merges organic phase saturated common salt water washing (10mL × 3), anhydrous Na2SO4It is dry, column layer Analyse to obtain white solid, ethyl alcohol recrystallization, obtain compound 8h (- 16 β of 4- azepine-(4- ((6-chloropurine -9- base) methyl) -1,2, 3- triazole -1- base) -5 α-androstane -3,17- diketone) (1.19g, 2.27mmol), yield 75.5%.
The analysis data of product are as follows:1H NMR(600 MHz,Chloroform-d)δ8.77(s,1H),8.35(s, 1H),7.83(s,1H),6.01(s,1H),5.68–5.50(m,2H),4.66(t,1H-16),3.10(d,1H),2.66(m, 1H),1.09(s,3H),0.96(s,3H).13C NMR(151 MHz,Chloroform-d)δ210.36,171.95,152.05, 151.53,151.22,145.13,141.20,131.58,123.92,64.75,60.51,51.44,47.88,46.78, 38.97,35.97,33.87,33.30,31.63,29.12,28.60,28.47,26.97,20.24,14.68,11.39.
Embodiment 9
Preparing R shown in general formula is fluorine atom, R2It isThat is compound 8i (- 16 β of 4- azepine-(4- ((the fluoro- 6- of 2- Chloropurine -9- base) methyl) -1,2,3- triazole -1- base) -5 α-androstane -3,17- diketone) preparation.
Compound 8i (- 16 β of 4- azepine-(4- ((the fluoro- 6-chloropurine -9- base of 2-) methyl) -1,2,3- triazole -1- base) - 5 α-androstane -3,17- diketone) preparation
Weigh Compound 3b (1g, 3mmol) and 7c (0.63g, 3mmol), is dissolved in tetrahydrofuran (25ml) and water In the mixed solution of (25ml), then add cupric sulfate pentahydrate (37.5mg, 0.15mmol), sodium ascorbate (120mg, 5h 0.6mmol) is stirred at room temperature.After completion of the reaction, it removes most of organic solvent under reduced pressure first, water (50ml) then is added, use Methylene chloride (50mL × 3) extraction, merges organic phase saturated common salt water washing (15mL × 3), anhydrous Na2SO4It is dry, column layer White solid is analysed to obtain, ethyl alcohol recrystallization obtains compound 8i (- 16 β of 4- azepine-(4- ((the fluoro- 6-chloropurine -9- base of 2-) first Base) -1,2,3- triazole -1- bases) -5 α-androstane -3,17- diketone) (1.3g, 2.4mmol), yield 80%.
The analysis data of product are as follows:1H NMR(600 MHz,DMSO-d6)δ8.81(s,1H),8.23(s,1H),7.28 (s, 1H), 5.58 (d, 2H), 5.25 (q, J=8.8,8.0 Hz, 1H), 3.32 (s, 1H), 2.99 (d, 1H), 1.02 (m, 4H), 0.83(s,3H).13C NMR(151 MHz,DMSO-d6)δ212.32,170.59,157.47,156.05,152.4,148.80, 141.61,130.36,125.26,64.76,60.13,51.18,47.55,45.82,39.43,35.66,33.62,33.29, 31.67,30.09,28.90,28.66,26.54,20.34,14.80,11.53.。
The number and chemical structure of involved noval chemical compound in 1 this patent of table
The inhibiting tumour cells activity test of target compound:
Using the steroidal purine nucleoside analogs (8a-8i) of the triazole containing 1,2,3- made from the embodiment of the present invention to forefront Adenocarcinoma cell strain (PC-3), gastric carcinoma cells (MGC-803), human esophagus cancer cell (EC-109) carry out cell toxicity test.It adopts With mtt assay, vitro cytotoxicity measurement is carried out.Containing for various concentration is added in the logarithmic growth phase cell cultivated in 96 orifice plates The steroidal purine nucleoside analogs of 1,2,3- triazole, 37 DEG C, volumn concentration 5%CO2Lower culture cell 72h, while into Three parallel laboratory tests of row, are compared with control group.MTT is added, continues to cultivate 3-4h, it is insoluble to form bluish violet in living cells Object first is jumped up, and culture solution is removed, and DMSO is added, and is vibrated 15 minutes at room temperature, so that first is jumped up abundant dissolution, is measured its extinction with microplate reader Degree is calculated separately the concentration of compound when inhibiting growth of tumour cell to 50%, is indicated with IC50 value, part of result such as table Shown in 2.
2 present invention of table contains steroidal purine nucleoside analogs anti-tumor activity test result (IC50, the μ of 1,2,3- triazoles M)
As can be seen from Table 2, surveyed compound has certain inhibitory activity to three kinds of cancer cells；Suppression of the compound 8d to PC-3 System activity is best.

Claims (1)

1. the preparation method of the steroidal purine nucleoside analogs containing 1,2,3- triazoles, which comprises the following steps:
(1) synthesis of compound 2a, 2b: compound 1a (- 55 alpha-androsterone-17-one of 3 beta-hydroxy) or 1b (- 5 α of 4- azepine-hero is taken Steroid -3,17- diketone) it is dissolved in methanol, bromide reagent is added, flows back, be stirred to react, reaction terminates, and post-processes to obtain compound 2a or 2b；
(2) synthesis of compound 4a: compound 2a is dissolved in acetone, subsequent ice-water bath condition agitation and dropping Jones reagent, drop It adds and continues to be stirred to react after finishing, reaction terminates, and post-processes to obtain compound 4a；
(3) synthesis of compound 3a, 3b, 5a: compound 2a or 2b or 4a are dissolved in n,N-Dimethylformamide, add nitrine Change sodium, reaction is then stirred at room temperature, reaction terminates, and post-processes to obtain compound 3a or 3b or 5a；
(4) synthesis of compound 7a, 7b, 7c: base is dissolved in n,N-Dimethylformamide, 3- propargyl bromide, potassium carbonate, room is added Temperature is stirred to react overnight, post-processes to obtain compound 7a or 7b or 7c；
(5) synthesis of the steroidal purine nucleoside analogs of compound triazole containing 1,2,3-: by compound 7a or 7b or 7c and 3a Or 3b or 5a are dissolved in the mixed solution of tetrahydrofuran and water, add catalyst, and reaction is stirred at room temperature, reaction terminates, rear to locate Manage the triazole containing 1,2,3- steroidal purine nucleoside analogs；
Bromide reagent in the step (1) is copper bromide or bromine；Base is that 2,6- dichloropurine, 6- chlorine are fast in step (4) Purine or the fluoro- 6- chlorine of 2- are fast；Catalyst is CuI, Cu in step (5)2O or CuSO4/NaAsc。
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