CN108503681A - Betulic acid derivative and its synthetic method and application - Google Patents
Betulic acid derivative and its synthetic method and application Download PDFInfo
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Abstract
The invention discloses a kind of formulas（Ⅰ）Shown in betulic acid derivative and its synthetic method and application, which contains there are one betulic acid part, with attachment（linker）1,2,3 triazole covalent bond at the C 2 of betulic acid part, attachment and 2 ' fluorine arabinoside nucleoside part of covalent bond.Compound provided by the invention is chemically to be designed to deal with the water-soluble low problem of betulic acid, and betulic acid and nucleoside compound are linked together by stable 1,2,3 triazole attachment.
Description
Technical field
It the invention belongs to medicine and its prepares and applied technical field, and in particular to a kind of betulic acid derivative and its conjunction
At methods and applications.
Background technology
Betulic acid (Betulinic acid, BA) is a kind of pentacyclic triterpenoid, and it is withered to be present in silver birch, summer
In the various plants such as grass, pawpaw.The study found that betulic acid has extensive physiological activity, there is AntiHIV1 RT activity, antitumor, anti-inflammatory
Etc. effectiveness.Compared to betulic acid, derivative has preferably activity, such as RPR103611 in AntiHIV1 RT activity, antitumor etc.
The clinical trial of AntiHIV1 RT activity is in PA457 (bevirimat), NVX-207 is carrying out antitumor clinical trial.
But since its dissolubility in water is too poor, cause bioavilability low and it is internal transmission, metabolism etc. the shortcomings that.
Invention content
The main purpose of the present invention is to provide a kind of betulic acid derivative, another object is to provide such compound
Synthetic method, a further object is to provide application of such compound in preparing antitumor and antiviral drugs.
The purpose of the present invention is what is realized in the following manner：
A kind of betulic acid derivative or its pharmaceutically acceptable salt, hydrate or prodrug, shown in structural formula such as formula (I)：
Wherein：X=NH or O, Y=OH or NH2, R1It is H, C1-C20Substitution or unsubstituted group.
Structural formula betulic acid derivative as shown in formula (I) is specially structural formula as shown in formula i, ii, iii, iv, v, vi
Compound：
Such as the synthetic method of above-mentioned betulic acid derivative, synthesis path are as follows：
Wherein：Y=OH or NH2, R1It is C1-C20Substitution or unsubstituted group；
Specific synthesis step is as follows：
The synthesis of compound 2：Compound 1 is dissolved in acetone or tetrahydrofuran, 0 DEG C of addition Jones reagent, after completion of the reaction
Methanol and water quenching is added to go out reaction, solvent evaporated extracts and uses column chromatography to obtain compound as white solid 2；
The synthesis of compound 3：Compound 2 is dissolved in dichloromethane, 0 DEG C is added 1- (3- dimethylamino-propyls) -3- ethyls carbon two
Inferior amine salt hydrochlorate (EDC), 4-dimethylaminopyridine (DMAP) stir 30min, add corresponding amine, are stirred at room temperature and reacted
Night, extraction are evaporated column chromatography for separation and obtain compound 3；
The synthesis of compound 4：Compound 3 is dissolved in tetrahydrofuran, and KN (SiMe are added3)2Tetrahydrofuran solution and Et3B's
Tetrahydrofuran solution；Propargyl bromide is added after being stirred to react 1h.Hydrochloric acid neutralization reaction after completion of the reaction, organic extractant phase obtain after being evaporated
To compound be dissolved in methanol, NaBH is added4It is stirred overnight, solvent evaporated and with the isolated compound of silica gel column chromatography 4；
The synthesis of compound 5：Compound 4 is dissolved in the mixed solvent of the tert-butyl alcohol and water, and n,N-diisopropylethylamine and corresponding is added
Nucleosides, stirring 30 minutes after be added CuI acetonitrile solution the reaction was continued overnight；Solvent evaporated after completion of the reaction, column chromatography for separation
Obtain compound 5；
The synthesis of compound 6：Compound 2 is dissolved in dichloromethane, and 0 DEG C of dropwise addition oxalyl chloride, solvent evaporated, is re-dissolved in after completion of the reaction
CH2Cl2, corresponding alcohol stirring is added, is evaporated to obtain compound 6；
The synthesis of compound 7：Compound 6 is dissolved in tetrahydrofuran, and KN (SiMe are added3)2Tetrahydrofuran solution and Et3B's
Tetrahydrofuran solution；Propargyl bromide is added after being stirred to react 1h；Hydrochloric acid neutralization reaction after completion of the reaction, organic extractant phase, which is evaporated, to be used in combination
The isolated compound as white solid of silica gel column chromatography 7；
The synthesis of compound 8：Compound 7 is dissolved in methanol, and NaBH is added4It is stirred overnight, solvent evaporated is simultaneously divided with silica gel column chromatography
From obtaining compound 8；
The synthesis of compound 9：Compound 8 is dissolved in n,N-Dimethylformamide, and lithium iodide is added and heats, after completion of the reaction acetic acid
Ethyl ester extracts, and salt acid elution is evaporated column chromatography for separation and obtains compound as white solid 9；
The synthesis of compound 10：Compound 9 is dissolved in the mixed solvent of the tert-butyl alcohol and water, and n,N-diisopropylethylamine and corresponding is added
Nucleosides, stirring 30 minutes after be added CuI acetonitrile solution the reaction was continued overnight；Solvent evaporated after completion of the reaction, column chromatography for separation
Obtain compound 10；
The synthesis of compound 11：Compound 8 is dissolved in the mixed solvent of the tert-butyl alcohol and water, and n,N-diisopropylethylamine and corresponding is added
Nucleosides, stirring 30 minutes after be added CuI acetonitrile solution the reaction was continued overnight.Solvent evaporated after completion of the reaction, column chromatography for separation
Obtain compound 11.
Such as above-mentioned betulic acid derivative application in preparation of anti-tumor drugs.
The apoptosis of the derivative induced tumour cell of betulic acid, inhibits tumour cell at the proliferation for inhibiting tumour cell
Migration.
Such as application of the above-mentioned betulic acid derivative in preparing antiviral drugs.
In preparation method of the present invention, the above reaction generally use thin plate chromatography method carrys out the performance level of tracking and measuring reaction,
The post-processing approach used after completion of the reaction includes concentration, extraction, column chromatography for separation etc., final product by nuclear magnetic resoance spectrum come
Verification.
Betulic acid derivative provided by the invention contains there are one betulic acid part, and attachment (linker) 1,2,
3- triazoles covalent bond at the C-2 of betulic acid part, attachment and the fluoro- arabinoside nucleoside part of covalent bond 2 '-.This hair
The compound of bright offer is chemically to be designed to deal with the water-soluble low problem of betulic acid, passes through stable 1,2,3-
Triazole attachment links together betulic acid and nucleoside compound.
Nucleoside compound usually has water solubility well, therefore can effectively improve compound provided by the invention and exist
Solubility in water, while the HIV-resistant activity position of betulic acid is C-3 and C-28, mechanism of action be prevent it is viral and
Cell fusion and prevention virus maturation discharge, and the mechanism of nucleoside compound AntiHIV1 RT activity is anti-reverse transcription enzyme, retains betulic acid
With the active site of nucleosides, 1,2, the 3- triazoles with antivirus action is selected to connect betulic acid and core as linker
Glycosides, can ensure the antiviral and antitumor activity of compound provided by the invention, while it is antiviral anti-to obtain new multiple target point
Tumour medicine.In addition, the toxicity of compound provided by the invention is relatively low.
Compared with the existing technology, the beneficial effects of the present invention are：By the transformation to betulic acid, make betulic acid and
Active nucleosides links together, and compensates for that current betulic acid class compound water soluble is poor, bioavailability is low and ucleosides
The problems such as compound toxic side effect is big；And the simple synthetic method is feasible, yield is higher, be applied to prepare it is antitumor or
AntiHIV1 RT activity or resisting HBV virus drug have preferable application value.
Specific implementation mode
Process, condition, reagent, the experimental method etc. for implementing the present invention are this in addition to the following content specially referred to
Content is not particularly limited in the common knowledge in field, the present invention.In following embodiments, compound structure is surveyed by Nuclear Magnetic Resonance
Fixed, reagent is mainly provided by Mike woods chemical reagents corporation, purifying products mainly by column chromatography, silica gel (200-300 mesh) by
Haiyang Chemical Plant, Qingdao produces.
The synthesis of 1 compound ii of embodiment
Synthesis path is as follows：
Wherein
The synthesis of compound 2：In 1000mL there-necked flasks, betulin (20.0g, 45.2mmol) and acetone (400mL) is added, so
Freshly prepd Jones reagent (100mL) is added dropwise under ice bath afterwards, the reaction was continued under ice bath, and recession in 30 minutes goes ice bath, room temperature to stir
8h is mixed, methanol (250mL) is added and water (250mL) terminates reaction, solvent evaporated is added water, is extracted with ethyl acetate, is associated with
Machine phase, dry concentration, pillar layer separation obtain white solid 2 (12.2g, 26.8mmol, 59.3%).1H NMR(DMSO-d6,
400MHz)δ：12.08 (s, 1H), 4.70 (s, 1H), 4.57 (s, 1H), 2.90~2.99 (m, 1H), 2.46~2.30 (m, 2H),
2.25 (dt, J=12.7,3.5Hz, 1H), 2.15~2.08 (m, 1H), 1.87~1.73 (m, 3H), 1.65 (s, 3H), 1.62
(s, 1H), 1.54 (t, J=11.3Hz, 1H), 1.48~1.00 (m, 15H), 0.98 (s, 3H), 0.95 (s, 3H), 0.93 (s,
3H),0.90(s,3H),0.85(s,3H)。
The synthesis of compound 6：In 100mL round-bottomed flasks, compound 2 (4.54g, 10.0mmol) is dissolved in CH2Cl2In,
0 DEG C is added dropwise oxalyl chloride (12.7g, 100mmol).Solvent evaporated after completion of the reaction, residue are added methanol and are heated to reflux, TLC prisons
Solvent evaporated after completion of the reaction is surveyed, ethyl acetate extraction, washing, organic phase Na is added2SO4Dry, pillar layer separation obtains white
Color solid chemical compound 6 (3.36g, 7.17mmol, 71.7%).1H NMR(CDCl3,400MHz)δ：4.74(s,1H),4.61(s,
1H), 3.68 (s, 3H), 3.05~2.94 (m, 1H), 2.56~2.32 (m, 2H), 2.31~2.17 (m, 2H), 1.96~1.83
(m, 3H), 1.77~1.66 (m, 1H), 1.69 (s, 3H), 1.65~1.52 (m, 6H), 1.51~1.11 (m, 13H), 1.07 (s,
3H),1.02(s,3H),0.97(s,3H),0.95(s,3H),0.92(s,3H)。13C NMR(CDCl3,100MHz)δ：218.2,
176.6,150.5,109.6,56.5,55.0,51.3,49.9,49.4,47.3,46.9,42.4,40.6,39.6,38.3,
36.9,36.9,34.2,33.6,32.1,30.6,29.6,26.6,25.5,21.4,21.0,19.6,19.4,15.9,15.7,
14.6。
The synthesis of compound 7：In 500mL round-bottomed flasks, compound 6 (2.54g, 5.42mmol) and 135mL tetra- is added
KN (the SiMe that 1mol/L is added are stirred at room temperature in hydrogen furans3)2Tetrahydrofuran solution (40mL), stir 1h after 1mol/L is added
NEt3The tetrahydrofuran solution (40mL) of B continues to stir 1.5h, propargyl bromide (4mL) is added.After completion of the reaction, 3mol/L is added
HCl (3.0mL) reaction is quenched, be extracted with ethyl acetate three times, merge organic phase, by organic phase saturated sodium bicarbonate solution
It washes twice, Na2SO4Dry, pillar layer separation obtains compound as white solid 7 (2.32g, 4.58mmol, 84.5%).1H NMR
(CDCl3,400MHz)δ：4.72 (s, 1H), 4.58 (s, 1H), 3.67 (s, 3H), 3.05~2.94 (m, 1H), 2.91~2.77
(m, 1H), 2.60 (ddd, J=17.1,4.4,2.7Hz, 1H), 2.33 (dd, J=12.9,5.6Hz, 1H), 2.29~2.10 (m,
3H), 1.94 (t, J=2.7Hz, 1H), 1.91~1.83 (m, 1H), 1.79~1.70 (m, 1H), 1.67 (s, 3H), 1.63~
1.14 (m, 14H), 1.17~1.01 (m, 3H), 1.12 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.94
(s,3H)。13C NMR(CDCl3,100MHz)δ：215.8,176.6,150.4,109.7,83.0,69.4,57.3,56.5,
51.3,50.1,49.4,48.3,47.0,46.6,42.5,41.2,40.8,38.2,37.4,36.9,34.1,32.1,30.5,
29.6,25.4,25.0,21.6,21.2,19.5,19.3,16.1,14.6。
The synthesis of compound 8：In 500mL round-bottomed flasks, compound 7 (2.03g, 4.0mmol), 120mL methanol is added
With sodium borohydride (303mg, 8.0mmol).After 5h is stirred at room temperature, the HCl (60.0mL) of 3mol/L, solvent evaporated acetic acid is added
Ethyl ester extracts three times, merges organic phase, and organic phase is washed twice with saturated sodium bicarbonate solution, organic phase is dried and is concentrated, column
Chromatographic isolation uses petroleum ether：Ethyl acetate=20:1 makees eluant, eluent, obtain compound as white solid 8 (1.67g, 3.28mmol,
82.1%).1H NMR(CDCl3,400MHz)δ：4.73 (s, 1H), 4.59 (s, 1H), 3.67 (s, 3H), 3.07~2.93 (m,
2H), 2.47~2.12 (m, 4H), 1.98 (t, J=2.4Hz, 1H), 1.68 (s, 3H), 1.58 (t, J=11.4Hz, 3H), 0.98
(s,3H),0.97(s,3H),0.92(s,3H),0.86(s,3H),0.78(s,3H)。13C NMR(CDCl3,100MHz)δ：
176.6,150.5,109.6,82.9,81.4,69.9,56.5,55.4,51.2,50.4,49.4,46.9,44.8,42.4,
40.6,39.1,38.2,37.3,36.9,34.7,34.2,32.1,30.5,29.6,28.3,25.5,22.3,20.9,19.3,
18.5,16.9,16.2,15.9,14.7。
The synthesis of compound iv：In 50mL round-bottomed flasks, compound 8 (112mg, 0.22mmol), 2 '-deoxidations-are added
2 '-fluoro- 4 '-nitrine cytidines (69mg, 0.24mmol), the tert-butyl alcohol (5mL), water (5.0mL) and DIPEA (50 μ L).It vacuumizes, nitrogen
Gas shielded is heated to 45 DEG C.After reaction 15 minutes, CuI (4.0mg) and acetonitrile (1.5mL) are added.48h is stirred at 45 DEG C.It steams
Methanol is added after dry solvent, filters, is evaporated methanol, pillar layer separation obtain faint yellow solid compound iv (144mg,
0.18mmol, 82.3%).1H NMR(CDCl3+MeOH-d4,400MHz)δ：7.81 (d, J=7.4,1H), 7.64 (s, 1H),
6.72 (dd, J=14.1,3.6Hz, 1H), 5.90 (d, J=7.1Hz, 1H), 5.31 (dt, J=54.0,4.7Hz, 1H), 4.74
(dd, J=19.2,3.0Hz, 1H), 4.66 (s, 1H), 4.53 (s, 1H), 4.31~4.15 (m, 2H), 3.62 (s, 3H), 3.03
~2.84 (m, 2H), 2.77 (d, J=10.7Hz, 1H), 2.54 (dd, J=14.6,7.3Hz, 1H), 2.26~2.03 (m, 2H),
1.97~1.70 (m, 3H), 1.69~1.57 (m, 1H), 1.62 (s, 3H), 1.53 (t, J=11.3Hz, 1H), 1.48~0.93
(m, 14H), 0.91 (s, 3H), 0.90 (s, 3H), 0.84 (s, 3H), 0.76 (s, 3H), 0.73 (s, 3H), 0.68~0.50 (m,
2H)。13CNMR(CDCl3+MeOH-d4, 100MHz), δ：177.5,150.7,146.3,137.3,122.5,109.8,98.0,
94.5,82.4,56.9,55.8,51.6,50.7,47.3,45.8,42.7,40.9,39.6,38.6,37.6,37.2,36.1,
34.5,32.4,30.8,29.9,28.5,25.7,2.1,19.4,18.8,17.0,16.4,16.1,14.9。
The synthesis of 2 compound ii of embodiment
Synthesis path is as follows：
Its
The synthesis of compound 2：In 1000mL there-necked flasks, betulin (20.0g, 45.2mmol) and acetone (400mL) is added, so
Freshly prepd Jones reagent (100mL) is added dropwise under ice bath afterwards, the reaction was continued under ice bath, and recession in 30 minutes goes ice bath, room temperature to stir
8h is mixed, methanol (250mL) is added and water (250mL) terminates reaction, solvent evaporated is added water, is extracted with ethyl acetate, is associated with
Machine phase, dry concentration, pillar layer separation obtain white solid 2 (12.2g, 26.8mmol, 59.3%).1H NMR(DMSO-d6,
400MHz)δ：12.08 (s, 1H), 4.70 (s, 1H), 4.57 (s, 1H), 2.90~2.99 (m, 1H), 2.46~2.30 (m, 2H),
2.25 (dt, J=12.7,3.5Hz, 1H), 2.15~2.08 (m, 1H), 1.87~1.73 (m, 3H), 1.65 (s, 3H), 1.62
(s, 1H), 1.54 (t, J=11.3Hz, 1H), 1.48~1.00 (m, 15H), 0.98 (s, 3H), 0.95 (s, 3H), 0.93 (s,
3H),0.90(s,3H),0.85(s,3H)。
The synthesis of compound 3：In 100mL round-bottomed flasks, compound 2 (454mg, 1.0mmol) is dissolved in CH2Cl2
In (5mL), 0 DEG C is added EDC (306mg, 1.6mmol) and DMAP (73mg, 0.6mmol), after being stirred to react 30min, adds
L-Leu methyl ester hydrochloride (543mg, 3mmol) and Et3N (303mg, 3mmol), is stirred overnight at room temperature, and TLC monitorings have been reacted
It is washed after finishing, organic phase Na2SO4It is dry, pillar layer separation obtain syrupy shape compound 3 (343mg, 0.59mmol,
58.9%).1H NMR(CDCl3,400MHz)δ：5.87 (1H, d, J=8.2Hz), 4.72 (1H, s), 4.64 (1H, dt, J=
), 8.2,5.3Hz 4.58 (1H, s), 3.73 (3H, s), 3.11 (1H, m), 2.45 (1H, dt, J=12.2,3.4Hz), 1.68
(3H, s), 0.96 (6H, d, J=7.2Hz), 0.95 (3H, s), 0.92 (3H, s), 0.84 (6H, s), 0.83 (3H, s).
The synthesis of compound 4：In 100mL round-bottomed flasks, compound 3 (470mg, 0.81mmol) and 20mL tetra- is added
KN (the SiMe that 1mol/L is added are stirred at room temperature in hydrogen furans3)2Tetrahydrofuran solution (6mL), stir 1h after 1mol/L is added
NEt3The tetrahydrofuran solution (6mL) of B continues to stir 1.5h, propargyl bromide (0.6mL) is added.After completion of the reaction, 1mol/L is added
HCl (2.0mL) reaction is quenched, be extracted with ethyl acetate three times, merge organic phase, by organic phase saturated sodium bicarbonate solution
It washes twice, Na2SO4Dry, the residue that solvent evaporated obtains methanol dissolves (20mL), addition sodium borohydride (60mg,
1.6mmol).It is stirred at room temperature and the HCl (15mL) of 3mol/L is added after 5h reaction is quenched, three are extracted with ethyl acetate after solvent evaporated
It is secondary, merge organic phase, saturated sodium bicarbonate solution washing, anhydrous Na2SO4Dry, pillar layer separation obtains compound as white solid
4 (340mg, 0.55mmol, 67.5%).1HNMR(CDCl3,400MHz)δ：5.88 (1H, d, J=8.2Hz), 4.73 (1H, s),
4.56-4.63 (1H, m), 4.59 (1H, s), 3.72 (3H, s), 3.15 (1H, d, J=9.8Hz), 3.10 (1H, m), 2.60
(ddd, J=17.1,4.4,2.7Hz, 1H), 2.42 (1H, dt, J=12.2,3.0Hz), 1.68 (3H, s), 0.96 (6H, d, J=
7.2Hz),0.95(3H,s),0.91(3H,s),0.82(6H,s),0.79(3H,s)。
The synthesis of compound 5：In 50mL round-bottomed flasks, compound 4 (136mg, 0.22mmol), 2 '-deoxidations-are added
2 '-fluoro- 4 '-nitrine cytidines (69mg, 0.24mmol), the tert-butyl alcohol (5mL), water (5.0mL) and n,N-diisopropylethylamine DIPEA
(50μL).It vacuumizes, nitrogen protection, is heated to 45 DEG C.After reaction 15 minutes, CuI (4.0mg) and acetonitrile (1.5mL) are added.
48h is stirred at 45 DEG C.Methanol is added after solvent evaporated, filters, is evaporated methanol, pillar layer separation obtains compound as white solid 5
(164mg, 0.18mmol, 82.0%).1H NMR(MeOH-d4,400MHz)δ：7.99 (d, J=7.6Hz, 1H), 7.88 (s,
1H), 6.80 (dd, J=11.9,5.0Hz, 1H), 6.01 (d, J=7.2Hz, 1H), 5.37 (dt, J=54.0,4.7Hz, 1H),
4.79 (dd, J=20.9,4.7Hz, 1H), 4.70 (d, J=2.0Hz, 1H), 4.54-4.65 (1H, m), 4.59 (1H, s), 4.40
~4.18 (2H, m), 3.65 (3H, s), 3.06~2.92 (m, 2H), 2.62 (dd, J=14.3,6.8Hz, 1H), 2.30~2.18
(m, 2H), 2.04 (dd, J=13.0,5.3Hz, 1H), 1.92~1.81 (m, 2H), 1.68 (s, 3H), 1.11 (s, 3H), 1.07
(6H, d, J=6.8Hz), 1.06 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H).
The synthesis of compound ii：Compound 5 (90mg, 0.10mmol) is dissolved in methanol (10mL) and THF (5mL), ice bath
2mol/L KOH (2mL) are added in lower stirring, continue to keep 0 DEG C of stirring 3h.2mol/L HCl are added after completion of the reaction and use second
Acetoacetic ester extracts, and column chromatography for separation obtains compound ii (85mg, 0.095mmol, 95%).1HNMR(MeOH-d4,400MHz)δ：
8.01 (d, J=7.6Hz, 1H), 7.89 (s, 1H), 6.82 (dd, J=11.9,5.0Hz, 1H), 6.01 (d, J=7.2Hz, 1H),
5.37 (dt, J=54.0,4.7Hz, 1H), 4.79 (dd, J=20.9,4.7Hz, 1H), 4.70 (d, J=2.0Hz, 1H), 4.54-
4.65 (1H, m), 4.59 (1H, s), 4.40~4.18 (2H, m), 3.10~2.95 (m, 2H), 2.66 (dd, J=13.6,
6.4Hz, 1H), 2.04 (dd, J=12.6,5.0Hz, 1H), 1.68 (s, 3H), 1.11 (s, 3H), 1.07 (6H, d, J=
6.8Hz),1.06(s,3H),1.04(s,3H),0.96(s,3H),0.88(s,3H)。
The synthesis of 3 compound i of embodiment
Synthesis path is as follows：
Wherein
The synthesis of compound 2：In 1000mL there-necked flasks, betulin (20.0g, 45.2mmol) and acetone (400mL) is added, so
Freshly prepd Jones reagent (100mL) is added dropwise under ice bath afterwards, the reaction was continued under ice bath, and recession in 30 minutes goes ice bath, room temperature to stir
8h is mixed, methanol (250mL) is added and water (250mL) terminates reaction, solvent evaporated is added water, is extracted with ethyl acetate, is associated with
Machine phase, dry concentration, pillar layer separation obtain white solid 2 (12.2g, 26.8mmol, 59.3%).1H NMR(DMSO-d6,
400MHz)δ：12.08 (s, 1H), 4.70 (s, 1H), 4.57 (s, 1H), 2.90~2.99 (m, 1H), 2.46~2.30 (m, 2H),
2.25 (dt, J=12.7,3.5Hz, 1H), 2.15~2.08 (m, 1H), 1.87~1.73 (m, 3H), 1.65 (s, 3H), 1.62
(s, 1H), 1.54 (t, J=11.3Hz, 1H), 1.48~1.00 (m, 15H), 0.98 (s, 3H), 0.95 (s, 3H), 0.93 (s,
3H),0.90(s,3H),0.85(s,3H)。
The synthesis of compound 6：In 100mL round-bottomed flasks, compound 2 (4.54g, 10mmol) is dissolved in CH2Cl2In, 0
DEG C be added dropwise oxalyl chloride (12.7g, 100mmol).Solvent evaporated after completion of the reaction, residue are added methanol and are heated to reflux, TLC monitorings
Ethyl acetate extraction, washing, organic phase Na is added in solvent evaporated after completion of the reaction2SO4Dry, pillar layer separation obtains white
Solid chemical compound 6 (3.36g, 7.17mmol, 71.7%).1H NMR(CDCl3,400MHz)δ：4.74(s,1H),4.61(s,
1H), 3.68 (s, 3H), 3.05~2.94 (m, 1H), 2.56~2.32 (m, 2H), 2.31~2.17 (m, 2H), 1.96~1.83
(m, 3H), 1.77~1.66 (m, 1H), 1.69 (s, 3H), 1.65~1.52 (m, 6H), 1.51~1.11 (m, 13H), 1.07 (s,
3H),1.02(s,3H),0.97(s,3H),0.95(s,3H),0.92(s,3H)。13C NMR(CDCl3,100MHz)δ：218.2,
176.6,150.5,109.6,56.5,55.0,51.3,49.9,49.4,47.3,46.9,42.4,40.6,39.6,38.3,
36.9,36.9,34.2,33.6,32.1,30.6,29.6,26.6,25.5,21.4,21.0,19.6,19.4,15.9,15.7,
14.6。
The synthesis of compound 7：In 500mL round-bottomed flasks, compound 6 (2.54g, 5.42mmol) and 135mL tetra- is added
KN (the SiMe that 1mol/L is added are stirred at room temperature in hydrogen furans3)2Tetrahydrofuran solution (40mL), stir 1h after 1mol/L is added
NEt3The tetrahydrofuran solution (40mL) of B continues to stir 1.5h, propargyl bromide (4mL) is added.After completion of the reaction, 3mol/L is added
HCl (3.0mL) reaction is quenched, be extracted with ethyl acetate three times, merge organic phase, by organic phase saturated sodium bicarbonate solution
It washes twice, Na2SO4Dry, pillar layer separation obtains compound as white solid 7 (2.32g, 4.58mmol, 84.5%).1H NMR
(CDCl3,400MHz)δ：4.72 (s, 1H), 4.58 (s, 1H), 3.67 (s, 3H), 3.05~2.94 (m, 1H), 2.91~2.77
(m, 1H), 2.60 (ddd, J=17.1,4.4,2.7Hz, 1H), 2.33 (dd, J=12.9,5.6Hz, 1H), 2.29~2.10 (m,
3H), 1.94 (t, J=2.7Hz, 1H), 1.91~1.83 (m, 1H), 1.79~1.70 (m, 1H), 1.67 (s, 3H), 1.63~
1.14 (m, 14H), 1.17~1.01 (m, 3H), 1.12 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.94
(s,3H)。13C NMR(CDCl3,100MHz)δ：218.2,176.6,150.4,109.7,83.0,69.4,57.3,56.5,
51.3,50.1,49.4,48.3,47.0,46.6,42.5,41.2,40.8,38.2,37.4,36.9,34.1,32.1,30.5,
29.6,25.4,25.0,21.6,21.2,19.5,19.3,16.1,14.6。
The synthesis of compound 8：In 500mL round-bottomed flasks, compound 7 (2.03g, 4.0mmol), 120mL methanol is added
With sodium borohydride (303mg, 8.0mmol).After 5h is stirred at room temperature, the HCl (60.0mL) of 3mol/L, solvent evaporated acetic acid is added
Ethyl ester extracts three times, merges organic phase, and organic phase is washed twice with saturated sodium bicarbonate solution, organic phase is dried and is concentrated, column
Chromatographic isolation uses petroleum ether：Ethyl acetate=20:1 makees eluant, eluent, obtain compound as white solid 8 (1.67g, 3.28mmol,
82.1%).1H NMR(CDCl3,400MHz)δ：4.73 (s, 1H), 4.59 (s, 1H), 3.67 (s, 3H), 3.07~2.93 (m,
2H), 2.47~2.12 (m, 4H), 1.98 (t, J=2.4Hz, 1H), 1.68 (s, 3H), 1.58 (t, J=11.4Hz, 3H), 0.98
(s,3H),0.97(s,3H),0.92(s,3H),0.86(s,3H),0.78(s,3H)。13C NMR(CDCl3,100MHz)δ：
176.6,150.5,109.6,82.9,81.4,69.9,56.5,55.4,51.2,50.4,49.4,46.9,44.8,42.4,
40.6,39.1,38.2,37.3,36.9,34.7,34.2,32.1,30.5,29.6,28.3,25.5,22.3,20.9,19.3,
18.5,16.9,16.2,15.9,14.7。
The synthesis of compound 9：In 25mL round-bottomed flasks, compound 8 (394mg, 0.77mmol), lithium iodide is added
(1.0g, 7.5mmol) and DMF (15mL), flow back 48h, and the HCl (10mL) of 3mol/L, ethyl acetate extraction are added after completion of the reaction
It takes three times, merges organic phase, organic phase is washed twice with saturated sodium bicarbonate solution, organic phase is dried and is concentrated, petroleum ether is used：
Ethyl acetate=3:1 makees eluant, eluent, obtains compound as white solid 9 (287mg, 0.58mmol, 74.9%).1H NMR(CDCl3,
400MHz)δ：4.74 (s, 1H), 4.60 (s, 1H), 3.05~2.95 (m, 2H), 2.47~2.14 (m, 4H), 1.98 (t, J=
2.6Hz, 1H), 1.83 (dd, J=12.8,3.7Hz, 1H), 1.69 (s, 3H), 0.98 (s, 6H), 0.95 (s, 3H), 0.87 (s,
3H),0.78(s,3H)。
The synthesis of compound i：In 50mL round-bottomed flasks, compound 9 (110mg, 0.22mmol), 2 '-deoxidations-are added
2 '-fluoro- 4 '-nitrine cytidines (69mg, 0.24mmol), the tert-butyl alcohol (5mL), water (5.0mL) and DIPEA (50 μ L).It vacuumizes, nitrogen
Gas shielded is heated to 45 DEG C.After reaction 15 minutes, CuI (4.0mg) and acetonitrile (1.5mL) are added.48h is stirred at 45 DEG C.It steams
Methanol is added after dry solvent, filters, is evaporated methanol, pillar layer separation obtain faint yellow solid compound i (144mg,
0.18mmol, 83.1%).1H NMR(DMSO-d6,400MHz)δ：12.08 (s, 1H), 7.91 (s, 1H), 7.77 (d, J=
7.6Hz, 1H), 6.76 (m, 1H), 6.24 (d, J=5.3Hz, 1H), 5.88 (m, 1H), 5.80 (d, J=7.7Hz, 1H), 4.78
~4.64 (m, 2H), 4.60 (d, J=6.3Hz, 1H), 4.55 (s, 1H), 4.14 (m, 2H), 3.14 (d, J=12.9Hz, 1H),
2.93(m,1H),2.67(m,1H),1.64(s,3H),0.91(s,3H),0.90(s,3H),0.83(s,3H),0.71(s,3H),
0.70 (s, 3H), 0.49 (t, J=12.9Hz, 1H).
Anticancer experiment in vitro
I, ii, iv compound of this experiment various concentration are respectively acting on A549 (lung cancer), SGC-7901 (gastric cancer), MCF-7
Different types of cancer cell 72h such as (breast cancer) and LUC-7721 (liver cancer) cell, cell growth inhibition is detected by mtt assay
Rate, to detect inhibition level of three kinds of compounds to different tumour cells.
I, ii, iv are dissolved in the DMSO of certain volume, 4 DEG C of preservations of mother liquor of a concentration of 80mmol/L is made into, uses
When take mother liquor to be diluted to the solution of certain multiple.
Concrete operation step is as follows：
(1) it takes A549, SGC-7901, MCF-7 and LUC-7721 cell in exponential phase, centrifugation to be resuspended, adjusts cell
Suspension density is to 8 × 104Cell/ml is inoculated in 96 well culture plates, and 100 μ l cell suspensions are added per hole, then place cell
Routine culture in incubator.
(2) after being incubated for 24 hours, original culture medium in hole is abandoned in each adherent homoepitaxial of hole cell monolayer of microscopically observation, suction,
Experimental group be added various concentration 100 μ l of i, ii, iv solution, make three kinds of final compound concentrations respectively be 25,50,100,200,
400 μm of ol/L, each concentration are all provided with 4 multiple holes；Blank group (culture medium is only added and is not added with cell suspension), negative control are set simultaneously
(cell suspension is only added) in group.
(3) after placing incubator culture 72h, 20 μ l MTT solution are added per hole, continue to cultivate 4h in the incubator.Then
Culture medium carefully is discarded, 150 μ l DMSO are added per hole keeps crystal fully molten as 37 DEG C of isothermal vibration 10min on shaking table
Solution.Each hole absorbance OD values are detected under enzyme-linked immunosorbent assay instrument 490nm wavelength.
(4) inhibiting effect of the sample to cell is calculated, formula is as follows：
Inhibiting rate (%)=(cell control well OD values-dosing holes OD values)/(cell control well OD values-blank well OD values) ×
100%
According to the inhibiting rate calculated, the cytostatic half-inhibition concentration IC of each sample is found out50。
By table it can be seen that：There are lung cancer, gastric cancer, breast cancer and liver cancer cells in i, ii, iv sample of doses
Different degrees of inhibiting effect；Identical in action time, with the increase of sample dose, inhibiting rate is gradually increasing,
Apparent dose-dependent effect is shown as to the inhibiting effect of cell；Iv is to lung cancer, gastric cancer, the inhibiting effect phase of breast cancer cell
It is more more notable than liver cancer cells, wherein, IC preferable to lung cancer inhibition50It is worth relatively low.Inhibition of the ii to lung cancer, breast cancer cell
Effect is more notable compared to gastric cancer, liver cancer cells, wherein, IC preferable to lung cancer inhibition50It is worth relatively low.I is to breast cancer cell
Inhibiting effect it is preferable compared to lung cancer, gastric cancer, liver cancer cells effect, IC50It is worth relatively low.
It is specifically shown in shown in the following table 1-2：
Table 1：Inhibiting effect of the iv to each cell
Table 2：Inhibiting effect of the ii to each cell
Table 3：Inhibiting effect of the i to each cell
What has been described above is only a preferred embodiment of the present invention, it is noted that for those skilled in the art,
Under the premise of not departing from general idea of the present invention, several changes and improvements can also be made, these should also be considered as the present invention's
Protection domain.
Claims (6)
1. a kind of betulic acid derivative or its pharmaceutically acceptable salt, hydrate or prodrug, it is characterised in that：Its structure
Shown in formula such as formula (I)：
Wherein：X=NH or O, Y=OH or NH2, R1It is H, C1-C20Substitution or unsubstituted group.
2. betulic acid derivative according to claim 1, it is characterised in that：Structural formula white birch fat as shown in formula (I)
Acid derivative is specially structural formula such as formula i, ii, iii, iv, v, vi compounds represented：
3. the synthetic method of betulic acid derivative as described in claim 1, it is characterised in that：Synthesis path is as follows：
Wherein：Y=OH or NH2, R is C1-C20Substitution or unsubstituted group；
Specific synthesis step is as follows：
The synthesis of compound 2：Compound 1 is dissolved in acetone or tetrahydrofuran, 0 DEG C of addition Jones reagent, after completion of the reaction
Methanol and water quenching is added to go out reaction, solvent evaporated extracts and uses column chromatography to obtain compound as white solid 2；
The synthesis of compound 3：Compound 2 is dissolved in dichloromethane, 0 DEG C is added 1- (3- dimethylamino-propyls) -3- ethyls carbon two
Inferior amine salt hydrochlorate (EDC), 4-dimethylaminopyridine (DMAP) stir 30min, add corresponding amine, are stirred at room temperature and reacted
Night, extraction are evaporated column chromatography for separation and obtain compound 3；
The synthesis of compound 4：Compound 3 is dissolved in tetrahydrofuran, and KN (SiMe are added3)2Tetrahydrofuran solution and Et3B's
Tetrahydrofuran solution；Propargyl bromide is added after being stirred to react 1h.Hydrochloric acid neutralization reaction after completion of the reaction, organic extractant phase obtain after being evaporated
To compound be dissolved in methanol, NaBH is added4It is stirred overnight, solvent evaporated and with the isolated compound of silica gel column chromatography 4；
The synthesis of compound 5：Compound 4 is dissolved in the mixed solvent of the tert-butyl alcohol and water, and n,N-diisopropylethylamine and corresponding is added
Nucleosides, stirring 30 minutes after be added CuI acetonitrile solution the reaction was continued overnight；Solvent evaporated after completion of the reaction, column chromatography for separation
Obtain compound 5；
The synthesis of compound 6：Compound 2 is dissolved in dichloromethane, and 0 DEG C of dropwise addition oxalyl chloride, solvent evaporated, is re-dissolved in after completion of the reaction
CH2Cl2, corresponding alcohol stirring is added, is evaporated to obtain compound 6；
The synthesis of compound 7：Compound 6 is dissolved in tetrahydrofuran, and KN (SiMe are added3)2Tetrahydrofuran solution and Et3B's
Tetrahydrofuran solution；Propargyl bromide is added after being stirred to react 1h；Hydrochloric acid neutralization reaction after completion of the reaction, organic extractant phase, which is evaporated, to be used in combination
The isolated compound as white solid of silica gel column chromatography 7；
The synthesis of compound 8：Compound 7 is dissolved in methanol, and NaBH is added4It is stirred overnight, solvent evaporated is simultaneously detached with silica gel column chromatography
Obtain compound 8；
The synthesis of compound 9：Compound 8 is dissolved in n,N-Dimethylformamide, and lithium iodide is added and heats, after completion of the reaction acetic acid
Ethyl ester extracts, and salt acid elution is evaporated column chromatography for separation and obtains compound as white solid 9；
The synthesis of compound 10：Compound 9 is dissolved in the mixed solvent of the tert-butyl alcohol and water, and n,N-diisopropylethylamine and corresponding is added
Nucleosides, stirring 30 minutes after be added CuI acetonitrile solution the reaction was continued overnight；Solvent evaporated after completion of the reaction, column chromatography for separation
Obtain compound 10；
The synthesis of compound 11：Compound 8 is dissolved in the mixed solvent of the tert-butyl alcohol and water, and n,N-diisopropylethylamine and corresponding is added
Nucleosides, stirring 30 minutes after be added CuI acetonitrile solution the reaction was continued overnight.Solvent evaporated after completion of the reaction, column chromatography for separation
Obtain compound 11.
4. betulic acid derivative application in preparation of anti-tumor drugs as described in any one of claims 1-3.
5. application as claimed in claim 4, it is characterised in that：The apoptosis of the derivative induced tumour cell of betulic acid,
Inhibit the proliferation of tumour cell, inhibit the migration of tumour cell.
6. application of the betulic acid derivative as described in any one of claims 1-3 in preparing antiviral drugs.
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| WO2020186588A1 (en) * | 2019-03-15 | 2020-09-24 | 河南真实生物科技有限公司 | Crystal form a of 2'-fluoro-4'-substituted nucleoside analog i and preparation method therefor and use thereof |
| CN112979743A (en) * | 2019-12-02 | 2021-06-18 | 河南省医药科学研究院 | Betulinic acid derivative and application thereof |
| CN114344313A (en) * | 2022-01-28 | 2022-04-15 | 河南省科学院高新技术研究中心 | Betulinic acid derivatives for preventing or treating degenerative diseases of nervous system |
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| CN117327140A (en) * | 2023-11-24 | 2024-01-02 | 潍坊赛宝工业技术研究院有限公司 | Betulinic acid derivative with bacteria inhibiting function |
| CN117327140B (en) * | 2023-11-24 | 2024-03-12 | 潍坊赛宝工业技术研究院有限公司 | Betulinic acid derivative with bacteria inhibiting function |
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