CN101130540A - Nucleoside derivative containing selenium and its preparation method - Google Patents
Nucleoside derivative containing selenium and its preparation method Download PDFInfo
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Abstract
The invention discloses a selenium nucleoside derivant and preparing method in medical chemistry technique domain, which is characterized by the following: setting the compound as right formula; setting B as one of adenine, guanine, cytosine, uracil and thymidine; reforming ribose riboside, base modified ribose riboside or base modified ribosyl nucleoside like as initial raw material; oxido-reducting; forming 2', 3' -non cyclic nucleotide; activating 2', 3'; introducing selenium atom; getting new type riboside compound with selenium cyclohexane as glycosyl. This invention possesses simple operation and higher receiving ratio (more than 70%), which can be used to antiviral compound and antineoplastic compound.
Description
Technical field
The present invention relates to derivative of a kind of pharmaceutical chemistry technical field and preparation method thereof, be specifically related to a kind of nucleoside derivative containing selenium and preparation method thereof.
Technical background
Since iodoxuridine since the clinical treatment that is used for bleb of nineteen fifty-nine, brought into play important role at antiviral and antineoplaston field nucleoside medicine in the decades in past.Be used for viral therapy as purine nucleoside analogs Ah former times Lip river crow etc., pyrimidine nucleosides medicine cytosine arabinoside etc. is used for oncotherapy.Nucleoside medicine still constantly is being developed application in recent years, in October, 2006 drugs approved by FDA L-thymus pyrimidine dezyribonucleoside (L-DT) be used for the treatment of viral hepatitis.A lot of nucleoside compound glycosyl parts have carried out modifying transforms or has introduced heteroatoms, as the zidovudine glycosyl part is 2 ', 3 '-dideoxy ribose has also been introduced azido-at 3 ', and Ah former times Lip river crow and cidofovir etc. are acyclic nucleotide, lamivudine with introduced fluorine atom.The some of them compound as zidovudine, has antiviral and antitumor action simultaneously.The existing very long history that selenium is used to keep healthy and treats is goed deep into its mechanism of action and new purposes still in constantly being excavated along with research means.As far back as 1913, Walker etc. once attempted treating tumour with electroselenium.Along with biochemical development, selenium begins to be familiar with and to accept as a kind of important nutritive and health protection components.Compare with inorganic selenium, the organic selenium compounds thing is safer, and is easy to absorb and metabolism, is widely used as a kind of selenium component extender as seleno-cysteine.At molecular level, selenium is glutathione peroxidase, iodine thyronine 5 '-Tuo iodine enzyme, and the active centre of plurality of enzymes also is present in some mammiferous seleno-proteins in the organisms such as Mammals thioredoxin reductase.These catalytic reaction pair cellular constituents of enzyme institute are anti-oxidant and the removing free radical is extremely important, and can influence the process that DNA forms and repairs, thereby can play restraining effect to virus and tumour cell.
Eighties of last century rises the seventies, selenium substituted nucleosides class medicine comes into one's own gradually, propose some and new contained the selenium nucleoside compound successively, contain the Se analog as Selenofurin (Selenazofurin) as thiazole furans (Thiazofurin), inhibition specific activity thiazole furans to Lymphocytic leukemia is high more than 3 times, and toxicity significantly reduces, and Selenofurin has entered clinical study at present.On the other hand, because dioxolane and oxathiolane nucleosides class medicine demonstrate good antiviral and anti-tumor activity, 3 '-CH
2The isostere oxygen selenium penta that is formed after the selenium atom replacement encircles the correlative study of nucleoside analog thereby receives publicity.In this compounds of having reported, cytosine(Cyt) and 5-flurocytosine derivative demonstrate anti-HIV of potential and anti-HBV activity.
Find through literature search prior art, Korean Patent Application No. is KR2003026487A, this patent report has 1 of fragrant group, 4-oxygen, the selenium hexanaphthene can be used for treatment for cancer such as uterus carcinoma and ovarian cancer, 1,4-oxygen, selenium cyclohexyl be in the compound structure with antitumor relevant active fragments.Studies show that 1,4-oxygen, sulphur (nitrogen, oxygen) hexanaphthene glycosyl nucleoside analog does not show restraining effect to the virus of some kinds.But in the above-mentioned technology, have 1,4-oxygen, there is yield low (33～40%) in the synthetic method of selenium hexanaphthene, raw material costliness and severe reaction conditions problems such as (wherein a step are-78 ℃ of reactions) such as Silver Nitrate, LDA.
Summary of the invention
The objective of the invention is to provides a kind of nucleoside derivative containing selenium and preparation method thereof at the deficiencies in the prior art.The present invention with seleno for 1,4-oxygen, the sulphur heteroatomss such as (nitrogen, oxygen) of 4 ' on sugar ring obtains the new selenium nucleoside analog that contains in sulphur (nitrogen, oxygen) the hexanaphthene glycosyl nucleoside analog, and is easy and simple to handle, the yield height.
The present invention is achieved by the following technical solutions:
The nucleoside derivative containing selenium that the present invention relates to, its structural formula is:
Wherein B be VITAMIN B4, guanine, cytosine(Cyt), uridylic and thymus pyrimidine any.
Described derivative, its glycosidic link are α-D configuration, or β-D configuration, or α-L configuration, or β-L configuration.
The preparation method of the above-mentioned nucleoside derivative containing selenium that the present invention relates to, be specially: the nucleoside analog of the ribonucleoside of crossing with ribonucleoside, base modification or the ribosyl of base transformation is a starting raw material, keep glycosidic link configuration in the primary structure, binding molecule structure activity relationship, bioelectronics row mechanism form 2 ' by redox simultaneously, 3 '-acyclic nucleotide, and further selenium atom is introduced in 2 ', 3 ' activation back, obtain with methylol-1,4-oxygen, the nucleoside compound of selenium cyclohexyl glycosyl.
The preparation method of described nucleoside derivative containing selenium specifically comprises the steps:
1. the oxidation open loop and the reduction of glycosyl part: the nucleoside analog sodium periodate oxidation open loop of the ribosyl that ribonucleoside that ribonucleoside, base modification are crossed or base are transformed obtains corresponding 2 ', 3 '-open loop nucleosides with sodium borohydride reduction then;
2. the activation of 2 ', 3 ' hydroxyl after the open loop: 2 ', 3 '-open loop nucleosides and methylsulfonyl chloride, Tosyl chloride or sulfur oxychloride and imidazoles reaction, 2 ', 3 ' sulphonate that forms methanesulfonates or replacement;
3. the nucleosides that is activated in the attack 2. of selenizing reagent is 2 ', 3 ', forms methylol-1,4-oxygen, the nucleoside analog of selenium hexanaphthene ribosyl;
4. hydroxyl on the sugar ring of 3. gained nucleoside analog and the amino on the base respectively deprotection obtain purpose product of the present invention---methylol-1; 4-oxygen; the nucleoside compound of selenium cyclohexyl glycosyl; as in acetic acid is water-soluble, removing the trityl on the hydroxyl, in ammonia methyl alcohol, remove the benzoyl on the amino.
Step 3. in, described selenizing reagent is selenium hydracid sodium (potassium or other metal-salts), or sodium selenide (potassium or other metal-salts).With selenium simple substance is that raw material is using prior art for preparing, and reaction formula is as follows:
4NaBH
4+2Se+7H
2O——→2NaHSe+Na
2B
4O
2+14H
2
Step 3. in, the mol ratio of described selenizing reagent and activatory 2 ', 3 '-open loop nucleosides is 1～5: 1.
Step 3. in, selenylation reaction carries out in the 4-dioxane isopolarity non-protonic solvent 1; Temperature of reaction is 80～100 ℃; Reaction times is 5～10 hours.
The preparation method of the nucleoside derivative containing selenium that the present invention is above-mentioned, its reaction scheme is as follows:
Wherein B ' has the base of protection for reactive group; B is the base of taking off protecting group; R
1For the primary hydroxyl protecting group, silica-based as tert-butyl diphenyl, benzene trimethylammonium and (replacement) benzene trimethylammonium, pivaloyl group, benzoyl and other acyl group protecting groups etc.; R
2Be the group of in substitution reaction, leaving away easily, as the methylsulfonic acid ester group, tosic acid ester group, halogen etc.
The present invention is based on the physiologically active that the selenium element is shown, with seleno for 1,4-oxygen, the sulphur heteroatomss such as (nitrogen, oxygen) of 4 ' on sugar ring obtains the new selenium nucleoside analog that contains in sulphur (nitrogen, oxygen) the hexanaphthene glycosyl nucleoside analog.Synthetic method raw material of the present invention is easy to get, and is easy and simple to handle, yield higher (＞70%).
Embodiment
Below embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
The preparation of 1-(6-(methylol)-1,4-oxygen, selenium hexanaphthene-2-alkyl) pyrimidine-2,4 (1 hydrogen, 3 hydrogen)-diketone.
5 '-oxygen-(4,4 '-dimethoxy) (5.47g 10mmol) is dissolved in the methyl alcohol (20ml) the trityl uridine, splashes into sodium periodate (3.21g under the stirring at room, in methyl alcohol 15mmol) (50ml)/water (50ml) solution, dropwise the back stirring at room to reacting completely.Add methyl alcohol (100ml) and stirred 5 minutes, make precipitation fully.Filter, filtrate decompression is steamed and is removed methyl alcohol, adds the methylene dichloride dissolving, and saturated sodium bicarbonate solution washing, saturated common salt water washing remove solvent under reduced pressure and get white foam shape solid behind the anhydrous sodium sulfate drying.Add the anhydrous methanol dissolving, ice-water bath stirs gradation adding sodium borohydride down, adds recession deicing water-bath stirring at room to reacting completely.Organic phase is steamed and is desolventized, and column chromatography purification is collected the steaming of product component and desolventized, and gets white foam shape solid 5 '-oxygen-(4,4 '-dimethoxy) trityl-2 ' 3, '-the open loop uridine (4.83g, 8.8mmol), yield 88.1%.
The gained solid is dissolved in anhydrous pyridine (45ml), and ice-water bath adds methylsulfonyl chloride down, stirred 30 minutes at 0 ℃ under the nitrogen protection, and stirring at room 3 hours, the TLC demonstration reacts completely.Remove solvent under reduced pressure, add the methylene dichloride dissolving, saturated sodium bicarbonate solution washing, saturated common salt water washing remove solvent under reduced pressure, column chromatography purification behind the anhydrous sodium sulfate drying, collecting the steaming of product component desolventizes, white foam shape solid 5 '-oxygen-(4,4 '-dimethoxy) trityl-2 ' 3, '-two methanesulfonates (5.28g of open loop uridine, 7.5mmol), yield 85.2%.
The gained solid is dissolved in DMF (10ml), and adding sodium selenide under the nitrogen protection (2.81g, in DMF suspension 22.5mmol), nitrogen protection was stirred 5 hours for following 100 ℃, and the TLC demonstration reacts completely.Remove solvent under reduced pressure, add the methylene dichloride dissolving, saturated sodium bicarbonate solution washing, saturated common salt water washing, remove solvent behind the anhydrous sodium sulfate drying under reduced pressure, column chromatography purification is collected the steaming of product component and is desolventized, (6-((4 to get white foam shape solid 1-, 4 '-Dimethoxyphenyl)-1,4-oxygen, selenium hexanaphthene-2-alkyl) pyrimidine-2,4 (1 hydrogen, 3 hydrogen)-and diketone (3.86g, 6.5mmol), yield 86.7%.
The gained solid is dissolved in 80% acetic acid aqueous solution (10ml), stirring at room 1 hour, and the TLC demonstration reacts completely.Remove solvent under reduced pressure, the steaming of adding 100 order chromatographic silica gels desolventizes after adding dissolve with methanol, dry method upper prop column chromatography purification is collected the steaming of product component and is desolventized, and gets white solid 1-(6-(methylol)-1,4-oxygen, selenium hexanaphthene-2-alkyl) pyrimidine-2,4 (1 hydrogen, 3 hydrogen)-diketone (1.66g, 5.7mmol), yield 87.7%.
Characterization parameter is: m.p.79-81 ℃; 1HNMR (CD3OH, 300MHZ), δ 7.74 (d, J=8.1Hz, H-6,1H); 5.92 (dd, J=1.8Hz and 10.5Hz, H-1 ', 1H); 5.90 (d, J=8.4Hz, H-5,1H); 4.07-4.16 (m, H-5 ', 1H); 3.58 (t, J=3.9Hz, H-5 ' a, H-5 ' b, 2H); 2.98 (t, J=10.8Hz, H-2 ' a, 1H); 2.72 (t, J=114Hz, H-2 ' b, 1H); 2.58 (d, J=12.0Hz, H-4 ' a, 1H); (d, J=12.6Hz, H-4 ' b, 1H) .13C NMR (CD3OH, 100MHZ) δ 16.833and 18.606 (CH2SeCH2), 65.143 (C-6 '), 83.786 (C-5 '), 83.807 (C-2 '), 101.475 (C-5), 140.919 (C-6), 150.359 (C-2), 164.882 (C-4); HRMS-ESI (m/z): (M+Na
+) calcd for C9H12N2O4Se, 314.9860; Found, 314.9863.
Embodiment 2
(6-(6-amino-9 hydrogen-purine-9-)-1,4-oxygen, the selenium cyclohexyl-2-) preparation of methyl alcohol.
With N-(9-((2R, 3S, 4R, 5R)-3,4-dihydroxyl-5-(trityl)-tetrahydrofuran (THF)-2-alkyl yl)-and 9 hydrogen-purine-6-alkyl) 1 condition redox obtains white foam shape solid 5 '-oxygen-trityl-2 ' 3 to benzene carbon amide (5 '-oxygen-trityl-6-benzoyl adenosine) with reference to embodiment for starting raw material, '-open loop-6-benzoyl adenosine.
With reference to embodiment 1 condition, with Tosyl chloride reaction, white solid 5 '-oxygen-trityl-2 ' 3, '-open loop-6-benzoyl adenosine 2 ' 3, '-two p-toluenesulfonic esters.
With reference to embodiment 1, adjusting temperature of reaction is 90 ℃, and other conditions are constant.Preparation N-(9-(6-(trityl)-1,4-oxygen, the benzamide of selenium cyclohexyl-2-)-9 hydrogen-purine-6-), yield 75.6%, white solid.
The gained solid (3.3g 5mmol) is dissolved in ammonia methyl alcohol saturated solution (30ml), stirring at room 24 hours, and the TLC demonstration reacts completely.Remove solvent under reduced pressure, add the dichloromethane solution stirring at room 1 hour of 10% trifluoroacetic acid, TLC shows and reacts completely, and adds the triethylamine neutralization.Remove solvent under reduced pressure, column chromatography purification is collected the product component and is steamed and desolventize, white solid (6-(and 6-amino-9 hydrogen-purine-9-)-1,4-oxygen, the methyl alcohol of selenium cyclohexyl-2-) (1.32g, 4.23mmol), yield 84.5%.
Characterization parameter is: m.p.194-196 ℃; 1HNMR (DMSO-d6,300MHZ), δ 8.34 (s, H-8,1H); 8.14 (s, H-2,1H); 7.30 (s ,-NH2,2H); 5.94 (dd, J=1.5 and 10.8Hz, H-1 ', 1H); 4.87 (s ,-OH, 1H); 3.99-4.09 (m, H-5 ', 1H); 3.56 (t, J=11.3Hz, H-6 ' a, 1H); 3.27-3.45 (coinciding with the peak of H2O, h-6 ' b, H-2 ' a, 2H); 2.74-2.82 (d, J=12.3Hz, H-2 ' b, 1H); 2.51-2.67 (m, H-4 ' a, h-4 ' b, 2H) .13CNMR (DMSO-d6,100MHZ) δ 18.354 and 19.382 (CH2SeCH2), 65.197 (C-6 '), 83.213 (C-5 '), 83.425 (C-2 '), 119.222 (C-5), 139.182 (C-8), 149.278 (C-4), 153.386 (C-2), 156.733 (C-6) .HRMS-ESI (m/z): (M+Na
+) calcd forC10H13N5O2Se, 338.0132; Found, 338.0137.
Embodiment 3
4-amino-1-1-(6-(methylol)-1,4-oxygen, the selenium cyclohexyl-2-) preparation of pyrimidine-2 (1 hydrogen)-ketone.
With ((2R, 3R, 4S, 5R)-5-(4-benzoylamino-2-oxygen pyrimidine-1 (2 hydrogen)-)-3, the methyl benzoic acid ester (4 of 4-dihydroxyl-tetrahydrofuran base-2-), 5 '-dibenzoyl-cytidine(C) is starting raw material, with selenium hydracid sodium water solution is selenizing reagent, with the dioxane is solvent, and adjusting temperature of reaction is 80 ℃, with reference to embodiment 1 condition preparation (6-(4-benzamide-2-oxygen pyrimidine-1 (2 hydrogen)-)-1,4-oxygen, the methyl benzoic acid ester of selenium cyclohexyl-2-), yield 72.3%, white solid.
The gained solid (3.0g 5mmol) is dissolved in ammonia methyl alcohol saturated solution (50ml), stirring at room 24 hours, and the TLC demonstration reacts completely.Remove solvent under reduced pressure, column chromatography purification is collected the product component and is steamed and desolventize, white solid 4-amino-1-(6-(methylol)-1,4-oxygen, pyrimidine-2 (1 the hydrogen)-ketone of selenium cyclohexyl-2-) (1.12g, 3.87mmol), yield 77.4%.
Characterization parameter is: m.p.320-322 ℃; 1HNMR (CD30H, 300MHZ), δ 7.72 (d, J=7.2Hz, H-6,1H); 5.94 (dd, J=1.5Hz and 10.5Hz, H-1 ', 1H); 5.90 (d, J=7.8Hz, H-5,1H); 4.05-4.16 (m, H-5 ', 1H); 3.58 (t, J=5.4Hz, H-5 ' a, H-5 ' b, 2H); 2.86 (t, J=11.4Hz, H-2 ' a, 1H); 2.72 (t, J=11.7Hz, H-2 ' b, 1H); 2.58 (d, J=11.4Hz, H-4 ' a, 1H); (d, J=12.6Hz, H-4 ' b, 1H);
13C NMR (CD
3OH, 100MHz) δ 16.947 and 19.298 (CH
2SeCH
2), 65.258 (C-6 '), 83.595 (C-5 '), 84.595 (C-2 '), 94.935 (C-5), 141.091 (C-6), 156.155 (C-2), 166.346 (C-4); HRMS-ESI (m/z): (M+Na
+) calcd for C9H13N3O3Se, 314.0020; Found, 314.0016.
Embodiment 4
2-amino-9-(6-(methylol)-1,4-oxygen, the preparation of selenium cyclohexyl-2-)-1 hydrogen-purine-6 (9 hydrogen)-ketone.
With ((2R, 3R, 4S, 5R)-5-(4-benzoylamino-2-oxygen pyrimidine-1 (2 hydrogen)-)-3, the methyl benzoic acid ester (4 of 4-dihydroxyl-tetrahydrofuran base-2-), 5 '-dibenzoyl-cytidine(C) is starting raw material, with selenium hydracid sodium water solution is selenizing reagent, with the dioxane is solvent, prepares N-(9-(6-((tertiary butyl diphenyl-methyl siloxy) methyl)-1,4-oxygen with reference to embodiment 3 conditions, the selenium cyclohexyl-2-)-6-oxygen-6, the isobutylamine of 9-dihydro-1 hydrogen-purine-2-), yield 70.5%, white solid.
The gained solid (3.19g 5.0mmol) is dissolved in tetrahydrofuran (THF) (50ml), add the tetrabutyl fluoridize by (3.16g, 10mmol) stirring at room is 1 hour, TLC shows and reacts completely.Remove solvent under reduced pressure, add methylene dichloride dissolving back water and the washing of 5% sodium hydrogen carbonate solution, steam behind the anhydrous sodium sulfate drying desolventize white solid 2-amino-9-(6-(methylol)-1,4-oxygen, preparation (the 1.43g of selenium cyclohexyl-2-)-1 hydrogen-purine-6 (9 hydrogen)-ketone, 4.3mmol), yield 86.4%.
Characterization parameter is: m.p.130-133 ℃; 1HNMR (DMSO-d6,300MHZ), δ 11.01 (s, H-1,1H); 7.87 (s, H-8,1H); 6.74 (s ,-NH2,2H); 5.72 (dd, J=1.2 and 10.5 Hz, H-1 ', 1H); 4.91 (s ,-OH, 1H); 3.89-4.00 (m, H-5 ', 1H); 3.28-3.46 (with
H 2The O peak partially overlaps, H-6 ' a, and h-6 ' b, H-2 ' a, h-2 ' b, H-, 4H); 2.51-2.72 (partially overlap with the DMSO-d6 peak, H-4 ' a, h-4 ' b, 2H); (DMSO-d6,100MHZ) δ 18.331 and19.618 (CH2SeCH2), 65.185 (C-6 '), 82.733 (C-5 '), 83.517 (C-2 '), 116.919 (C-5), 135.300 (C-8), 150.869 (C-4), 154.766 (C-2), 157.743 (C-6); HRMS-ESI (m/z): (M+Na
+) calcd for C10H13N5O3Se, 354.0081; Found, 354.0087.
Claims (9)
1. a nucleoside derivative containing selenium is characterized in that, its structural formula is:
Wherein B be VITAMIN B4, guanine, cytosine(Cyt), uridylic and thymus pyrimidine any.
2. nucleoside derivative containing selenium according to claim 1 is characterized in that, described derivative, its glycosidic link are α-D configuration, or β-D configuration, or α-L configuration, or β-L configuration.
3. the preparation method of a nucleoside derivative containing selenium as claimed in claim 1 is characterized in that, specifically comprises the steps:
1. the oxidation open loop and the reduction of glycosyl part: the nucleoside analog sodium periodate oxidation open loop of the ribosyl that ribonucleoside that ribonucleoside, base modification are crossed or base are transformed obtains corresponding 2 ', 3 '-open loop nucleosides with sodium borohydride reduction then;
2. the activation of 2 ', 3 ' hydroxyl after the open loop: 2 ', 3 '-open loop nucleosides and methylsulfonyl chloride, Tosyl chloride or sulfur oxychloride and imidazoles reaction, 2 ', 3 ' sulphonate that forms methanesulfonates or replacement;
3. the nucleosides that is activated in 2. of selenizing reagent attack step is 2 ', 3 ', forms methylol-1,4-oxygen, the nucleoside analog of selenium hexanaphthene ribosyl;
4. step 3. the hydroxyl on the sugar ring of gained nucleoside analog and the amino on the base respectively deprotection obtain methylol-1,4-oxygen, the nucleoside compound of selenium cyclohexyl glycosyl.
4. the preparation method of nucleoside derivative containing selenium according to claim 3 is characterized in that, step 3. in, described selenizing reagent is selenium hydracid sodium, selenium hydracid potassium, sodium selenide or potassium selenide.
5. according to the preparation method of claim 3 or 4 described nucleoside derivative containing seleniums, it is characterized in that, step 3. in, the mol ratio of described selenizing reagent and activatory 2 ', 3 '-open loop nucleosides is 1～5: 1.
6. the preparation method of nucleoside derivative containing selenium according to claim 3 is characterized in that, step 3. in, step 3. in, selenylation reaction carries out in polar aprotic solvent.
7. the preparation method of nucleoside derivative containing selenium according to claim 6 is characterized in that, step 3. in, step 3. in, described polar aprotic solvent is 1, the 4-dioxane.
8. according to the preparation method of claim 3 or 6 described nucleoside derivative containing seleniums, it is characterized in that, step 3. in, step 3. in, the selenylation reaction temperature is 80～100 ℃.
9. according to the preparation method of claim 3 or 6 described nucleoside derivative containing seleniums, it is characterized in that, step 3. in, step 3. in, the selenylation reaction time is 5～10 hours.
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| CN106336443A (en) * | 2015-07-06 | 2017-01-18 | 扬州硒瑞恩生物医药科技有限公司 | Synthesis method of nucleoside compound |
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| CN106336443A (en) * | 2015-07-06 | 2017-01-18 | 扬州硒瑞恩生物医药科技有限公司 | Synthesis method of nucleoside compound |
| CN106336443B (en) * | 2015-07-06 | 2018-08-31 | 扬州硒瑞恩生物医药科技有限公司 | The synthetic method of a kind of nucleoside compound |
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