CN109897081A - A kind of 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods - Google Patents
A kind of 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 40
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 35
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 238000000926 separation method Methods 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 11
- 230000004044 response Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- 230000006837 decompression Effects 0.000 claims description 7
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 4
- 229940045145 uridine Drugs 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 12
- 238000005893 bromination reaction Methods 0.000 abstract description 7
- 230000031709 bromination Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000007867 post-reaction treatment Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 15
- VZGDMQKNWNREIO-UHFFFAOYSA-N carbon tetrachloride Substances ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- -1 oxygen radical Chemical class 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000002777 nucleoside Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- GGZRVXCSRWTOME-UHFFFAOYSA-N pyridine;toluene Chemical compound C1=CC=NC=C1.CC1=CC=CC=C1 GGZRVXCSRWTOME-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 230000003450 growing effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Inorganic materials Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
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- 230000035800 maturation Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000005450 thionucleoside Substances 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
Abstract
The invention belongs to the field of chemical synthesis, disclose a kind of 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods.The reaction system that the present invention provides a kind of novel environmental close friend prepares 5-Br-2 ', 3 ', 5 '-O- triacetyl uridines with NBS bromination reaction.A kind of 5-Br-2 ' provided by the invention, 3 ', 5 '-O- triacetyl uridine synthetic methods, not only improved Examination on experimental operation, but also substantially increase bromination efficiency.Preparation method technique provided by the invention is simpler, and post-reaction treatment is simple and convenient.
Description
Technical field
The invention belongs to the field of chemical synthesis, and the present invention relates to a kind of substitution conventional constant voltage titrations to prepare 5-Br-2 ',
The method of 3 ', 5 '-O- triacetyl uridines.
Background technique
In research life development process, nucleic acid: DNA and RNA play a decisive role in large biological molecule.And cancer is sent out
The main reason for raw is DNA damage[1].It is well known that the method for the treatment of cancer has: radiotherapy (radiation therapy x-ray and gamma-rays,
It is used for a long time carcinogenic)；Chemotherapy (drug therapy, but toxicity is big)；Operative treatment (risk is high)；Ultraviolet light and nucleosides treat (UV
Sulfur-bearing nucleoside analog is activated to generate oxygen radical).Photochemotherapy, wherein ultraviolet radioactive (UVR:280-400nm) or visible
Light photosensitive drug is combined to generate therapeutic effect[2], it is the non-malignant increasing of maturation that drug or radiation, which cannot all be implemented separately,
Growing property treats skin and various cancers.
A large number of studies show that, shown through glycosyl and base modification nucleoside compound antitumor well according to nowadays
Activity, 5- substituted nucleosides analog is as antiviral[3], anti-tumor drug be widely used in clinic[4], such as 5- iodine deoxidation
Uridine (IdU), 5-bromouracil deoxyribose (BrdU), floxuridine (FdU), can be used as the increasing of antiviral and antitumor drug
Quick dose[5,6].Such as 5- ioduria glycosides has been used as anti-tumor drug to be applied to clinic, 4- sulphur thymidine is in cooperation black light for another example
(UVA) the kill tumour cell of energy specificity under conditions of irradiating[7-11], to epidermis and apart from the closer neoplastic lesion of epidermis
Play good lethal effect[12-13], nucleoside base 4 thio-modifications propose the treatment of cancer under black light cooperation
New way is supplied.
Method for synthesizing thionucleoside reagent has very much, but existing method is not environmentally protective.
[1]T.Lindahl.Instability and decay of the primary structure of DNA
[J].Nature,1993,362:709-715.
[2] REELFS O, XU Y Z, MASSEY A, et al.s [J] .Mol Cancer Ther, 2007,6 (9):
2487-2495
[3] it pays close attention to, Zhang Yongmin, application [J] the chemical progress of metathesis reaction in nucleoside analog synthesis, 2010,22
(8):1583-1590.
[4]P.Wigerinck,C.Pannecouque,R.Snoeck,et al.5-(5-Bromothien-2-yl)-2'-
deoxyuridine and5-(5-chlorothien-2-yl)-2'-deoxyuridine are equipotent to(E)-
5-(2-bromovinyl)-2'-deoxyuridine in the inhibition of herpes simplex virus
type I replication[J].Med.Chem,1991,34:2883-2389.
[5]R.L.Erikson,W.Szybalski.5-Iodo-2’-Deoxyuridine[J].Radiat.Res,1963,
20:252-622.
[6]N.A.Franken,C.Van Bree,M.A.Veltmaat,H.M.Rodermond,J.Haveman,
G.W.J.Barendsen.
[7]Massey A.；Xu Y.-Z.and Karran,P.Photoactivation of DNA thiobases as
A potential novel therapeutic option, Current Biology, 2001,11,1142-1146.
[8]Massey A,Xu YZ,Karran P.Ambiguous coding is required for the
lethal interaction between methylated DNA bases and DNA mismatch repair[J]
.DNA Repair(Amst),2002,1(4):275-286.
[9]Reelfs O,Xu YZ,Massey A,et al.Thiothymidine plus low-dose UVA
kills hyperproliferative human skin cells independently of their human
papilloma virus status[J].Mol Cancer Ther,2007,6(9):2487-2495.
[10]Harada Y,Suzuki T,Ichimura T,et al.Triplet formation of 4-
thiothymidine and its photosensitization to oxygen studied by time-resolved
thermal lensing technique[J].J Phys Chem B,2007,111(19):5518-5524.
[11] Pridgeon S W, Heer R, Taylor G A, et al.Thiothymidine combined with
UVA as a potential novel therapy for bladder cancer [J] .Br.J.Cancer, 2011,104
(12):1869-1876.
[12] Gemenetzidis E, Shavorskaya O, Xu Y Z, et al.Topical4-thiothymidine
is a viable photosensitiser for the photodynamic therapy of skin malignancies
[J/OL].J.Dermatol.Treatment.[2011-11-10].http://informahealthcare.com/toc/
jdt/0/0.
Summary of the invention
For overcome the deficiencies in the prior art, the object of the present invention is to provide a kind of reaction system of novel environmental close friend use
NBS bromination reaction prepares 5-Br-2 ', 3 ', 5 '-O- triacetyl uridines.A kind of 5-Br-2 ' provided by the invention, 3 ', 5 '-
O- triacetyl uridine synthetic method, not only improved Examination on experimental operation, but also substantially increased bromination efficiency.The present invention
The preparation method technique of offer is simpler, and post-reaction treatment is simple and convenient.
Above-mentioned purpose of the invention is achieved through the following technical solutions:
A kind of 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods, with 2 ', 3 ', 5 '-O- of compound shown in formula (I)
Triacetyl uridine is raw material, and with N-bromosuccinimide (NBS) for bromating agent, chemistry occurs using anhydrous pyridine as solvent
Reaction, is finally prepared formula (II) 5-Br-2 ', 3 ', 5 '-O- triacetyl uridines；
Further, 2 ', 3 ', 5 '-O- triacetyl uridines and NBS molar ratio are 1:1-3.
Further, the feed way of NBS is to be added dropwise.
Further, the feed way of NBS is the addition of direct filler one kettle way.
Synthetic method of the present invention, reaction temperature are 65-95 DEG C, preferably 85 DEG C；Reaction time is 2-3 hours, excellent
It selects 2 hours.
Compared with the prior art, the invention has the advantages that:
2 ', 3 ', 5 '-O- triacetyl uridines in the technical solution provided by the invention reaction system are i.e. as reaction
Object, anhydrous pyridine is as solvent.Existing nucleosides bromination process is mostly directly to react by halogenation with halogen, passes through Br2/ water, Br2/
DMF, Br2/CCl4Reaction realize C-5 to the bromination of pyrimidinium moiety, most of in these existing methods have some lack
The low yield etc. of point, such as peracidity reaction condition, longer reaction time, complicated post processor and product.And this hair
It is bright to avoid using Br2/ water, Br2/ DMF, Br2/CCl4Effumability organic solvent and environmentally harmful traditional catalyst, with temperature
The reaction system of novel environmental close friend a kind of is provided for 5-Br-2 ', 3 ', 5 '-O- three with the NBS of green, environmental protection for bromating agent
The synthesis of acetyl group uridine.Avoid experimental implementation high risk, the disadvantages such as complexity post-processing and low yield.It is more other kinds of
Bromating agent has higher stability.Preparation method of the invention is safe, inexpensive, green.The reaction system is applied widely, grasps
It is higher, environmentally friendly to make simple, inexpensive safety, yield, is suitable for industrial production, pairing is studied at cyclohexyl benzene class compound
It is of great significance.
Unlike the prior art, the present invention works as base for Br is replaced on base C-5 for the position that Br of the invention replaces
When there is electron-withdrawing group or the group that can be conjugated with heterocycle on the position C-5, the longer nucleoside compound of wavelength is formed.And pass through light
The quick dose of ability for penetrating tissue is related with the wavelength, and wavelength is longer, and it is stronger to penetrate organizational capacity, easily enters tissue inner-layer thin
Born of the same parents.5-Br-2 ' through the invention, 3 ', 5 '-O- triacetyl uridine synthetic methods are made for further synthesis 4-S-5-Br- uridine
It is of great importance for potentiality anticancer drug to treatment of cancer.
The NBS that technical solution of the present invention is added, is not need to increase other initiators, settles at one go, directly in base c-5
Position adds Br, and post-processing is also relatively easy, and crossing column, only there are two points.It does not need handling initiator.
5-Br-2 ' of the invention, 3 ', 5 '-O- triacetyl uridine synthetic methods, both changed Examination on experimental operation
Into, and substantially increase bromination efficiency.Preparation method technique provided by the invention is simpler, and post-reaction treatment is simple and convenient,
By-product polarity relative product is very big, and post separation directly uses ethyl acetate petroleum ether system (EA:PE=1:1) to collect and produces
Object.Compared to bromine system is used, the use of strong corrosive drug is avoided, also avoids the strong acidic environment occurred in experiment,
More green, safety.
Specific embodiment
The present invention is described in detail below by specific embodiment, but is not limited the scope of the invention.Unless otherwise specified, originally
Experimental method used by inventing is conventional method, and experiment equipment used, material, reagent etc. commercially obtain.
The instrument selected in embodiment and comparative example is as shown in the table
Embodiment 1
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in the anhydrous pyridine of 40mL, is heated to
85 DEG C, stirring dissolves it sufficiently, then " direct filler one kettle way " is used to be added at one time NBS2.70mmol (0.48g), leads to
Cross TLC monitoring response situation；2h raw material point disappears, it was demonstrated that fully reacting；Solvent is steamed under the conditions of 65 DEG C of decompression: being taken out of with toluene
Pyridine；Crude product carries out post separation (PE:EA=1:1), with dehydrated alcohol and petroleum ether mixing recrystallization after separation, filters drying
Solid 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine 0.96g, yield 80% are obtained afterwards.
Embodiment 2
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in the anhydrous pyridine of 40mL, is heated to
85 DEG C, stirring dissolves it sufficiently, and NBS 2.7mmol (0.48g) is dissolved in 20ml anhydrous pyridine and is placed in constant pressure funnel
In, it is added dropwise in the anhydrous pyridine solution of 2 ', 3 ', 5 '-O- triacetyl uridines, is added dropwise in 30min, continue to fill it
Divide stirring, response situation is monitored by TLC；2.5h raw material point disappears, it was demonstrated that fully reacting；It is steamed under the conditions of 65 DEG C of decompression molten
Agent: pyridine is taken out of with toluene；Crude product carries out post separation (PE:EA=1:1), with dehydrated alcohol and petroleum ether mixing weight after separation
Crystallization obtains solid 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine 0.958g, yield 79% after filtering drying.
Embodiment 3
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in the anhydrous pyridine of 40mL, is heated to
85 DEG C, stirring dissolves it sufficiently, then " direct filler one kettle way " is used to be added at one time NBS 5.4mmol (0.96g), leads to
Cross TLC monitoring response situation；2h raw material point disappears, it was demonstrated that fully reacting；Solvent is steamed under the conditions of 65 DEG C of decompression: being taken out of with toluene
Pyridine；Crude product carries out post separation (PE:EA=1:1), with dehydrated alcohol and petroleum ether mixing recrystallization after separation, filters drying
Solid 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine 1.08g, yield 83% are obtained afterwards.
Embodiment 4
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in the anhydrous pyridine of 40mL, is heated to
85 DEG C, stirring dissolves it sufficiently, and NBS 5.4mmol (0.96g) is dissolved in 20ml anhydrous pyridine and is placed in constant pressure funnel
In, it is added dropwise in the anhydrous pyridine solution of 2 ', 3 ', 5 '-O- triacetyl uridines, is added dropwise in 30min, continue to fill it
Divide stirring, response situation is monitored by TLC；2.5h raw material point disappears, it was demonstrated that fully reacting；It is steamed under the conditions of 65 DEG C of decompression molten
Agent: pyridine is taken out of with toluene；Crude product carries out post separation (PE:EA=1:1), with dehydrated alcohol and petroleum ether mixing weight after separation
Crystallization obtains solid 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine 0.99g, yield 82% after filtering drying.
Embodiment 5
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in the anhydrous pyridine of 40mL, is heated to
85 DEG C, stirring dissolves it sufficiently, then " direct filler one kettle way " is used to be added at one time NBS 8.1mmol (1.44g), leads to
Cross TLC monitoring response situation；2h raw material point disappears, it was demonstrated that fully reacting；Solvent is steamed under the conditions of 65 DEG C of decompression: being taken out of with toluene
Pyridine；Crude product carries out post separation (PE:EA=1:1), with dehydrated alcohol and petroleum ether mixing recrystallization after separation, filters drying
Solid 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine 0.95g, yield 79% are obtained afterwards.
Embodiment 6
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in the anhydrous pyridine of 40mL, is heated to
85 DEG C, stirring dissolves it sufficiently, and NBS8.1mmol (1.44g) is dissolved in 20ml anhydrous pyridine and is placed in constant pressure funnel
In, it is added dropwise in the anhydrous pyridine solution of 2 ', 3 ', 5 '-O- triacetyl uridines, is added dropwise in 30min, continue to fill it
Divide stirring, response situation is monitored by TLC；2.5h raw material point disappears, it was demonstrated that fully reacting；It is steamed under the conditions of 65 DEG C of decompression molten
Agent: pyridine is taken out of with toluene；Crude product carries out post separation (PE:EA=1:1), with dehydrated alcohol and petroleum ether mixing weight after separation
Crystallization obtains solid 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine 0.945g, yield 78% after filtering drying.
The reaction condition of embodiment 1-6 is as shown in the table:
Comparative example 1
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in 60mL methylene chloride, stirring at normal temperature
It dissolves it sufficiently, bromine 2.7mmol (0.43g) is taken to be dissolved in 30mL carbon tetrachloride, the carbon tetrachloride solution of bromine is placed in perseverance
It presses in dropping funel, is added dropwise in the dichloromethane solution of 2 ', 3 ', 5 '-O- triacetyl uridines, is added dropwise in 30min,
Continue that it is sufficiently stirred, response situation is detected by thin-layered chromatography, 1.5h raw material point disappears, and is extracted and is reacted with deionized water
Liquid takes subnatant, 3-5 times, is extracted to colourless then dry with sodium sulphate, suction filtration, solvent evaporated.It is bromo- to obtain white solid 5-
2 ', 3 ', 5 '-O- triacetyl uridine 0.96g, yield 82%.
Comparative example 2
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in 60mL methylene chloride, stirring at normal temperature
It dissolves it sufficiently, bromine 5.4mmol (0.86g) is taken to be dissolved in 30mL carbon tetrachloride, the carbon tetrachloride solution of bromine is placed in perseverance
It presses in dropping funel, is added dropwise in the dichloromethane solution of 2 ', 3 ', 5 '-O- triacetyl uridines, is added dropwise in 30min,
Continue that it is sufficiently stirred, response situation is detected by thin-layered chromatography (TLC), 2h raw material point disappears, extracted with deionized water
Reaction liquid takes subnatant, 3-5 times, is extracted to colourless then dry with sodium sulphate, suction filtration, solvent evaporated.Obtain white solid 5-
Bromo- 2 ', 3 ', 5 '-O- triacetyl uridine 1.08g, yield 83%.
Comparative example 3
By 2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol (1.00g), it is dissolved in 60mL methylene chloride, stirring at normal temperature
It dissolves it sufficiently, bromine 8.1mmol (1.29g) is taken to be dissolved in 30mL carbon tetrachloride, the carbon tetrachloride solution of bromine is placed in perseverance
It presses in dropping funel, is added dropwise in the dichloromethane solution of 2 ', 3 ', 5 '-O- triacetyl uridines, is added dropwise in 30min,
Continue that it is sufficiently stirred, response situation is detected by thin-layered chromatography (TLC), 2h raw material point disappears, extracted with deionized water
Reaction liquid takes subnatant, 3-5 times, is extracted to colourless then dry with sodium sulphate, suction filtration, solvent evaporated.Obtain white solid 5-
Bromo- 2 ', 3 ', 5 '-O- triacetyl uridine 0.95g, yield 79%.
The reaction condition of comparative example 1-3 is as shown in the table:
The constant pressure titration of bromine water adds NBS before not only being used due to the present invention, but also has used " direct filler one kettle way "
Disposable filler NBS has found that two kinds of filling methods have no too big influence to experiment yield, uses NBS as solid powdery bromine
Agent was disposably both easy to operate by bromating agent addition raw material, and the experimental implementation in turn avoiding constant pressure titration is dangerous, and bromine
Change efficiency to be not much different.
Embodiment described above is merely a preferred embodiment of the present invention, and simultaneously the whole of the feasible implementation of non-present invention implement
Example.For persons skilled in the art, the appointing to made by it under the premise of without departing substantially from the principle of the invention and spirit
What obvious change, should all be contemplated as falling within claims of the invention.
Claims (5)
1. a kind of 5-Br-2 ', 3 ', 5 '-O- triacetyl uridine synthetic methods, characterized in that with compound 2 ' shown in formula (I),
3 ', 5 '-O- triacetyl uridines are raw material, using N-bromosuccinimide as bromating agent, are occurred using anhydrous pyridine as solvent
Chemical reaction, is finally prepared 5-Br-2 ' shown in formula (II), 3 ', 5 '-O- triacetyl uridines；
Reaction equation is as shown above；
Described 2 ', 3 ', 5 '-O- triacetyl uridines and NBS molar ratio are 1:1-3.
2. a kind of 5-Br-2 ' as described in claim 1,3 ', 5 '-O- triacetyl uridine synthetic methods, characterized in that described
NBS feed way be added dropwise.
3. a kind of 5-Br-2 ' as described in claim 1,3 ', 5 '-O- triacetyl uridine synthetic methods, characterized in that described
NBS feed way be direct filler one kettle way addition.
4. a kind of 5-Br-2 ' as described in claim 1,3 ', 5 '-O- triacetyl uridine synthetic methods, characterized in that reaction
Temperature is 65-95 DEG C, and the reaction time is 2-3 hours.
5. a kind of 5-Br-2 ' as described in claim 1,3 ', 5 '-O- triacetyl uridine synthetic methods, characterized in that will
2 ', 3 ', 5 '-O- triacetyl uridine 2.70mmol, are dissolved in the anhydrous pyridine of 40mL, are heated to 85 DEG C, stirring makes it sufficiently
Dissolution, is then added at one time NBS2.70mmol using direct filler one kettle way, monitors response situation by TLC；2h raw material point
It disappears, fully reacting；Solvent is steamed under the conditions of 65 DEG C of decompression: taking pyridine out of with toluene；Crude product carries out post separation PE:EA=1:
1, dehydrated alcohol and petroleum ether mixing recrystallization are used after separation, obtain solid 5-Br-2 ', 3 ', 5 '-O- triacetyls after filtering drying
Uridine.
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| CN1653077A (en) * | 2002-05-06 | 2005-08-10 | 健亚生物科技公司 | Nucleoside derivatives for treating hepatitis C virus infection |
| WO2009120878A2 (en) * | 2008-03-26 | 2009-10-01 | Alnylam Pharmaceuticals, Inc. | Non-natural ribonucleotides, and methods of use thereof |
| US20170136131A1 (en) * | 2014-06-19 | 2017-05-18 | Modema Therapeutics, Inc. | Alternative nucleic acid molecules and uses thereof |
| CN106699826A (en) * | 2016-12-20 | 2017-05-24 | 江南大学 | Nucleoside derivative and preparation method thereof |
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| CN1653077A (en) * | 2002-05-06 | 2005-08-10 | 健亚生物科技公司 | Nucleoside derivatives for treating hepatitis C virus infection |
| WO2009120878A2 (en) * | 2008-03-26 | 2009-10-01 | Alnylam Pharmaceuticals, Inc. | Non-natural ribonucleotides, and methods of use thereof |
| US20170136131A1 (en) * | 2014-06-19 | 2017-05-18 | Modema Therapeutics, Inc. | Alternative nucleic acid molecules and uses thereof |
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