CN105646629A - L-nucleoside compounds and application thereof - Google Patents

L-nucleoside compounds and application thereof Download PDF

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CN105646629A
CN105646629A CN201410693152.4A CN201410693152A CN105646629A CN 105646629 A CN105646629 A CN 105646629A CN 201410693152 A CN201410693152 A CN 201410693152A CN 105646629 A CN105646629 A CN 105646629A
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compound
alkyl
spin
dried
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张健存
周溢谦
张菊福
顾自强
张袁超
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Guangzhou Hengnuokang Pharmaceutical Technology Co Ltd
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Guangzhou Hengnuokang Pharmaceutical Technology Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses L-nucleoside compounds having the structure characteristic represented by the formula (I) or pharmaceutically acceptable salts thereof, and belongs to the technical field of pharmaceutical chemistry. The compounds can inhibit the activity of RNA viral polymerase, so the compounds can be used as potential drugs for prevention and treatment of infection of RNA viruses such as HCV, influenza virus, HRV (rhinovirus), RSV, Ebola virus, dengue virus, intestinal virus and the like.

Description

L-nucleoside compound and application thereof
Technical field
The present invention relates to a kind of technical field of medical chemistry, particularly relate to a kind of L-nucleoside compound and application thereof.
Background technology
Viral epiphytotics outburst happens occasionally. As far back as 1997, H5N1 bird flu broke out in Hong Kong, caused 18 people to infect, and 6 people are dead. Subsequently, this virus is repeatedly wreaked havoc in Asia, especially attaches most importance to 2005. The influenza virus of other hypotypes causes no small impact equally in worldwide, including the H7N9 etc. of the H1N1 of 2009,2013. And recently, broken out Ebola's epidemic situation that mortality rate is very high in area, West Africa, break out Epidemic Situation of Dengue Fever in Guangzhou, infect tens of thousands of people. The pathogen causing these epidemic situations above-mentioned broadly falls into RNA viruses, it is seen that RNA viruses is serious all the more to the harm of human health.
Further, except causing acute infectious disease, RNA viruses can also cause chronic disease. Such as, HCV is the pathogen causing hepatitis C, and chronic hepatitis c can be further development of liver cirrhosis, hepatocarcinoma etc. Estimating according to WHO, the whole world there are about 1.5 hundred million people and suffers from chronic hepatitis c, and, have more than 350,000 people every year and die from the hepatic disease that hepatitis C is relevant.
The disease caused currently for RNA viruses generally lacks particularly effective therapeutic scheme. And vaccine is prevention at present and treatment viral disease most efficient method, but the high catastrophe characteristics of RNA viruses makes a lot of vaccine to be quickly invalidated. Equally, can be there is drug resistance by a lot of RNA viruses that also have that current therapeutic scheme causes puzzlement after a procedure in antiviral drugs.
For the treatment of HCV, up to now, due to the high mutability of virus, remain without the vaccine for HCV and list. Before 2010, the therapeutic scheme of HCV is mainly the associating ribavirin medication of PEG interferon-ALPHA, but the responsiveness of this scheme only has about 50%, and long-term prescription patient is difficult to tolerate. Until in recent years, along with the listing of the hepatitis C protease inhibitor such as Boceprevir, Telaprevir and AG14361 Suo Feibuwei (Sofosbuvir) is just eased. And for RNA viruses such as Ebola virus, at present still without marketed drug, cause that epidemic situation is difficult to control to.
Therefore, need the research dynamics strengthened RNA viruses replication inhibitors badly, to obtaining the medicine that can effectively suppress RNA viruses.
Summary of the invention
Based on this, it is an object of the invention to overcome the defect of prior art, it is provided that a kind of L-nucleoside compound, this compounds can optionally suppress the activity of viral rna polymerase, thus suppressing the duplication of RNA viruses.
For achieving the above object, the present invention takes techniques below scheme:
There is L-nucleoside compound or its pharmaceutically acceptable salt of structure shown in formula I feature:
Wherein:
R1It is selected from: CH3,CF3,CF2H,CFH2, H;
R2It is selected from: CH3,CF3,CF2H,CFH2, H;
R3It is selected from: H, replaces or do not replace phosplate, replace or do not replace biphosphonate, replace or do not replace triguaiacyl phosphate;
X is selected from: H, OH, OCOR4,OCOCH(NHR5)R6;
Y is selected from: H, N3;
Z is selected from: OH, F, Cl, OCOR4,OCOCH(NHR5)R6;
R4Being selected from: H, C1-C6 alkyl, C1-C6 replaces alkyl, aryl, substituted aryl;
R5It is selected from: H, C1-C6 alkyl, aralkyl;
R6Being selected from: H, C1-C6 alkyl, aralkyl, C1-C6 replaces alkyl, natural and alpha-non-natural amino acid side chain radical;
B is selected from group:
Wherein:
R7It is selected from: H, Cl, C1-C6 alkyl, COR18, COOR18;
R8It is selected from: H, Cl, C1-C6 alkyl, COR18;
R9It is selected from: H, C1-C6 alkyl, COR18,F,Cl,CN,CONHR18;
R10It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl, C1-C6 alkynyl, NHR18, OR18, CN, CONHR18, F, Cl;
R11It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl, C1-C6 alkynyl, NHR18, OR18, CN, CONHR18, F, Cl;
R12It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl, C1-C6 alkynyl, CN, CONHR18, F, Cl;
R13It is selected from: H, C1-C6 alkyl, COR18, COOR18;
R14It is selected from: H, C1-C6 alkyl;
R18It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl;
R is selected from: H, COR6, CO (NH2)R6, COOR18
W is selected from: O, NH, NOH, NOR6,NNHR6,NNHCOR6��
In general, L-nucleoside micromolecular compound has good antiviral activity. Further, research finds, L-nucleoside derivates often shows better selectivity. The little molecule of the L-nucleoside glycosyl that be in that it different from natural nucleus glycoside compound is to be made up of L-nucleoside, rather than natural D-nucleoside. Owing to the polymerase in human body tends to identification L-nucleoside derivates triphosphate substrate very well, but the polymerase of virus cannot identify L-nucleoside derivates triphosphate substrate preferably. Therefore, L-nucleoside derivates can suppress the activity of varial polymerases, but will not be integrated in the nucleic acid chains of duplication by the polymerase of human body, so that L-nucleoside derivates shows good drug selectivity.
But, the research of the L-nucleoside micromolecular compound in past is primarily directed to archaeal dna polymerase or reverse transcriptase, and the research for the L-nucleoside derivates of RNA viruses polymerase is relatively fewer. Due to archaeal dna polymerase it is generally required to three phospholipid substrate of 2-deoxynucleoside, and RNA polymerase is it is desirable that ribose three phospholipid substrate. Both ribosyl conformations have bigger gap, for instance, the former ribosyl often takes the built-in conformation of C2-, and the latter's built-in conformation that is often C3-. Therefore, the present invention is in conjunction with the construction features of RNA viruses polymerase, the little molecule L-nucleoside compound of the RNA virus resisting polymerase of design and synthesis type I architectural feature.
Wherein in some embodiments, R3It is selected from group:
Wherein:
R15It is selected from: C1-C6 alkyl, aralkyl;
R16Being selected from: H, C1-C2 alkyl, C1-C2 replaces alkyl;
R17Being selected from: H, C1-C6 alkyl, C1-C6 replaces alkyl, F, Cl, Br, ester group, amide groups, ether, hydroxyl;
R19Be selected from: amino acid whose side-chain radical, H, C1-C6 alkyl, containing O, S, amino, croak base, imidazoles, carboxyl, amide groups C1-C6 alkyl, aryl replace C1-C6 alkyl, containing the aryl of substituted-phenyl, containing the aryl of substituted indolyl;
Ar is selected from: phenyl, substituted-phenyl, aryl, substituted aryl, naphthyl, substituted naphthyl.
Wherein in some embodiments, R3It is selected from: H, or following group:
Wherein in some embodiments, R3It is selected from group:
Wherein:
Ar is selected from: phenyl, substituted-phenyl, naphthyl, substituted naphthyl, it is preferable that phenyl;
R19It is selected from: the side-chain radical of natural amino acid, it is preferable that methyl;
R15It is selected from: methyl, ethyl, isopropyl, benzyl, it is preferable that isopropyl.
Wherein in some embodiments, B is selected from group:
R1It is selected from: CH3,CF3, H;
R2It is selected from: CH3,CF3, H;
Wherein in some embodiments, R1It is selected from: H; X is selected from: H, OH.
Wherein in some embodiments, R2It is selected from: H, CH3; Z is selected from: OH, halogen.
Wherein in some embodiments, R1It is selected from: H; X is selected from: H, OH, R2It is selected from: H, CH3; Z is selected from: OH, F; Y is selected from: H, N3��
Wherein in some embodiments, it is selected from compound:
Invention additionally discloses a kind of above-mentioned L-nucleoside compound or its pharmaceutically acceptable salt and suppress the application in medicine in preparation RNA viruses.
Described RNA viruses includes HCV, influenza virus, HRV (rhinovirus), RSV, Ebola virus, dengue virus and enterovirus.
Described application includes individually or with other medicines coupling as in the medicine prevention for picornavirus infection and treatment.
Compared with prior art, the method have the advantages that
The L-nucleoside compound with structure shown in formula I feature of the present invention or its pharmaceutically acceptable salt, it it is the construction features in conjunction with RNA viruses polymerase, the compound of one class new construction of design and synthesis, this compounds can suppress the activity of RNA viruses polymerase, such that it is able to as preventing and treating such as HCV, influenza virus, HRV (rhinovirus), RSV, Ebola virus, the potential drug of the picornavirus infection such as dengue virus and enterovirus.
Detailed description of the invention
Except known in the literature or except the standard method of illustration, the reaction of display in following scheme can be adopted to prepare the compounds of this invention in laboratory procedure. Therefore, following illustrative approach is for descriptive purpose rather than is confined to listed compound or any specific substituent group. In scheme, the substituent group number of display not necessarily meets the number used by claim, and for clarity sake, shows that monosubstituted base is linked on the compound allowing multi-substituent above under the definition of formula I.
Term used herein, " aryl " refers to any from the functional group that simple aromatic rings derives or substituent group, and " phenyl " refers to unsubstituted aryl.
Embodiment 1
The preparation of L-3-deoxynucleoside compounds.
Prepare according to following reaction scheme:
(1) preparation of 1,2-O-isopropylidene-��-L-furyl xylose (compound 1)
Take a 500mL there-necked flask; add L-xylose (20g; 133mmol), acetone (300mL); it is cooled to 0 DEG C; the lower dropping 20mL concentrated sulphuric acid of stirring; 6h is stirred at 0 DEG C; reactant liquor is clarified; being cooled to-10 DEG C, the NaOH solution adding 1M (i.e. 1mol/L) adjusts pH to neutral, and acetone is evaporated off; add saturated aqueous common salt, EA (ethyl acetate) extracts; dry, it is spin-dried for obtain colourless oil liquid, for the mixture of single acetonylidene protection xylose (compound 1) with diacetone fork protection xylose. Being dissolved in 100mL methanol by this mixture, add 50mL water, 40g732 type cation exchange resin, be stirred at room temperature one day, filter, filtrate is spin-dried for obtain pale yellow oily liquid body product 24.77g, is compound 1, productivity 97.79%.
The sign data of compound 1:1HNMR (400MHz, Chloroform-d): �� 5.99 (d, J=3.7Hz, 1H), 4.53 (d, J=3.7Hz, 1H), 4.33 (t, J=2.5Hz, 1H), 4.19 4.11 (m, 2H), 4.09 4.02 (m, 1H), 3.96 (d, J=3.4Hz, 1H), 2.60 (s, 1H), 1.49 (s, 3H), 1.33 1.31 (m, 3H).
(2) preparation of 1,2-O-isopropylidene-5-O-benzoyl-��-L-furyl xylose (compound 2)
Compound 1 (10g, 52.63mmol) is dissolved in the DCM (dichloromethane) (100mL) heavily steamed, under nitrogen protection, adds dry triethylamine (TEA; 8mL, 57.89mmol, 1.1 equivalent); it is cooled to-20 DEG C; it is slowly added dropwise DCM solution (6.1mL, 52.63mmol, 1.0 equivalent of Benzenecarbonyl chloride.; 10mLDCM); reacting at this temperature overnight, be warming up to room temperature, reactant liquor pours saturated NaHCO into3Solution stirs 10min, DCM extract, dry, it is spin-dried for, crosses post and obtain white solid product 12.946g, be compound 2, productivity 83.67%.
The sign data of compound 2:1HNMR (400MHz, Chloroform-d): �� 8.08 8.03 (m, 2H), 7.62 7.56 (m, 1H), 7.46 (dd, J=8.5,7.1Hz, 2H), 5.96 (d, J=3.6Hz, 1H), 4.80 (dd, J=12.9,9.3Hz, 1H), 4.60 (d, J=3.6Hz, 1H), 4.42 4.35 (m, 2H), 4.18 (d, J=2.2Hz, 1H), 3.28 (s, 1H), 1.51 (s, 3H), 1.32 (s, 3H).
(3) preparation of 1,2-O-isopropylidene-5-O-benzoyl-��-D-erythro-furan pentose-3-Tosylhydrazone (compound 3)
Take a 250mL two-mouth bottle, add Pyridinium dichromate (PDC, 11.54g, 30.68mmol, 1.1 equivalent), DCM (50mL), be slowly added dropwise acetic anhydride (8.6mL, 92.04mmol, 3.3 equivalent). The DCM solution (8.2g, 27.89mmol, 50mL) of compound 2 is added drop-wise in reactant liquor, 4h, TLC detection raw material reaction is stirred at room temperature complete. Reactant liquor EA dilutes, and produces a large amount of solid, filtered through silica gel, EA eluting, filtrate is dissolved in after being spin-dried in 100mL ethanol, adds unifor (5.45g, 29.28mmol, 1.05 equivalents), heating is to refluxing, stirring is overnight, precipitate out a large amount of white solid, filter, obtain product 6.861g, it is compound 3, productivity 53.48%.
The sign data of compound 3:1HNMR (400MHz, Chloroform-d): �� 9.05 (s, 1H), 8.00 7.93 (m, 2H), 7.83 (d, J=8.0Hz, 2H), 7.61 (t, J=7.5Hz, 1H), 7.46 (t, J=7.7Hz, 2H), 7.28 (s, 2H), 5.93 (d, J=4.3Hz, 1H), 5.04 (d, J=4.0Hz, 1H), 4.95 4.88 (m, 1H), 4.58 (dd, J=12.6,2.7Hz, 1H), 4.41 (dd, J=12.5,4.3Hz, 1H), 2.39 (s, 3H), 1.37 (s, 3H), 1.25 (s, 3H).
(4) preparation of 3-deoxidation-1,2-O-isopropylidene-5-O-benzoyl-��-D-erythro-furan pentose (compound 4)
Take a 250mL two-mouth bottle, add compound 3 (5g, 10.86mmol), MeCN (25mL) and acetic acid (25mL), be cooled to 0 DEG C, be dividedly in some parts NaBH3CN (2.73g, 43.43mmol, 4 equivalent), stirs at 0 DEG C overnight, and TLC shows that raw material reaction is complete, is spin-dried for by reactant liquor, adds the saturated NaHCO of 100mL3Solution, DCM extracts, dry, is spin-dried for obtain oily liquids. This oily liquids is dissolved in 100mL ethanol, adds NaOAc 3H2O (5.9g, 43.43mmol, 4 equivalent), reactant liquor, to backflow, overnight, is spin-dried for by heating, adds the saturated NaHCO of 100mL3Solution, DCM extracts, dry, is spin-dried for, and crosses post (PE:EA=6:1) and obtains colourless oil liquid product 2.100g, is compound 4, productivity 69.54%.
The sign data of compound 4: 1HNMR (400MHz, Chloroform-d): �� 8.08 8.02 (m, 2H), 7.59 7.54 (m, 1H), 7.44 (dd, J=8.4,7.1Hz, 2H), 5.88 (d, J=3.7Hz, 1H), 4.78 (t, J=4.3Hz, 1H), 4.55 (ddd, J=14.3,10.6,4.2Hz, 2H), 4.40 4.34 (m, 1H), 2.19 (dd, J=13.3,4.3Hz, 1H), 1.76 (ddd, J=13.2,10.7,4.8Hz, 1H), 1.54 (s, 3H), 1.34 (s, 3H).
(5) preparation of the double; two-O-acetyl group-5-O-benzoyl-D-erythro-furan pentose (compound 5) of compound 3-deoxidation-1,2-
Compound 4 (2.1g, 7.55mmol) is dissolved in AcOH/Ac2O/conc.H2SO4In (acetic acid/acetic anhydride/concentrated sulphuric acid is 60mL/10mL/4mL), stirred overnight at room temperature, reactant liquor is poured into the saturated NaHCO of 200mL3In solution, stirring 10min, EA extract, dry, are spin-dried for, and cross post (PE:EA=6:1) and obtain colourless oil liquid product 1.939g, and productivity 79.79%, this product includes two kinds of isomers.
The sign data of isomer 1: 1HNMR (400MHz, Chloroform-d): �� 8.09 8.05 (m, 2H), 7.60 7.55 (m, 1H), 7.44 (dd, J=8.3,7.1Hz, 2H), 6.20 (s, 1H), 5.27 5.20 (m, 1H), 4.76 4.68 (m, 1H), 4.54 (dd, J=11.9,3.7Hz, 1H), 4.34 (dd, J=11.9,5.4Hz, 1H), 2.28 2.19 (m, 2H), 2.10 (s, 3H), 1.97 (s, 3H).
The sign data of isomer 2:1HNMR (400MHz, Chloroform-d): �� 8.09 7.98 (m, 2H), 7.58 (t, J=7.4Hz, 1H), 7.45 (t, J=7.6Hz, 2H), 6.89 (d, J=3.7Hz, 1H), 5.38 5.30 (m, 1H), 5.22 (dt, J=8.3,4.3Hz, 1H), 4.50 (dd, J=12.0,3.5Hz, 1H), 4.35 (dd, J=12.1,5.8Hz, 1H), 2.20 2.10 (m, 2H), 2.09 (s, 3H), 2.08 (s, 3H).
(6) preparation of L-1-benzoyl-2-acetyl group-3-BrdU (compound 6)
The ammonium sulfate of uridnine and excessive hexamethyldisilane and catalytic amount adding heating in 1,2-dichloroethanes and, to dissolving, adds compound 5 and Trimethylsilyl trifluoromethanesulfonate (TMSOTf) after being cooled to room temperature, heating is to reacting complete. Add saturated NaHCO3Neutralize, and use CH2Cl2Extract, be spin-dried for, it is thus achieved that compound 6, yield 85%.
1HNMR ((400MHz, Chloroform-d) �� 8.55 (brs, 1H), 8.03-8.00 (m, 2H), 7.61-7.57 (m, 1H), 7.46 (t, J=8.1,3H), 5.80 (d, J=1.6,1H), 5.53 (dd, J=8.1,2.2,1H), 5.34 (m, 1H), 4.69 (dd, J=12.2,2.7,1H), 4.66-4.62 (m, 1H), 4.51 (dd, J=12.2,4.2,1H), 2.35-2.27 (m, 1H), 2.17 (ddd, J=14.0,5.6,1.7,1H), 2.11 (s, 3H)
In the present embodiment, in compound 6, B is uracil. It should be understood that when synthesizing this compounds, uridnine is replaced, namely chooses different B substituent groups.
(7) preparation of L-3-BrdU (compound 7)
Compound 6 is dissolved in oxolane (THF), adds 1MNaOH (i.e. the NaOH of the 1mol/L) solution of 5 equivalents, at room temperature stir to reacting complete, neutralize, filter and obtain compound 7, yield 90%.
1HNMR (400MHz, DMSO-d6): �� 11.27 (s, 1H, 3-NH), 7.95 (d, 1H, J=8.0Hz, 6-H), 5.62 (d, 1H, J=1.2Hz, 1 '-H), 5.53 (d, 1H, J=8.0Hz, 5-H), 5.52 (s, 1H, 2 '-OH), 5.07 (t, 1H, 5 '-OH), 4.26 (m, 1H, 4 '-H), 4.21 (m, 1H, 2 '-H), 3.71 (m, 1H, 5 '-H), 3.51 (m, 1H, 5 '-Hb), 1.94 (m, 1H, 3 '-H), 1.74 (m, 1H, 3 '-Hb).
(8) preparation of L-5-(O-phenylol-N-isopropyl alaninyl)-phosphate-3-BrdU (compound 8)
Compound 7 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester (No. CAS: 1334513-02-8) and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for the compound obtaining compound 8 class.
Embodiment 2
The preparation of L-2-methyl-2-fluorine nucleoside compound.
Prepare according to following reaction scheme:
(1) preparation of (2E)-3-[(4R)-2,2-dimethyl-1,3-dioxolanes-4-base]-2-methyl-2-ethyl acrylate (compound 10)
By Ph3PC(Me)CO2Et (152g; 419.85mmol; 2.2 equivalents) it is dissolved in the 500mL DCM heavily steamed, it is cooled to-40 DEG C, under nitrogen protection, is slowly added dropwise compound 9 ((S)-(-)-2; 2-dimethyl-1; 3-dioxolanes-4-formaldehyde) DCM solution (50g, 190.84mmol, 100mL); rise to room temperature, stir 17h. Reactant liquor is spin-dried for, adds EA and stir 1h, filter. Filtrate is spin-dried for again, adds t-butyl methyl ether, and stirring overnight, is filtered, is spin-dried for obtain oily liquids 81.86g, takes and crosses post (PE:EA=10:1) on a small quantity to determine structure and content, and calculating productivity is 90.07%.
The sign data of compound 10:1HNMR (400MHz, Chloroform-d): �� 6.69 (d, J=8.0Hz, 1H), 4.86 (q, J=7.2Hz, 1H), 4.19 (m, 3H), 3.63 (t, J=7.6Hz, 1H), 1.90 (s, 3H), 1.45 (s, 3H), 1.41 (s, 3H), 1.30 (t, J=7.2,3H).
(2) preparation of 2-C-methyl-4,5-O-isopropylidene-L-arabinose acetoacetic ester (compound 11)
Compound 10 (73.67g, 344.25mmol) is dissolved in acetone, is cooled to 0 DEG C, add KMnO4(65.27g, 413.10mmol, 1.2 equivalent), stirs 5h, adds saturated NH at 0 DEG C4Cl solution 150mL cancellation is reacted, and after stirring 0.5h, reactant liquor becomes clarification, filters, and acetone rotation in filtrate is evaporated off, and surplus solution EA extracts, dry, is spin-dried for, obtains product as white crystals 26.16g with EA/PE recrystallization, is compound 11, productivity 30.64%.
The sign data of compound 11:1HNMR(400MHz,Chloroform-d):��4.34�C4.24(m,2H),4.21(q, J=6.6Hz, 1H), 4.12 3.98 (m, 2H), 3.91 (t, J=6.4Hz, 1H), 3.59 (s, 1H), 2.43 (d, J=7.0Hz, 1H), 1.48 1.38 (m, 6H), 1.37 (s, 3H), 1.35 1.29 (m, 3H).
(3) (4S, 5R)-5-[(4R)-2,2-dimethyl-1,3-dioxolanes-4-base]-4-methyl isophthalic acid, the preparation of 3,2-diazole thiophene-4 carboxylic acid, ethyl ester-2,2-dioxide (compound 12)
Compound 11 (10g, 40.28mmol) is dissolved in the 100mL DCM heavily steamed, adds dry TEA (16.8mL, 120.84mmol, 3 equivalent), be cooled to 0 DEG C, be slowly added dropwise SOCl2(4.4mL, 60.42mmol, 1.5 equivalent), after stirring 0.5h, adds DCM dilution, reactant liquor cold water and saturated common salt washing at 0 DEG C, dry, is spin-dried for. Residue is dissolved in MeCN, it is cooled to 0 DEG C, adds TEMPO (50mg, cat.), it is slowly added dropwise 13%NaClO solution (100mL), dropwise and at latter 0 DEG C, continue stirring 20min, rise to and 1h is stirred at room temperature, separate organic facies, dry, it is spin-dried for post (PE:EA=10:1) and obtained colourless oil liquid 10.294g, be compound 12, productivity 82.35%.
The sign data of compound 12:1HNMR (400MHz, Chloroform-d): �� 5.07 (d, J=9.7Hz, 1H), 4.39 (ddd, J=9.2,6.1,3.2Hz, 1H), 4.33 (q, J=7.1Hz, 2H), 4.20 (dd, J=9.4,6.3Hz, 1H), 4.08 (dd, J=9.4,3.1Hz, 1H), 1.83 (s, 3H), 1.41 (s, 3H), 1.38 1.32 (m, 6H).
(4) preparation of (2R)-2-deoxidation-2 fluoro-2-methyl-4,5-O-isopropylidene-D-erythro-pentonic acid ethyl ester (compound 13)
Compound 12 (10g, 32.26mmol) is dissolved in the 100mL dioxane heavily steamed, adds the THF solution (1M of tetrabutyl ammonium fluoride (TBAF), 66mL, 66mmol, 2 equivalents), 100 DEG C of heating 1h, it is down to room temperature, it is sequentially added into 2,2-dimethoxypropane (100mL) and concentrated hydrochloric acid (6mL), under room temperature, stirs 3h, add EA dilution, the saturated NaHCO of reactant liquor3Solution and saturated common salt washing, dry, it is spin-dried for, crosses post (PE:EA=4:1) and obtain white solid product 6.749g, be compound 13, productivity 83.68%.
The sign data of compound 13:1HNMR (400MHz, Chloroform-d): �� 4.24 (dtd, J=24.5,12.5,10.6,6.8Hz, 2H), 4.10 (dq, J=16.6,6.3Hz, 2H), 4.01 (t, J=7.2Hz, 1H), 3.93 (dd, J=23.9,6.2Hz, 1H), 2.43 (s, 1H), 1.65 (dd, J=22.3,1.6Hz, 3H), 1.37 (s, 3H), 1.35 1.28 (m, 6H).
(5) preparation of the fluoro-2-methyl D-erythro-pentonic acid-gamma lactone (compound 14) of (2R)-2-deoxidation-2
Being dissolved in 50mL ethanol by compound 13 (6.749g, 27.00mmol), add 1mL concentrated hydrochloric acid, 15h is stirred at room temperature, is spin-dried for, MeOH/EA recrystallization obtains white solid product 4.207g, is compound 14, productivity 95.03%.
The sign data of compound 14:1HNMR(400MHz,Methanol-d4): �� 4.35 (ddt, J=8.1,4.0,1.8Hz, 1H), 4.12 4.01 (dd, J=22.0,8.0,1H), 3.98 (dt, J=13.0,1.9Hz, 1H), 3.78 3.72 (m, 1H), 1.57 (d, J=23.3Hz, 3H).
(6) preparation of the double; two-O-benzoyl-D-erythro-pentonic acid-gamma lactone (compound 15) of the fluoro-2-methyl-3,5-of (2R)-2-deoxidation-2
By compound 14 (4.207g; 25.65mmol) be dissolved in the 100mL THF heavily steamed; add DMAP (DMAP) and the TEA (7.3mL, 52.59mmol, 2.05 equivalent) of catalytic amount; it is cooled to 0 DEG C; Benzenecarbonyl chloride. (6.1mL, 52.59mmol, 2.05 equivalent) it is slowly added dropwise under nitrogen protection; 2h is stirred at room temperature, reactant liquor is poured into saturated NaHCO3Solution stirs 10min, EA extract, dry, it is spin-dried for, obtains white solid product 8.899g after crossing post (PE:EA=6:1), obtain compound 15, productivity 93.25%.
The sign data of compound 15:1HNMR (400MHz, Chloroform-d): �� 8.08 (d, J=7.9Hz, 2H), 7.99 (d, J=7.9Hz, 2H), 7.64 (t, J=7.4Hz, 1H), 7.57 (t, J=7.5Hz, 1H), 7.48 (t, J=7.6Hz, 2H), 7.41 (t, J=7.6Hz, 2H), 5.51 (dd, J=17.6,7.3Hz, 1H), 5.00 (dt, J=8.1,4.4Hz, 1H), 4.75 (dd, J=12.6,3.5Hz, 1H), 4.59 (dd, J=12.7,5.2Hz, 1H), 1.75 (d, J=23.3Hz, 3H).
(7) preparation of the double; two-O-benzoyl-D-erythro-furan pentose (compound 17) of (2R)-2-deoxidation-2 fluoro-2-methyl isophthalic acid-O-acetyl group-3,5-
Compound 15 (6.477g, 17.40mmol) is dissolved in the 50mL THF heavily steamed, is cooled to-20 DEG C, under nitrogen protection, be slowly added dropwise Li (Ot-Bu)3The THF solution (1M, 21mL, 21mmol, 1.2 equivalent) of AlH, stirs 6h at-20 DEG C. Addition 1M dilute hydrochloric acid (10mL) in reactant liquor, rises to room temperature, and stirring 0.5h, EA extract, dry, are spin-dried for, and cross post (PE:EA=4:1) and obtain colourless oil liquid 6.481g, are compound 16, productivity 99.52%.
By compound 16 (6.481g, 17.33mmol) be dissolved in the 100mL DCM heavily steamed, add dry TEA (2.5mL, 18.20mmol, 1.05 equivalent) and DMAP (cat.), it is cooled to 0 DEG C, it is slowly added dropwise chloroacetic chloride (1.3mL, 18.20mmol, 1.05 equivalent), stir 2h under room temperature, reactant liquor is poured into saturated NaHCO3Solution stirs 10min, DCM extract, dry, being spin-dried for, obtain colourless oil liquid product 7.065g after crossing post (PE:EA=6:1), room temperature is placed and is become white solid two days later, for the isomer mixture of compound 17, ratio is 1:3, productivity 98.02%.
The sign data of compound 17:1HNMR (400MHz, Chloroform-d): �� 8.11 8.05 (m, 2H), 8.04 7.98 (m, 2H), 7.64 7.52 (m, 2H), 7.41 (ddt, J=27.7,20.0,7.6Hz, 4H), 6.18 (d, J=2.1Hz, 1H), 5.26 (t, J=6.0Hz, 1H), 4.79 4.62 (m, 2H), 4.56 (dd, J=12.2,4.9Hz, 1H), 2.18 (s, 3H), 1.71 (d, J=22.4Hz, 3H).
(8) 3, the preparation of the 5-fluoro-L-cytosine of dibenzoyl-2-methyl-2-(compound 18)
The ammonium sulfate of uridnine and excessive hexamethyldisilane and catalytic amount adding heating in 1,2-dichloroethanes and, to dissolving, adds compound 17 and TMSOTf after being cooled to room temperature, heating is to reacting complete. Add saturated NaHCO3Neutralize, and use CH2Cl2Extract, be spin-dried for, it is thus achieved that compound 6, yield 85%.
In the present embodiment, in compound 18, B is uracil. It should be understood that when synthesizing this compounds, uridnine is replaced, namely chooses different B substituent groups.
(9) preparation of the fluoro-L-cytosine of 2-methyl-2-(compound 19)
Compound 18 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 19, yield 90%.
1HNMR(400MHz,DMSO-d6):��11.44(brs,1H,NH),7.95(d,1H,C-6H),5.97(d,1H,C-1��H),5.64(d,1H,C-5H),3.84-3.77(m,3H,C-5��-Ha,C-3��H,C-4��H),3.63-3.60(m,1H,C5��-Hb),1.23(d,3H,C-2��-CH3).
(10) preparation of L-5-(O-phenylol-N-isopropyl alaninyl)-phosphate-2-fluoro-cytosine of methyl-2-(compound 20)
Compound 19 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for the compound obtaining compound 20 class.
1HNMR (400MHz, DMSO-d6): �� 1.13-1.28 (m, 12H), 3.75-3.81 (m, 2H), 3.95-4.08 (m, 1H), 4.20-4.45 (m, 2H), 4.83-4.86 (m, 1H), 5.53-5.58 (m, 1H), 5.84-6.15 (m, 3H), 7.18-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54-7.57 (m, 1H), (11.50 s, 1H);13CNMR (125MHz, DMSO-d6) �� 173.70,173.66,173.59,173.54,163.70,151.60,151.40,140.25,130.63,125.55,121.04,120.99,120.95,103.28,103.21,102.20,100.37,89.42,80.33,72.33,68.98,68.95,65.60,65.14,50.88,50.72,27.79,22.37,22.32,20.77,20.71,20.64,20.57,17.60,17.36; ESI-MS:m/z530.2 [M+H]+.
Embodiment 3
The preparation of 3-beta-methyluracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 23
L-ribose (10g) is suspended in 100mL absolute methanol, adds 0.8mL chloroacetic chloride, be heated to reflux 2h, be spin-dried for, obtain compound 21 crude product.
Being dissolved in the 100mL pyridine dried by compound 21 crude product, add the DMAP of catalytic amount, be cooled to 0 DEG C, be slowly added dropwise Benzenecarbonyl chloride. (24mL, 206.7mmol, 3.1 equivalent), rise to room temperature after dripping, reaction is overnight. Reactant liquor is spin-dried for, adds DCM, saturated NaHCO3In solution, separatory after stirring 10min, aqueous phase DCM extracts, and merges organic facies, with 1N dilute hydrochloric acid, saturated NaHCO3Solution, saturated common salt are washed, dry, are spin-dried for obtain compound 22 crude product.
Compound 22 crude product is dissolved in AcOH/Ac2O/conc.H2SO4In (25mL/25mL/5 drips), 4h is stirred at room temperature, places reaction liquid into refrigerator overnight, generate crystallization. Reactant liquor is poured in frozen water, filter to obtain solid.Solid is dissolved in EA, uses saturated NaHCO3Solution, saturated common salt are washed, dry, are spin-dried for, and in methanol, recrystallization obtains white crystal 13.44g, is compound 23, three step gross production rates 40%.
The sign data of compound 23:1HNMR(400MHz,CDCl3): 8.09-7.32 (m, 15H), 6.43 (s, 1H), 5.91 (dd, 1H, J=4Hz), 5.79 (d, lH, J=8Hz), 4.81-4.76 (m, 2H), 4.54-4.49 (m, 1H), 2.00 (s, 3H).
(2) preparation of compound 24
Compound 23 (5g, 9.92mmol) is dissolved in 50mLDCM, is cooled to 0 DEG C, add AcCl (0.5mL), under stirring, pass into HCl gas 1.5h. Placing reaction liquid in refrigerator and take out after 12h, be spin-dried for, methylbenzene azeotropic is spin-dried for, and gained residue is redissolved in 10mL acetonitrile, is cooled to 0 DEG C, the lower dropping 13mL water of stirring. After 30min, precipitate out solid. Placing reaction liquid in refrigerator and take out after 2h, filter, solid ether is washed. Solid is redissolved in EA, uses saturated NaHCO3Solution is washed, dry, is spin-dried for obtain solid 2.92g, is compound 24, productivity 63.7%.
The sign data of compound 24:1HNMR(400MHz,CDCl3): 7.31��8.19 (m, 15H), 6.69 (d, lH, J=4.6Hz), 5.59 (dd, lH, J=6.7,1.8Hz), 4.64��4.80 (m, 4H), 2.30 (brs, 1H).
(3) preparation of compound 25
Being dissolved in 130mLDCM by compound 24 (13.3g, 28.7mmol), add Dess-Martin oxidant (20g, 47.1mmol, 1.64 equivalent) at 0 DEG C, rise to room temperature, stirring is overnight. Reactant liquor is evaporated, adds ether stirring 10min, filter, by filtrate and Na2S2O3��5H2O (16.3g, 65.68mmol, 2.3 equivalent) and saturated NaHCO3(130mL) solution mixing, stirring is to colourless, and separatory, organic facies saturated common salt is washed, dry, is spin-dried for obtain oily liquids. Take a 1L two-mouth bottle, add 350mL absolute ether, be cooled to-78 DEG C, be slowly added dropwise TiCl4The diethyl ether solution (37mL, 111mmol, 3.8 equivalent) of (12mL, 109mmol, 3.8 equivalent) and 3MMeMgBr, is warming up to-30 DEG C, drips the diethyl ether solution of above-mentioned oily liquids, stirs 3h, add 400mL water, rise to room temperature after dripping. Separatory, organic phase washed with water and saturated common salt washing, dry, it is spin-dried for obtain compound 25 crude product.
(4) preparation of compound 26
Above-claimed cpd 25 crude product is dissolved in 330mLDCM, adds the DMAP of TEA (4.8mL, 34.44mmol, 1.2 equivalent) and catalytic amount, it is cooled to 0 DEG C, drips Benzenecarbonyl chloride. (4mL, 34.44mmol, 1.2 equivalents), 3h is stirred at room temperature, reactant liquor is poured into saturated NaHCO3Solution stirs 10min, separatory, organic facies 1N dilute hydrochloric acid, saturated NaHCO3Solution, saturated common salt are washed, dry, are spin-dried for, and PE:EA recrystallization obtains product 8.41g, are compound 26 liang step gross production rate 51%.
The sign data of compound 26:1HNMR(400MHz,CDCl3):��1.88(3H,s,CH3), 4.7-4.5 (2H, ABX, H-5, H-5 ', J=12.1,4.1and4.7Hz), 4.74 (1H, m, H-4), 5.87 (1H, d, H-3, J=8.1Hz), 6.99 (1H, s, H-1), 7.1-8.3 (20H, m, C6H5CO).
(5) 3, the preparation of 5-dibenzoyl-2-methyl-L-cytosine (compound 27)
The ammonium sulfate of uridnine and excessive hexamethyldisilane and catalytic amount adding heating in 1,2-dichloroethanes and, to dissolving, adds compound 16 and TMSOTf after being cooled to room temperature, heating is to reacting complete. Add saturated NaHCO3Neutralize, and use CH2Cl2Extract, be spin-dried for, it is thus achieved that compound 27, yield 85%
In the present embodiment, in compound 6, B is uracil.It should be understood that when synthesizing this compounds, uridnine is replaced, namely chooses different B substituent groups.
(6) preparation of 2-methyl-L-cytosine (compound 28)
Compound 27 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 28, yield 90%.
(7) preparation of L-5-(O-phenylol-N-isopropyl alaninyl)-phosphate-2-methylcystein (compound 29)
Compound 28 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 29 compounds.
Embodiment 4
The preparation of 2-deoxidation-2-fluorine nucleoside compound.
Prepare according to following reaction scheme:
(1) preparation of compound 30
Being suspended in the 30mL pyridine dried by L-arabinose (1.83g, 12.24mmol), be cooled to 0 DEG C, dropping TBDPSCl (3.83mL, 14.9mmol, 1.2 equivalent), 4 DEG C of reactions are overnight. In reactant liquor, add ethanol cancellation, stir 15min, reactant liquor was spin-dried for post (PE:EA=1:1) and obtains yellow oily liquid (compound 30) 3.547g, productivity 75%.
The sign data of compound 30:1HNMR(400MHz,CDCl3) ��=7.83 7.56 (m, 4H, Ar), 7.56 7.27 (m, 6H, Ar), 5.41 (s, 1H, H1), 5.29 (d, 1H, J=3.8, H1), 4.39 3.57 (m, 5H), 1.21 0.97 (s, 9H, 3 �� CH3).
(2) preparation of compound 31
Being dissolved in 190mLDCM by compound 30 (3.216g, 8.278mmol), be cooled to 4 DEG C, add DMP (2.18mL, 17.79mmol, 2 equivalent) and p-methyl benzenesulfonic acid (143mg, 0.828mmol, 0.1 equivalent), stirring is overnight. After 14h, add TEA and be adjusted to neutrality, be spin-dried for post (PE:EA=4:1) and obtain yellow oily liquid (compound 31) 2.69g, productivity 76%.
The sign data of compound 31:1HNMR(400MHz,CDCl3) ��=7.78 7.59 (m, 4H, Ar), 7.50 7.31 (m, 6H, Ar), 5.89 (d1H, J=4.0, H1), 4.55 (d, 1H, J=4.0, H2), 4.43 (d, 1H, J=1.9, H3), 4.19 3.98 (m, 1H, H4), 3.98 3.72 (m, 2H, 2 �� H5), 1.34 (s, 3H, CH3), 1.29 (s, 3H, 3H, CH3), 1.10 (s, 9H, 3 �� CH3).
(3) preparation of compound 32
By compound 31 (1.29g, 3.01mmol) it is dissolved in 20mLTHF, add the THF solution (1M of TBAF, 9mL, 9mmol, 3 equivalent), 1h is stirred at room temperature, it is spin-dried for, crosses post (PE:EA=1:1) and obtain colourless oil liquid (compound 32) 458mg, productivity 80%.
(4) preparation of compound 33
Compound 32 (1.25g, 6.58mmol) is dissolved in 20mLTHF, adds cylite (3.1mL, 26.32mmol, 4 equivalent), be dividedly in some parts NaH (60%, 0.55g, 13.82mmol, 2.1 equivalents), 3h is stirred at room temperature. Being poured into by reactant liquor in saturated NaHO3 solution, stirring 10min, EA extract, dry, are spin-dried for obtain colourless oil liquid (compound 33 crude product) 2.31g, productivity 95%.
The sign data of compound 33:1HNMR(400MHz,CDCl3) ��=7.31 (m, 10H), 5.90 (d, J=4.4,1H), 4.64 (d, J=4.0,1H), 4.57 (m, 4H), 4.27 (m, 1H), 4.03 (d, J=3.1,1H), 3.63 (d, J=6.0,2H), 1.44 (s, 3H), 1.32 (s, 3H)
(5) preparation of compound 34
Compound 33 (2.31g, 6.24mmol) is dissolved in 20mL acetonitrile, adds p-methyl benzenesulfonic acid (215mg, 1.25mmol, 0.2 equivalent) and water (20mL), heat to 60 DEG C of stirring 3h, be down to room temperature, add TEA and be adjusted to neutrality, acetonitrile is evaporated off, and residue DCM extracts, dry, it is spin-dried for obtain colourless oil liquid (compound 34 crude product) 2.06g, productivity 100%.
(6) preparation of compound 35
Compound 34 (2.06g, 6.24mmol) is dissolved in 20mL methanol, adds 0.1mL chloroacetic chloride, it is heated to reflux 1h, is down to room temperature, be spin-dried for, cross post (PE:EA=4:1) and obtain colourless oil liquid (compound 35) 2.06g, productivity 96%.
The sign data of compound 35:1HNMR(400MHz,CDCl3) 7.30 (m, 10H), 4.90 (s, 0.6H), 4.86 (d, J=4.8,0.4H), 4.59 (m, 4H), 4.25 (m, 1H), 4.13 (m, 1H), 3.84 (m, 1H), 3.64 (m, 0.6H), 3.53 (d, J=5.6,0.8H), 3.41 (s, 3H; M, 0.6H), 3.32 (d, J=10.7,0.6H), 2.58 (d, J=9.6,0.4H)
(7) preparation of compound 37
By compound 35 (2.06g; 5.99mmol) it is dissolved in the DCM (20mL) heavily steamed; dry TEA (1mL, 7.19mmol, 1.2 equivalent) is added under nitrogen protection; it is cooled to 0 DEG C; it is slowly added dropwise trifluoromethanesulfanhydride anhydride (1.2mL, 7.19mmol, 1.2 equivalent); after stirring 1h, add saturated NaHCO3Solution stirring 10min, DCM extract, dry, are spin-dried for obtain compound 36 crude product.
Being dissolved in the THF heavily steamed by above-mentioned crude product, be cooled to 0 DEG C, add the THF solution 12mL of 1MTBAF under nitrogen protection, overnight, TLC shows that raw material reaction is complete, is spin-dried for, and adds EA, uses saturated NaHCO in stirring3Solution, saturated common salt are washed, dry, are spin-dried for post (PE:EA=4:1) and obtain colourless oil liquid (compound 37) 725mg, productivity 35%.
The sign data of compound 37:1HNMR(400MHz,CDCl3) ��=7.30 (m, 10H), 5.01 (d, J=10.5,1H), 4.81 4.61 (m, 5H), 4.30 (m, 1H), 4.07 (m, 1H), 3.64 (m, 1H), 3.54 (m, 1H), 3.32 (s, 3H)
(8) preparation of compound 38
Compound 37 (725mg, 2.10mmol) is dissolved in 10mL methanol, adds 10%Pd/C70mg, it is heated to reflux 1h under hydrogen, is cooled to room temperature, filter, filtrate is spin-dried for obtain light gray oily liquids (compound 38) 348mg, productivity 100%. (9) preparation of compound 39
Compound 38 (348mg, 2.10mmol) is dissolved in 10mLDCM, adds DMAP and TEA (0.32mL, the 2.31mmol of catalytic amount, 1.1 equivalents), it is cooled to 0 DEG C, drips Benzenecarbonyl chloride. (0.27mL, 2.31mmol, 1.1 equivalents), 3h is stirred at room temperature. Reactant liquor is poured into saturated NaHCO3Solution stirs 10min, DCM extract, dry, it is spin-dried for obtain colourless oil liquid (compound 39) 785mg, productivity 100%.
The sign data of compound 39:1HNMR (400MHz, Chloroform-d): �� 8.05 (dd, J=7.6,5.3Hz, 4H), 7.59 (t, J=7.4Hz, 1H), 7.54 (t, J=7.4Hz, 1H), 7.45 (t, J=7.6Hz, 2H), 7.39 (t, J=7.6Hz, 2H), 5.57 (ddd, J=23.6,7.9,3.8Hz, 1H), 5.26 5.07 (m, 2H), 4.73 4.63 (m, 2H), 4.52 4.43 (m, 1H), 3.37 (s, 3H).
(10) preparation of compound 40
Compound 39 (785mg, 2.10mmol) is dissolved in 10mLAcOH/Ac2O/conc.H2SO4In (ratio is that 5mL/5mL/1 drips), 2h is stirred at room temperature, reactant liquor is poured into saturated NaHCO3Solution stirs 10min, DCM extract, dry, it is spin-dried for, crosses post (PE:EA=6:1) and obtain colourless oil liquid (compound 40) 642mg, productivity 76%.
The sign data of compound 40:1HNMR (400MHz, Chloroform-d): �� 8.12 7.99 (m, 4H), 7.64 7.52 (m, 2H), 7.43 (dt, J=27.4,7.4Hz, 4H), 6.37 (d, J=10.2Hz, 1H), 5.58 (ddd, J=23.7,7.6,4.1Hz, 1H), 5.31-5.18 (dd, J=52.4,3.9Hz, 1H), 4.78 4.72 (m, 2H), 4.50 4.43 (m, 1H), 1.95 (s, 3H).
(11) preparation of compound 41
The ammonium sulfate of uridnine and excessive hexamethyldisilane and catalytic amount adding heating in 1,2-dichloroethanes and, to dissolving, adds compound 40 and TMSOTf after being cooled to room temperature, heating is to reacting complete.Add saturated NaHCO3Neutralize, and use CH2Cl2Extract, be spin-dried for, it is thus achieved that compound 41, yield 85%.
In the present embodiment, in compound 6, B is uracil. It should be understood that when synthesizing this compounds, uridnine is replaced, namely chooses different B substituent groups.
(12) preparation of compound 42
Compound 41 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 42, yield 90%.
(13) preparation of compound 43
Compound 42 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 43 compounds.
Embodiment 5
2 '-beta-methyl-3 ' preparation of-Brdurd compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 44
Compound 28 is dissolved in pyridine, adds DMTCl (1.1 equivalent), stirred overnight at room temperature, reactant liquor is evaporated, add EA, saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 44, productivity 88%.
(2) preparation of compound 45
Being dissolved in DCM by compound 44, add TBAB (0.1 equivalent), KBr (0.1 equivalent) and Tempo (0.05 equivalent), be cooled to 0 DEG C, (3.3 equivalents use saturated NaHCO to dropping NaClO solution3Solution adjusts pH to 9.5), stir 1h, separatory, organic facies has 5%Na2S2O3Solution and saturated common salt washing, dry, it is spin-dried for obtain compound 45 crude product.
(3) preparation of compound 46
Compound 45 crude product is dissolved in ethanol, adds unifor (1.2 equivalent), heated overnight at reflux. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution and saturated common salt washing, dry, it is spin-dried for obtain crude intermediate. This intermediate is dissolved in acetonitrile/acetic anhydride (1:1), is cooled to 0 DEG C, add NaBH3CN (4 equivalent), reacts at 0 DEG C overnight, and TLC shows that raw material reaction is complete, is spin-dried for by reactant liquor, adds saturated NaHCO3Solution, DCM extracts, dry, is spin-dried for obtain oily liquids. This oily liquids is dissolved in ethanol, adds NaOAc 3H2O (4 equivalent), reactant liquor, to backflow, overnight, is spin-dried for, adds saturated NaHCO by heating3Solution, DCM extracts, dry, is spin-dried for, and crosses post and obtains compound 46, productivity 69.54%.
(4) preparation of compound 47
Compound 46 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 47, yield 90%.
The sign data of compound 47:1HNMR (400MHz, DMSO-d6): �� 11.32 (s, 1H), 8.13 (d, J=8.1Hz, 1H), 5.77 (s, 1H), 5.59 (d, J=8.1,1H), 5.44 (s, 1H), 5.18 (t, J=4.7,1H); 4.3 (m, 1H); 3.9 3.5 (m, 2H); 1.9 1.7 (m, 2H); 1.09 (s, 3H).
(5) preparation of compound 48
Compound 47 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 48 compounds.
Embodiment 6
2 '-beta-methyl-2 ' preparation of-fluoro-3 '-Brdurd compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 49
Compound 19 is dissolved in pyridine, adds DMTCl (1.1 equivalent), stirred overnight at room temperature, reactant liquor is evaporated, add EA, saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 49, productivity 88%.
(2) preparation of compound 50
Being dissolved in DCM by compound 49, add TBAB (0.1 equivalent), KBr (0.1 equivalent) and Tempo (0.05 equivalent), be cooled to 0 DEG C, (3.3 equivalents use saturated NaHCO to dropping NaClO solution3Solution adjusts pH to 9.5), stir 1h, separatory, organic facies has 5%Na2S2O3Solution and saturated common salt washing, dry, it is spin-dried for obtain compound 50 crude product.
(3) preparation of compound 51
Compound 50 crude product is dissolved in ethanol, adds unifor (1.2 equivalent), heated overnight at reflux. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution and saturated common salt washing, dry, it is spin-dried for obtain crude intermediate. This intermediate is dissolved in acetonitrile/acetic anhydride (1:1), is cooled to 0 DEG C, add NaBH3CN (4 equivalent), reacts at 0 DEG C overnight, and TLC shows that raw material reaction is complete, is spin-dried for by reactant liquor, adds saturated NaHCO3Solution, DCM extracts, dry, is spin-dried for obtain oily liquids. This oily liquids is dissolved in ethanol, adds NaOAc 3H2O (4 equivalent), reactant liquor, to backflow, overnight, is spin-dried for, adds saturated NaHCO by heating3Solution, DCM extracts, dry, is spin-dried for, and crosses post and obtains compound 51, productivity 69.54%.
(4) preparation of compound 52
Compound 51 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 52, yield 90%.
The sign data of compound 52:1HNMR (400MHz, DMSO-d6): �� 11.43 (s, 1H), 8.03 (d, 1H), 6.00 (d, 1H), 5.65 (dd, 1H), 5.26 (brs, 1H), 4.27 (m, 1H), 3.81 (dd, 1H), 3.60 (dd, 1H), 2.3 2.0 (m, 2H), 1.33 (d, 3H); ESI-MS:m/z244.8 [M+H]+.
(5) preparation of compound 53
Compound 52 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 53 compounds.
Embodiment 7
2 '-deoxidation-2 ' preparation of-fluoro-3 '-Brdurd compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 54
Compound 42 is dissolved in pyridine, adds DMTCl (1.1 equivalent), stirred overnight at room temperature, reactant liquor is evaporated, add EA, saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 54, productivity 88%.
(2) preparation of compound 55
Being dissolved in DCM by compound 54, add TBAB (0.1 equivalent), KBr (0.1 equivalent) and Tempo (0.05 equivalent), be cooled to 0 DEG C, (3.3 equivalents use saturated NaHCO to dropping NaClO solution3Solution adjusts pH to 9.5), stir 1h, separatory, organic facies has 5%Na2S2O3Solution and saturated common salt washing, dry, it is spin-dried for obtain compound 55 crude product.
(3) preparation of compound 56
Compound 55 crude product is dissolved in ethanol, adds unifor (1.2 equivalent), heated overnight at reflux. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution and saturated common salt washing, dry, it is spin-dried for obtain crude intermediate. This intermediate is dissolved in acetonitrile/acetic anhydride (1:1), is cooled to 0 DEG C, add NaBH3CN (4 equivalent), reacts at 0 DEG C overnight, and TLC shows that raw material reaction is complete, is spin-dried for by reactant liquor, adds saturated NaHCO3Solution, DCM extracts, dry, is spin-dried for obtain oily liquids. This oily liquids is dissolved in ethanol, adds NaOAc 3H2O (4 equivalent), reactant liquor, to backflow, overnight, is spin-dried for, adds saturated NaHCO by heating3Solution, DCM extracts, dry, is spin-dried for, and crosses post and obtains compound 56, productivity 69.54%.
(4) preparation of compound 57
Compound 56 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 57, yield 90%.
The sign data of compound 57: ESI-MS:m/z230.1 [M+H]+��
(5) preparation of compound 58
Compound 57 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 58 compounds.
Embodiment 8
2 '-beta-methyl-4 ' preparation of-nitrine uracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 59
Compound 28 is dissolved in dry DMF, adds imidazoles (1.2 equivalent) and Ph3P (1.2 equivalent), is cooled to 0 DEG C, the DMF solution (1.1 equivalent) of dropping iodine, dropwises stirring 10min at latter 0 DEG C, rises to room temperature, stirs 18h. Reactant liquor DCM is diluted, 0.5MNa2S2O3Solution and saturated NaHCO3Solution is washed, dry, is spin-dried for, and crosses post and obtains compound 59, productivity 72%.
(2) preparation of compound 60
Being dissolved in the methanol solution of 0.16MNaOMe by compound 59, heating, to 60 DEG C, stirs 20h. Being cooled to 0 DEG C, add the cation exchange resin tune pH extremely neutrality that pyridine processes, rise to and 5min is stirred at room temperature, filter, filtrate was spin-dried for post and obtained compound 60, productivity 98%.
(3) preparation of compound 61
By NaN3(3 equivalent) adds in THF, is cooled to 0 DEG C, dropping ICl (2 equivalent), after 10min, and the THF solution of dropping compound 60, rise to stirred overnight at room temperature after dropwising. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 61, productivity 64.6%.
(4) preparation of compound 62
Compound 61 is dissolved in pyridine, adds the DMAP of catalytic amount, be cooled to 0 DEG C, drip BzCl, 1h is stirred at room temperature. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 62, productivity 93%.
The sign data of compound 62 are:1HNMR(400MHz,CD3OD): �� 7.93 8.16 (m, 4H), 7.65 (d, J=8.0Hz, 1H), 7.41 7.62 (m, 6H), 5.98 (s, 1H), 5.74 (d, J=8.0Hz, 1H), 3.79 (d, J=11.2Hz, 1H), 3.70 (d, J=11.2Hz, 1H), 3.32 (s, 1H), 1.30 (s, 3H).
(5) preparation of compound 63
Being dissolved in DCM by compound 62, add (NH4) HSO4 (2 equivalent) and m-CBA (1.1 equivalent), be cooled to 0 DEG C, add m-CPBA (3 equivalent), rise to room temperature, stirring is overnight. Add Na2SO3 solution, extract with EA after stirring 10min, dry, it is spin-dried for post and obtains compound 63, productivity 57.5%.
(6) preparation of compound 64
Compound 63 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 64, yield 90%.
The sign data of compound 64 are:1HNMR(400MHz,CD3OD): �� 8.04 (d, J=8.0Hz, 1H), 6.22 (s, 1H), 5.70 (d, J=8.0Hz, 1H), 4.03 (s, 1H), 3.78 (d, J=12.0Hz, 1H), 3.67 (d, J=12.0Hz, 1H), 1.19 (s, 3H); ESI-MS:m/z298 [M-H]-.
(7) preparation of compound 65
Compound 64 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 65 compounds.
Embodiment 9
2 '-beta-methyl-2 ' preparation of-fluoro-4 '-nitrine uracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 66
Compound 19 is dissolved in dry DMF, adds imidazoles (1.2 equivalent) and Ph3P (1.2 equivalent), is cooled to 0 DEG C, the DMF solution (1.1 equivalent) of dropping iodine, dropwises stirring 10min at latter 0 DEG C, rises to room temperature, stirs 18h. Reactant liquor DCM is diluted, 0.5MNa2S2O3Solution and saturated NaHCO3Solution is washed, dry, is spin-dried for, and crosses post and obtains compound 66, productivity 72%.
(2) preparation of compound 67
Being dissolved in the methanol solution of 0.16MNaOMe by compound 66, heating, to 60 DEG C, stirs 20h. Being cooled to 0 DEG C, add the cation exchange resin tune pH extremely neutrality that pyridine processes, rise to and 5min is stirred at room temperature, filter, filtrate was spin-dried for post and obtained compound 67, productivity 98%.
(3) preparation of compound 68
By NaN3(3 equivalent) adds in THF, is cooled to 0 DEG C, dropping ICl (2 equivalent), after 10min, and the THF solution of dropping compound 67, rise to stirred overnight at room temperature after dropwising. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 68, productivity 64.6%.
(4) preparation of compound 69
Compound 68 is dissolved in pyridine, adds the DMAP of catalytic amount, be cooled to 0 DEG C, drip BzCl, 1h is stirred at room temperature. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 69, productivity 93%.
(5) preparation of compound 70
Compound 69 is dissolved in DCM, adds (NH4)HSO4(2 equivalent) and m-chlorobenzoic acid (m-CBA, 1.1 equivalents), be cooled to 0 DEG C, adds metachloroperbenzoic acid (m-CPBA, 3 equivalents), rises to room temperature, and stirring is overnight. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 70, productivity 57.5%.
(6) preparation of compound 71
Compound 70 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 71, yield 90%.
The sign data of compound 71:1HNMR(400MHz,CD3OD): �� 7.93 (d, J=8.4Hz, 1H), 6.36 (s, 1H), 5.71 (d, J=8.0Hz, 1H), 4.17 (d, J=24.4Hz, 1H), 3.78 (dd, J1=46.4Hz, J2=12.0Hz, 2H), 1.36 (d, J=22.4Hz, 3H); ESI-MS:m/z324.07 [M+Na]+.
(7) preparation of compound 72
Compound 71 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 72 compounds.
Embodiment 10
2 '-deoxidation-2 ' preparation of-fluoro-4 '-nitrine uracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 73
Compound 42 is dissolved in dry DMF, adds imidazoles (1.2 equivalent) and Ph3P (1.2 equivalent), is cooled to 0 DEG C, the DMF solution (1.1 equivalent) of dropping iodine, dropwises stirring 10min at latter 0 DEG C, rises to room temperature, stirs 18h. Reactant liquor DCM is diluted, 0.5MNa2S2O3Solution and saturated NaHCO3Solution is washed, dry, is spin-dried for, and crosses post and obtains compound 73, productivity 72%.
(2) preparation of compound 74
Being dissolved in the methanol solution of 0.16MNaOMe by compound 73, heating, to 60 DEG C, stirs 20h. Being cooled to 0 DEG C, add the cation exchange resin tune pH extremely neutrality that pyridine processes, rise to and 5min is stirred at room temperature, filter, filtrate was spin-dried for post and obtained compound 74, productivity 98%.
(3) preparation of compound 75
By NaN3(3 equivalent) adds in THF, is cooled to 0 DEG C, dropping ICl (2 equivalent), after 10min, and the THF solution of dropping compound 74, rise to stirred overnight at room temperature after dropwising. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 75, productivity 64.6%.
(4) preparation of compound 76
Compound 75 is dissolved in pyridine, adds the DMAP of catalytic amount, be cooled to 0 DEG C, drip BzCl, 1h is stirred at room temperature. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 76, productivity 93%.
(5) preparation of compound 77
Compound 76 is dissolved in DCM, adds (NH4)HSO4(2 equivalent) and m-CBA (1.1 equivalent), be cooled to 0 DEG C, adds m-CPBA (3 equivalent), rises to room temperature, and stirring is overnight. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 77, productivity 57.5%.
(6) preparation of compound 78
Compound 77 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 78, yield 90%.
The sign data of compound 78:1HNMR(400MHz,CD3OD): �� 7.83 (d, J=8.4Hz, 1H), 6.15 (dd, J1=2.0Hz, J2=15.2Hz, 1H), 5.70 (d, J=8.0Hz, 1H), 5.27 (dd, J1=1.2Hz, J2=5.2Hz, 1H), 5.14 (dd, J1=1.2Hz, J2=5.2HZ, 1H), 4.57 (dd, J1=5.6Hz, J2=10.8Hz, 1H), 3.81 (d, J=12.0Hz, 1H), 3.71 (d, J=12.0Hz, 1H); ESI-MS:m/z=287 [M+H]+.
(7) preparation of compound 79
Compound 78 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 79 compounds. The sign data of this compound 79 are:1HNMR(400MHz,CD3OD): �� 7.62 (d, J=7.2Hz, 1H), 7.15-7.62 (m, 5H), 6.03 (d, J=16.4Hz, 1H), 5.63 (d, J=8.0Hz, 1H), 5.28 (dd, J1=5.6Hz, J2=54Hz, 1H), 4.91-4.95 (m, 1H), 4.66 (dd, J1=5.2Hz, J2=60Hz, 1H), 4.21-4.35 (m, 2H), 3.88-3.92 (m, 1H), 1.31 (d, J=7.2Hz, 3H), 1.18-1.21 (m, 6H);31PNMR(162MHz,CD3OD): 81.77; ESI-MS:m/z=557 [M+H]+.
Embodiment 11
3 '-deoxidation-4 ' preparation of-nitrine uracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 80
Compound 7 is dissolved in dry DMF, adds imidazoles (1.2 equivalent) and Ph3P (1.2 equivalent), is cooled to 0 DEG C, the DMF solution (1.1 equivalent) of dropping iodine, dropwises stirring 10min at latter 0 DEG C, rises to room temperature, stirs 18h. Reactant liquor DCM is diluted, 0.5MNa2S2O3Solution and saturated NaHCO3Solution is washed, dry, is spin-dried for, and crosses post and obtains compound 80, productivity 72%.
(2) preparation of compound 81
Being dissolved in the methanol solution of 0.16MNaOMe by compound 80, heating, to 60 DEG C, stirs 20h. Being cooled to 0 DEG C, add the cation exchange resin tune pH extremely neutrality that pyridine processes, rise to and 5min is stirred at room temperature, filter, filtrate was spin-dried for post and obtained compound 81, productivity 98%.
(3) preparation of compound 82
By NaN3(3 equivalent) adds in THF, is cooled to 0 DEG C, dropping ICl (2 equivalent), after 10min, and the THF solution of dropping compound 81, rise to stirred overnight at room temperature after dropwising.Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 82, productivity 64.6%.
(4) preparation of compound 83
Compound 82 is dissolved in pyridine, adds the DMAP of catalytic amount, be cooled to 0 DEG C, drip BzCl, 1h is stirred at room temperature. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 83, productivity 93%.
(5) preparation of compound 84
Compound 83 is dissolved in DCM, adds (NH4)HSO4(2 equivalent) and m-CBA (1.1 equivalent), be cooled to 0 DEG C, adds m-CPBA (3 equivalent), rises to room temperature, and stirring is overnight. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 84, productivity 57.5%.
(6) preparation of compound 85
Compound 84 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 85, yield 90%.
The sign data of compound 85:1HNMR(400MHz,CD3: �� 7.20 (d, J=8.2Hz, 1H), OD) 5.78-5.72 (m, 2H), 5.45-5.41 (m, 1H), 4.40 (s, 2H), 2.80-2.88 (m, 1H), 2.16-2.12 (m, 1H); ESI-MS:m/z=270.1 [M+H]+.
(7) preparation of compound 86
Compound 85 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 86 compounds.
Embodiment 12
The preparation of 2 '-beta-methyl-3 '-deoxidation-4 '-nitrine uracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 87
Compound 47 is dissolved in dry DMF, adds imidazoles (1.2 equivalent) and Ph3P (1.2 equivalent), is cooled to 0 DEG C, the DMF solution (1.1 equivalent) of dropping iodine, dropwises stirring 10min at latter 0 DEG C, rises to room temperature, stirs 18h. Reactant liquor DCM is diluted, 0.5MNa2S2O3Solution and saturated NaHCO3Solution is washed, dry, is spin-dried for, and crosses post and obtains compound 87, productivity 72%.
(2) preparation of compound 88
Being dissolved in the methanol solution of 0.16MNaOMe by compound 87, heating, to 60 DEG C, stirs 20h. Being cooled to 0 DEG C, add the cation exchange resin tune pH extremely neutrality that pyridine processes, rise to and 5min is stirred at room temperature, filter, filtrate was spin-dried for post and obtained compound 88, productivity 98%.
(3) preparation of compound 89
By NaN3(3 equivalent) adds in THF, is cooled to 0 DEG C, dropping ICl (2 equivalent), after 10min, and the THF solution of dropping compound 88, rise to stirred overnight at room temperature after dropwising. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 89, productivity 64.6%.
(4) preparation of compound 90
Compound 89 is dissolved in pyridine, adds the DMAP of catalytic amount, be cooled to 0 DEG C, drip BzCl, 1h is stirred at room temperature. Reactant liquor is evaporated, adds EA, use saturated NaHCO3Solution is washed, dry, was spin-dried for post and obtains compound 90, productivity 93%.
(5) preparation of compound 91
Compound 90 is dissolved in DCM, adds (NH4)HSO4(2 equivalent) and m-CBA (1.1 equivalent), be cooled to 0 DEG C, adds m-CPBA (3 equivalent), rises to room temperature, and stirring is overnight. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 91, productivity 57.5%.
(6) preparation of compound 92
Compound 91 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 92, yield 90%.
The sign data of compound 92: ESI-MS:m/z283.1 [M+H]+.
(7) preparation of compound 93
Compound 92 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 93 compounds.
Embodiment 13
The preparation of 2 '-beta-methyl-2 '-fluoro-3 '-deoxidation-4 '-nitrine uracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 94
Compound 52 is dissolved in dry DMF, adds imidazoles (1.2 equivalent) and Ph3P (1.2 equivalent), is cooled to 0 DEG C, the DMF solution (1.1 equivalent) of dropping iodine, dropwises stirring 10min at latter 0 DEG C, rises to room temperature, stirs 18h. Reactant liquor DCM is diluted, 0.5MNa2S2O3Solution and saturated NaHCO3Solution is washed, dry, is spin-dried for, and crosses post and obtains compound 94, productivity 72%.
(2) preparation of compound 95
Being dissolved in the methanol solution of 0.16MNaOMe by compound 94, heating, to 60 DEG C, stirs 20h. Being cooled to 0 DEG C, add the cation exchange resin tune pH extremely neutrality that pyridine processes, rise to and 5min is stirred at room temperature, filter, filtrate was spin-dried for post and obtained compound 95, productivity 98%.
(3) preparation of compound 96
By NaN3(3 equivalent) adds in THF, is cooled to 0 DEG C, dropping ICl (2 equivalent), after 10min, and the THF solution of dropping compound 95, rise to stirred overnight at room temperature after dropwising. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 96, productivity 64.6%.
(4) preparation of compound 97
Compound 96 is dissolved in DCM, adds (NH4)HSO4(2 equivalent) and m-CBA (1.1 equivalent), be cooled to 0 DEG C, adds m-CPBA (3 equivalent), rises to room temperature, and stirring is overnight. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 97, productivity 57.5%.
(5) preparation of compound 98
Compound 97 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 98, yield 90%. The sign data of this compound 98: ESI-MS:m/z286.1 [M+H]+.
(6) preparation of compound 99
Compound 98 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 99 compounds.
Embodiment 14
The preparation of 2 '-deoxidation-2 '-fluoro-3 '-deoxidation-4 '-nitrine uracil compounds.
Prepare according to following reaction scheme:
(1) preparation of compound 100
Compound 57 is dissolved in dry DMF, adds imidazoles (1.2 equivalent) and Ph3P (1.2 equivalent), is cooled to 0 DEG C, the DMF solution (1.1 equivalent) of dropping iodine, dropwises stirring 10min at latter 0 DEG C, rises to room temperature, stirs 18h. Reactant liquor DCM is diluted, 0.5MNa2S2O3Solution and saturated NaHCO3Solution is washed, dry, is spin-dried for, and crosses post and obtains compound 100, productivity 72%.
(2) preparation of compound 101
Being dissolved in the methanol solution of 0.16MNaOMe by compound 100, heating, to 60 DEG C, stirs 20h. Being cooled to 0 DEG C, add the cation exchange resin tune pH extremely neutrality that pyridine processes, rise to and 5min is stirred at room temperature, filter, filtrate was spin-dried for post and obtained compound 101, productivity 98%.
(3) preparation of compound 102
By NaN3(3 equivalent) adds in THF, is cooled to 0 DEG C, dropping ICl (2 equivalent), after 10min, and the THF solution of dropping compound 101, rise to stirred overnight at room temperature after dropwising.Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 102, productivity 64.6%.
(4) preparation of compound 103
Compound 102 is dissolved in DCM, adds (NH4)HSO4(2 equivalent) and m-CBA (1.1 equivalent), be cooled to 0 DEG C, adds m-CPBA (3 equivalent), rises to room temperature, and stirring is overnight. Add Na2SO3Solution, extracts with EA after stirring 10min, dry, was spin-dried for post and obtains compound 103, productivity 57.5%.
(5) preparation of compound 104
Compound 103 is dissolved in THF, adds the 1NNaOH solution of 5 equivalents, at room temperature stirs to reacting complete, neutralizes, and filters and obtains compound 104, yield 90%. The sign data of this compound 104: ESI-MS:m/z272.2 [M+H]+.
(6) preparation of compound 105
Compound 104 is dissolved in CH2Cl2In, add (O-phenyl-pentafluoride phenolic group-O-phenylol-N-isopropyl alaninyl)-phosphate ester and triethylamine, heat to reacting complete, saturated NaHCO3Neutralize, CH2Cl2Extract, be spin-dried for acquisition compound 105 compounds.
Screening active ingredients
Three phospholipid of the compound above-mentioned experiment obtained carry out HCV polymerase and the screening of other RNA viruses rna polymerase activity, and carry out relevant picornavirus infection cell on a cellular level and include HCV replicon model and carry out screening active ingredients, result shows, the polymerase of RNA viruses is had good inhibitory activity by this compounds, and its IC50 is in the level of 0.1-10 ��m of ol/L. This compounds has suppression virus replication activity preferably at cellular level simultaneously.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention. It should be pointed out that, for the person of ordinary skill of the art, without departing from the inventive concept of the premise, it is also possible to making some deformation and improvement, these broadly fall into protection scope of the present invention. Therefore, the protection domain of patent of the present invention should be as the criterion with claims.

Claims (10)

1. there is L-nucleoside compound or its pharmaceutically acceptable salt of structure shown in formula I feature:
Wherein:
R1It is selected from: CH3,CF3,CF2H,CFH2, H;
R2It is selected from: CH3,CF3,CF2H,CFH2, H;
R3It is selected from: H, replaces or do not replace phosplate, replace or do not replace biphosphonate, replace or do not replace triguaiacyl phosphate;
X is selected from: H, OH, OCOR4,OCOCH(NHR5)R6;
Y is selected from: H, N3;
Z is selected from: H, OH, F, Cl, OCOR4,OCOCH(NHR5)R6;
R4Being selected from: H, C1-C6 alkyl, C1-C6 replaces alkyl, aryl, substituted aryl;
R5It is selected from: H, C1-C6 alkyl, aralkyl;
R6Being selected from: H, C1-C6 alkyl, aralkyl, C1-C6 replaces alkyl, natural and alpha-non-natural amino acid side chain radical;
B is selected from group:
Wherein:
R7It is selected from: H, Cl, C1-C6 alkyl, COR18, COOR18;
R8It is selected from: H, Cl, C1-C6 alkyl, COR18;
R9It is selected from: H, C1-C6 alkyl, COR18,F,Cl,CN,CONHR18;
R10It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl, C1-C6 alkynyl, NHR18, OR18, CN, CONHR18, F, Cl;
R11It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl, C1-C6 alkynyl, NHR18, OR18, CN, CONHR18, F, Cl;
R12It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl, C1-C6 alkynyl, CN, CONHR18, F, Cl;
R13It is selected from: H, C1-C6 alkyl, COR18, COOR18;
R14It is selected from: H, C1-C6 alkyl;
R18It is selected from: H, C1-C6 alkyl, C1-C6 thiazolinyl;
R is selected from: H, COR6, CO (NH2)R6, COOR18;
W is selected from: O, NH, NOH, NOR6,NNHR6,NNHCOR6��
2. L-nucleoside compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that R3 is selected from group:
Wherein:
R15It is selected from: C1-C6 alkyl, aralkyl;
R16Being selected from: H, C1-C2 alkyl, C1-C2 replaces alkyl;
R17Being selected from: H, C1-C6 alkyl, C1-C6 replaces alkyl, F, Cl, Br, ester group, amide groups, ether, hydroxyl;
R19Be selected from: the side-chain radical of natural amino acid, H, C1-C6 alkyl, containing O, S, amino, croak base, imidazoles, carboxyl, amide groups C1-C6 alkyl, aryl replace C1-C6 alkyl, containing the aryl of substituted-phenyl, containing the aryl of substituted indolyl;
Ar is selected from: phenyl, substituted-phenyl, aryl, substituted aryl, naphthyl, substituted naphthyl.
3. L-nucleoside compound according to claim 2 or its pharmaceutically acceptable salt, it is characterised in that R3It is selected from: H, or following group:
4. L-nucleoside compound according to claim 3 or its pharmaceutically acceptable salt, it is characterised in that R3It is selected from group:
Wherein:
Ar is selected from: phenyl, substituted-phenyl, naphthyl, substituted naphthyl;
R19It is selected from: the side-chain radical of natural amino acid;
R15It is selected from: methyl, ethyl, isopropyl, benzyl.
5. L-nucleoside compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that B is selected from group:
R1It is selected from: CH3,CF3, H;
R2It is selected from: CH3,CF3,H��
6. L-nucleoside compound according to any one of claim 1-5 or its pharmaceutically acceptable salt, it is characterised in that R1It is selected from: H;
X is selected from: H, OH.
7. L-nucleoside compound according to any one of claim 1-5 or its pharmaceutically acceptable salt, it is characterised in that R2It is selected from: H, CH3;
Z is selected from: OH, halogen.
8. L-nucleoside compound according to any one of claim 1-5 or its pharmaceutically acceptable salt, it is characterised in that R1It is selected from: H;
X is selected from: H, OH,
R2It is selected from: H, CH3;
Z is selected from: OH, F;
Y is selected from: H, N3��
9. L-nucleoside compound according to claim 1 or its pharmaceutically acceptable salt, it is characterised in that be selected from compound:
10. L-nucleoside compound described in any one of claim 1-9 or its pharmaceutically acceptable salt suppress the application in medicine in preparation RNA viruses.
CN201410693152.4A 2014-11-25 2014-11-25 L-nucleoside compounds and application thereof Pending CN105646629A (en)

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Cited By (12)

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CN112062800A (en) * 2020-09-02 2020-12-11 广东东阳光药业有限公司 Phosphoramidate derivatives of nucleoside compounds and uses thereof
US11352387B2 (en) 2014-11-28 2022-06-07 NuCana plc 2′ and/or 5′ amino-acid ester phosphoramidate 3′-deoxy adenosine derivatives as anti-cancer compounds
US11414452B2 (en) 2017-06-14 2022-08-16 NuCana plc Synthesis of phosphate derivatives
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US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
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WO2018134343A1 (en) * 2017-01-19 2018-07-26 Sandoz Ag Synthesis of phosphoramidates
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US11414452B2 (en) 2017-06-14 2022-08-16 NuCana plc Synthesis of phosphate derivatives
US11560400B2 (en) 2017-12-05 2023-01-24 NuCana plc Salts of diphosphate phosphoramidate of nucleosides as anticancer compounds
JPWO2019172394A1 (en) * 2018-03-09 2021-02-18 国立研究開発法人科学技術振興機構 β-modified phosphoric acid compound precursor, β-modified phosphoric acid compound, reaction inhibitor and drugs containing it, and reaction inhibition method
US11597745B2 (en) 2018-03-09 2023-03-07 Japan Science And Technology Agency β-modified phosphoric acid compound precursor, β-modified phosphoric acid compound, reaction inhibitor and medicine containing the same, and method for inhibiting reaction
JP7266896B2 (en) 2018-03-09 2023-05-01 国立研究開発法人科学技術振興機構 β-modified phosphate compound precursor, β-modified phosphate compound, reaction inhibitor, drug containing the same, and reaction inhibition method
WO2019172394A1 (en) * 2018-03-09 2019-09-12 国立研究開発法人科学技術振興機構 β-MODIFIED PHOSPHORIC ACID COMPOUND PRECURSOR, β-MODIFIED PHOSPHORIC ACID COMPOUND, REACTION INHIBITOR, AND MEDICINE INCLUDING SAME, AND REACTION INHIBITION METHOD
US11690860B2 (en) 2018-04-10 2023-07-04 Atea Pharmaceuticals, Inc. Treatment of HCV infected patients with cirrhosis
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11707480B2 (en) 2020-02-27 2023-07-25 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US11738038B2 (en) 2020-02-27 2023-08-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
US11813278B2 (en) 2020-02-27 2023-11-14 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
CN112062800A (en) * 2020-09-02 2020-12-11 广东东阳光药业有限公司 Phosphoramidate derivatives of nucleoside compounds and uses thereof
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides

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