CN101333235A - Nucleoside derivates with ethynyl and fluor substituted glycosyl - Google Patents
Nucleoside derivates with ethynyl and fluor substituted glycosyl Download PDFInfo
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- CN101333235A CN101333235A CNA2007100577860A CN200710057786A CN101333235A CN 101333235 A CN101333235 A CN 101333235A CN A2007100577860 A CNA2007100577860 A CN A2007100577860A CN 200710057786 A CN200710057786 A CN 200710057786A CN 101333235 A CN101333235 A CN 101333235A
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Abstract
The invention discloses a nucleoside derivative with the glycosylation part having ethynyl and fluorine atom substituent, with the following general formula. The invention can increase the chemical or enzyme hydrolysis resistance of molecules, and improve the chemical stability of the fluorinated nucleoside molecules; at the same time, the nucleoside derivative disclosed in the invention has good anti-virus activity and anti-tumor activity.
Description
Technical field
The present invention relates to a kind of nucleoside derivate, particularly relate to the nucleoside derivates that a kind of glycosyl part has ethynyl and fluorine atom replacement.
Background technology
Acquired immune deficiency syndrome (AIDS) (AIDS) is a kind of global lethality transmissible disease, still incompetent at present specific medicament of curing, and preventible vaccine also in development, can not produce antibody because acquired immune deficiency syndrome (AIDS) is fallen ill in the human body of back, so anti-AIDS vaccine research and development difficulty is bigger.The treating AIDS difficulty is more greatly because hiv virus (HIV) usually can morph in breeding and communication process, makes original effectively drug failure.
The antiviral therapy of hepatitis B is to remove hepatitis B virus (HBV), reduces complication, prevents the essential measure of hepatic fibrosis.The maximum difficult point of antiviral therapy is still viral original copy template at present---and covalently closed circular DNA (cccDNA) is difficult to remove, thereby resists the cccDNA that viral therapy has relevant antagonism, makes liver cell for good and all keep the state that is infected by HBV.Hepatitis B virus then is another difficult point in the antiviral therapy process because of variation produces resistance.
Nucleoside medicine has been subjected to the successful development of efficient low toxicity antiviral such as extensive concern, particularly lamivudine, for extensive patients has been brought Gospel in recent years as the main medicine of virus type disease.Be used for the treatment of clinically at present the HIV infectious effect preferably nucleoside medicine mainly contain zidovudine (Zidovudine, AZT), lamivudine (lamivudine, 3TC), stavudine (stavudine, D4T), Combivir (combivir, AZTP3TC) and Abacavir (abacavir, ABC).Be used for the treatment of the HBV infectious effect preferably nucleoside medicine mainly contain lamivudine (lamivudine, 3TC), Adefovir (adefovir, PMEA), Entecavir (entecavir, ETV).Yet, still there are problems such as toxic side effect is big, resistance in the ucleosides antiviral of Shi Yonging clinically, in addition, virus type diseases such as hepatitis, acquired immune deficiency syndrome (AIDS) still lack the effectively preventing means, and these are indicating that all the research of antiviral still is the task of top priority.
Tumour is still common, the most serious a kind of disease that the world today directly jeopardizes the human life.In recent years, chemotherapy of tumors has been obtained suitable progress, some tumour patient survival time is prolonged, but aspect the strongest treatment of solid tumors of mortality, do not obtain gratifying curative effect yet, simultaneously, the ucleosides metabolic antagonist medicine of using clinically as one of tumor chemotherapeutic drug still exists untoward reaction serious at present, and easily produces chemical sproof defective.Therefore press for and carry out structure of modification, the ucleosides metabolic antagonist of composite structure novelty filters out the brand-new medicine of high-efficiency low-toxicity.
In recent years nucleoside compound is discovered that ethynyl is an important active group, it gives nucleoside compound multiple biological activity:
At first, the compound that antiviral activity: 4 '-α-ethynyl replaces has been proved to be the activity of have the strongest anti-HIV-1 [comprising several multidrug resistances (multidrug-resistant) virus strain (MDR)] and anti-HIV-2, this compounds can become corresponding 5 '-triphosphoric acid compound by intracellular anabolism, hiv reverse transcriptase (HIV RT) mixes it in Nucleotide effectively, thereby stop DNA chain synthetic of virus and prolong, duplicating of virus is suppressed and brings into play antivirus action.Simultaneously to mix its speed of mixing HIV RT of speed ratio of cell aggregation enzyme a lot of slowly for 5 '-triphosphoric acid compound, and can stop the prolongation of DNA chain by the metamorphosis of the primer of this growth of mixing initiation, thereby cause the DNA chain termination that postpones.This compounds receives much concern because of its brand-new mechanism of action and to the powerful activity of the virus strain of MDR HIV-1.In addition, studies show that fully that the activity of the nucleoside compound that 4 '-α-ethynyl replaces is better than this compounds of other group replacement.
Secondly, the nucleoside compound that anti-tumor activity: 3 '-β-ethynyl replaces can be by halfcystine (cys 439) reaction of avtive spot in the R2 subunit of alkynyl and ribonucleoside diphosphate reductase (RDPR), generate alkyl thiazolinyl thioether, and making the RDPR inactivation of tumour cell, the DNA that suppresses tumour cell is synthetic.RDPR is one of synthetic important target enzyme that suppresses of DNA, it is in a kind of mode of de novo synthesis, 5 '-nucleoside diphosphate compound (rNDPs) of the common nucleosides of catalysis four classes changes into corresponding 2 '-deoxynucleoside diphosphate compound (dNDPs), dNDPs is further changed into 5 '-ribonucleoside triphosphote compound (dNTPs) by nucleoside diphosphokinase, and dNTPs is synthetic most important for DNA's.In the nucleoside compound that 3 '-β-ethynyl replaces, ECyd and EUrd are more much better than than clinical antimetabolic preparation commonly used to the anti-tumor activity of solid tumor, and do not have serious toxic side effect, are expected to be applied to clinical as a class new antitumoral nucleoside compound.
For the acquisition of such nucleoside compound, existing a series of relevant reports now exemplify as follows:
1.Hideshi?Hattori，Motohiro?Tanaka，Masakazu?Fukushima，et?al.J.Med.Chem，1996，39，5005-5011.
2.Akira?Matsuda，Hideshi?Hattori，Motohiro?Tanaka，et?al.Bioorganic&Medicinal?ChemistryLetters，1996，6(16)，1887-1892.
3.Makoto?Nomura，Tsutomu?Sato，Masato?Washinosu，et?al.Tetrahedron，2002，58，1279-1288.
4.Hiroshi?Ohrui，Satoru?Kohgo，Kenji?Kitano，et?al.J.Med.Chem，2000，43，4516-4525.
5.Maqbool?A.Siddiqui，Stephen?H.Hughes，Paul?L.Boyer?et?al.J.Med.Chem，2004，47，5041-5048.
In addition, discover, fluorine atom is incorporated into 2 '-position of nucleoside compound sugar ring, especially purine nucleoside compounds, can the stabilizing sugar glycosidic bond, improve the resistance of molecule, the chemical stability of fluorizated nucleoside molecule is improved, make this compounds have good antiviral activity simultaneously for the hydrolytic action of chemistry or enzyme.As: replace natural thymidine with fluorine atom and can obtain having antiviral activity FMAU, use together with carbon fluorin radical (CF
2-) replacement Deoxyribose cytidine sugar ring 2 '-position methylene radical (CH
2-), can obtain having the gemcitabine (Gemcitabine) of anti-tumor activity.Structure activity study shows: its 2 '-position of 2 ' of biologically active-fluorizated nucleoside analog all has beta configuration, and its corresponding α-configurational isomer does not then have activity.
Relevant report exemplifies as follows:
1.Shifeng?Pan，Jianwu?Wang，Kang?Zhao.J.Org.Chem.1999，64，4-5.
2.Herdewijn，P.；Pauwels，R.；Baba，M.；et?al.J.Med.Chem.1987，30，2131.
3.Victor?E.Marquez，Christopher?K-H.Tseng，Hiroaki?Mitsuya，et.al.J.Med.Chem.1990，33，978-985.
4.Marquez，V.E.；Lim，B.B.；Barchi，J.J.et?al.In?Nucleosides?and?Nucleoties?as?Antitumorand?Antiviral?Agents；Chu，C.K.，Baker，D.C.，Eds.；Plenum：NewYork，1993，pp?265-284.
Replacing and then do not met relevant report yet the sugared loop section of nucleoside compound molecule is carried out ethynyl and fluorine atom simultaneously, may be to be the comparison difficulty because the sugar ring is directly fluoridized.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, provide a kind of glycosyl part to have the nucleoside derivates of ethynyl and fluorine atom replacement.
Technical scheme of the present invention is summarized as follows:
A kind of glycosyl part has the nucleoside derivates of ethynyl and fluorine atom replacement, has following general formula:
X represents base
(I)
Wherein, base is represented
Preferably:
Described R
1Expression hydroxyl or amino;
Described R
2Expression hydrogen atom or fluorine atom or bromine atoms or iodine atom or methyl;
Described R
3The expression hydroxyl or amino or-NHR ' or-NR " R " ' or C
1-C
4Alkoxyl group or C
1-C
3Alkylthio;
Described R
4Expression amino or fluorine atom;
Described R
5Expression amino or-NHR ' ,-NR " R " ' or alkoxyl group or carbamyl or ammonia formyl sulfide base;
Described R ' is C
1-C
4Alkyl, described R " be C
1-C
3Alkyl, described R " ' be C
1-C
3Alkyl;
Described R
6Expression amino or fluorine atom;
Described R
7Expression amino or hydrogen atom;
Described R
8Expression is amino.
A kind of glycosyl part of the present invention has the nucleoside derivates of ethynyl and fluorine atom replacement, can improve the resistance of molecule for the hydrolytic action of chemistry or enzyme, the chemical stability of fluorizated nucleoside molecule is improved, had good antiviral activity and anti-tumor activity simultaneously.
Embodiment
It is as follows that a kind of glycosyl part has nucleoside derivates (3 '-alkynyl-2 '-deoxidation-2 '-fluoro-beta (the α)-D-pectinose yl nucleosides analog derivative) reaction scheme that ethynyl and fluorine atom replace:
A) be raw material with D-wood sugar (II), under acid catalysis, with copper sulfate as dewatering agent, D-wood sugar (II) carries out dehydration condensation with acetone in room temperature condition, after reaction finishes, remove by filter copper sulfate, dropping ammonia in filtrate, steaming desolventize the crude product of midbody compound (III), D-wood sugar (II) is 1 with the mol ratio of anhydrous cupric sulfate: 1.0-3.0, an acidic catalyst are sulfuric acid, tosic acid, and preferred catalyst is a sulfuric acid, with the mol ratio of D-wood sugar (II) be 0.10-0.50: 1, the reaction times is 24-36h;
B) compound (III) is purified without separating, and directly issues unboiled water at acidic conditions in solvent and separates reaction, and after reaction finished, steaming desolventized, and obtains midbody compound (IV) through column chromatography, and compound (III) is about 1 with the mol ratio of acid: 0.05-0.20., the reaction times is 2-5h, and temperature of reaction is a room temperature, and used acid is hydrochloric acid, acetate, tosic acid or trifluoroacetic acid, preferred hydrochloric acid, solvent is water or acetonitrile, preferably water;
C) described compound (IV) carries out the reaction of 4-chlorobenzoyl and obtains compound (V) under alkaline condition, employed alkali can be triethylamine, and pyridine or 4-dimethylamino pyridine are preferably triethylamine, employed solvent can be methylene dichloride, chloroform or 1, the 2-ethylene dichloride is preferably methylene dichloride, wherein, the mol ratio of 4-chloro-benzoyl chloride and alkali and raw material is 1.1-1.5: 3.0: 1, the reaction times was 5h, temperature of reaction be 0 ℃ to room temperature;
D) described compound (V) gets compound (VI) through TEMPO free radical/clorox system oxidation in solvent, oxidation system also can be TEMPO free radical/TCCA, available solvent is a methylene dichloride, chloroform or 1, the 2-ethylene dichloride is preferably methylene dichloride, and the mol ratio of compound (V), TEMPO free radical, clorox is 1: 0.01-0.09: 1.03-2.20, temperature of reaction be 0 ℃ to room temperature, the reaction times is 2-6 hour;
E) described compound (VI) adding ethynyl bromination magnesium Grignard reagent carries out addition reaction, after reaction finishes, add the reaction in 5% ammonium chloride solution, tell organic phase, steam desolventize compound (VII), available solvent is tetrahydrofuran (THF) or ether, be preferably tetrahydrofuran (THF), the mol ratio of compound (VI), ethynyl bromination magnesium Grignard reagent is 1: 1.5-5.5, and temperature of reaction is 0 ℃, the reaction times is 1-3 hour;
F) described compound (VII) generates compound (VIII) with the benzoylation reagent react under the catalytic condition of organic bases and catalyzer in solvent, employed acylating reagent is benzoyl oxide or Benzoyl chloride, preferred Benzoyl chloride, used catalyzer is the 4-dimethylamino pyridine, solvent is a methylene dichloride, 1,2-ethylene dichloride or chloroform etc., preferred methylene dichloride, employed organic bases is a triethylamine, pyridine, preferred triethylamine, catalyzer is 4-dimethylamino pyridine (DMAP), wherein, Benzoyl chloride, alkali, catalyzer (DMAP) is 1.10-2.20: 2.0-3.0: 0.02-0.05 with the mol ratio of raw material: 1.00, reaction times is 4-10h, temperature of reaction be 0 ℃ to room temperature;
G) described compound (VIII) in solvent under acidic conditions the hydrolysis methyl-etherified generate midbody compound (IX), used acid is hydrochloric acid, acetate, tosic acid or trifluoroacetic acid, preferred hydrochloric acid, solvent for use is a methyl alcohol, the mixed system of water and tetrahydrofuran (THF), compound (VIII) and hydrochloric acid mol ratio are 1: 126.9-190.3, and the reaction times is 4-10h, temperature of reaction is 65-75 ℃;
H) described compound (IX) generates compound (X) through fluoridizing in solvent, used fluorination reagent is the etching acid salt Potassium monofluoride or the potassium bifluoride of diethylin sulfur trifluoride (DAST) or triethylamine, preferred diethylin sulfur trifluoride (DAST), solvent for use is methylene dichloride, chloroform or 1, the 2-ethylene dichloride, preferred methylene dichloride, wherein the preferred molar ratio of compound (IX) and DAST is 1: 1.5-5.5, reaction times is 24h, and temperature of reaction is-78 to 40 ℃;
I) described compound (X) is under the acid catalysis condition, the 1-position is carried out acylation reaction and is obtained compound (XI), the 1-position used acylating reagent of acylation reaction is diacetyl oxide or benzoyl oxide, preferred diacetyl oxide, solvent for use is a Glacial acetic acid, and catalyzer is the vitriol oil, and the mol ratio of compound (X), diacetyl oxide and the catalyzer vitriol oil is 1: 10-18: 2.0-3.5, reaction times is 5-12h, temperature of reaction be 0 ℃ to room temperature;
J) linked reaction takes place with the base of silanization protection in described compound (XI) under the effect of Lewis acid catalyst in solvent, generate compound (XII), the used appropriate catalyst of coupling reaction is trifluoromethanesulfonic acid trimethylsilyl group (TMSOTf) or Iodotrimethylsilane or tin tetrachloride, preferred tin tetrachloride, solvent for use is a methylene dichloride, chloroform, 1,2-ethylene dichloride or acetonitrile, preferred 1,2-ethylene dichloride or acetonitrile, wherein compound (XI) is 1 with the mol ratio of base and Lewis acid catalyst: 2.0-4.0: 2.0-4.5, reaction times is 8-10h, temperature of reaction is a room temperature, and described base is the pyrimidine heterocyclic derivative, the purine heterocycle derivative, pyrrolopyrimidine ring derivatives and pyrrolopyridine ring derivatives;
K) described compound (XII); in solvent, under alkaline condition, carry out deprotection reaction and substitution reaction obtains compound (I); used alkali is: ammonia, amine, sodium alkoxide, triethylamine, sodium hydroxide or salt of wormwood, and the alkali difference that different compounds is used, the general formula of described compound (I) is:
X represents base
(I)
Wherein, base is represented: pyrimidine heterocyclic derivative, purine heterocycle derivative, pyrrolopyrimidine ring derivatives and its structure of pyrrolopyridine ring derivatives:
Described R
1Expression hydroxyl or amino;
Described R
2Expression hydrogen atom or fluorine atom or bromine atoms or iodine atom or methyl;
Described R
3The expression hydroxyl or amino or-NHR ' or-NR " R " ' or C
1-C
4Alkoxyl group or C
1-C
3Alkylthio;
Described R
4Expression amino or fluorine atom;
Described R
5Expression amino or-NHR ' ,-NR " R " ' or alkoxyl group or carbamyl or ammonia formyl sulfide base;
Described R ' is C
1-C
4Alkyl, described R " be C
1-C
3Alkyl, described R " ' be C
1-C
3Alkyl;
Described R
6Expression amino or fluorine atom;
Described R
7Expression amino or hydrogen atom;
Described R
8Expression is amino.
3 '-ethynyl-2 ' that we design and synthesize-fluorine all has a series of brand-new nucleoside analog of beta configuration, and this compounds has antiviral and antineoplastic active structure feature.
The present invention is further illustrated below in conjunction with specific embodiment.
Embodiment 1
3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-1, the preparation of 2-O-isopropylidene-D-ribofuranose (VIII)
In the there-necked flask of 1000mL, add acetone (500mL), the vitriol oil (3.75mL) continuously, copper sulfate (26.7g) and D-wood sugar (25.0g), stirring at room, TLC monitoring reaction to D-wood sugar reacts completely, and reacts completely in about 33 hours.Remove by filter copper sulfate, dropping ammonia in filtrate (8mL) is steamed and to be desolventized to such an extent that directly carry out next step reaction after the yellow oil product;
The resulting product of previous step is joined in the 500mL round-bottomed flask, add after 1.0% hydrochloric acid (47.88mL) at room temperature reacts 5.5 hours, the TLC monitoring reaction is complete.Remove the rear pillar chromatography (ethyl acetate: sherwood oil=3: 4) obtain yellow oil (14.6g), productive rate 92.4% of desolvating.
With the resulting product (6.8g of previous step, 35.79mmol) join in the methylene dichloride (66.3mL), add triethylamine (29.8mL, 214.74mmol), the mixed solution ice-water bath is cooled to 0 ℃, and slow dropping parachlorobenzoyl chloride under stirring (7.43mL, 58.57mmol), dropwise, reaction solution continues to stir 5 hours.Add NaHCO3 solution (48mL) stopped reaction, methylene dichloride (3 * 30mL) extractions, anhydrous sodium sulfate drying, steam solvent, residuum separates (ethyl acetate: sherwood oil=3: 7), get white solid (7.2g) through column chromatography, productive rate 61% connects and is used for next step reaction;
To the there-necked flask of 100ml, add resulting product 1.60 grams (4.87mmol) of previous step, TEMPO free radical 22.8mg (0.15mmol), methylene dichloride (8.1ml).Ice-water bath drip down contain sodium bicarbonate (1.26g, 15mmol) and chlorine bleach liquor (34ml, 0.35M, mixed solution 11.0mmol).Drip to finish, continue to stir 5h, and dichloromethane extraction (3 * 20ml) merge organic phases, anhydrous sodium sulfate drying, column chromatography (ethyl acetate: sherwood oil=1: 4) separate and obtain white solid (1.19g), productive rate: 75.2%, directly apply to next step reaction;
In the there-necked flask of 500ml, add ethynyl bromination magnesium Grignard reagent (0.5M, 86.1ml, 43.1mmol) tetrahydrofuran solution, mixed solution is cooled to 0 ℃, stirs slowly to drip the resulting product of previous step (22.48g down, 68.84mmol) tetrahydrofuran solution (22.4ml), drip and finish, continue to stir 3h, reaction finishes the back organic layer and washes with saturated sodium-chloride (5.8ml).Tell organic phase, steaming desolventizes, and (ethyl acetate: sherwood oil=1: 4) separation obtains white solid (3.6g) to column chromatography, and productive rate 60% is directly used in next step reaction;
With the resulting product (4.0g of previous step, 11.35mmol) join in the methylene dichloride (80.0mL), add triethylamine (4.77mL, 34.0mmol), with 4-dimethylamino pyridine (DMAP) (0.056g, 0.46mmol). mixed solution is cooled to 0 ℃, and slow dropping Benzoyl chloride under stirring (1.44mL, 12.48mmol).Dropwise, reaction mixture continues to stir 10 hours in room temperature.Add H2O (32mL), stopped reaction, methylene dichloride (3 * 30mL) extractions, anhydrous sodium sulfate drying steams solvent, and column chromatography for separation obtains white solid (VIII) (3.42g), fusing point: 168 ℃, productive rate 67%;
1H-NMR(CDCl
3)δ：8.00～8.04(m，4H)，7.57～7.60(m，1H)，7.26～7.42(m，4H)，6.01～6.02(d，1H，J＝3.5Hz)，5.31(d，1H，J＝3.5Hz，)，4.78～4.81(m，1H)，4.71～4.74(m，1H)，4.63～4.66(m，1H)，2.74(s，1H)，1.51(s，1H)，1.34(s，3H)。
Embodiment 2:
The preparation of 1-methyl-3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-D-ribofuranose (IX):
In the there-necked flask of the 100mL that reflux condensing tube is housed, (1.0g 2.19mmoL), concentrated hydrochloric acid (8.25mL), methyl alcohol (23.6mL) and water (5.1mL), is heated to 70 ℃ to add sample (VIII), TLC monitoring reaction to sample (VIII) reacts completely, and reacts completely in about 10 hours.Be cooled to room temperature, add triethylamine (12.3mL), remove and desolvate, ethyl acetate extraction (3 * 10ml), merge organic phase, washing, anhydrous sodium sulfate drying, column chromatography (ethyl acetate: sherwood oil=2: 4) separation obtains faint yellow solid (IX) (0.707g), productive rate 74.9%, fusing point: 106-107 ℃.
1H-NMR(CDCl
3)δ：8.04～8.09(m，4H)，7.59～7.63(m，1H)，7.41～7.48(m，4H)，5.55(d，1H，J＝2.5Hz)，5.16～5.17(d，1H，J＝2.0Hz，)，4.70～4.73(m，1H)，4.59～4.63(m，1H)，4.44～4.46(m，1H)，3.46(s，3H)，2.75(brs，1H)，2.73(s，1H)。
Embodiment 3:
The preparation of 1-methyl-3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-2-deoxidation-2-fluoro-D-ribofuranose (X):
With methyl-3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-D-ribofuranose (IX) (0.946g; 2.20mmoL) be dissolved in the methylene dichloride (13.2mL); mixed solution is cooled to-78 ℃; stir and drip diethylin sulfur trifluoride (DAST) (0.71mL down; 5.5mmoL); dropwise reaction solution room temperature 24 hours.Reaction mixture is poured in the water, dichloromethane extraction, after saturated sodium bicarbonate solution is washed, the saturated common salt washing, anhydrous sodium sulfate drying, (ethyl acetate: sherwood oil=5: 19) separation obtains faint yellow oily thing (X) (0.333g), productive rate 30% to column chromatography;
1H-NMR(CDCl
3)δ：8.02～8.07(m，4H)，7.60～7.63(m，1H)，7.41～7.49(m，4H)，5.60～5.75(d，1H，J＝12.5Hz)，5.12(s，1H)，4.70～4.76(m，2H)，4.64～4.68(m，1H)，3.49(s，3H)，2.78～2.79(d，1H，J＝5.5Hz)。
Embodiment 4:
The preparation of 1-ethanoyl-3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-2-deoxidation-2-fluoro-D-ribofuranose (XI):
Compound 1-first is continued-3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-2-deoxidation-2-fluoro-D-ribofuranose (X) (0.9569g; 2.21mmoL) cool off with the mixture of Glacial acetic acid (17.3mL) and aceticanhydride (1.50mL); to wherein dripping the catalyzer vitriol oil (0.23mL); drip and finish; move to room temperature, the continuous stirring 13 hours.Reaction mixture is poured in the water, and chloroform extraction merges organic phase, after saturated sodium bicarbonate solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying.Column chromatography for separation (ethyl acetate: sherwood oil=2: 9) get faint yellow oily compound (XI) (0.6547g), productive rate 64%;
1H-NMR(CDCl
3)δ：8.02～8.06(m，4H)，7.61～7.64(m，1H)，7.41～7.50(m，4H)，6.34(s，1H)，5.70～5.73(d，1H，J＝12.0Hz)，4.81～4.84(m，1H)，4.73～4.79(m，1H)，4.63～4.67(m，1H)，2.80～2.82(d，1H，J＝8.0Hz)，2.15(s，3H)。
Embodiment 5:
6-chloro-9-[3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-2-deoxidation-2-fluoro-α-D-arbinofuranose base]-preparation of 9H-purine (XII):
With 6-chloropurine (0.66g, 4.26mmol), hexamethyldisilazane (8ml), ammonium sulfate (0.34g, mixing suspension reflux 5h 2.58mmol) removes remaining hexamethyldisilazane under reduced pressure, yellow solid;
The above-mentioned white solid that obtains is dissolved in 1; get settled solution in the 2-ethylene dichloride (2mL); then with 1-acetoxy-3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-2-deoxidation-2-fluoro-D-ribofuranose (XI) (0.65g; 1.42mmol) be dissolved in 1; the solution that 2-ethylene dichloride (2mL) forms joins in the above-mentioned clarifying reaction liquid; (0.75mL, 6.39mmol), this reaction solution continues at room temperature to stir 14h to drip tin tetrachloride.Steaming desolventizes, and gets oily matter, after the ethyl acetate extraction dissolving, and after saturated sodium bicarbonate solution is washed, saturated common salt washing, anhydrous sodium sulfate drying.Steaming desolventizes, and column chromatography gets white solid (XII) (0.517g), and fusing point: 211-212 ℃, productive rate: 65%;
1H-NMR(CDCl
3)δ：8.94(s，1H)，8.67(s，1H)，8.09～8.11(m，2H)，8.03～8.05(m，2H)，7.67～7.70(m，1H)，7.51～7.54(m，2H)，7.44～7.46(m，2H)，6.88(s，1H)，5.90～5.93(dd，1H，J＝1.50Hz，J＝12.0Hz)，4.93～4.97(m，1H)，4.82～4.90(m，2H)，2.93～2.94(d，1H，J＝5.5Hz)。
Embodiment 6:
6-methoxyl group-9-[3-ethynyl-2-deoxidation-2-fluoro-beta (α)-D-arbinofuranose base]-preparation of 9H-purine (Ia):
To be equipped with in the there-necked flask of 100mL of reflux condensing tube; add 6-chloro-9-[3-benzoyl-5-(4-chlorobenzene formacyl)-3-ethynyl-2-deoxidation-2-fluoro-beta (α)-D-arbinofuranose base]-9H-purine (XII) (0.174g; 0.314mmol); salt of wormwood (0.132g; 0.942mmol); methyl alcohol (2.5mL); reflux 5 hours 20 minutes; stopped reaction; steaming desolventizes; column chromatography for separation (methyl alcohol: methylene dichloride=3: 97) get white solid compound (Ia), fusing point: 112-115 ℃, productive rate: 70%.
1H-NMR(DMSO-d6)δ：8.87(s，1H)，8.63(s，1H)，7.03(t，1H，J＝3.0Hz，J＝2.0Hz)，5.97(d，1H，J＝6Hz)，5.66～5.72(dd，1H，J＝6.0Hz，J＝26.5Hz)，5.637～5.642(d，1H，J＝2.5Hz)，5.01～5.03(t，1H，J＝5.0Hz，J＝6.0Hz，)，4.21～4.26(m，1H)，4.07(s，3H)，3.79～3.83(m，1H)，3.67～3.72(m，1H)。
The above, only being part embodiment of the present invention, is not that the present invention is done any pro forma restriction, any simple modification that every foundation technical spirit of the present invention is done the foregoing description, equivalent variations and modification all belong in the technical solution of the present invention scope.
Claims (2)
1. a glycosyl part has the nucleoside derivates that ethynyl and fluorine atom replace, and it is characterized in that having following general formula:
X represents base
(I)
Wherein, base is represented
2. the nucleoside derivate that has ethynyl and fluorine atom to replace in a kind of glycan molecule according to claim 1 is characterized in that:
Described R
1Expression hydroxyl or amino;
Described R
2Expression hydrogen atom or fluorine atom or bromine atoms or iodine atom or methyl;
Described R
3The expression hydroxyl or amino or-NHR ' or-NR " R ' " or C
1-C
4Alkoxyl group or C
1-C
3Alkylthio;
Described R
4Expression amino or fluorine atom;
Described R
5Expression amino or-NHR ' ,-NR " R ' " or alkoxyl group or carbamyl or ammonia formyl sulfide base;
Described R ' is C
1-C
4Alkyl, described R " be C
1-C
3Alkyl, described R ' " be C
1-C
3Alkyl;
Described R
6Expression amino or fluorine atom;
Described R
7Expression amino or hydrogen atom;
Described R
8Expression is amino.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100577860A CN101333235A (en) | 2007-06-29 | 2007-06-29 | Nucleoside derivates with ethynyl and fluor substituted glycosyl |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100577860A CN101333235A (en) | 2007-06-29 | 2007-06-29 | Nucleoside derivates with ethynyl and fluor substituted glycosyl |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101333235A true CN101333235A (en) | 2008-12-31 |
Family
ID=40196146
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100577860A Pending CN101333235A (en) | 2007-06-29 | 2007-06-29 | Nucleoside derivates with ethynyl and fluor substituted glycosyl |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101333235A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7902202B2 (en) | 2006-12-28 | 2011-03-08 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US8680071B2 (en) | 2010-04-01 | 2014-03-25 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US9243025B2 (en) | 2011-03-31 | 2016-01-26 | Idenix Pharmaceuticals, Llc | Compounds and pharmaceutical compositions for the treatment of viral infections |
-
2007
- 2007-06-29 CN CNA2007100577860A patent/CN101333235A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7902202B2 (en) | 2006-12-28 | 2011-03-08 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US7951789B2 (en) | 2006-12-28 | 2011-05-31 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US8691788B2 (en) | 2006-12-28 | 2014-04-08 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US9249173B2 (en) | 2006-12-28 | 2016-02-02 | Idenix Pharmaceuticals, Llc | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US8680071B2 (en) | 2010-04-01 | 2014-03-25 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| US9243025B2 (en) | 2011-03-31 | 2016-01-26 | Idenix Pharmaceuticals, Llc | Compounds and pharmaceutical compositions for the treatment of viral infections |
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Open date: 20081231 |