CN104530049A - Method for synthesizing fluorine-containing noncyclic nucleoside analog - Google Patents

Method for synthesizing fluorine-containing noncyclic nucleoside analog Download PDF

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CN104530049A
CN104530049A CN201410753737.0A CN201410753737A CN104530049A CN 104530049 A CN104530049 A CN 104530049A CN 201410753737 A CN201410753737 A CN 201410753737A CN 104530049 A CN104530049 A CN 104530049A
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acyclonucleosides
fluorine
thf
degrees celsius
fbsm
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CN104530049B (en
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郭海明
韩瑞杰
王东超
谢明盛
王海霞
张倩
渠桂荣
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Henan Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

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Abstract

The invention discloses a method for synthesizing fluorine-containing noncyclic nucleoside analog. The reaction equation is shown in the specification, wherein R1 is selected from one of methoxyl, ethyoxyl, piperidine, morpholine, dimethylamino and phenmethyl; and R2 is selected from one of H, NH2 and methoxyl. 5% of catalyst is adopted to obtain a product in a high-yield manner; the reaction method has the advantages that the operation is simple, the reaction condition is mild, the catalyst is cheap and easy to get, gram-grade reaction can be carried out, and the reaction can acquire more favorable products, therefore, a simple and practical synthetic method for synthesizing fluorine-containing noncyclic nucleoside analog is provided.

Description

A kind of method of synthesizing fluorine-containing acyclonucleosides analogue
Technical field
The present invention relates to chemistry and medical art, be specifically related to a kind of method of synthesizing fluorine-containing acyclonucleosides analogue.
Background technology
The nucleosides of structural modification and nucleotide derivative have good biological activity.Up to the present, gone on the market or dropped in the antiviral of clinical application, nucleoside medicine is seized of very large ratio.Nucleoside medicine can insert and be attached in the DNA chain of virus and suppress the synthesis of virus protein and the extension of DNA chain.So far, though acyclonucleosides and the nucleic acid drug of antiviral, anti-AIDS and the disease such as antitumor have obtained extensively research and development and application, but along with going deep into of studying nucleoside medicine, find that this medicine has the very shortcoming such as strong cytotoxicity and resistance, the discovery of acyclonucleosides class medicine, effectively solves this problem.Along with deepening continuously in recent years to acyclonucleosides research, had multiple acyclonucleosides class medicine to go on the market or dropped into clinical application, the antiviral therapy for the mankind opens new epoch.
The special status of acyclonucleosides class medicine in nucleoside medicine, has attracted the extensive concern of increasing chemist to the research of this compounds.The shortcomings such as the approach that report in the past synthesizes this compounds often exists complex steps, expensive starting materials, chiral source are not easy to obtain, develop acyclonucleosides class medicine that a kind of efficient method synthesis has potential source biomolecule activity remain chemist will faced by problem.The synthesis of nucleoside compound has attracted increasing scientist, and expects to find out to have excellent bioactive compound.
Summary of the invention
In order to solve the deficiencies in the prior art, seek a kind of acyclonucleosides nucleoside analog that is easy, green, the fluorine-containing side chain of synthesis efficiently, expensive based on this type of compou nd synthesis process Raw of solution, the problem of process complexity, the invention provides a kind of method of synthesizing fluorine-containing acyclonucleosides analogue.
Technical scheme of the present invention is: a kind of method of synthesizing fluorine-containing acyclonucleosides analogue, and reaction equation is as follows:
Wherein: R1 is selected from the one in following groups: methoxyl group, oxyethyl group, piperidines, morpholine, dimethylin, benzyl; R2 is selected from the one in following groups: H, NH2, methoxyl group.
Further improvement of the present invention comprises:
Make solvent with tetrahydrofuran (THF), to add catalyzer silver fluoride and raw material under air conditions, stirred at ambient temperature 20-40min, then adds FBSM and triethylamine, reacts to the end that reacts completely under subzero 5 degrees celsius, thin-layer chromatography chromatography detection reaction; Wherein: the structural formula of FBSM is:
Described fluorine-containing acyclonucleosides and analogue thereof are selected from any one in following 9 particular compound:
Preferred version of the present invention is: under-5 degrees celsius, by purine (10.0mmol), silver fluoride (0.5mmol, in THF 0.05eq) joining 50mL and tetrahydrofuran (THF), after stirring 30min, then added by FBSM (12mmol), slowly add triethylamine (20.0mmol), thin-layer chromatography detects to reacting completely.
The present invention, by using specific metal catalyst and reaction conditions, can obtain product with high yield.This reaction have simple to operate, reaction conditions is gentle, catalyzer is cheaply easy to get, can carry out several advantages such as gram order reaction, provides the synthetic method of a brief and practical for synthesizing fluorine-containing acyclonucleosides analogue.For the synthesis of nucleoside medicine and application provide reference value, for the research of novel antiviral and antitumor drug provides raw material.There is provided effective ways for other compounds build fluorine-containing side chain compound simultaneously, there is potential industrial application value.
Accompanying drawing explanation
Fig. 1 is the monocrystalline molecular structure of the embodiment of the present invention 1 product.
Fig. 2 is the monocrystalline molecular structure of extension products of the present invention.
Embodiment
Embodiment 1
Fluorine-containing acyclonucleosides reaction formula provided by the invention is as follows:
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 95% through column chromatography
1H NMR(CDCl 3,400MHz)δ8.55(s,1H),8.03(s,1H),7.92(d,J＝8.4Hz,4H),7.70(t,J＝7.2Hz,2H),7.54(t,J＝7.6Hz,4H),7.05(d,J＝14.4Hz,1H),6.41-6.34(m,1H),4.20(s,J＝3H),3.36(dd,J＝17.6,7.6Hz,2H). 13C NMR(CDCl 3,100MHz)δ.161.7,159.7,152.7,136.3,135.4,135.2,130.9,129.3,129.1,125.4,115.8,115.8,108.6,108.5,54.0,31.5,31.3. 19FNMR(CDCl 3,376MHz)-142.3.HRMS:calcd for C 22H 19FN 4O 5S 2[M+Na +]525.0673,found 525.0673
The synthesis of raw material:
Get a 100.0mL round-bottomed flask, add 6-chloropurine (10mmol, 1.92g), salt of wormwood (20.0mmol, 2.76g), methyl alcohol (50mL), refluxes 1 hour, question response bottle is cooled to room temperature, by solvent under reduced pressure distillation removing, then divide three extractions with H2O/EtOAc, organic phase is merged, with anhydrous sodium sulfate drying, crude product is through column chromatography for separation.Obtain target compound, productive rate 65%.White solid. 1H NMR(CDCl 3,400MHz)δ8.56(s,1H),8.06(s,1H),7.36(t,J＝6.6Hz,1H),5.70(d,J＝6.8Hz,2H),4.20(s,3H). 13C NMR(CDCl 3,100MHz)δ202.6,161.2,152.6,150.8,139.8,121.7,92.8,88.9,54.4.HRMS:calcd for C 9H 8N 4NaO[M+Na +]211.0590,found 211.0595.
The preparation of FBSM:
Under nitrogen protection; get 100mL round-bottomed flask; after nitrogen replacement, add (27.0g, 9.0mmol) two (benzenesulfonyl) methane under zero degrees celsius, be dissolved in 25ml tetrahydrofuran (THF); slowly add (240mg; 6mmol) sodium hydride, after stirring half an hour, adds 9mmol Selectfluor fluorine reagent; after reaction half hour, transfer to room temperature reaction 12 hours.After reaction terminates, add saturated ammonium chloride cancellation reaction, be extracted with ethyl acetate, anhydrous sodium sulfate drying, carry out column chromatography.
The synthesis of product:
1) synthesis of product 1
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 99%. through column chromatography 1h NMR (CDCl 3, 400MHz) and δ 8.55 (s, 1H), 8.03 (s, 1H), 7.92 (d, J=8.4Hz, 4H), 7.70 (t, J=7.2Hz, 2H), 7.54 (t, J=7.6Hz, 4H), 7.05 (d, J=14.4Hz, 1H), 6.41-6.34 (m, 1H), 4.20 (s, J=3H), 3.36 (dd, J=17.6,7.6Hz, 2H). 13c NMR (CDCl 3, 100MHz) and δ .161.7,159.7,152.7,136.3,135.4,135.2,130.9,129.3,129.1,125.4,115.8,115.8,108.6,108.5,54.0,31.5,31.3. 19f NMR (CDCl 3, 376MHz) and-142.3.HRMS:calcd for C 22h 19fN 4o 5s 2[M+Na +] 525.0673, found 525.0673
We have taken the monocrystalline of this product, specifically as shown in Figure 1,
Embodiment 2
2) synthesis of product 2
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 85%. through column chromatography
1H NMR(CDCl 3,400MHz)δ7.91(d,J＝7.6Hz,4H),7.80(s,1H),7.69(t,J＝7.2Hz,2H),7.52(t,J＝7.6Hz,4H),6.95(d,J＝14.4Hz,1H),6.47-6.40(m,1H),4.16(s,3H),4.04(s,3H),3.36(dd,J＝17.2,7.6Hz,2H),
13C NMR(CDCl 3,100MHz)δ162.2,152.3,138.0,135.5,135.4,135.1,130.9,130.9,129.2,125.3,117.7,109.6,109.5,55.4,54.5,31.7,31.5, 19F NMR(CDCl 3,376MHz)-141.7.
HRMS:calcd for C 23H 21FN 4O 6S 2[M+Na +]555.0779,found 555.0779
Embodiment 3
3) synthesis of product 3
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 86%. through column chromatography
1H NMR(CDCl 3,400MHz)δ8.32(s,1H),7.94(d,J＝8.4Hz,4H),7.82(s,1H),7.70(t,J＝7.2Hz,2H),7.55(t,J＝7.6Hz,4H),7.0(d,J＝14.4Hz,1H),6.22-6.15(m,1H),3.55-3.30(m,8H),
13C NMR(CDCl 3,100MHz)δ154.8,152.8,149.6,135.4,135.2,135.1,130.9,129.2,125.3,120.2,115.6,112.9,108.9,108.9,60.4,38.6,38.6,31.6,31.4,14.2, 19F NMR(CDCl 3,376MHz)-142.2.
HRMS:calcd for C 23H 22FN 5O 4S 2[M+Na +]538.0989,found 538.0985,
Embodiment 4
4) synthesis of product 4
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 84%. through column chromatography
1H NMR(CDCl 3,400MHz)δ7.74(s,1H),7.18(t,J＝6.4Hz,1H),5.63(d,J＝6.4Hz,2H),4.94(s,2H),4.07(s,3H),
13C NMR(CDCl 3,100MHz)δ202.5,161.7,159.6,137.0,115.8,95.4,92.8,88.4,54.0, 19FNMR(CDCl 3,376MHz)-142.3HRMS:calcd for C 22H 20FN 5O 5S 2[M+Na +]540.0782,found540.0784
Embodiment 5
5) synthesis of product 5
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 89%. through column chromatography
1H NMR(CDCl 3,400MHz)δ8.30(s,1H),7.92(d,J＝7.6Hz,4H),7.81(s,1H),7.69(t,J＝7.6Hz,2H),7.54(t,J＝8Hz,4H),6.99(d,J＝14.8Hz,1H),6.21-6.13(m,1H),4.22((s,4H),3.32(dd,J＝18,7.6Hz,2H),1.71(s,6H),
13C NMR(CDCl 3,100MHz)δ153.7,152.9,149.8,135.5,135.1,134.9,130.9,129.2,125.3,119.8,115.5,112.8,109.0,108.9,46.6,46.5,46.5,46.4,46.3,31.7,31.5,26.1,24.8,
19F NMR(CDCl 3,376MHz)-142.1
HRMS:calcd for C 26H 26FN 5O 4S 2[M+H +]556.1483,found 556.1483
Embodiment 6
6) synthesis of product 6
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 89%. through column chromatography
1H NMR(CDCl 3,400MHz)δ8.28(s,1H),7.93(d,J＝8Hz,4H),7.78(s,1H),7.65(t,J＝7.2Hz,2H),7.50(t,J＝8Hz,4H),6.96(d,J＝14.4Hz,1H),6.19-6.12(m,1H),4.09(s,2H),3.70(s,2H),3.30(dd,J＝17.6,7.6Hz,2H),2.36(s,1H),1.99(d,J＝22.4Hz,4H),
13C NMR(CDCl 3,100MHz)δ161.0,152.8,150.9,139.3,135.5,135.0,130.9,129.2,125.1,121.7,115.5,110.4,110.4,63.4,31.6,31.4,14.5,
19F NMR(CDCl 3,376MHz)-142.2
HRMS:calcd for C 25H 24FN 5O 4S 2[M+Na +]546.1146,found 546.1149
Embodiment 7
7) synthesis of product 7
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 80%. through column chromatography
1H NMR(CDCl 3,400MHz)δ8.52(s,1H),8.01(s,1H),7.92(d,J＝7.6Hz,4H),7.69(t,J＝7.6Hz,2H),7.53(t,J＝7.6Hz,4H),7.04(d,J＝14.4Hz,1H),6.39-6.32(m,1H),3.36(dd,J＝17.2,7.2Hz,2H),1.51(t,J＝6.8Hz,3H),
13C NMR(CDCl 3,100MHz)δ161.0,152.8,150.9,139.3,135.5,135.0,130.9,129.2,125.1,121.7,110.4,110.4,63.4,31.6,31.4,14.5,
19F NMR(CDCl 3,376MHz)-142.2
HRMS:calcd for C 23H 21FN 4O 5S 2[M+Na +]539.0830,found 539.0830
Embodiment 8
8) synthesis of product 8
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, solvent is made with the THF newly steamed and tetrahydrofuran (THF), stir 30min under subzero 5 degrees Celsius, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 80%. through column chromatography
1H NMR(CDCl 3,400MHz)δ8.89(s,1H),8.20(s,1H)7.93(d,J＝8.4Hz,4H),7.71(d,J＝7.2Hz,2H),7.55(t,J＝7.6Hz,4H),7.10(d,J＝14.4Hz,1H),6.52-6.44(m,1H),3.40(dd,J＝17.2,7.6Hz,2H),1.47(s,18H),
13C NMR(CDCl 3,100MHz)δ152.7,152.1,150.7,150.3,142.1,135.5,135.0,130.9,129.2,129.1,124.8,111.2,111.2,84.0,31.6,31.5,27.7,
19F NMR(CDCl 3,376MHz)-142.7
HRMS:calcd for C 31H 33FN 5O 8S 2[M+Na +]744.1335,found 744.1334
Embodiment 9
(9) synthesis of product 9
Get a Xiu Langke pipe, with the silver fluoride of 5mol% and (0.3mmol) purine, make solvent with the THF newly steamed, under subzero 5 degrees Celsius, stir 30min, then add FBSM substrate (0.36mmol) successively, slowly inject (0.6mmol) triethylamine with syringe.Subzero 5 degrees Celsius of reactions.(TLC) is detected by thin layer plate; Target product is obtained, yield 87%. through column chromatography
1H NMR(CDCl 3,400MHz)δ8.32(s,1H),7.92(d,J＝7.6Hz,4H),7.84(s,1H),7.69(t,J＝7.6Hz,2H),7.53(t,J＝7.6Hz,4H),7.01(d,J＝14.4Hz,1H),6.27-6.20(m,1H),4.28(s,4H),3.82(t,J＝4.4Hz,4H),3.33(dd,J＝17.6,7.6Hz,2H),
13C NMR(CDCl 3,100MHz)δ153.8,152.8,150,135.6,135.5,135.0,130.9,129.2,125.2,120,115.5,112.8,109.4,109.3,67.0,45.7,45.6,45.6,45.5,45.5,31.7,31.5,
19F NMR(CDCl 3,376MHz)-141.9
HRMS:calcd for C 25H 24FN 5O 5S 2[M+H +]558.1276,found 558.1275
According to the inventive method, synthesize 9 compounds altogether, specific as follows:
And we have carried out next step extension to the product of our synthesis, react as follows
In order to determine the configuration of extension products, we have cultivated the monocrystalline of this product, and characterize it, specifically as shown in Figure 2.
Embodiment 10
Under-5 degrees celsius, by purine (10.0mmol), silver fluoride (0.5mmol, in THF 0.05eq) joining 50mL and tetrahydrofuran (THF), after stirring 30min, then added by FBSM (12mmol), slowly add triethylamine (20.0mmol), thin-layer chromatography detects to reacting completely.
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.

Claims (4)

1. synthesize a method for fluorine-containing acyclonucleosides analogue, it is characterized in that, reaction equation is as follows:
Wherein: R1 is selected from the one in following groups: methoxyl group, oxyethyl group, piperidines, morpholine, dimethylin, benzyl;
R2 is selected from the one in following groups: H, NH2, methoxyl group.
2. a kind of method of synthesizing fluorine-containing acyclonucleosides analogue according to claim 1, it is characterized in that, solvent is made with tetrahydrofuran (THF), to add catalyzer silver fluoride and raw material under air conditions, stirred at ambient temperature 20-40min, then add FBSM and triethylamine, react under subzero 5 degrees celsius to the end that reacts completely, thin-layer chromatography chromatography detection reaction; Wherein: the structural formula of FBSM is:
3. a kind of method of synthesizing fluorine-containing acyclonucleosides analogue according to claim 1, is characterized in that, described fluorine-containing acyclonucleosides and analogue thereof are selected from any one in following 9 particular compound:
4. a kind of method of synthesizing fluorine-containing acyclonucleosides analogue according to claim 1, it is characterized in that, it is characterized in that, under-5 degrees celsius, by purine (10.0mmol), silver fluoride (0.5mmol, in THF 0.05eq) joining 50mL and tetrahydrofuran (THF), after stirring 30min, then FBSM (12mmol) is added, slowly add triethylamine (20.0mmol), thin-layer chromatography detects to reacting completely.
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