CN114249730A - One-step synthesis method of 2 '3' -dideoxynucleoside - Google Patents
One-step synthesis method of 2 '3' -dideoxynucleoside Download PDFInfo
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- 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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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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Abstract
The invention discloses a one-step synthesis method of 2 '3' -dideoxynucleoside. Mixing alkaloid (I) and saturated ether R4OCH2R5Under the action of a catalyst and an oxidant, the reaction is directly carried out at a certain temperature, and the 2 '3' -dideoxy nucleoside is synthesized in one step; in the synthetic method of the invention, ether can be converted into a highly electrophilic carbonyl ylide intermediate under the combined action of a catalyst, a ligand and an oxidant, the alkaloid (I) has better nucleophilic reaction activity due to the lone electron pair on the nitrogen atom, can attack the electrophilic carbonyl ylide intermediate generated in situ in the reaction, and the two are combined to react to generate the final 2 '3' -dideoxynucleoside product.The reaction byproducts are only water and tert-butyl alcohol, and the method has no pollution to the environment.
Description
Technical Field
The invention belongs to the field of organic chemical industry, relates to preparation of organic compound molecules, and particularly relates to a one-step synthesis method of 2 '3' -dideoxynucleoside.
Background
2 '3' -dideoxynucleosides are basic frameworks of a plurality of medicines, are core components of DNA sequencing reagents by a dideoxy method, and are widely regarded and applied. For example, 2 '3' -dideoxynucleosides are the core structures of many antiviral drugs, and particularly have good inhibition effect on HIV. For example, dideoxyinosine (ddI), dideoxycytidine (ddC), dideoxythymidine (ddT) have been approved for clinical use in some countries, and dideoxythymidine (D4T) has been introduced into phase I/II clinical trials. Common drugs include didanosine and zalcitabine. Meanwhile, the 2 '3' -dideoxynucleoside is also a core fragment of a chain reaction terminator in a DNA sequencing reagent and can be used for DNA sequence analysis. The main components of sequencing reagents are commonly used, such as Amino-Terminated 18-ddUTP.
Currently, there are three main methods for synthesizing 2 '3' -dideoxynucleosides. Firstly, modifying the base part or glycosyl part of the existing N-alkyl alkaloid; secondly, the compound is synthesized by directly constructing glycosidic bonds; thirdly, it is constructed by de novo synthesis of sugar or base moieties:
(1) modifying the base moiety or the glycosyl moiety of an existing N-alkyl alkaloid. In 1988, Hiroshi group reported that uridine was converted to 2',3' -O-methoxymethylene uridine under the action of catalytic amount of p-toluenesulfonic acid, followed by elimination reaction in the presence of anhydrous acetic acid to obtain dideoxy unsaturated uridine, which was subjected to palladium-carbon catalytic hydrogenation to obtain saturated dideoxy uridine (Hiroshi, S.; Yasuo, I.; Hideyuki, S.; Kenzo, Y.; Naohiko, Y. Synthesis of 2',3' -dideoxyuridine via deoxidation of 2',3' -O- (methoxethylene) uridine [ J. J.Org. Chem.1988,53: 5170-. In 2011, Nicolai et al reported that a benzimidazole substituent could be introduced at the 5-position of a pyrimidine nucleoside via a CuAAC (copper catalyzed alkyl azide cycloaddition) reaction. Pi-pi overlap of the benzimidazole moieties of these two pyrimidine nucleosides can form oligosaccharide nucleic acids RNA and DNA with extremely high thermal stability in duplex and triple helix structures (Nicolai, K.A.; Holger, D.; Frank, J.; Birte, V.; Poul, N.duplex and triple formation of mixed pyridine oligonucleotides with standing of phenyl-triazine moieties in the major groove [ J ]. J.Org.Chem.2011,76: 6177-. This method is generally lengthy, requires the use of toxic catalysts, and is difficult to precisely target a specific site.
(2) Synthesized by direct construction of glycosidic linkages. The direct construction of glycosidic linkages generally employs the reaction of alpha-halo, alpha-acetyl, alpha-thioribose with alkaloids. In 1995, Helmut reacted TMS-protected thymine with an α -halogenated furanose derivative in toluene solvent using tin chloride as a catalyst to obtain an N-alkyl compound of thymine (a. Helmut, V.Adventure, in silica [ J ]. Org.Chem.1995,28:509-520. b.Niedbaila, U.S.; Vorbrugen, H.Synthesis of nucleotides.9. general synthesis of N-glycosides.I.Synthesis of pyridine nucleotides [ J.. J.Org.Chem.1974,39: 3654-. In 1990 Lee et al used acetonitrile as a solvent to catalyze the reaction of TMS-protected purine and alpha-acetyl deoxyfuranose with cesium chloride to successfully construct N-alkyl alkaloids (Lee, C.H.; Kim, J.Y.; Kim, W.J.; Kim, Y.H. simple synthesis of tetrahydro-2-alkylated pyrimidines and hydrocarbons using a new catalyst of medium chloride [ J ]. Heterocycles.1990,31:211- "214). In 1991, Sugimura et al activated α -phenylthiofuranose in dichloromethane solvent in the presence of NBS and reacted with TMS-protected thymine to construct an N-alkyl compound of thymine (Sugimura, H.; Osumi, K.; Yamazaki, T.; Coupling reaction of 1-thiofuran with a substituted pyridine bases by activation with N-bromosuccinimide: synthesis of 3'-azido-3' -deoxyribose and related substituted nucleoside analog [ J ]. Terhe Lett.1991,32: 1813-one 1816). The method can successfully synthesize the N-alkyl alkaloid with high efficiency, but the Lewis acid and the multi-step synthesis of the alpha-substituted ribose and the ribose protected by the sugar hydroxyl are all needed.
(3) Construction is by de novo synthesis of sugar or base moieties. In 2007, the Kim group used 1, 3-dihydroxyacetone as the starting material, synthesized alpha-acetylfuranose derivatives through multi-step reactions, and then acted on alkaloids under the catalysis of Lewis acid, successfully constructed N-alkyl alkaloids (Aihong, K.; Joon, H.H. Recemic synthesis and antiviral evaluation of 4 '-alpha-hydroxy-ethoxy and 6' -alpha-methyl substistuted immunogenic Nucleotides [ J ]. Nucleotides, nucleotide acids.2007,26: 291-302). In 1988, Masami et al used glutamic acid as a starting material, and obtained TBS-protected α -acetyl deoxyribose through multi-step reaction, and then the ribose further reacted with TMS-protected cytosine under the catalysis of Lewis acid to obtain an important anti-HIV drug ddC (Masami, O.; Ruen, C.S.; Setve, Y.K.T.; Louis, J.T.; David, L.C.Synthesis of the dideoxynucleosides ddC and CNT from glutamic acid riboside lactone, and pyridine bases [ J.Org.Chem.1988,53: 4780-4786). The direct synthesis method has the disadvantages of multiple steps, long reaction time and low final yield, and limits the popularization and application of the technology.
Therefore, it is necessary to develop a novel, efficient and simple method for synthesizing 2',3' -dideoxynucleosides. In recent years, transition metal catalyzed vicinal sp heteroatoms have been used3C-H direct functional groups have been extensively studied, using copper or iron catalyzed ortho-sp positions of saturated ether oxygen atoms3Many advances have also been made with direct C-H amination. Based on the basis, the invention provides that the 2 '3' -dideoxynucleosides can be directly constructed by catalyzing the reaction of saturated ether and alkaloid by redox transition metal salt (such as copper salt or iron salt).
Disclosure of Invention
The invention aims to provide a simple and efficient novel method for synthesizing 2',3' -dideoxynucleosides aiming at the defects of the existing synthetic method. The method avoids the defects of long steps, low efficiency, need of using toxic and harmful reagents and the like of the traditional production method, and is convenient to use in laboratories and industrial production.
The invention provides a method for preparing alkaloid (I) and saturated ether R4OCH2R5Under the action of a catalyst and an oxidant, the reaction is directly carried out at a certain temperature, and the 2 '3' -dideoxy nucleoside is synthesized in one step; the reaction equation is as follows:
wherein, X is selected from one of O atom or H atom; y is selected from one of N atom, methine CH or Boc protected methine; z is selected from carbonyl C ═ O, C-NBoc2One of (1); r2And R3Each independently selected from Cl, H, NBoc2One of (1); n represents one of 0 or 1; r4And R5Each independently selected from one of open-chain or cyclic alkyl, aryl or heteroaryl with 1-6 carbon atoms; the dotted line represents that the bond may or may not be presentAre present.
Preferably, the alkaloid (I) is one selected from 2, 6-dichloropurine, 6-chloropurine, bis-Boc-adenine, bis-Boc-6-chloro-2-aminopurine, Boc-thymine and bis-Boc-cytosine alkaloid;
preferably, the saturated ether is one selected from tetrahydrofuran, n-butyl ether, tetrahydropyran, 1, 4-dioxane, isochroman, 2-methyltetrahydrofuran and formaldehyde diethyl acetal.
Preferably, the catalyst employs a redox transition metal salt; the main role in the reaction is to promote the decomposition of the oxidant, assisting the dehydrogenation of saturated ethers to produce highly electrophilic carbonyl ylide intermediates.
More preferably, the catalyst is copper salt or iron salt.
Preferably, the molar ratio of the alkaloid (I) to the catalyst is 1: 0.5% -500%; the catalyst is used in a small amount because the catalyst can be recycled in the reaction and is not consumed in the whole reaction. According to the reaction principle, the reaction rate is closely related to the amount of the catalyst used in the reaction, the reaction speed is slow when the concentration of the catalyst is low, and the reaction speed is fast when the concentration of the catalyst is low, but the reaction cost is increased and waste is caused when the amount of the catalyst is increased infinitely instead of increasing the reaction rate infinitely.
Preferably, a ligand can also be added; the ligand has the main function of improving the solubility and catalytic activity of the catalyst by coordinating with catalytic metal ions in the reaction.
More preferably, the ligand is a bidentate nitrogen ligand, and 2,2 '-bipyridyl, 1, 10-phenanthroline, N-dimethylethylenediamine, N' -tetramethylethylenediamine can be adopted.
Preferably, the molar ratio of the alkaloid (I) to the ligand is 1: 0.01-1; the ligand is used in a small amount because the ligand can be recycled in the reaction and is not consumed in the whole reaction. According to the reaction principle, the ligand plays a role in improving the reaction efficiency by coordinating with the catalyst.
The oxidant mainly plays a role in decomposing to form an oxidizing species and promoting the dehydrogenation of saturated ether to generate the high electrophilic carbonyl ylide in the reaction, so the oxidant adopts an inorganic oxidant or an organic oxidant.
Preferably, the oxidizing agent is an organic peroxide.
Preferably, the molar ratio of the alkaloid (I) to the oxidant is 1: 1-20. The amount of the oxidizing agent to be used is not less than the stoichiometric amount required in the present invention in order to ensure sufficient conversion of the reaction materials because it is consumed and decomposed in the reaction, and too little lowers the reaction yield. However, excessive oxidizing agents do not lead to infinite increase in reaction yield, and are associated with risks of explosion and waste.
Preferably, the molar ratio of the saturated ether to the alkaloid is not less than 2: 1. The saturated ether serves as a substrate for the reaction and also serves as a reaction solvent to fully dissolve the reaction reagent, so that a condition that the reaction substrates are contacted with each other and the reaction is carried out is provided. Thus, the saturated ethers are used in large excess in the present invention.
Preferably, the reaction temperature is 25-70 ℃ and the reaction time is 3-72 hours.
The beneficial effects of the invention are as follows:
(1) the synthesis route is direct, a one-pot method is adopted, and various substrate reactions have better yield;
(2) ether is used for replacing protected ribose or alpha is used for replacing ribose to directly react with alkaloid, and the multi-step reaction of the traditional method is shortened to one step;
(3) cheap and nontoxic copper salt or iron salt is used as a catalyst, so that precious metal and toxic Lewis acid are avoided;
(4) the ligand selection range is wide.
(5) The ether is a substrate and a solvent in the reaction, and other solvents are not required to be added;
(6) the reaction byproducts are only water and tert-butyl alcohol, so that the environment is not polluted;
(7) the reaction condition is mild, the time is short, and inert gas protection is not needed.
Detailed Description
As described above, in view of the deficiencies of the prior art, the present inventors have made extensive studies and extensive practices, and propose a technical solution of the present invention, which is mainly based on at least: (1) in the synthetic method of the invention, ether can be converted into a highly electrophilic carbonyl ylide intermediate under the combined action of a catalyst, a ligand and an oxidant, the alkaloid (I) has better nucleophilic reaction activity due to the lone electron pair on the nitrogen atom, can attack the electrophilic carbonyl ylide intermediate generated in situ in the reaction, and the two are combined to react to generate the final 2 '3' -dideoxynucleoside product. (2) the synthesis method disclosed by the invention for synthesizing the 2 '3' -dideoxynucleoside has the following conditions: one of the substrates should have an amino NH structure containing a lone electron pair, and the other substrate should have a-OCH-saturated ether structure containing at least one hydrogen atom; and secondly, the reaction is carried out in the presence of a catalyst, a ligand and an oxidant. From these results, it is understood that 2 '3' -dideoxynucleosides can be synthesized using alkaloids and saturated ethers having different structures, provided that the above-described two conditions are satisfied, and that sufficient time is available.
In order to make the objects, technical schemes and advantages of the present invention more clear, the reaction principle of the 2 '3' -dideoxynucleoside synthesis method of the present invention is further explained.
The catalyst in this example is exemplified by a copper catalyst and the oxidizing agent is exemplified by t-butanol peroxide, TBHP. The reaction of the invention mainly comprises five steps: in the first step, tert-butyl peroxy alcohol is decomposed into tert-butyl peroxy radical (I) and proton under the action of copper catalyst, and bivalent copper is reduced into monovalent copper; secondly, the generated monovalent copper reacts with tert-butyl peroxide to generate tert-butyl oxygen free radical (II), and the tert-butyl oxygen free radical is re-oxidized into bivalent copper; thirdly, reacting the tert-butyl oxygen free radical (II) with saturated ether to obtain an alkyl free radical (III); fourthly, reacting the alkaloid with alkyl free radical (III) or tert-butyl oxygen free radical (II) to generate amino free radical (IV); in the fifth step, the amino radical (IV) is combined with the alkyl radical (III) to give the final product 2 '3' -dideoxynucleoside.
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To determine the most preferred reaction conditions for the process of the invention, 24 experiments were carried out in sequence with the most commonly used alkaloids 2, 6-dichloropurine and THF as substrates in the presence of different catalysts, different ligands, different oxidants, different reaction temperatures, different reaction times and different saturated ether volumes, etc. according to Table 1. Wherein the dosage of each raw material is as follows: 1mmol of 2, 6-dichloropurine, 0.1mmol of catalyst, 0.1mmol of ligand and 5mmol of oxidant.
TABLE 1 comparison of experimental data for the synthesis of 2 '3' -dideoxynucleosides under different reaction conditions
From the above experimental results, it can be seen that: the reaction can be carried out under the condition of no ligand, and the product yield is 38%; the reaction can be promoted by adding the bidentate nitrogen ligand, and when 2, 2' -bipyridine is used as the ligand, the reaction yield reaches 65 percent at most; various monovalent and divalent copper salt catalysts can promote the reaction, and the reaction yield is between 38 and 65 percent; the reaction can be smoothly carried out in ether with different molar dosages, and when the ether dosage is 1-74 millimole, the reaction yield is 20-74%; various different types of oxidants can be used, and the product yield is 20-74%; the reaction can be carried out in a certain temperature range, and when the reaction temperature is set between room temperature and 70 ℃, the reaction yield is between 30 and 74 percent; the reaction time can be shortened and prolonged, and when the reaction time is 3-48 hours, the reaction yield is 29-74%.
The technical solutions of the present invention are further explained below with reference to some preferred embodiments, but the experimental conditions and the setting parameters should not be construed as limitations of the basic technical solutions of the present invention. And the scope of the present invention is not limited to the following examples.
Example 1
1mmol of 2, 6-dichloropurine, 24.7mmol of tetrahydrofuran, 5mmol of tert-butyl peroxide, 0.1mmol of 2, 2' -bipyridine and 0.1mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive tetrahydrofuran is evaporated in a rotary manner, and the reaction yield is 74 percent calculated by the ratio of 191 mg of the product to 258 mg of the theoretical yield through silica gel column chromatography separation. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ8.23(s,1 H),6.32(t,J＝4.2Hz,1H),4.21(dd,J＝14.4Hz,7.8Hz,1H),4.10(dd,J＝16.0Hz,7.6 Hz,1H),2.56(m,2H),2.17(m,2H)；13C NMR(100MHz,CDCl3) δ 152.7,152.1,151.6, 144.1,131.4,86.7,70.1,32.7,24.2. the product was subjected to high resolution mass spectrometry and the test data were: HRMS (EI) Calcd for C9H8Cl2N4O:[M]+258.0075；Found,258.0079.
Example 2
1mmol of 6-chloropurine, 24.7mmol of tetrahydrofuran, 5mmol of tert-butanol peroxide, 0.1mmol of 2, 2' -bipyridine and 0.1mmol of copper chloride were placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive tetrahydrofuran is distilled out, 146 mg of product is obtained by silica gel column chromatography, and the reaction yield is 65 percent calculated by the ratio of the theoretical yield to 225 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows: 1H NMR (400MHz, CDCl3, TMS) δ 8.75(s, 1H), 8.24(s,1H),6.36(dd, J ═ 5.6Hz,2.6Hz,1H),4.32(dd, J ═ 10.8Hz,6.6Hz,1H),4.11 (dd, J ═ 10.8Hz,7.8Hz,1H),2.59(m,2H),2.18(m, 2H); 13C NMR (100MHz, CDCl3) delta 151.8,151.0,150.9,143.4,132.4,86.6,69.9,32.5,24.2 the product was tested by high resolution mass spectrometry to give the following data: HRMS (ESI) Calcd for C9H9ClN4O:[M+H]+225.0538；Found,225.0546.
Example 3
1mmol of bis-Boc-adenine, 24.7mmol of tetrahydrofuran, 5mmol of t-butanol peroxide, 0.1mmol of 2, 2' -bipyridine and 0.1mmol of copper chloride were charged in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive tetrahydrofuran is evaporated in a rotary manner, and the product 207 mg is obtained by silica gel column chromatography separation, and the reaction yield is 51 percent calculated by the ratio of the theoretical yield to 406 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,d6-DMSO)δ8.85(s,1H), 8.75(s,1H),6.41(dd,J＝6.4Hz,3.6Hz,1H),4.16(dd,J＝14.8Hz,7.6Hz,1H),3.94(dd, J＝14.4Hz,7.0Hz,1H),2.44-2.55(m,2H),2.23(m,1H),2.06(m,1H),1.38(s,18H)；13C NMR(100MHz,CDCl3)δ152.5,151.9,150.5,150.2,142.9,129.5,86.2,83.7,69.8, 32.4,27.8,24.3. the product was subjected to high resolution mass spectrometry and the test data was: HRMS (ESI) Calcd for C19H27N5O5:[M+H]+406.2085；Found,406.2094.
Example 4
1mmol of bis-Boc-6-chloro-2-aminopurine, 24.7mmol of tetrahydrofuran, 5mmol of t-butanol peroxide, 0.1mmol of 2, 2' -bipyridine and 0.1mmol of copper chloride were charged in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive tetrahydrofuran is evaporated in a rotary manner, and the product 242 mg is obtained by silica gel column chromatography separation, and the reaction yield is 55 percent calculated by the ratio of the theoretical yield of 439 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ8.24(s,1 H),6.30(dd,J＝6.0Hz,2.4Hz,1H),4.29(dd,J＝14.4Hz,6.4Hz,1H),4.08(dd,J＝13.0 Hz,7.4Hz,1H),2.47-2.60(m,2H),2.12-2.19(m,2H),1.45(s,18H)；13C NMR(100 MHz,CDCl3) δ 151.7,151.6,151.0,150.6,144.4,130.7,86.8,83.6,70.0,32.5,27.9,24.2. the product was subjected to high resolution mass spectrometry and the data obtained were: HRMS (EI) Calcd for C19H26ClN5O5:[M]+ 439.1622；Found,439.1635.
Example 5
1mmol of 4-chloro-pyrrolo [2,3-d ] pyrimidine, 24.7mmol of ml of tetrahydrofuran, 5mmol of tert-butanol peroxide, 0.1mmol of 2, 2' -bipyridine and 0.2mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive tetrahydrofuran is evaporated in a rotary manner, and the reaction yield is 55 percent by calculating the ratio of 123 mg of the product to 224 mg of the theoretical yield through silica gel column chromatography separation. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ8.64(s,1 H),7.37(d,J＝4.4Hz,1H),6.62(d,J＝4.0Hz,1H),6.53(dd,J＝6.8Hz,3.6Hz,1H), 4.21-4.27(m,1H),4.01-4.07(m,1H),2.46-2.55(m,1H),2.25-2.42(m,1H),2.12-2.21(m, 2H)；13C NMR(100MHz,CDCl3) δ 152.0,150.6,150.5,126.2,118.2,99.9,85.3,69.3,32.5, 24.7. the product was subjected to high resolution mass spectrometry and the test data were: HRMS (ESI) Calcd for C10H10ClN3O: [M+H]+224.0580；Found,224.0592
Example 6
1mmol of Boc-thymine, 24.7mmol of tetrahydrofuran, 5mmol of tert-butyl peroxide, 0.1mmol of 1, 10-phenanthroline-5, 6-dione and 0.2mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive tetrahydrofuran is distilled out, 172 mg of product is obtained by silica gel column chromatography, and the reaction yield is 58 percent calculated by the ratio of the theoretical yield to 296 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ7.58(m,1 H),6.64(dd,J＝8.0Hz,4.4Hz,1H),4.33(dd,J＝15.2Hz,6.8Hz,1H),3.93(m,1H), 2.46(m,1H),2.35(m,1H),2.22(m,1H),1.99(m,1H),1.93(d,J＝1.2Hz,1H),1.59(s, 9H)；13C NMR(100MHz,CDCl3) δ 163.2,148.6,147.8,133.5,111.6,86.5,85.1,70.6,28.8, 27.8,26.5,13.2. the product was subjected to high resolution mass spectrometry and the test data were: HRMS (EI) Calcd for C14H20N2O5:[M]+296.1372；Found,296.1372.
Example 7
1mmol of bis-Boc-cytosine, 24.7mmol of tetrahydrofuran, 5mmol of tert-butyl peroxide, 0.1mmol of 1, 10-phenanthroline-5, 6-dione and 0.2mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive tetrahydrofuran is distilled out, and 153 mg of the product is obtained by silica gel column chromatography separation, and the reaction yield is 40 percent calculated by the ratio of the theoretical yield to 382 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ7.73(d,J ＝7.6Hz,1H),7.03(d,J＝7.6Hz,1H),6.00(dd,J＝6.0Hz,2.4Hz,1H),4.23(m,1H), 4.03(m,1H),2.47(m,1H),2.14(m,1H),2.02(m,1H),1.79(m,1H),1.56(s,18H)；13C NMR(100MHz,CDCl3) δ 162.4,154.4,149.7,142.6,95.6,88.9,84.8,70.5,33.2,27.7,23.4. the product was subjected to high resolution mass spectrometry and the test data were: HRMS (EI) Calcd for C18H27N3O6:[M+H]+ 382.1973；Found,382.1980.
Example 8
1mmol of 2, 6-dichloropurine, 12mmol of n-butyl ether, 5mmol of tert-butyl alcohol peroxide, 0.1mmol of 1, 10-phenanthroline-5, 6-diketone and 0.2mmol of copper chloride are put into a reactor and stirred for 24 hours at the temperature of 70 ℃. After the reaction is finished, excessive ether is evaporated in a rotary manner, and the product of 127 mg is obtained by silica gel column chromatography, and the reaction yield is 40 percent calculated by the ratio of the theoretical yield to 316 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ8.29(s,1 H),5.79(dd,J＝7.2Hz,6.0Hz,1H),3.49(m,1H),3.30(m,1H),2.13(m,1H),1.92(m,1 H),1.47-1.57(m,4H),1.29-1.38(m,4H),0.97(t,J＝7.6Hz,3H),0.88(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3) Delta 153.1,153.1,151.8,143.6,130.7,85.6,69.7,38.4,31.2,19.1, 18.1,13.7,13.5. the product was tested by high resolution mass spectrometryThe test data obtained were: HRMS (EI) Calcd for C13H18Cl2N4O:[M]+316.0858；Found,316.0856.
Example 9
1mmol of 2, 6-dichloropurine, 20.5mmol of tetrahydropyran, 5mmol of tert-butyl peroxide, 0.1mmol of 2, 2' -bipyridine and 0.1mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive ether is evaporated in a rotary manner, and the product 158 mg is obtained by silica gel column chromatography separation, and the reaction yield is 58 percent calculated by the ratio of the theoretical yield to 272 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ8.34(s,1 H),5.77(dd,J＝10.8Hz,2.4Hz,1H),4.19(m,1H),3.78(m,1H),2.18(m,1H),2.09(m, 1H),1.98(m,1H),1.72-1.86(m,2H),1.67-1.70(m,1H)；13C NMR(100MHz,CDCl3) δ 152.9,152.2,151.7,143.7,130.8,82.5,68.9,32.0,24.7,22.5. the product was subjected to high resolution mass spectrometry and the test data were: HRMS (EI) Calcd for C10H10Cl2N4O:[M]+272.0232；Found,272.0236.
Example 10
1mmol of 2, 6-dichloropurine, 23.5mmol of 1, 4-dioxane, 5mmol of tert-butyl peroxide, 0.1mmol of 2, 2' -bipyridine and 0.2mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive ether is evaporated in a rotary manner, and the product of 140 mg is obtained by silica gel column chromatography separation, and the reaction yield is 51 percent calculated by the ratio of the theoretical yield to 275 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ8.55(s,1 H),6.02(dd,J＝5.6Hz,2.8Hz,1H),4.21(dd,J＝12.4Hz,3.2Hz,1H),4.05(dd,J＝11.2 Hz,5.2Hz,1H),3.87-3.96(m,4H)；13C NMR(100MHz,CDCl3) δ 153.4,152.8,152.1, 144.4,130.6,77.7,68.3,66.3,64.2. the product was subjected to high resolution mass spectrometry and the test data were: HRMS (ESI) Calcd for C9H8Cl2N4O2:[M+H]+275.0097；Found,275.0101.
Example 11
1mmol of 2, 6-dichloropurine, 16mmol of isochroman, 5mmol of tert-butyl peroxide, 0.1mmol of 2, 2' -bipyridine and 0.1mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive ether is evaporated in a rotary manner, and the product 243 mg is obtained by silica gel column chromatography separation, and the reaction yield is 76 percent calculated by the ratio of the theoretical yield to 320 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ7.83(s,1 H),7.40(t,J＝6.8Hz,1H),7.32(d,J＝7.6Hz,1H),7.27(t,J＝7.6Hz,1H),7.22(s,1H), 6.97(d,J＝8.0Hz,1H),4.10(m,1H),3.94(m,1H),3.12(m,1H),2.98(dt,J＝16.8Hz, 4.0Hz,1H)；13C NMR(100MHz,CDCl3) δ 153.5,153.5,152.0,144.8,135.1,130.9,129.7, 129.5,129.3,127.4,126.5,79.2,61.3,27.6. the product was tested by high resolution mass spectrometry and the test data were: HRMS (EI) Calcd for C14H10Cl2N4O:[M]+320.0232；Found,320.0234.
Example 12
1mmol of 2, 6-dichloropurine, 20mmol of 2-methyltetrahydrofuran, 5mmol of tert-butyl peroxide, 0.1mmol of 2, 2' -bipyridine and 0.1mmol of copper chloride are placed in a reactor and stirred at 70 ℃ for 24 hours. After the reaction is finished, excessive ether is evaporated in a rotary manner, 170 mg of a pair of isomer products with the content of 1:1 is obtained through silica gel column chromatography, and the total reaction yield is 70 percent calculated according to the ratio of the theoretical yield to 272 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,d6-DMSO)δ8.85(s,1H), 8.80(s,1H),6.36(dd,J＝6.8Hz,4.4Hz,1H),6.25(dd,J＝6.8Hz,3.2Hz,1H),4.52(m, 1H),4.20(m,1H),2.44-2.62(m,4H),2.30(m,1H),2.14(m,1H),1.87(m,1H),1.65(m, 1H),1.31(d,J＝6.0Hz,3H),1.22(d,J＝6.0Hz,3H)；13C NMR(100MHz,d6-DMSO) δ 153.2,153.0,152.3,152.2,151.4,150.2,147.1,146.8,131.6,131.5,86.0,85.6,78.4,77.3, 32.5,31.9,31.6,21.1,20.9 the product was tested by high resolution mass spectrometry yielding test data: HRMS (EI) Calcd for C10H10Cl2N4O:[M]+272.0232；Found,272.0229.
Example 13
1mmol of 2, 6-dichloropurine, 16mmol of formaldehyde diethyl acetal, 2ml of DMSO,5mmol of tert-butyl peroxide, 0.1mmol of 1, 10-phenanthroline-5, 6-diketone and 0.1mmol of copper chloride are filled in a reactor and stirred for 48 hours at 70 ℃. And (3) after the reaction is finished, evaporating excessive solvent, and separating by silica gel column chromatography to obtain 136 mg of a product, wherein the total reaction yield is 55% calculated by the ratio of the theoretical yield to 247 mg. The reaction equation is as follows:
the product passes a nuclear magnetic resonance test, and the data is as follows:1H NMR(400MHz,CDCl3,TMS)δ8.27(s,1 H),5.64(s,2H),3.59(q,J＝7.2Hz,2H),1.20(t,J＝6.8Hz,1H)；13C NMR(100MHz, CDCl3) δ 153.5,153.4,152.0,145.8,130.6,73.3,66.0,14.8. the product was subjected to high resolution mass spectrometry and the test data were: HRMS (ESI) Calcd for C8H8Cl2N4O:[M+H]+247.0148；Found,247.0159.
The above embodiments are not intended to limit the present invention, and the present invention is not limited to the above embodiments, and all embodiments are within the scope of the present invention as long as the requirements of the present invention are met.
Claims (10)
1. A one-step synthesis method of 2 '3' -dideoxynucleoside is characterized in that alkaloid (I) and saturated ether R are added4OCH2R5Under the action of a catalyst and an oxidant, the reaction is directly carried out at a certain temperature, and the 2 '3' -dideoxy nucleoside is synthesized in one step; the reaction equation is as follows:
wherein, X is selected from one of O atom or H atom; y is selected from one of N atom, methine CH or Boc protected methine-group; z is selected from carbonyl C ═ O, C-NBoc2One of (1); r2And R3Each independently selected from Cl, H, NBoc2One of (1); n is 0 or 1; r4And R5Each independently selected from one of open-chain or cyclic alkyl, aryl or heteroaryl with 1-6 carbon atoms; the dotted line represents the possible presence or absence of this chemical bond.
2. The one-step synthesis method of 2',3' -dideoxynucleosides according to the claim 1, characterized in that the alkaloid (I) is selected from one of 2, 6-dichloropurine, 6-chloropurine, bis-Boc-adenine, bis-Boc-6-chloro-2-aminopurine, Boc-thymine, bis-Boc-cytosine alkaloid.
3. The one-step synthesis method of a 2 '3' -dideoxynucleoside according to claim 1 or 2, wherein the saturated ether is selected from the group consisting of tetrahydrofuran, n-butyl ether, tetrahydropyran, 1, 4-dioxane, isochroman, 2-methyltetrahydrofuran, and formaldehyde-diethyl acetal.
4. The one-step synthesis method of 2',3' -dideoxynucleosides according to the claim 1, characterized in that the catalyst uses redox transition metal salt; the molar ratio of the alkaloid (I) to the catalyst is 1: 0.5 to 500 percent.
5. The method of claim 4, wherein the catalyst is selected from the group consisting of copper salts and iron salts.
6. A one-step synthesis method of 2 '3' -dideoxynucleosides according to the claim 1, characterized in that bidentate nitrogen ligands can be added; the molar ratio of the alkaloid (I) to the ligand is 1: 0.01-1.
7. The one-step synthesis method of 2',3' -dideoxynucleoside according to claim 6, wherein the ligand is one of 2,2 '-bipyridine, 1, 10-phenanthroline, N-dimethylethylenediamine, N' -tetramethylethylenediamine.
8. The one-step synthesis method of 2',3' -dideoxynucleosides according to the claim 1, characterized in that the oxidant is organic oxidant; the molar ratio of the alkaloid (I) to the oxidant is 1: 1-20.
9. The one-step synthesis method of 2 '3' -dideoxynucleosides according to the claim 1, characterized in that the mol ratio of the saturated ether to the alkaloid is not less than 2: 1.
10. The one-step synthesis method of 2',3' -dideoxynucleosides according to the claim 1, characterized in that the reaction temperature is 25-70 ℃, and the reaction time is 3-72 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017011920A1 (en) * | 2015-07-22 | 2017-01-26 | The Royal Institution For The Advancement Of Learning/Mcgill University | Compounds and uses thereof in the treatment of cancers and other medical conditions |
| CN107573346A (en) * | 2017-09-29 | 2018-01-12 | 华南理工大学 | N9 is alkylated the simple synthesis of nucleoside analog on a kind of purine skeleton |
| CZ2017237A3 (en) * | 2017-04-28 | 2018-11-07 | Univerzita Palackého v Olomouci | 9-(2-oxacycloalkyl)-9H-purine-2,6-diamine derivatives, preparations containing these derivatives and their use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017011920A1 (en) * | 2015-07-22 | 2017-01-26 | The Royal Institution For The Advancement Of Learning/Mcgill University | Compounds and uses thereof in the treatment of cancers and other medical conditions |
| CZ2017237A3 (en) * | 2017-04-28 | 2018-11-07 | Univerzita Palackého v Olomouci | 9-(2-oxacycloalkyl)-9H-purine-2,6-diamine derivatives, preparations containing these derivatives and their use |
| CN107573346A (en) * | 2017-09-29 | 2018-01-12 | 华南理工大学 | N9 is alkylated the simple synthesis of nucleoside analog on a kind of purine skeleton |
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| Title |
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| HUANG, RUI等: "《Copper-catalyzed N-alkoxyalkylation of nucleobases involving direct functionalization of sp3 C-H bonds adjacent to oxygen atoms》", 《TETRAHEDRON》 * |
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