CN110015996B - Method for synthesizing 2' -spiro-substituted ternary carbocyclic nucleoside - Google Patents
Method for synthesizing 2' -spiro-substituted ternary carbocyclic nucleoside Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- 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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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Abstract
The invention discloses a method for synthesizing 2' -spiro-substituted ternary carbocyclic nucleoside, which belongs to the technical field of organic chemistry, wherein α -pyrimidine-substituted acrylate and α -chlorocycloalkanone are used as raw materials, and a cyclopropyl cyclization reaction started by Michael reaction is used for synthesizing series-structure novel spiro-nucleoside.
Description
Technical Field
The invention relates to a synthesis method of spiro nucleoside, in particular to a method for synthesizing 2' -spiro substituted ternary carbocyclic nucleoside by adopting cyclopropyl cyclization reaction, belonging to the technical field of organic chemistry.
Background
Most of the spiro nucleosides belong to conformation-restricted nucleosides, and the molecular conformation composition is relatively single. Before the substrate is combined with the enzyme, the conformation of the enzyme activity center is changed according to the conformation of the substrate, and then the substrate is combined with the substrate to form an active complex, and the substrate with single conformation is more favorable for the conformational transformation of the enzyme activity center, so that the development of the conformation-restricted nucleoside has certain advantages compared with a non-conformation-restricted nucleoside medicament. At present, publicly reported methods for synthesizing spiro nucleosides have complicated steps and poor universality, and mainly introduce spiro rings at the 4' position of a sugar ring, and typical representative synthetic routes are as follows:
1. synthesis of spiro pyrimidine nucleosides G and F, the reaction equations are as follows:
the method has long synthesis steps, expensive metal palladium is needed for catalyzing during C-N bond condensation, the obtained product is an isomer mixture with two configurations, and the separation is difficult.
2. The synthesis of spiro pyrimidine nucleoside D has the following reaction equation:
the method has long synthesis steps and poor substrate universality, firstly adopts o-bromoaniline condensation, and finally adopts n-Bu3The SnH method debrominates free radicals, adding unwanted reactions.
In view of the important components of the conformation-restricted nucleosides, there remains a great need to find simple and efficient methods for synthesizing spirocyclic nucleosides.
Disclosure of Invention
In order to overcome the defects, the invention provides a method for synthesizing 2' -spiro-substituted ternary carbocyclic nucleoside, which takes α -pyrimidine substituted acrylate and α -chlorocycloalkanone as raw materials, and initiates cyclopropyl cyclization reaction through Michael reaction under the action of inorganic base to synthesize a series of novel spiro nucleoside compounds.
A method for synthesizing 2' -spiro-substituted three-membered carbocyclic nucleoside is characterized by comprising the following steps of taking α -pyrimidine substituted acrylate 1 and α -chlorocycloalkanone 2 as raw materials, and reacting in an organic solvent under the action of alkali to obtain spiro-pyrimidine nucleoside 3, wherein the reaction equation is as follows:
wherein R is1Selected from hydrogen, C1-C6 alkyl, alkoxy; r2Selected from C1-C4 alkyl, benzyl, phenyl; r3Selected from benzoyl and tert-butoxycarbonyl; in particular, R1Selected from methyl, ethyl, hydrogen, halogen, methoxy or trifluoromethyl; r2Selected from methyl, ethyl, tert-butyl, phenyl or benzyl.
Further, in the technical scheme, the molar ratio of the α -pyrimidine substituted acrylate 1, α -chlorocycloalkanone 2 to the alkali is 1:1.2-1.5:1.2-2.0, and the preferred molar ratio is 1:1.5: 1.5.
Further, in the above technical solution, the solvent is selected from acetonitrile, methanol, dichloromethane, tetrahydrofuran, toluene or dioxane.
Further, in the above technical solution, the base is selected from: sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, DBU, sodium tert-butoxide or potassium tert-butoxide. Potassium carbonate, DBU, cesium carbonate or potassium tert-butoxide are preferred.
Further, in the above technical scheme, the reaction temperature is selected from-30 ℃ to 50 ℃.
Further, in the technical scheme, the whole reaction process does not need inert gas protection.
Further, in the above technical scheme, the spiro pyrimidine product 3 can be further subjected to derivatization reaction to obtain different types of derivative products 4 or 5. The reaction equation is as follows:
wherein the reducing agent is selected from sodium borohydride or lithium aluminum hydride; the deprotection reaction adopts ammonia/methanol or trifluoroacetic acid. Specifically, the reduction reaction is carried out in a solvent selected from dichloromethane and methanol, preferably dichloromethane in volume ratio: methanol 2: 1. use of ammonia/methanol solutions for R removal3For benzoyl protection, trifluoroacetic acid is used to remove R3Is tert-butyloxycarbonyl protection.
The invention has the beneficial effects that:
the method provides a simple, convenient, cheap and efficient way for synthesizing the spiro nucleoside compound. The adopted raw materials are simple and easy to obtain, and the defects of multiple steps, low yield and poor universality in the conventional method are overcome in the synthesis process. The yield of the spiro pyrimidine nucleoside synthesized by the method is up to 84%, and the product structure is rich.
Detailed Description
Example 1
aUnless otherwise specifiedThe reaction steps are as follows: 1a (0.1mmol), 2a (1.5equiv), and base (1.5equiv) were reacted in air for 5 hours.bIsolation yieldcPotassium tert-butoxide (1.2equiv)dPotassium tert-butoxide (2.0equiv)e1hf0.5h。
In the course of screening of the reaction conditions, the effect of the base on the reaction was first examined (entries 1-6). Secondly, the solvent and the temperature are investigated, and the yield is compared to finally determine that the potassium tert-butoxide is the optimal base, the acetonitrile is the optimal solvent and the temperature of minus 20 ℃ is the optimal temperature.
Typical reaction conditions operate:
α -pyrimidine substituted methyl acrylate 1a (0.1mmol) and 1.5eq (0.15mmol) of potassium tert-butoxide are dissolved in 1m L acetonitrile in a reaction flask and placed at-20 ℃ for stirring and cooling for 10 minutes, then α -chlorocycloalkanone 2a (0.15mmol) is added to the reaction solution for reaction at 0.5 h.T L C for monitoring the reaction completion, water is added for quenching, ethyl acetate is added for extraction, the combined organic phases are dried, filtered and concentrated in vacuum to obtain a crude oil, and then column chromatography is carried out to obtain the target compound 3aa, with the yield of 83%.
3aa:White solid,m.p.227.2-232.5℃；33mg,83％yield；
1H NMR(400MHz,CDCl3):7.90-7.88(d,J＝8.0Hz,2H),7.62(d,J＝7.6Hz,1H),7.48(t,J＝8.0Hz,2H),7.06(d,J＝3.2Hz,1H),3.77(s,3H),2.44(m,1H),2.36-2.27(m,1H),2.27-2.17(m,2H),2.08(m,2H),2.01-1.95(m,4H),1.89(s,1H).13C NMR(100MHz,CDCl3):212.1,167.7,139.4,135.0,131.5,130.7,129.1,111.5,77.3,53.6,50.4,42.6,38.9,28.5,26.2,20.2,12.7.HRMS(ESI-TOF):exact mass calcd for C21H20N2NaO6(M+Na)+requires m/z 419.1214,found m/z 419.1206.
Example 2
α - (3-benzoyl-5-methyl) uracil substituted ethyl acrylate 1b and 1.5eq (0.15mmol) potassium tert-butoxide were dissolved in 1m L acetonitrile in a 10m L vacuum tube and cooled under stirring at-20 ℃ for 10 minutes, then α -chlorocycloalkanone 2a (0.15mmol) was added to the reaction mixture to react, reaction 0.5 h.T L C monitored for completion of the reaction, quenched with water, extracted with ethyl acetate, the combined organics were dried, filtered and concentrated in vacuo to give a crude oil, which was then column chromatographed to give the title compound 3ba in 85% yield.
Example 3
α - (3-benzoyl-5-methyl) uracil substituted tert-butyl acrylate 1C and 1.5eq (0.15mmol) potassium tert-butoxide were dissolved in 1m L acetonitrile in a 10m L vacuum tube and stirred at-20 ℃ for cooling for 10 minutes, then α -chlorocycloalkanone 2a (0.15mmol) was added to the reaction solution for reaction for 0.5h, the reaction was monitored for completion by T L C, quenched with water, extracted with ethyl acetate, the combined organics were dried, filtered and concentrated in vacuo to give a crude oil, which was then chromatographed to give the title compound 3ca in 83% yield.
Example 4
α - (3-benzoyl-5-methyl) uracil-substituted benzyl acrylate 1d and 1.5eq (0.15mmol) potassium tert-butoxide were dissolved in 1m L acetonitrile in a 10m L vacuum and cooled under stirring at-20 ℃ for 10 minutes, then α -chlorocycloalkanone 2a (0.15mmol) was added to the reaction solution to react at 0.5 h.T L C for monitoring completion of the reaction, quenched with water, extracted with ethyl acetate, the combined organics were dried, filtered and concentrated in vacuo to give a crude oil, which was then column chromatographed to give the title compound 3da in 83% yield.
Example 5
α - (3-tert-butoxycarbonyl-5-methyl) uracil substituted methyl acrylate 1f and 1.5eq (0.15mmol) of potassium tert-butoxide were dissolved in 1m L acetonitrile in a vacuum of 10m L, and stirred and cooled at-20 ℃ for 10 minutes, then α -chlorocycloalkanone 2a (0.15mmol) was added to the reaction solution to carry out a reaction, the reaction was monitored for completion at 0.5 h.T L C, quenched with water, extracted with ethyl acetate, the combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil, and then column chromatography was carried out to give the title compound 3fa in 79% yield.
3fa:White solid,m.p.180.0-185.4℃；31mg,79％yield；
1H NMR(600MHz,CDCl3):6.94-6.92(m,1H),3.74(s,3H),2.65-2.44(m,2H),2.33-2.18(m,3H),2.03(d,J＝4.8Hz,1H),1.93-1.92(m,3H),1.89(d,J＝5.4Hz,1H),1.68(s,1H),1.56(s,9H).13C NMR(100MHz,CDCl3):211.2,167.8,147.7,139.0,111.1,86.5,53.6,50.6,42.4,38.8,28.6,27.5,26.3,20.2,12.7.HRMS(ESI-TOF):exact mass calcd forC19H24N2NaO7(M+Na)+requires m/z 415.1476,found m/z 415.1471.
Example 6
α - (3-benzoyl-5-ethyl) uracil substituted methyl acrylate 1i and 1.5eq (0.15mmol) of potassium tert-butoxide are dissolved in 1m L acetonitrile in a vacuum tube of 10m L and stirred at-20 ℃ for cooling for 10 minutes, α -chlorocycloalkanone 2a (0.15mmol) is added to the reaction solution for reaction, reaction is monitored at 0.5 h.T L C for completion of the reaction, water is added for quenching, ethyl acetate is added for extraction, the combined organic phases are dried, filtered and concentrated in vacuo to give a crude oil, and the desired compound 3ia is obtained by column chromatography in 81% yield.
3ia Colorless oil,33mg,81％yield；
1H NMR(400MHz,CDCl3):7.88(d,J＝7.6Hz,2H),7.61(d,J＝7.2Hz,1H),7.47(d,J＝7.6Hz,2H),6.98(s,1H),3.77(s,3H),2.47-2.37(m,3H),2.35-2.18(m,3H),2.14-2.08(m,2H),1.96(d,J＝5.2Hz,1H),1.90-1.85(m,1H),1.17(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3):212.1,168.6,167.7,138.5,135.0,131.5,130.6,129.1,117.1,53.6,50.5,42.6,38.9,28.5,26.2,20.3,20.1,12.5.HRMS(ESI-TOF):exact mass calcd for C22H22N2NaO6(M+Na)+requires m/z 433.1370,found m/z 433.1365.
Example 7
α - (3-benzoyl-5-fluoro) uracil substituted methyl acrylate 1j and 1.5eq (0.15mmol) of potassium tert-butoxide are dissolved in 1m L acetonitrile in a vacuum tube of 10m L, stirred and cooled at-20 ℃ for 10 minutes, then α -chlorocycloalkanone 2a (0.15mmol) is added to the reaction solution for reaction, reaction is monitored at 0.5 h.T L C for completion of the reaction, water is added for quenching, ethyl acetate is added for extraction, the combined organic phases are dried, filtered and concentrated in vacuum to obtain a crude oil, and then column chromatography is carried out to obtain the target compound 3ja with a yield of 68%.
Example 8
α - (3-benzoyl-5-methyl) uracil substituted methyl acrylate 1a and 1.5eq (0.15mmol) potassium tert-butoxide are dissolved in 1m L acetonitrile in a vacuum tube of 10m L, stirred and cooled at-20 ℃ for 10 minutes, then α -chlorocyclohexanone 2b (0.15mmol) is added to the reaction solution for reaction, the reaction is monitored for completion at 12 h.T L C, water is added for quenching, ethyl acetate is added for extraction, the combined organic phases are dried, filtered and concentrated in vacuum to obtain a crude oil, and then column chromatography is carried out to obtain the target compound 3ab with the yield of 66%.
Example 9
α - (3-benzoyl-5-methyl) uracil substituted methyl acrylate 1a and 1.5eq (0.15mmol) potassium tert-butoxide were dissolved in 1m L acetonitrile in a vacuum of 10m L, and stirred and cooled at-20 ℃ for 10 minutes, then 0.15mmol α -chlorocycloheptanone 2C was added to the reaction solution to carry out the reaction, the reaction was monitored for 0.5 h.T L C for completion, the reaction mixture was partitioned between ethyl acetate and water, the combined organic phases were dried, filtered and concentrated in vacuo to give a crude oil, which was then subjected to column chromatography to give the title compound 3ac in 72% yield.
3ac:White solid,m.p.213.0-218.4℃；31mg,72％yield；
1H NMR(400MHz,CDCl3):7.87(d,J＝8.0Hz,2H),7.62(t,J＝7.2Hz,1H),7.48(t,J＝8.0Hz,2H),7.04(s,1H),3.76(s,3H),2.82(t,J＝12.0Hz,1H),2.34-2.29(m,1H),2.21-2.15(m,3H),2.00-1.73(m,8H),1.38-1.25(m,2H).13C NMR(100MHz,CDCl3):207.6,168.4,167.6,150.5,139.7,135.0,131.5,130.6,129.1,111.4,53.7,51.3,46.1,44.0,30.6,27.5,27.1,26.4,25.6,12.6.HRMS(ESI-TOF):exact mass calcd for C23H24N2NaO6(M+Na)+requires m/z 447.1527,found m/z 447.1532.
Example 10
According to the reaction conditions and operations of examples 2 to 9, only the reaction substrate was changed, and the reaction results were as follows:
example 11
Adding cyclopropanation product 3aa (39.6mg,0.1mmol) into a vacuum tube of 10m L, adding mixed solvent 1.5m L with the volume ratio of dichloromethane to methanol being 2:1, stirring and cooling the reaction liquid in a low-temperature reaction bath at-20 ℃ for 10 minutes, then weighing sodium borohydride (11.3mg,0.3mmol) and slowly adding the sodium borohydride into the reaction liquid in batches, reacting the reaction liquid at-20 ℃ for 30 minutes, detecting that the reaction is complete by T L C, adding 0.5m L saturated ammonium chloride solution into the reaction liquid to quench the reaction, then adding dichloromethane and water to extract, and separating and purifying the product by column chromatography to finally obtain the ketone carbonyl reduction product 4aa (24mg,0.06 mmol).
4aa:White solid,m.p.175.5-180.1℃；24mg,60％yield；
1H NMR(400MHz,CDCl3):7.97-7.95(m,2H),7.66-7.63(m,1H),7.50(t,J＝8.0Hz,2H),7.13(s,1H),3.74(s,3H),3.54(d,J＝3.2Hz,1H),2.30(s,1H),2.13-2.02(m,1H),1.99-1.94(m,3H),1.90-1.70(m,6H),1.34(d,J＝5.2Hz,1H).13C NMR(150MHz,CDCl3):169.2,167.8,153.5,139.8,135.3,131.2,130.5,129.3,112.8,77.4,53.3,49.8,47.0,32.9,27.9,26.6,20.9,12.6.HRMS(ESI-TOF):exact mass calcd for C21H22N2NaO6(M+Na)+requires m/z 421.1370,found m/z 421.1366.
Example 12
Accurately weighing 4aa (39.8mg,0.1mmol) in a vacuum tube of 10m L, adding into the reaction tube, plugging a rubber plug and sealing with a sealing film, performing nitrogen exchange to ensure that the reaction can be performed under a nitrogen atmosphere, sucking ammonia/methanol solution (with the concentration of 1 mol/L) 1m L with a needle tube, adding into the reaction tube, reacting the reaction solution at room temperature for 3 hours, detecting that the reaction is complete by T L C, evaporating the reaction solution under reduced pressure, and separating and purifying the product by column chromatography to finally obtain 5aa (24mg, 0.08 mmol).
Representative compound characterization data are as follows:
5aa:White solid,m.p.233.0-238.4℃；26mg,87％yield；
1H NMR(400MHz,CDCl3):9.36(s,1H),7.00(s,1H),4.23(s,1H),3.71(s,3H),3.52(d,J＝3.2Hz,1H),2.38(s,1H),2.11(s,1H),1.95-1.72(m,8H),1.69(d,J＝5.3Hz,1H),1.27(d,J＝5.2Hz,1H).13CNMR(150MHz,CDCl3):169.4,163.4,154.3,140.1,112.7,77.2,53.3,49.3,47.0,32.8,27.9,26.9,20.9,12.5.HRMS(ESI-TOF):exact mass calcd forC14H18N2NaO5(M+Na)+requires m/z 317.1108,found m/z 317.1107.
the foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and such changes and modifications are within the scope of the present invention.
Claims (5)
1. A method for synthesizing 2' -spiro substituted three-membered carbocyclic nucleoside 3 has the following reaction equation:
wherein R is1Selected from hydrogen, C1-C6 alkyl, alkoxy; r2Selected from C1-C4 alkyl, benzyl, phenyl; r3Selected from benzoyl and tert-butoxycarbonyl;
the method is characterized by comprising the following steps of taking α -pyrimidine substituted acrylate 1 and α -chlorocycloalkanone 2 as raw materials, and reacting in acetonitrile or methanol under the action of potassium tert-butoxide to obtain the spiro pyrimidine nucleoside 3, wherein the reaction temperature is selected from-30 ℃ to-10 ℃.
2. The method of synthesizing a 2' -spirocyclic substituted tri-carbocyclic nucleoside 3 according to claim 1, wherein: r1Selected from methyl, ethyl, hydrogen or methoxy; r2Selected from methyl, ethyl, tert-butyl, phenyl or benzyl.
3. The method according to claim 1, wherein the molar ratio of α -pyrimidine-substituted acrylate 1, α -chlorocycloalkanone 2 to base is 1:1.5: 1.5.
4. A method for synthesizing a 2' -spirocyclic group substituted ternary carbocyclic nucleoside 5, characterized in that: preparing a 2 '-spirocyclic-substituted-ternary carbocyclic nucleoside 3 according to the method of claim 1, followed by adding a reducing agent to the 2' -spirocyclic-substituted-ternary carbocyclic nucleoside 3 to react to obtain a compound 4, followed by deprotection to obtain a compound 5; the reaction equation is as follows:
wherein R is1Selected from hydrogen, C1-C6 alkyl, alkoxy; r2Selected from C1-C4 alkyl, benzyl, phenyl; r3Selected from benzoyl and tert-butyloxycarbonyl.
5. The method of synthesizing a 2' -spirocyclic substituted tri-carbocyclic nucleoside 5 according to claim 4, wherein: the reducing agent is selected from sodium borohydride or lithium aluminum hydride; liquid ammonia/methanol or trifluoroacetic acid is selected for deprotection reaction.
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