CN109761984B - Method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric hydrogen transfer - Google Patents
Method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric hydrogen transfer Download PDFInfo
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Abstract
The invention discloses a method for synthesizing chiral penta-carbocyclic purine nucleoside by asymmetric hydrogen transfer, which belongs to the field of asymmetric synthesis in organic chemistry.A racemic α -purine substituted cyclopentanone 1 is taken as a raw material, equivalent formic acid and triethylamine are added into a dioxane solvent in the presence of a chiral ruthenium catalyst, and the penta-carbocyclic purine nucleoside 2 with two chiral centers is obtained after dynamic kinetic resolution.
Description
Technical Field
The invention particularly relates to a method for synthesizing chiral five-membered carbocyclic purine nucleosides by asymmetric hydrogen transfer, belonging to the field of asymmetric synthesis in organic chemistry.
Background
Chiral carbocyclic purine nucleosides have a wide range of physiological activities, such as the chiral five-membered carbocyclic nucleosides Abacavir, Entecavir and Carbovir can be used for the treatment of HIV and HBV, respectively; chiral four-membered carbocyclic ring Lobucavir has been used for the treatment of HBV; chiral, three-membered carbocyclic nucleoside a-5021 has been used clinically to treat HSV. Other chiral carbocyclic nucleosides such as: oxetanocin A, Lamivudine, Amdoxovir and SPD754, all have different pharmaceutical activities. Meanwhile, the product configuration of the chiral compound has great influence on the biological activity of the chiral compound. Therefore, the synthesis and preparation of the optically pure chiral nucleoside compound and the research on the physiological and pharmacological activities of the chiral nucleoside compound have important significance.
The traditional method for synthesizing chiral carbocyclic purine nucleosides by asymmetric hydrogenation reaction of dynamic kinetic resolution is characterized in that a metal ruthenium catalyst and hydrogen are used for reducing racemic α -aminocycloalkanone to obtain a hydrogenated product with two chiral centers, and a metal ruthenium catalyst is used for hydrogenating racemic α -aminocycloalkanone by using formic acid as a hydrogen source through asymmetric hydrogen transfer reaction of dynamic kinetic resolution to synthesize the hydrogenated product with two chiral centers.
Disclosure of Invention
In order to overcome the defects, α -purine substituted cyclopentanone 1 is used as a raw material to synthesize the chiral carbocyclic purine nucleoside compound under the action of a ruthenium metal catalyst.
The invention discloses a method for synthesizing chiral five-membered carbocyclic purine nucleoside by asymmetric hydrogen transfer, which has the following reaction equation:
the method comprises the following steps of using α -purine substituted cyclopentanone 1 as a raw material, and reacting in an organic solvent in the presence of a chiral ruthenium catalyst, formic acid and triethylamine to obtain five-membered carbocyclic purine nucleoside 2 with two chiral centers.
Further, in the above technical solution, R1Selected from: hydrogen, halogen, alkoxy, propylthio, phenyl or amino; r2Selected from:hydrogen, halogen or amine groups.
Further, in the above technical solution, the chiral catalyst is selected from one of the following catalysts, and the structural formula is as follows:
further, in the above technical scheme, the reaction solvent is selected from dioxane, dichloromethane, chloroform, methanol, ethyl acetate, tetrahydrofuran or acetonitrile. Dioxane, dichloromethane, chloroform and ethyl acetate are preferred.
Further, in the technical scheme, the molar ratio of the α -purine substituted cyclopentanone 1 to the formic acid to the triethylamine to the chiral ruthenium catalyst is 1-2:3-10:3-10: 0.005-0.02.
Further, in the technical scheme, the reaction temperature is 0-30 ℃.
Further, in the above technical scheme, the chiral five-membered carbocyclic purine nucleoside can be further diversely derived.
For example: the carbocyclic purine nucleoside 2 reacts with methylsulfonyl chloride to obtain a compound 3, then reacts with sodium azide to obtain a compound 4, and then reacts with phenylacetylene to obtain chiral trans-five-membered carbocyclic triazole purine nucleoside 5, wherein the reaction equation is as follows:
wherein, in the scheme, the compound 4 is catalytically reacted with an organic base and a copper salt to generate a product 5; the organic base is diisopropylethylamine and the copper salt is copper acetate.
The invention has the beneficial effects that:
the invention provides a simple, cheap and efficient synthesis method for synthesizing chiral carbocyclic purine nucleoside, reaction raw materials are easy to obtain, the product structure is rich, the chiral five-membered carbocyclic purine nucleoside compound can be obtained in one step, the reaction diastereoselectivity and enantioselectivity are good, only a cis-form product is obtained, the corresponding selectivity can reach 99% at most, and the trans-triazole purine nucleoside derivative is obtained after the product is further derivatized.
Detailed Description
Example 1
[a]Unless otherwise stated, the reaction was carried out by the following steps, catalyst (1 mol%), 1a (0.1mmol), dioxane (1mL) as solvent, HCO2H/TEA (1:1) 70. mu.L was reacted at 27 ℃ for 1 day. [ b ] a]>99:1dr, dr values the crude product was tested by nuclear magnetic testing. [ c ] is]The isolation yield. [ d]The ee values were separated by high performance liquid chromatography. [ e ] a]HCO2H/TEA＝2.5:1。[f]HCO2H/TEA＝0.2:1。
In the screening of the reaction conditions, the effect of the metal catalyst on the reaction was first examined (entries 1-4). Meanwhile, by contrasting the influence of different ligands on the reaction and considering the price factor, the catalyst D is finally determined to be the optimal catalyst. Then the optimum solvent dioxane, HCO is selected2H/TEA＝1:1。
Examination of reaction conditions in a 10mL reaction flask, α - (6-methoxy) purine-substituted cyclopentanone 1a (23.2mg,0.1mmol), catalyst D (0.7mg,1 mol%) and 1mL dioxane were added, followed by HCO2H/TEA ═ 1:1 mixed solvent 70 μ L. The reaction tube was left at 27 ℃ for 24 hours. The reaction was followed by TLC, after the reaction was terminated, the organic phase was concentrated in vacuo and then subjected to column chromatography to give the desired compound 2a in 96% yield and 97% ee. ee value detection method: HPLC CHIRALCELID, n-hexane/2-propanol 80/20, flow rate 0.7mL/min, λ 250nm, retentition time 23.893min,25.767 min; TLC Rf＝0.31(dichloromethane:methanol＝30:1)[UV]；1H NMR(600MHz,CD3OD)δ8.49(s,1H),8.38(s,1H),4.91-4.87(m,1H),4.36-4.34(m,1H),4.17(s,3H),2.41-2.34(m,1H),2.27-2.22(m,1H),2.15-2.04(m,2H),1.90-1.84(m,1H),1.83-1.77(m,1H)；13C NMR(150MHz,CDCl3)δ159.8,151.5,151.4,142.2,119.9,71.3,59.7,54.1,32.3,27.7,20.3；HRMS(ESI-TOF):exact mass calcd for C11H15N4O2(M+H)+requires m/z235.1190,found m/z 235.1190.
Example 2
In a 10mL reaction flask, α - (6-ethoxy) purine-substituted cyclopentanone 1b (24.8mg,0.1mmol), catalyst D (0.7mg,1 mol%) and 1mL dioxane were added, followed by HCO2H/TEA ═ 1:1 mixed solvent 70 μ L, and the reaction tube was left to stand at 27 ℃ for reaction for 24 hours. The reaction was followed by TLC, after the reaction was terminated, the organic phase was concentrated in vacuo and then subjected to column chromatography to give the target compound 2b in 96% yield and 90% ee. ee value detection method: HPLC CHIRALCEL ASH, n-hexane/2-propanol 90/10, flow rate 0.8mL/min, lambda 256nm, retentition time 9.870min,25.590 min; TLC Rf＝0.34(dichloromethane:methanol＝30:1)[UV]；1H NMR(600MHz,CD3OD)δ8.46(s,1H),8.37(s,1H),4.90-4.87(m,1H),4.67-4.63(m,2H),4.36-4.34(m,1H),2.39-2.35(m,1H),2.26-2.21(m,1H),2.15-2.04(m,2H),1.89-1.87(m,1H),1.80-1.77(m,1H),1.49(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ159.3,151.4,151.2,141.9,119.6,71.1,63.1,59.5,32.1,27.6,20.3,14.5；HRMS(ESI-TOF):exact mass calcd for C12H17N4O2(M+H)+requiresm/z 249.1346,found m/z 249.1345.
Example 3
In a 10mL vacuum tube α - (6-propylthio) purine-substituted cyclopentanone 1c (27.6mg,0.1mmol), catalyst D (0.7mg,1 mol%) and 1mL dioxane were added, followed by HCO2H/TEA ═ 1:1 mixed solvent 70 μ L. The reaction tube was left at 27 ℃ for 24 hours. The reaction is followed by TLC, after the reaction has ended, concentrated in vacuo to giveThe organic phase was then subjected to column chromatography to give the desired compound 2c in 88% yield and 86% ee. ee value detection method: HPLC CHIRALCEL IA, n-hexane/2-propanol 90/10, flow rate 0.7mL/min, λ 250nm, retentition time 14.080min,15.787 min; TLC Rf＝0.36(dichloromethane:methanol＝30:1)[UV]；1H NMR(600MHz,CD3OD)δ8.66(s,1H),8.42(s,1H),4.91-4.88(m,1H),4.35-4.33(m,1H),3.39-3.36(m,2H),2.41-2.34(m,1H),2.27-2.22(m,1H),2.15-2.04(m,2H),1.89-1.84(m,1H),1.82-1.78(m,3H),1.08(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ160.6,151.5,148.1,142.6,130.2,71.7,59.4,32.4,30.8,27.9,22.9,20.3,13.7；HRMS(ESI-TOF):exact mass calcd forC13H19N4OS(M+H)+requires m/z 279.1274,found m/z 279.1271.
Example 4
According to the reaction conditions in examples 2 to 3, only the reaction substrates were changed to obtain the following reaction results:
example 5
In a 50mL round bottom flask, the carbocyclic nucleoside analog 2a (117mg,0.5mmol) and 10mL of dichloromethane were added, the reaction was cooled to 0 deg.C, and triethylamine (173. mu.L, 1.25mmol) and methanesulfonyl chloride (58. mu.L, 0.75mmol) were added and reacted for 3-4 hours. Detecting by TLC, concentrating the reaction solution in vacuum after complete reaction, and performing column Chromatography (CH)2Cl2MeOH 80:1) yielded the title compound 3a (97% yield, 97% ee).
3aWhite solid,m.p.130.5-141.7℃,151.4mg,97％yield,98％ee；[α]D 20＝-133.85(c＝0.130,CH2Cl2)；HPLC CHIRALCEL ODH,n-hexane/2-propanol＝80/20,flowrate＝0.8mL/min,λ＝250nm,retention time:31.213min,44.790min；TLC:Rf＝0.45(dichloromethane:methanol＝30:1)[UV]；1H NMR(600MHz,CDCl3)δ8.55(s,1H),8.12(s,1H),5.30-5.28(m,1H),5.06-5.02(m,1H),4.19(s,3H),2.52(s,3H),2.46-2.38(m,2H),2.33-2.28(m,2H),2.22-2.15(m,1H),1.94-1.86(m,1H)；13C NMR(150MHz,CDCl3)δ161.3,152.4,152.2,141.1,121.3,81.6,57.4,54.5,38.0,31.4,27.4,19.9；HRMS(ESI-TOF):exact mass calcd for C12H17N4O4S(M+H)+requires m/z 313.0965,found m/z 313.0965.
In a 25mL round bottom flask, the carbocyclic nucleoside analogue 3a (93.6mg,0.3mmol), DMF3mL and NaN were added3(97.5mg,1.5mmol), the reaction was heated to 50 ℃ and reacted for 24 hours. After completion of the reaction, 10mL of distilled water was added, extraction was carried out three times with 30mL of ethyl acetate by TLC, and the organic phase was concentrated in vacuo and then subjected to column chromatography (PE/EA ═ 2:1) to obtain the objective compound 4a (yield 81%, 97% ee).
4a Yellow oil,63.0mg,81％yield,97％ee；[α]D 20＝46.35(c＝0.320,CH2Cl2)；HPLC CHIRALCEL ID,n-hexane/2-propanol＝70/30,flow rate＝0.8mL/min,λ＝250nm,retention time:15.488min,17.397min；TLC:Rf＝0.75(dichloromethane:methanol＝30:1)[UV]；1H NMR(600MHz,CD3OD)δ8.52(s,1H),8.38(s,1H),4.81(q,J＝8.4Hz,1H),4.54(q,J＝7.8Hz,1H),4.18(s,3H),2.37-2.29(m,3H),2.10-2.06(m,1H),1.98-1.92(m,1H),1.87-1.82(m,1H)；13C NMR(150MHz,CD3OD)δ162.3,153.1,143.7,122.5,66.8,63.3,54.8,30.4,30.3,21.7；HRMS(ESI-TOF):exact mass calcd for C11H14N7O(M+H)+requires m/z260.1254,found m/z 260.1257.
Example 6:
in a 10mL vacuum tube, a carbocyclic purine nucleoside 4a (25.9mmol,0.1mmol) was added. Acetonitrile 1mL, diisopropylethylamine (16.5. mu.l, 0.15mmol), and Cu (OAc)2(0.9mg,0.005mmol), reaction solutionThe reaction was stirred at room temperature for 6 hours. The reaction was followed by TLC, after the reaction was terminated, extraction was performed, the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and then column chromatography (PE/EA ═ 2:1) was performed to obtain the target compound 5a in 92% yield and 98% ee.
5a White oil,33.2mg,92％yield,98％ee；[α]D 25＝222.22(c＝0.072,CH2Cl2)；HPLC CHIRALCEL ODH,n-hexane/2-propanol＝60/40,flow rate＝0.8mL/min,λ＝250nm,retention time:15.358min,20.422min；TLC:Rf＝0.53(dichloromethane:methanol＝30:1)[UV]；1H NMR(600MHz,CDCl3)δ8.54(s,1H),7.92(s,1H),7.73(d,J＝7.8Hz,2H),7.62(s,1H),7.38(t,J＝7.8Hz,2H),7.31(t,J＝7.8Hz,1H),5.74-5.70(m,1H),5.47-5.42(m,1H),4.18(s,3H),2.68-2.64(m,2H),2.51-2.43(m,2H),2.30-2.21(m,2H)；13C NMR(150MHz,CDCl3)δ161.4,152.1,148.0,142.3,130.3,129.0,128.4,125.8,119.8,64.4,62.8,54.5,31.6,29.8,21.7；HRMS(ESI-TOF):exact mass calcd for C19H22N7O(M+H)+requires m/z362.1724,found m/z 362.1718.
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 merely illustrative 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 the invention is intended to be covered by the appended claims.
Claims (4)
1. The asymmetric hydrogen transfer process of synthesizing chiral five-membered carbocyclic purine nucleoside has the following reaction equation:
α -purine substituted cyclopentanone 1 is used as a raw material, and reacts in an organic solvent in the presence of a chiral ruthenium catalyst, formic acid and triethylamine to obtain five-membered carbocyclic purine nucleoside 2 with two chiral centers;
wherein R is1Selected from: hydrogen, halogen, alkoxy, propylthio, phenyl or amino; r2Selected from: hydrogen, halogen or amine groups; the reaction solvent is selected from dioxane, dichloromethane, chloroform, methanol, ethyl acetate, tetrahydrofuran or acetonitrile.
2. The method for synthesizing chiral five-membered carbocyclic purine nucleoside according to claim 1, wherein the molar ratio of α -purine substituted cyclopentanone 1, formic acid, triethylamine and chiral ruthenium catalyst is 1-2:3-10:3-10: 0.005-0.02.
3. The method for synthesizing chiral five-membered carbocyclic purine nucleosides according to claim 1, wherein the asymmetric hydrogen transfer comprises: the reaction temperature is 0-30 ℃.
4. A synthetic method for synthesizing chiral trans-quinary carbocycle triazole purine nucleoside is characterized in that: the nucleoside product 2 obtained by the method of claim 1 reacts with methylsulfonyl chloride to obtain a compound 3, then reacts with sodium azide to obtain a compound 4, and then reacts with phenylacetylene to obtain chiral trans-form five-membered carbocyclic triazole purine nucleoside 5, wherein the reaction equation is as follows:
wherein, the compound 4 reacts under the catalysis of organic base and copper salt to generate a product 5; the organic base is diisopropylethylamine and the copper salt is copper acetate.
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| WO2004096286A2 (en) * | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
| CN105294694A (en) * | 2014-06-18 | 2016-02-03 | 四川海思科制药有限公司 | Amino hexatomic ring derivative and application thereof to medicine |
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| WO2003105770A2 (en) * | 2002-06-17 | 2003-12-24 | Merck & Co., Inc. | Carbocyclic nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
| WO2004096286A2 (en) * | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
| CN105294694A (en) * | 2014-06-18 | 2016-02-03 | 四川海思科制药有限公司 | Amino hexatomic ring derivative and application thereof to medicine |
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