New method for preparing natural nucleoside nebularine

Abstract

The invention discloses a new method for preparing natural nucleoside nebularine. According to the method disclosed by the invention, cheap inosine is used as a raw material and is subjected to three reactions including acyl protection, sulfuration and desulfuration to finally obtain the target product nebularine; in the desulfuration step, since 50% nitric acid is used as a desulfuration agent, such reaction conditions easily causing explosion as diazotization in the conventional synthesis method can be avoided, no heavy metal catalyst is used, no column chromatography is needed in the whole process, large-scale synthesis can be realized easily; and moreover, the new method for preparing natural nucleoside nebularine is suitable for research on medicine activity and further large-scale preparation.

Description

technical field

[0001] The invention belongs to the field of chemistry and medicine, in particular, it relates to a preparation method of natural nucleoside goulashin. technical background

[0002] Mushroom goulash, also known as nebularine, is a nucleoside compound isolated from mushrooms. Later activity tests found that it has antifungal and other effects. Shuifen mushroom can also synthesize a variety of unnatural nucleoside compounds.

[0003] The existing methods of fenugreek include:

[0004] (1) Using adenosine as a raw material, after group protection, a diazotization-deamination reaction occurs, and then the protecting group is removed to obtain the target product; reference: Xia Ran, et al., Green Chem.2014, 16, 1077- 1081; Iwamura; Hashiizume; Journal of Organic Chemistry, 1968, 33, 1796.

[0005] (2) Halopurine nucleosides reduce halogen atoms under metal catalysis to obtain the target product; references: Gupta, P.K.; Bhakuni, D.S.; Indian Journal of Chemistr...

Examples

Embodiment 1

[0026] 2′,3′,5′-tri-O-acetylinosine (3)

[0027] Inosine (1g, 3.7mmol) was added to acetic anhydride (10mL), heated to 60°C under stirring, and reacted at this temperature for 2h, TLC showed that the reaction was complete, and cooled to room temperature, the solvent was removed in vacuo, and ethanol (5mL× 2) With residual acetic anhydride and acetic acid, recrystallize with water, filter, and dry to obtain 1.4 g of white flaky crystals with a yield of 95%.

[0028] White solid.m.p.234-236℃; 1 H NMR (CDCl 3 ,400MHz)δ:8.04(s,1H),7.97(s,1H),6.96(brs,H),6.16(d,J=5.6Hz,1H),5.78(t,J=5.6Hz,1H), 5.59-5.57(m,1H),4.42-4.37(m,3H),2.13(s,3H),2.10(s,3H),2.06(s,3H); 13 C NMR (CDCl 3 ,100MHz) δ:170.5,169.7,169.6,156.4,154.4,150.6,138.8,118.5,85.8,80.4,73.2,70.6,63.1,20.8,20.6,20.5.

Embodiment 2

[0030] 6-Mercapto-2′,3′,5′-tri-O-acetylpurine nucleoside (4)

[0031] 2′,3′,5′-Tri-O-acetylinosine (3, 1 g, 2.5 mmol) was added to toluene (10 mL), slowly added P 2 S 5 (0.28g, 1.3mmol), heated to 80°C, and reacted at this temperature for 2h, TLC showed that the reaction was complete, lowered to room temperature, removed the solvent in vacuo, carried residual pyridine with ethanol (5mL×2), and used absolute ethanol Recrystallized, filtered, and dried to obtain 0.89 g of a light yellow flake solid, with a yield of 87%.

[0032] White solid.m.p.168-170℃. 1 H NMR (CDCl 3 ,400MHz)δ8.33(s,1H),7.95(s,1H),6.17(d,J=5.2Hz,1H),5.92(t,J=5.2Hz,1H),5.66(t,J=4.4 Hz,1H),4.45-4.33(m,3H),2.12(s,3H),2.09(s,3H),2.06(s,3H); 13 C NMR (CDCl 3 ,100MHz)δ170.3,169.6,169.4,155.6,153.0,149.7,138.9,120.1,86.3,80.3,73.2,70.7,63.1,20.7,20.5,20.4.; HRMS calcd for C 16 h 19 N 4 o 7 S[M+H + ]411.0969, found 411.0969.

Embodiment 3

[0034] 6-Mercapto-2′,3′,5′-tri-O-acetylpurine nucleoside (4)

[0035] 2',3',5'-tri-O-acetyl inosine (100g, 250mmol) was added to toluene (500mL), and P was added slowly under stirring 2 S 5 (28g, 130mmol), heated to 80°C, and reacted at this temperature for 5h, TLC showed that the reaction was complete, lowered to room temperature, removed the solvent in vacuo, carried residual pyridine with ethanol (5mL×2), and recrystallized with absolute ethanol , filtered, and dried to obtain 0.89 g of a pale yellow flake solid, with a yield of 87%.

technical field

[0001] The invention belongs to the field of chemistry and medicine, in particular, it relates to a preparation method of natural nucleoside goulashin. technical background

[0002] Mushroom goulash, also known as nebularine, is a nucleoside compound isolated from mushrooms. Later activity tests found that it has antifungal and other effects. Shuifen mushroom can also synthesize a variety of unnatural nucleoside compounds.

[0003] The existing methods of fenugreek include:

[0004] (1) Using adenosine as a raw material, after group protection, a diazotization-deamination reaction occurs, and then the protecting group is removed to obtain the target product; reference: Xia Ran, et al., Green Chem.2014, 16, 1077- 1081; Iwamura; Hashiizume; Journal of Organic Chemistry, 1968, 33, 1796.

[0005] (2) Halopurine nucleosides reduce halogen atoms under metal catalysis to obtain the target product; references: Gupta, P.K.; Bhakuni, D.S.; Indian Journal of Chemistr...

Examples

Embodiment 1

[0026] 2′,3′,5′-tri-O-acetylinosine (3)

[0027] Inosine (1g, 3.7mmol) was added to acetic anhydride (10mL), heated to 60°C under stirring, and reacted at this temperature for 2h, TLC showed that the reaction was complete, and cooled to room temperature, the solvent was removed in vacuo, and ethanol (5mL× 2) With residual acetic anhydride and acetic acid, recrystallize with water, filter, and dry to obtain 1.4 g of white flaky crystals with a yield of 95%.

[0028] White solid.m.p.234-236℃; 1 H NMR (CDCl 3 ,400MHz)δ:8.04(s,1H),7.97(s,1H),6.96(brs,H),6.16(d,J=5.6Hz,1H),5.78(t,J=5.6Hz,1H), 5.59-5.57(m,1H),4.42-4.37(m,3H),2.13(s,3H),2.10(s,3H),2.06(s,3H); 13 C NMR (CDCl 3 ,100MHz) δ:170.5,169.7,169.6,156.4,154.4,150.6,138.8,118.5,85.8,80.4,73.2,70.6,63.1,20.8,20.6,20.5.

Embodiment 2

[0030] 6-Mercapto-2′,3′,5′-tri-O-acetylpurine nucleoside (4)

[0031] 2′,3′,5′-Tri-O-acetylinosine (3, 1 g, 2.5 mmol) was added to toluene (10 mL), slowly added P 2 S 5 (0.28g, 1.3mmol), heated to 80°C, and reacted at this temperature for 2h, TLC showed that the reaction was complete, lowered to room temperature, removed the solvent in vacuo, carried residual pyridine with ethanol (5mL×2), and used absolute ethanol Recrystallized, filtered, and dried to obtain 0.89 g of a light yellow flake solid, with a yield of 87%.

[0032] White solid.m.p.168-170℃. 1 H NMR (CDCl 3 ,400MHz)δ8.33(s,1H),7.95(s,1H),6.17(d,J=5.2Hz,1H),5.92(t,J=5.2Hz,1H),5.66(t,J=4.4 Hz,1H),4.45-4.33(m,3H),2.12(s,3H),2.09(s,3H),2.06(s,3H); 13 C NMR (CDCl 3 ,100MHz)δ170.3,169.6,169.4,155.6,153.0,149.7,138.9,120.1,86.3,80.3,73.2,70.7,63.1,20.7,20.5,20.4.; HRMS calcd for C 16 h 19 N 4 o 7 S[M+H + ]411.0969, found 411.0969.

Embodiment 3

[0034] 6-Mercapto-2′,3′,5′-tri-O-acetylpurine nucleoside (4)

[0035] 2',3',5'-tri-O-acetyl inosine (100g, 250mmol) was added to toluene (500mL), and P was added slowly under stirring 2 S 5 (28g, 130mmol), heated to 80°C, and reacted at this temperature for 5h, TLC showed that the reaction was complete, lowered to room temperature, removed the solvent in vacuo, carried residual pyridine with ethanol (5mL×2), and recrystallized with absolute ethanol , filtered, and dried to obtain 0.89 g of a pale yellow flake solid, with a yield of 87%.

Images