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Purine compounds, intermediates, preparation methods and applications thereof
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A compound, xanthine technology, applied in the field of pharmaceutical chemical synthesis, can solve the problems of β-cell function damage in patients
Active Publication Date: 2016-01-13
SHANGHAI INST OF PHARMA IND CO LTD +1
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At present, the treatment of type 2 diabetes is mainly based on small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for the treatment of type 2 diabetes, but long-term use of these hypoglycemic drugs can lead to Adverse reactions such as hypoglycemia, weight gain, and β-cell function damage occurred in patients
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Embodiment 1
[0066] Synthesis of 8-hydroxymethyl-3-methylxanthine (Formula V)
[0067] 5,6-diamino-1-methyluracil (10g, 64.1mmol) (5,6-diamino-1-methyluracil for the synthesis method see document J.Med.Chem.2009,52,6433 -6446) was added to 30mL of water, glycolic acid (4.87g, 128.2mmol) was added, and after reacting at 100°C for 3.5 hours, sodiumhydroxide (4.3g, 107.5mmol) was added, reacting at 100°C for 5 hours, and the solid was precipitated at room temperature. After suction filtration, the filter cake was recrystallized with water to obtain 6.2 g with a yield of 78.8%. m.p: more than 250°C. 1 HNMR (δppm, DMSO): 4.33 (s, 2H), 3.30 (s, 3H).
Embodiment 2
[0069]Synthesis of 7-(2-cyanobenzyl)-8-hydroxymethyl-3-methylxanthine (Formula IV)
[0070] Mix 8-hydroxymethyl-3-methylxanthine (10.0g, 51.0mmol) with DMSO70mL, add diisopropylethylamine (6.6g, 51.0mmol), add o-cyanobenzyl chloride (6.8g , 51.0mmol), stirred at room temperature for 1.5 hours, TLC showed that the raw materials disappeared, 1000mL of water was added to the reaction solution, and a solid was precipitated, filtered by suction to obtain 9.1g of the product, with a yield of 53.5%. m.p: greater than 250°C, 1 HNMR (δppm, DMSO): 7.85-7.87 (m, 1H), 7.58-7.62 (m, 1H), 7.47-7.49 (m, 1H), 6.92 (d, 1H), 5.76 (s, 2H), 4.58 ( d, 2H), 3.38 (s, 3H).
Embodiment 3
[0072] Synthesis of 1,7-bis(2-cyanobenzyl)-8-hydroxymethyl-3-methylxanthine (Formula III)
[0073] Mix 7-(2-cyanobenzyl)-8-hydroxymethyl-3-methylxanthine (5.0g, 16.1mmol) with DMF50mL, add anhydrouspotassiumcarbonate (3.6g, 25.8mmol) and 2- Cyanobenzyl chloride (2.7g, 17.7mmol), react at 50°C for 3 hours, TLC shows that the raw material disappears, add 500mL of water, filter with suction, dissolve the filter cake with ethyl acetate, wash with saturated saline three times, and dry over anhydroussodiumsulfate , concentrated, column chromatography, to obtain 5.2g, yield 75.8%. m.p.: 220-222°C, 1 HNMR (δppm, DMSO): 7.86(d, 1H), 7.78(d, 1H), 7.55-7.63(m, 2H), 7.40-7.49(m, 2H), 7.19(d, 1H), 6.95(d, 1H), 5.82 (s, 2H), 5.17 (s, 2H), 4.62 (d, 2H), 3.48 (s, 3H).
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Abstract
The invention discloses a xanthine compound I, wherein R1 is 2-cyanophenyl or hydrogen; R2 is 2-cyanobenzyl; R3 is amino or wherein n=2-4, m=2-3, D is H or NH2 and E is CH2 or NH. A preparation method of the xanthine compound I comprises the following steps of: performing nucleophilic substitution reaction on a compound II and R3H; or (1) performing the nucleophilic substitution reaction on the compound II and R-3-tert-oxyacyl aminopiperidine; and (2) removing a tert-oxyacyl protecting group. The invention further discloses any intermediate of the xanthine compound I, wherein R1 and R2 are as described above. The invention further relates to an application of the xanthine compound I in preparation of a DPP-4 (dipeptidyl peptidase-4) enzyme activity inhibitor or medicaments for treating and / or preventing relevant diseases by inhibiting a DPP-4 enzyme. The xanthine compound I disclosed by the invention provides a new direction for research and development of the DPP-4 inhibitor, and has important significance in development of the potential DPP-4 inhibitors. Formula III, formula II and formula I are shown in the specification.
Description
technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a xanthine compound, an intermediate thereof, a preparation method and an application thereof. Background technique [0002] Diabetes is a disease that seriously threatens human health. According to the World Health Organization, there are about 180 million diabetics in the world, 90% of whom are type 2 diabetics, and this number is expected to double by 2030. At present, the treatment of type 2 diabetes is mainly based on small molecule oral drugs. Sulfonylureas, glinides, biguanides and thiazolidinediones are commonly used drugs for the treatment of type 2 diabetes, but long-term use of these hypoglycemic drugs can lead to Adverse reactions such as hypoglycemia, weight gain, and β-cell function damage occurred in patients. The discovery of DPP-4 inhibitors can effectively avoid the deficiency of traditional oral hypoglycemic drugs, and DP...
Claims
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Application Information
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