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Xanthine compound intermediate and preparation method thereof

A compound and intermediate technology, applied in the field of pharmaceutical chemical synthesis, can solve the problems of patients' β-cell function damage and other problems

Active Publication Date: 2013-08-21
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

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

Method used

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  • Xanthine compound intermediate and preparation method thereof
  • Xanthine compound intermediate and preparation method thereof
  • Xanthine compound intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Synthesis of 8-hydroxymethyl-3-methylxanthine (Formula V)

[0079] 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, sodium hydroxide (4.3g, 107.5mmol) was added and reacted at 100°C for 5 hours. 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

[0081] Synthesis of 7-(but-2-ynyl)-8-hydroxymethyl-3-methylxanthine (Formula IV)

[0082] Mix 8-hydroxymethyl-3-methylxanthine (10g, 51.0mmol) with DMSO 70mL, add diisopropylethylamine (6.6g, 51.0mmol), add 1-bromo-2-butyne at room temperature (7.8g, 51.0mmol), stirred at room temperature for 1.5 hours, TLC showed that the raw material disappeared, 1300mL of dichloromethane was added to the reaction solution, a solid was precipitated, filtered by suction to obtain 10.4g of white product, yield 82.5%. m.p: greater than 250°C, 1 HNMR (δppm, DMSO): 5.13 (s, 2H), 4.61 (d, 2H), 3.32 (s, 3H), 1.76 (s, 3H).

Embodiment 3

[0084] Synthesis of 7-(2-cyanobenzyl)-8-hydroxymethyl-3-methylxanthine (Formula IV)

[0085] 8-Hydroxymethyl-3-methylxanthine (10.0g, 51.0mmol) was mixed with DMSO 70mL, diisopropylethylamine (6.6g, 51.0mmol) was added, and o-cyanobenzyl chloride (6.8 g, 51.0 mmol), stirred at room temperature for 1.5 hours, TLC showed that the raw materials disappeared, 1000 mL of water was added to the reaction solution, and a solid was precipitated, filtered by suction to obtain 9.1 g 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).

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Abstract

The invention discloses an intermediate III for preparation of a xanthine compound. In addition, the invention also discloses an intermediate compound for preparing the intermediate III. The intermediate III provided in the invention for preparation of the xanthine compound provides a new direction for development of a DPP-4 inhibitor, and has great significance for development of the DPP4 inhibitor. Formula III is shown as the following.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a xanthine compound, its intermediate, its pharmaceutically acceptable salt, its preparation method and its application. 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 h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04C07D473/06A61K31/522A61P3/10A61P5/50
Inventor 林快乐蔡正艳周伟澄
Owner SHANGHAI INST OF PHARMA IND CO LTD