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Miazine compounds, intermediates of miazine compounds, preparation method of intermediates and miazine compounds as well as application of miazine compound

A technology of compounds, pyrimidines, applied in the field of pharmaceutical chemical synthesis

Inactive Publication Date: 2011-06-01
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to literature research, it is found that the 4-position of the pyrimidine ring is generally directly connected to p-fluorophenyl, and there are no reports on compounds connected through heteroatoms (such as O, S, etc.)

Method used

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  • Miazine compounds, intermediates of miazine compounds, preparation method of intermediates and miazine compounds as well as application of miazine compound
  • Miazine compounds, intermediates of miazine compounds, preparation method of intermediates and miazine compounds as well as application of miazine compound
  • Miazine compounds, intermediates of miazine compounds, preparation method of intermediates and miazine compounds as well as application of miazine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1 2-ethoxycarbonyl-4-methyl-2-pentenoic acid ethyl ester (F)

[0103] In a 500ml three-necked flask equipped with a water separator, add diethyl malonate (15.4g, 0.096mol), isobutyraldehyde (10.6g, 0.153mol), piperidine (0.33g, 0.004mol) and acetic acid (1.14g, 0.02mol), benzene (9.3ml), stirred and refluxed for 15h. Washed with water to neutral, washed with saturated brine, anhydrous Na 2 SO 4 Dry, filter and concentrate. Distillation under reduced pressure gave 19.5 g of a colorless oily substance, yield 94.7%, bp: 107-109° C. (3 mmHg). Literature bp: 135-137°C (27mmHg). (Cope AC, Hofmamn MC, Wyckoff C, et al. Condensation reactions. II. Alkylidene cyanoacetic and malonic esters [J]. J Am Chem Soc, 1941, 63(12): 3452-3456).

Embodiment 2

[0104] Example 2 Ethyl 6-isopropyl-2-methylthio-4-hydroxy-5-6-dihydropyrimidin-5-ylcarboxylate (G)

[0105] In a 1L four-necked flask, add F (10.0g, 0.047mol), S-methylisothiourea sulfate (10.0g, 0.072mol), triethylamine (23.5ml, 0.17mol) and tetrahydrofuran (50ml), Stirring and reflux for 24h. The insolubles were filtered off, the mother liquor was concentrated, diluted with water (60ml), extracted with ethyl acetate, washed with saturated brine, anhydrous Na 2 SO 4 After drying, concentration and washing with petroleum ether, 7.0 g of white solid was obtained, with a yield of 58.0%. mp: 114-116°C. 1 H-NMR (400MHz, CDCl 3 )δ (ppm): 7.76 (s, 1H), 4.27-4.21 (m, 2H), 3.87 (q, 1H, J = 9.6, 4.0Hz), 3.36 (d, 1H, J = 9.2Hz), 2.42 ( s, 3H), 1.82-1.78 (m, 1H), 1.28 (t, 3H, J = 7.2Hz), 1.06 (d, 3H, J = 6.8Hz), 0.92 (d, 3H, J = 6.8Hz).

Embodiment 3

[0106] Example 3 Ethyl 6-isopropyl-2-methylthio-4-hydroxy-pyrimidin-5-ylcarboxylate (H)

[0107] In a 2L four-necked flask, add G (12.0g, 0.046mol), DDQ (14.0g, 0.062mol) and 1,4-dioxane (100ml), stir at room temperature for 24h, concentrate the reaction solution, and weigh Crystallized to obtain 8.2 g of white crystals, with a yield of 68.9%. mp: 152-154°C. 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 12.4(brs, 1H), 4.39(q, 2H, J=6.8Hz), 3.18(t, 1H, J=6.8Hz), 2.58(s, 3H), 1.38(t, 3H, J=6.8Hz), 1.21 (d, 6H, J=6.4Hz).

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Abstract

The invention discloses miazine compounds as shown in a formula A which is disclosed in the specification and reaction intermediate compounds as shown in formulas B, C and D, wherein X is O or S, R is H,F,C1-C3 alkyl or C1-C3 alkoxy. The invention also discloses preparation methods of the intermediates and miazine compounds and an application of the miazine compounds in preparing medicaments for inhibiting HMG-CoA reductase and / or treating hyperlipidemia diseases. Compared with the pitavastatin, osuvastatin and atorvastatin in the prior art, the 6-isopropyl-2-(N-methyl-N-sulfonyl) amino-4-substituted phenoxy (or thiphenyl) miazine compounds have better or at least comparative activity for inhibiting the HMG-CoA reductase, and can be used for treating the hyperlipidemia diseases.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a class of pyrimidine compounds and their intermediates, preparation methods and applications. Background technique [0002] Since hypercholesterolemia was recognized as a major risk factor for atherosclerosis and cardiovascular disease, the research on lipid-lowering drugs has developed rapidly. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (also known as "statins") are the mainstream products of hypolipidemic drugs (Cai Zhengyan, Zhou Weicheng, HMG CoA reductase inhibitors research Progress, Chinese Journal of New Drugs, 2006, 15(22): 1907-1911). Fully synthetic statin drugs that have been marketed include fluvastatin, atorvastatin, rosuvastatin, and pitavastatin. But relative to the needs of human beings, new and more efficient drugs must be found. [0003] In the prior art, the structure of a fully synthetic stati...

Claims

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Application Information

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IPC IPC(8): C07D239/47C07D405/06A61K31/505A61P3/06
Inventor 潘竞蔡正艳周伟澄沈芳毛黎光
Owner SHANGHAI INST OF PHARMA IND
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