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Dihydroxyl protection method of lovaamide and preparation method of simvastatin

A technology of lovastatin and hydroxyl protecting agent, which is applied in the field of simvastatin intermediate and simvastatin preparation, can solve the problems of increasing production cost, polluting the environment, inconvenient recycling of dimethylformamide, etc., and achieve reduction in production costs, effects of avoiding negative impacts

Active Publication Date: 2015-04-29
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This method is in the process of preparing lovaamide disiloxane, with dimethylformamide (DMF) as reaction solvent, the boiling point of dimethylformamide (DMF) is high and soluble in water, so the current production process is inconvenient to recycle Dimethylformamide not only pollutes the environment, but also increases production costs

Method used

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  • Dihydroxyl protection method of lovaamide and preparation method of simvastatin
  • Dihydroxyl protection method of lovaamide and preparation method of simvastatin

Examples

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Effect test

Embodiment 1

[0047] Add 84ml of n-butylamine to 100g of lovastatin, heat up to 80°C under stirring, reflux for 1-1.5 hours, cool down to 50°C, recover excess n-butylamine under reduced pressure (put it into the next batch for use), and obtain lovastatin for direct use. react in the next step.

[0048] Add 150ml of tetrahydrofuran to dissolve the lovaamide prepared by the above reaction, add 42g of imidazole, 86g of tert-butyldimethylsilyl chloride, and 2g of dimethylaminopyridine, heat to reflux, and TLC detects that the reactant completely disappears. Cool, filter, and wash the filter cake with 50ml of tetrahydrofuran, suck it dry, and recover imidazole. The filtrate was concentrated to dryness, and the recovered solvent was applied mechanically. After the residue was dissolved in 500ml cyclohexane, the filtrate was dissolved with 500ml of 1% NH 3 Wash twice with water, then wash with 500ml water, separate the organic layer, wash with anhydrous Na 2 SO4 Dry for 4 hours, filter, and conc...

Embodiment 2

[0050] Dissolve the lovaamide prepared by the method in Example 1 in 150 ml of acetonitrile, add 42 g of imidazole, 86 g of tert-butyldimethylsilyl chloride, and 5 g of potassium iodide, and heat to 75° C. to react, and TLC detects that the reactant completely disappears. Cool, filter, wash the filter cake with 50ml of acetonitrile, pump dry to recover imidazole, concentrate the filtrate to dryness, recover the acetonitrile for mechanical use, add 500ml of cyclohexane to dissolve the residue, and dissolve the filtrate with 500ml of 1% NH 3 Wash twice with water, then wash with 500ml water, separate the organic layer, wash with anhydrous Na 2 SO 4 Dry for 4 hours, filter, and concentrate the filtrate to dryness to obtain 176.5 g of the product lovaamide disiloxane, which is directly used in subsequent reactions.

Embodiment 3

[0052] Dissolve the lovaamide prepared by the method in Example 1 in 200ml of methylation recovery solvent (containing tetrahydrofuran, cyclohexane and n-hexane), add imidazole 42g, tert-butyldimethylsilyl chloride 86g, potassium iodide 5g, dimethyl Aminopyridine 2g, heat up to reflux with stirring, keep warm for reaction, TLC detects that the reactant completely disappears, cool until the insoluble matter is completely precipitated, remove the insoluble matter, and the filtrate is directly used for the methylation reaction.

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Abstract

The invention provides a dihydroxyl protection method of lovaamide and a preparation method of simvastatin. The dihydroxyl protection method of lovaamide disclosed by the invention comprises the following steps of: (1) reacting lovastatin with primary amine or secondary amine to generate lovaamide; and (2) adding an acid-binding agent into a low-boiling-point water-soluble solvent, and reacting the lovaamide with a hydroxyl protection agent to protect the dihydroxyl of the lovaamide. Compared with the prior art, the method has the positive effects of simplification of the production process, recyclability of the used solvent, high economic efficiency, environmental friendliness and suitability for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a dihydroxy protection method of a simvastatin intermediate—lovastatin, and a preparation method of simvastatin. Background technique [0002] Simvastatin is a kind of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor developed by Merck Company of the United States, and its structural formula is shown in Formula I. Simvastatin has a strong lipid-lowering effect and is one of the commonly used "statin" blood-lipid-lowering drugs in the world. It is widely used in the treatment of hyperlipidemia and also in the prevention of cardiovascular and cerebrovascular diseases. [0003] [0004] US patent document US4820850 discloses a synthetic method of simvastatin, which has the advantages of good reaction specificity and guaranteed product quality, and thus is currently used by many manufacturers. [0005] At present, the synthesis methods of simvastatin ar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/30C07F7/18
Inventor 马德银
Owner NEW FOUNDER HLDG DEV LLC
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