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Process for Preparing Compound Having HIV Integrase Inhibitory Activity

Inactive Publication Date: 2014-01-09
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention allows for the efficient and high-yield production of anti-HIV drugs that target HIV integrase. The invention avoids the use of toxic or harmful reagents, reducing safety risks and costs. Additionally, the resulting compounds have high stability and purity, making them easier to handle and produce. This invention provides a useful tool for the industrial production of anti-HIV drugs.

Problems solved by technology

However, the above production methods of these documents are not satisfactory for the industrial manufacturing method because of the followings:
the total yield is low, thus being inefficient,
a high toxic and harmful reaction is used.
an expensive reagent is used,
an environmentally harmful reagent is used.

Method used

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  • Process for Preparing Compound Having HIV Integrase Inhibitory Activity
  • Process for Preparing Compound Having HIV Integrase Inhibitory Activity
  • Process for Preparing Compound Having HIV Integrase Inhibitory Activity

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0307]

Step 1

[0308]A THF (3 ml) solution of benzyl alcohol (1.00 g, 9.25 mmol) was added to a THF (4 ml) suspension of sodium tert-pentoxide (2.55 g, 23.2 mmol) at room temperature in a nitrogen atmosphere, and the mixture was stirred at 40° C. for 2 hours. This reaction solution was cooled in an ice bath, and a THF (3 ml) solution of compound 1A (1.53 g, 10.2 mmol) was added dropwise thereto at 0-10° C. The reaction solution was stirred at room temperature for 2 hours, and 2 N hydrochloric acid (15 ml) was then added thereto, followed by extraction two times with ethyl acetate. The combined extracts were washed with water, a saturated aqueous solution of sodium bicarbonate, water, and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained oil was purified by silica gel column chromatography (n-hexane-ethyl acetate: 4:1, v / v) to obtain 1.89 g (yield: 92%) of compound 1B as an oil.

[0309]1H-NMR (CDCl3) δ: 3.56 (2H, s...

example 2

[0314]

Step 1

[0315]A DMI (3 ml) solution of benzyl alcohol (0.66 g, 6.1 mmol) was added to a DMI (4 ml) suspension of sodium tert-pentoxide (1.67 g, 15.2 mmol) at room temperature in a nitrogen atmosphere, and the mixture was stirred at 40° C. for 2 hours. This reaction solution was cooled in an ice bath, and a DMI (3 ml) solution of compound 2A (1.10 g, 6.68 mmol) was added dropwise thereto at 0-10° C. The reaction solution was stirred at 0-5° C. for 2 hours and at room temperature for 3 hours, and 2 N hydrochloric acid (15 ml) was then added thereto, followed by extraction two times with ethyl acetate. The combined extracts were washed with water, a saturated aqueous solution of sodium bicarbonate, water, and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained oil was purified by silica gel column chromatography (n-hexane-ethyl acetate: 4:1, v / v) to obtain 1.29 g (yield: 90%) of compound 2B as an oil.

[0316]1H-...

example 3

[0321]

Step 1

[0322]N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol) was added dropwise to compound 3A (5.0 g, 30.4 mmol) under cooling at 0° C. After stirring at 0° C. for 1 hour, 100 ml of ethyl acetate was added to the reaction solution, and the organic layer was washed with a 0.5 N aqueous hydrochloric acid solution (50 ml). The aqueous layer was separated, followed by extraction with ethyl acetate (50 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate: 1:1 (v / v)→ethyl acetate) to obtain 4.49 g (yield: 67%) of compound 3B as an oil.

[0323]1H-NMR (CDCl3) δ: 1.32 (3H, t, J=7.1 Hz), 2.90 (3H, br s), 3.29 (3H, br s), 4.23 (2H, q, J=7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).

Step 2

[0324]Lithium hexamethyldisilazide (1.0 M solut...

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Abstract

A process for preparing a compound represented by formula (Y1) or (Y2) [wherein Rx is an optionally substituted carbocyclyl lower alkyl, or the like] or a salt thereof, using a novel process for preparing a pyridone derivative represented by formula (X4) [wherein R1d is hydrogen, halogen, or the like; R2d is hydrogen, a lower alkyl optionally substituted with substituent E, or the like; R4d is a lower alkyl optionally substituted with substituent E, or the like; and R6d is a lower alkyl group optionally substituted with substituent group E, or the like].

Description

TECHNICAL FIELD[0001]The present invention relates to a method of producing compounds having HIV integrase inhibitory activity, using a novel method of producing pyrone derivatives and pyridone derivatives.BACKGROUND ART[0002]Patent Document 1 describes compounds (I) and (II), which are useful as anti-HIV drugs and shown by formulae:This document describes the following reaction formula as a method of producing compound (I).[0003]Furthermore, Patent Documents 2 to 6 describe the following reaction formula as an improved method of producing compound (I).[0004]However, the above production methods of these documents are not satisfactory for the industrial manufacturing method because of the followings:these reaction processes for obtaining compound (I) include 16 or 11 steps, respectively, and are very long,the total yield is low, thus being inefficient,a high toxic and harmful reaction is used.an expensive reagent is used,an environmentally harmful reagent is used.[0005]Therefore, th...

Claims

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Application Information

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IPC IPC(8): C07D498/14
CPCC07D498/14C07D213/79C07B2200/13A61K31/5365C07D213/80C07D211/94A61P31/18A61P43/00
Inventor SUMINO, YUKIHITOMASUI, MORIYASUYAMADA, DIASUKEIKARASHI, FUMIYAOKAMOTO, KAZUYA
Owner SHIONOGI & CO LTD
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