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Process for the preparation of substituted imidazoquinoline

A technology of compounds and solvates, applied in the field of imidazoquinoline derivatives, can solve the problem that the clinical proof of concept of TLR7 agonists is yet to be determined, etc.

Pending Publication Date: 2021-10-19
DEBIOTECH SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for systemic routes of administration, clinical proof of concept for TLR7 agonists is pending

Method used

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  • Process for the preparation of substituted imidazoquinoline
  • Process for the preparation of substituted imidazoquinoline
  • Process for the preparation of substituted imidazoquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] Embodiment 1-use the method of the present invention to synthesize N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo [4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

[0185] Step a): providing a compound of formula (3)

[0186] Compound 1 (1 eq), p-toluenesulfonic acid monohydrate (0.05 eq) and toluene (10 vol) were charged to the reactor. After addition of 1,1,1,3-tetramethoxypropane (1.2 equiv), the contents of the reactor were adjusted to reflux at about 95°C and the content of compound 1 was monitored using HPLC.

[0187] Step b): preparing the compound of formula (4)

[0188] When the content of Compound 1 drops to ≤1.0% area of ​​the initial area (determined by HPLC), adjust the contents of the reactor to 10 °C to 15 °C and add 6N HCl (5 vol) to the reactor over about 1 h , so as to maintain the temperature ≤ 25 ℃. The contents of the reactor were stirred at 20°C to 25°C for at least 2 hours and the reaction was monitored for completion by HPLC....

Embodiment 2

[0209] Example 2 - Comparative synthesis of N-(4-(4-amino-2-(2-methoxyethane) using a chromatographic purification step (comparative method B) Base)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

[0210] N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro- 2H-pyran-4-yl)acetamide according to Figure 11 prepared by the method shown in , which is similar to the method of the present invention, but which uses 3 chromatographic purification steps (one after removal of the Boc protecting group; one after reaction with tetrahydropyrone; and one after amine oxide after transformation). The overall yield of Comparative Method B, the amount of compound of formula (I) produced by the method and the time required for the synthesis are given in Table 6 below.

[0211] Table 6

[0212] Method of the invention Comparison Method B total yield 31％ 11％ Chromatographic purification 0 3 amount...

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Abstract

The present invention relates to a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide of formula (I), an imidazoquinoline derivative useful as toll-like receptor agonist, in particular as an agonist of TLR7, which promotes induction of certain cytokines. Furthermore, the present invention also provides intermediates useful in the synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide.

Description

technical field [0001] The present invention relates to the synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)- The method of N-(tetrahydro-2H-pyran-4-yl)acetamide, said compound being an imidazoquinoline derivative useful as a toll-like receptor agonist, especially as an agonist of TLR7, which Promotes the induction of specific cytokines. In addition, the present invention also provides a compound that can be used to synthesize N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl) Butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide intermediate. Background technique [0002] The present disclosure relates generally to the field of organic synthetic methodology for the preparation of Toll-like receptor 7 agonists and their synthetic intermediates. Toll-like receptors (Toll-like receptors, TLRs) currently contain 13 gene families of receptors with different specificities, 11 of which are found in humans, which are part of the pattern re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46C07D471/04
CPCC07D471/04C07D215/46Y02A50/30Y02P20/55
Inventor 克里斯托夫·亨里
Owner DEBIOTECH SA