RELATED SUBSTANCE OF LINAGLIPTIN INTERMEDIATE AND SYNTHESIS METHOD THEREOF

Abstract

A related substance of linagliptin intermediate 2-(chloromethyl)-4-methylquinazoline, 4,4′-(2-methylpropane-1,3-diyl)bis(2-(chloromethyl)quinazoline) and a method for synthesizing the related substance (impurity) by reacting 2-(chloromethyl)-4-methylquinazoline with acetaldehyde under an alkaline condition and a purification method are provided. The preparation method is simple and convenient to operate, short in reaction time, high in product purity, and high in yield. The synthesized related substance can be used for qualitative and quantitative analysis of the linagliptin intermediate 2-(chloromethyl)-4-methylquinazoline and API impurities of linagliptin, so that the medication safety of the linagliptin is improved.

Claims

1. A related substance of linagliptin intermediate 2-(chloromethyl)-4-methylquinazoline, being 4,4′(2-methylpropane-1,3-diyl)bis(2-(chloromethyl)quinazoline) (formula I), wherein the related substance has the following chemical structure: ##STR00005##

2. A preparation method of 4,4′-(2-methylpropane-1,3-diyl)bis(2-(chloromethyl)quinazoline) (formula I), comprising the following steps: (1) fully dissolving 2-(chloromethyl)-4-methylquinazoline and 1,4-dioxane under stirring to obtain a first mixture; (2) adding a 30% aqueous sodium hydroxide solution to the first mixture at a controlled temperature of 10-25° C. to obtain a second mixture; (3) controlling the temperature at 10-25° C., slowly adding acetaldehyde dropwise to the second mixture, and reacting for 16 h under stirring at a controlled temperature of 10-25° C. to obtain a third mixture; (4) adding water to the third mixture, stirring, filtering to obtain a first filter cake, and vacuum-drying the first filter cake to obtain a crude product of an impurity shown in formula I; and (5) fully dissolving the crude product obtained in step (4) in dichloromethane, passing the dichloromethane through a short silica gel column, concentrating a filtrate to dryness, pulping with methyl tert-butyl ether (MBTE), filtering to obtain a second filter cake, and vacuum-drying the second filter cake to obtain the impurity shown in formula I.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0020] It should be understood that, based on the disclosure provided herein, those skilled in the art can make various modifications and improvements to the present disclosure without departing from the spirit and scope of the present disclosure. They should fall within the scope of patent protection defined by the claims of this application. In addition, it should be understood that the examples provided herein are only intended to illustrate the present disclosure, and should not be construed as limiting the present disclosure.

[0021] The present disclosure will be further described in detail below in conjunction with specific examples.

Example 1

[0022] 2-(Chloromethyl)-4-methylquinazoline (10.0 g, 51.91 mmol) and 1,4-dioxane (50.0 mL) solution were added into a reaction flask, and stirred until fully dissolved; a 30% aqueous sodium hydroxide solution (50.0 mL) was slowly added at 10-25° C., and acetaldehyde (22.87 g, 519.09 mmol) was slowly added dropwise at 10-25° C., and the reaction was conducted for 16 h under stirring at a controlled temperature of 10-25° C.; water (300 mL) was slowly added, the temperature was controlled at 10-25° C., and the reaction was conducted for 1.5 h, filtered, and vacuum dried at 50° C. to obtain a yellow solid, namely 2.7 g of crude product of an impurity shown in formula I, with a molar yield of 25.29%.

Example 2

[0023] 2.7 g of crude product of an impurity shown in formula I was added to the reaction flask, and stirred with dichloromethane (50.0 mL) until fully dissolved; the mixture was passed through a short silica gel column (5.0 g). The filtrate was evaporated to dryness under reduced pressure at 40° C., and stirred with MBTE (10.0 mL) at 25° C. for 30min, and filtered; the resulting solid was vacuum dried at 50° C. to obtain an off-white solid, namely, 2.1 g of pure impurity shown in formula I, with a yield 77.78%.

[0024] The molecular formula of the impurity shown in formula I was: C.sub.22H.sub.20Cl.sub.2N.sub.4; m/z: 410.11

[0025] The characterization data of the impurity shown in formula I are as follows:

[0026] 1. Mass spectrum data MS (ESI-Pos): [M+H].sup.+=411.11;

[0027] 2. Nuclear magnetic instrument model: BRUKER 400 MHz;

##STR00004##

[0028] The .sup.1H-NMR spectrum attribution of the hydrogen spectrum data is as follows:

TABLE-US-00001 Chemical shift Number of (ppm) hydrogen atoms Peak splitting Attribution 1.12-1.15 2 d (J = 6.0 Hz) 12 3.21-3.26 3 m 10,11,13 3.35-3.62 2 m 4.79 4 s 8,16 7.65-7.70 2 t (J = 7.2 Hz) 1,20 7.88-7.92 2 t (J = 7.2 Hz) 2,19 8.02-8.05 2 d (J = 8.4 Hz) 6,21 8.26-8.28 2 d (J = 8.4 Hz) 3,18

[0029] The .sup.13C-NMR spectrum attribution is as follows:

TABLE-US-00002 Chemical shift (δ ppm) Attribution 20.57 12 32.32 11 41.49 10,13 47.87 8,16 122.86 5,22 125.01 6,21 128.03 1,20 129.09 3,18 134.01 2,19 150.16 4,17 160.85 9,14 171.26 7,15

[0030] 3. The chemical structure of the impurity shown in formula I was further determined by single crystal culture and diffraction of single crystal structures, as shown below: