CN113072454A

CN113072454A - Novel crystal form of oxoethylamine compound

Info

Publication number: CN113072454A
Application number: CN202110384231.7A
Authority: CN
Inventors: 付明伟; 葛书旺; 陈怡�; 葛敏; 林峰
Original assignee: Nanjing Zhengji Pharmaceutical Research Co ltd
Current assignee: Nanjing Zhengji Pharmaceutical Research Co ltd
Priority date: 2021-04-09
Filing date: 2021-04-09
Publication date: 2021-07-06
Anticipated expiration: 2041-04-09
Also published as: CN113072454B

Abstract

The invention relates to a novel crystal form of an intermediate for preparing tricyclic pyridine derivatives, in particular to a novel crystal form of fumarate of an oxoethylamine compound. In particular, the invention provides a compound fumarate crystal form I shown as a formula (I), and the crystal form I has a good crystal habit and is suitable for industrial production.

Description

Novel crystal form of oxoethylamine compound

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a new crystal form of an intermediate for preparing tricyclic pyridine derivatives, in particular to a new fumarate crystal form of an oxoethylamine compound.

Background

Tricyclic pyridine derivatives such as 7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione are used as the core backbone of substituted polycyclic pyridone derivatives having cap-dependent endonuclease inhibitory activity and as a common backbone for other compounds used as medicaments, such as those having HIV integrase inhibitory activity. CN111386276A discloses a method for preparing substituted polycyclic pyridone derivatives, wherein the intermediate compound of formula (I) is involved, and whether the phosphate, benzoic acid, hydrochloric acid, sulfate, etc. of the compound of formula (I) are in crystalline state is studied, wherein the phosphate, methanesulfonate, p-chlorobenzoate are in crystalline state, but the crystals of methanesulfonate and p-chlorobenzoate can deliquesce in air, thus industrial production can not be realized, only the phosphate can not deliquesce,

CN111574386A discloses that the purity of the compound of formula (I) is greatly related to the subsequent reaction results, and discloses a method for purifying the compound of formula (I), which comprises the steps of preparing propionate, acetate, citrate, oxalate, phosphate crystals of the compound of formula (I), adding alkali for free, extracting with dichloromethane, and distilling.

Disclosure of Invention

The invention provides a crystal form I of fumarate of a compound shown as a formula (I), which is characterized in that X-ray powder diffraction spectrum 2 theta values have diffraction peaks at 8.28 +/-0.2 degrees, 13.54 +/-0.2 degrees, 13.97 +/-0.2 degrees, 16.47 +/-0.2 degrees, 18.66 +/-0.2 degrees, and 19.94 +/-0.2 degrees.

In some embodiments, form I has a diffraction peak at an X-ray powder diffraction spectrum 2 Θ value of 8.28 ± 0.2 °, 13.54 ± 0.2 °, 13.97 ± 0.2 °, 16.47 ± 0.2 °, 18.66 ± 0.2 °, 19.94 ± 0.2 °, 22.61 ± 0.2 °, 23.71 ± 0.2 °, 24.74 ± 0.2 °, 25.15 ± 0.2 °, 27.21 ± 0.2 °.

In some embodiments, the form I has an X-ray powder diffraction spectrum 2 Θ value at 6.88 ± 0.2 °, 8.28 ± 0.2 °, 13.54 ± 0.2 °, 13.97 ± 0.2 °, 15.00 ± 0.2 °, 16.47 ± 0.2 °, 17.64 ± 0.2 °, 18.66 ± 0.2 °, 19.94 ± 0.2 °, 22.61 ± 0.2 °, 22.99 ± 0.2 °, 23.71 ± 0.2 °, 24.74 ± 0.2 °, 25.15 ± 0.2 °, 27.21 ± 0.2 °, 27.95 ± 0.2 °, 29.08 ± 0.2 °, 33.91 ± 0.2 °, and a diffraction peak.

In some embodiments, the form I has an X-ray powder diffraction spectrum as in figure 1.

The invention also provides a preparation method of the crystal form I of the fumarate of the compound shown in the formula (I), which comprises the steps of dissolving the compound shown in the formula (I) in a proper amount of solvent, carrying out salt forming reaction with fumaric acid, and separating out a solid. In some embodiments, the solvent is selected from 2-methyltetrahydrofuran, dichloromethane, tetrahydrofuran.

Advantageous effects

The crystal form I of the fumarate of the compound shown in the formula (I) is suitable for industrial production, and the crystal form I is suitable for post-treatment in the preparation process of the crystal form I of the fumarate of the compound shown in the formula (I) and is beneficial to the suction filtration process, so that the compound shown in the formula (I) is simpler and more convenient to purify.

Drawings

FIG. 1: a compound of formula (1) fumarate salt form I XRD pattern;

FIG. 2 is a drawing: crystal habit pattern (100 times) of phosphate solid of compound of formula (1);

FIG. 3: crystal habit pattern (200 times) of fumarate salt solid of compound of formula (1).

Detailed Description

XRD diffractometer

The manufacturer model is as follows: brooks (D8 advance) determination

X-ray light pipe: the concentration of Cu, K alpha,

x-ray light pipe setting: 40kV and 40mA

Scanning range (2 θ (°)): 3 to 40

Scanning mode: continuous

Scanning time of each step: 0.12s

Optical microscope

Olympus BX53 microscope

Example 1: screening for salts

The method comprises the following steps: 1g of the compound of the formula (1) was taken out in 3ml of methyltetrahydrofuran, 1 equivalent of an acid was added thereto, and whether or not a solid precipitated was observed with stirring at room temperature (temperature: 15 ℃ C.).

During the salt formation of 11 kinds of acids, only phosphoric acid, fumaric acid, L-tartaric acid and succinic acid appear as solids. But the L-tartaric acid and the succinic acid have obvious moisture absorption during suction filtration, and the phosphate and the fumarate have good solid states. The crystal habit patterns of the phosphate and fumarate solid are respectively shown in figures 2 and 3 when observed under an optical microscope.

Solid suction filtration time comparison of phosphate and fumarate:

the phosphate can prolong the suction filtration time and is not beneficial to industrial scale-up production.

The fumarate salt solid of the compound shown in the formula (1) is defined as a crystal form I, the X-ray powder diffraction spectrum characteristic peak position and the intensity of the fumarate salt solid are shown in a table 1, and the X-ray powder diffraction spectrum characteristic peak diagram is shown in an attached figure 1.

TABLE 1 XRD Pattern characterization data for fumarate salt form I of Compound of formula (1)

Example 2

CN111574386 example 6 was repeated

Adding 20.2g of potassium hydroxide and 24.5g of ethanolamine into a 1000ml four-mouth bottle, heating to 100 ℃, adding 10.0g of 2-chloroacetaldehyde dimethyl acetal, and keeping the temperature for reaction for 10 hours. Cooling to room temperature, adding 70ml of water-soluble clear solution, cooling to room temperature, extracting with dichloromethane for later use, adding 2.02g of oxalic acid, stirring, adding 0.05g of oxalate seed crystal, keeping the temperature at 0 ℃, stirring for 2h, filtering, and taking 1h for colloidal draining.

Example 3

1g of the compound of the formula (1) was taken in 5ml of methylene chloride, and 0.39g of fumaric acid was added to precipitate a solid, which was then subjected to suction filtration to obtain 1.20 g. XRD detection shows that the solid is fumarate crystal form I, and its crystal habit map is the same as that shown in figure 3.

Claims

1. Form I of the fumarate salt of a compound of formula (I), characterized by X-ray powder diffraction spectrum 2 theta values having diffraction peaks at 8.28 + -0.2 deg., 13.54 + -0.2 deg., 13.97 + -0.2 deg., 16.47 + -0.2 deg., 18.66 + -0.2 deg., 19.94 + -0.2 deg.,

2. form I according to claim 1, having an X-ray powder diffraction spectrum with diffraction peaks, in terms of 2 θ, at 8.28 ± 0.2 °, 13.54 ± 0.2 °, 13.97 ± 0.2 °, 16.47 ± 0.2 °, 18.66 ± 0.2 °, 19.94 ± 0.2 °, 22.61 ± 0.2 °, 23.71 ± 0.2 °, 24.74 ± 0.2 °, 25.15 ± 0.2 °, 27.21 ± 0.2 °.

3. Form I according to claim 1, having an X-ray powder diffraction spectrum 2 θ value at 6.88 ± 0.2 °, 8.28 ± 0.2 °, 13.54 ± 0.2 °, 13.97 ± 0.2 °, 15.00 ± 0.2 °, 16.47 ± 0.2 °, 17.64 ± 0.2 °, 18.66 ± 0.2 °, 19.94 ± 0.2 °, 22.61 ± 0.2 °, 22.99 ± 0.2 °, 23.71 ± 0.2 °, 24.74 ± 0.2 °, 25.15 ± 0.2 °, 27.21 ± 0.2 °, 27.95 ± 0.2 °, 29.08 ± 0.2 °, 33.91 ± 0.2 °, with diffraction peaks.

4. Form I according to claim 1 having an X-ray powder diffraction spectrum according to figure 1.

5. The crystal form I of claim 1, which is prepared by dissolving the compound of formula (I) in a proper amount of solvent, and reacting with fumaric acid to obtain a salt, wherein a solid is separated out.

6. The process according to claim 5, wherein the solvent is selected from the group consisting of 2-methyltetrahydrofuran, dichloromethane, tetrahydrofuran. .