New crystal form of linaggolicholine and preparation method thereof

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a novel crystal form of oral gonadotropin-releasing hormone receptor antagonist linaggoliril and a preparation method thereof.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to new crystal forms of linzagolix choline and a preparation method thereof. Background Art

[0002] Linzagolix choline, with the English name Linzagolix Choline, has the chemical name: choline 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylate (Formula (A)). Linzagolix choline has antagonistic activity against gonadotropin-releasing hormone and can be used as a prophylactic or therapeutic agent for sex hormone-dependent diseases such as benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine myomas, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, etc. The structural formula of linzagolix choline is as follows:

[0003]

[0004] Patent CN102753557B describes the crystal form characterization data of linzagolix choline and its preparation method. For the crystal form of linzagolix choline described in this patent, using Cu-Kα radiation, it has characteristic peaks at the following diffraction angles (2θ(°)) in the powder X-ray diffraction pattern: 7.1, 11.5, 19.4, 20.3, 21.5, 22.0, 22.6, 23.5 and 26.2. The above crystal form has characteristic peaks at the following chemical shift values (δ(ppm)) in the 13C solid-state NMR spectrum: 155.8, 149.8, 145.3, 118.0, 113.7, 111.6, 110.3, 98.1, 69.8, 58.7, 57.1 and 55.5. The above crystal form has characteristic peaks at the following chemical shift values (δ(ppm)) in the 19F solid-state NMR spectrum: -131.6, -145.2 and -151.8. The above crystal form has an endothermic peak at about 213°C in the differential thermal analysis graph. Summary of the Invention

[0005] The object of the present invention is to provide crystal form I, crystal form II, crystal form III of linzagolix choline and a preparation method thereof on the basis of the prior art.

[0006] The present invention relates to crystal form I of linzagolix choline, which is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angle has characteristic peaks at 5.2±0.2°, 9.1±0.2° and 10.4±0.2°.

[0007] More specifically, the crystal form I has an X-ray powder diffraction pattern that is substantially consistent with Figure 1 the one shown.

[0008] The present invention relates to a method for preparing crystalline form I of linzagolix choline, which is characterized in that linzagolix choline is dissolved in water until clear and then freeze-dried.

[0009] The present invention relates to crystalline form II of linzagolix choline, which is characterized in that the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 15.4±0.2°, 16.4±0.2°, 21.0±0.2°, 28.1±0.2° when using Cu-Kα radiation.

[0010] Specifically, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 21.0±0.2°, 23.8±0.2°, 26.2±0.2°, 26.8±0.2°, 28.1±0.2° when using Cu-Kα radiation.

[0011] More specifically, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 13.9±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 18.5±0.2°, 20.1±0.2°, 20.4±0.2°, 21.0±0.2°, 22.8±0.2°, 23.8±0.2°, 26.2±0.2°, 26.8±0.2°, 28.1±0.2°, 33.1±0.2° when using Cu-Kα radiation.

[0012] Further specifically, the crystalline form II has an X-ray powder diffraction pattern that is substantially consistent with that Figure 2 shown.

[0013] Further specifically, it has a TGA-DSC pattern that is substantially consistent with that Figure 3 shown.

[0014] The present invention relates to a method for preparing crystalline form II of linzagolix choline, which is characterized in that crystalline form I of linzagolix choline is slurried at room temperature in ethyl formate / water.

[0015] The present invention relates to crystalline form III of linzagolix choline, which is characterized in that the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 6.4±0.2°, 11.9±0.2°, 16.5±0.2°, 23.8±0.2° when using Cu-Kα radiation.

[0016] Specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 6.4 ± 0.2°, 11.9 ± 0.2°, 12.9 ± 0.2°, 16.5 ± 0.2°, 20.6 ± 0.2°, 22.6 ± 0.2°, 23.8 ± 0.2°, 27.0 ± 0.2°.

[0017] More specifically, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in terms of 2θ angle has characteristic peaks at 6.4 ± 0.2°, 8.9 ± 0.2°, 9.4 ± 0.2°, 11.9 ± 0.2°, 12.9 ± 0.2°, 14.2 ± 0.2°, 14.9 ± 0.2°, 16.5 ± 0.2°, 17.1 ± 0.2°, 18.0 ± 0.2°, 18.9 ± 0.2°, 20.6 ± 0.2°, 22.3 ± 0.2°, 22.6 ± 0.2°, 23.0 ± 0.2°, 23.8 ± 0.2°, 25.4 ± 0.2°, 27.0 ± 0.2°.

[0018] Even more specifically, the crystalline form III has an Figure 4 X-ray powder diffraction pattern that is substantially consistent with that shown.

[0019] Even more specifically, it has a Figure 5 TGA-DSC pattern that is substantially consistent with that shown.

[0020] The present invention relates to a method for preparing crystalline form III of linzagolix choline, which is characterized in that crystalline form I of linzagolix choline is subjected to polymorphic transformation at room temperature or crystalline form I of linzagolix choline is subjected to polymorphic transformation by pulping at room temperature in n-heptane. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 X-ray powder diffraction pattern of crystalline form I of the compound of formula (A).

[0022] Figure 2 X-ray powder diffraction pattern of crystalline form II of the compound of formula (A).

[0023] Figure 3 TGA-DSC thermal pattern of crystalline form II of the compound of formula (A).

[0024] Figure 4 X-ray powder diffraction pattern of crystalline form III of the compound of formula (A).

[0025] Figure 5 TGA-DSC thermal pattern of crystalline form III of the compound of formula (A).

[0026] Figure 6 1H-NMR spectrum of crystalline form III of the compound of formula (A). Detailed Embodiments

[0027] The following provides further detailed descriptions of the above content of the present invention through specific embodiments, but this should not be construed as any limitation on the protected subject matter of the present invention. All technical solutions implemented based on the above content of the present invention fall within the scope of the present invention. The present invention generally and / or specifically describes the materials and test methods used in the experiments.

[0028] In the following text, unless otherwise specified, the operations performed in the present invention are carried out under the conventional room temperature conditions in the art. The term "room temperature" has the technical meaning well-known in the art, generally referring to 20 - 35°C, preferably 20 - 30°C, and more preferably 25 - 30°C.

[0029] The reagents used in the present invention are all conventional reagents and can be obtained through market purchases. The starting materials and reactants used can be prepared through existing technologies or publicly available existing literature, or can also be obtained through market purchases.

[0030] In the present invention, unless otherwise specified, the amounts of the solvents and inorganic reagents used are the conventional amounts for the reactions, which can be determined by those skilled in the art based on existing technologies.

[0031] Example 1 Preparation of Crystal Form I of the Compound of Formula (A)

[0032] The compound of formula (A) was prepared according to the method in Patent CN102753557B. Weigh 1.1623 g of the compound of formula (A) into a single-neck flask, add 250 mL of purified water, and heat to 50°C until it dissolves clearly. Filter to obtain a solution. The filtrate was freeze-dried in an Advantage EL-85 type freeze dryer at -45°C for 2 h, then heated to 0°C in 1 h and continued freeze-drying for 10 h; heated to 25°C in 1 h and continued drying for 10 h to obtain a solid. The obtained solid was characterized by XRPD test, see attachment Figure 1 , and this solid is Crystal Form I.

[0033] Example 2 Preparation of Crystal Form II of the Compound of Formula (A)

[0034] Weigh 19.9 mg of Crystal Form I into a vial, add 1 mL of ethyl formate / water (9:1, v / v), and perform slurry at room temperature for 5 days. Filter and dry at room temperature. Characterized by XRPD, TGA-DSC tests, see attachment Figure 2 , 3 , and this solid is Crystal Form II.

[0035] Example 3 Preparation of Crystal Form III of the Compound of Formula (A)

[0036] After Crystal Form I was stored at room temperature for 7 days, it was characterized by XRPD, TGA-DSC, H-NMR tests, see attachmentFigure 4 , 5 , 6, and the solid is Polymorph III.

[0037] Preparation of Polymorph II of the Compound of Formula (A) in Example 4

[0038] Weigh 19.4 mg of Polymorph I, add 1 mL of n-heptane, and slurry for 5 days at room temperature. After filtration, dry at room temperature. XRPD and TGA-DSC tests were carried out for characterization, as shown in Appendix Figure 4 , 5 , and the solid is Polymorph III.

Claims

1. Linzagolicholine crystal form I, characterized in that Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 5.2±0.2°, 9.1±0.2° and 10.4±0.2°. More specifically, the crystalline form I has an X-ray powder diffraction pattern substantially consistent with that shown in FIG1 .

2. Linzagolicholine crystal form II, characterized in that Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 15.4±0.2°, 16.4±0.2°, 21.0±0.2°, and 28.1±0.2°. Specifically, using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 21.0±0.2°, 23.8±0.2°, 26.2±0.2°, 26.8±0.2°, and 28.1±0.2°. More specifically, using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 13.9±0.2°, 15.4±0.2°, 16.0±0.2°, 16.4±0.2°, 18.5±0.2°, 20.1±0.2°, 20.4±0.2°, 21.0±0.2°, 22.8±0.2°, 23.8±0.2°, 26.2±0.2°, 26.8±0.2°, 28.1±0.2°, and 33.1±0.2°, More specifically, the crystalline form II has an X-ray powder diffraction pattern substantially consistent with that shown in FIG2 .

3. The linzagolicholine crystal form II according to claim 2, characterized in that The TGA-DSC spectrum is substantially consistent with that shown in FIG3 .

4. Linzagolicholine crystal form III, characterized in that Using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 6.4±0.2°, 11.9±0.2°, 16.5±0.2°, and 23.8±0.2°. Specifically, using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 6.4±0.2°, 11.9±0.2°, 12.9±0.2°, 16.5±0.2°, 20.6±0.2°, 22.6±0.2°, 23.8±0.2°, and 27.0±0.2°. More specifically, using Cu-Ka radiation, the X-ray powder diffraction pattern expressed in 2θ angles has characteristic peaks at 6.4±0.2°, 8.9±0.2°, 9.4±0.2°, 11.9±0.2°, 12.9±0.2°, 14.2±0.2°, 14.9±0.2°, 16.5±0.2°, 17.1±0.2°, 18.0±0.2°, 18.9±0.2°, 20.6±0.2°, 22.3±0.2°, 22.6±0.2°, 23.0±0.2°, 23.8±0.2°, 25.4±0.2°, and 27.0±0.2°, More specifically, the Form III has an X-ray powder diffraction pattern substantially consistent with that shown in FIG4 .

5. The linzagolicholine crystal form III according to claim 4, characterized in that The TGA-DSC spectrum is substantially consistent with that shown in FIG5 .

6. The method for preparing the linzagolicholine crystal form I according to claim 1, wherein Linzagolcholine was dissolved in water and then freeze-dried.

7. The method for preparing the linzagolicholine crystal form II according to claim 2, wherein: Linzagolicholine Form I was slurried in ethyl formate / water at room temperature.

8. The method for preparing the linzagolicholine crystal form III according to claim 4, wherein: The linzagolicholine crystal form I is crystallized at room temperature or the linzagolicholine crystal form I is crystallized by slurrying in n-heptane at room temperature.

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