CRYSTALLINE FORM OF DI-P-TOLUOYL-L-TARTRATE OF UPADACITINIB

Abstract

The present application provides a upadacitinib salt compound and a preparation method therefor. The salt involved in the method in the present application has an easy preparation operation, a cheap raw material easy to get, and a good purification effect on upadacitinib, and is beneficial to industrial production.

Claims

1-4. (canceled)

5. Di-p-toluoyl-L-tartrate of a compound of formula I: ##STR00001## or a hydrate of the di-p-toluoyl-L-tartrate.

6. The di-p-toluoyl-L-tartrate or hydrate of the di-p-toluoyl-L-tartrate of claim 5 being in crystalline form.

7. The di-p-toluoyl-L-tartrate or hydrate of the di-p-toluoyl-L-tartrate of claim 6 wherein the crystalline form is Form A of the compound of formula I Di-p-toluoyl-L-tartrate characterized by a X-ray powder diffraction pattern comprising peaks at angles (° 2θ) of 3.9°±0.2° 2θ, 7.7°±0.2° 2θ, and 15.2°±0.2° 2θ.

8. The di-p-toluoyl-L-tartrate or hydrate of the di-p-toluoyl-L-tartrate of claim 7, wherein the X-ray powder diffraction pattern further comprises peaks at angles (° 2θ) of 7.5°±0.2° 2θ, 10.4°±0.2° 2θ, and 23.4°±0.2° 2θ.

9. (canceled)

10. A pharmaceutical composition comprising the di-p-toluoyl-L-tartrate or hydrate of the di-p-toluoyl-L-tartrate of claim 5.

Description

DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 is the XRPD image of Di-p-toluoyl-L-tartrate crystal form A of compound I;

[0021] FIG. 2 is a DSC chart of Di-p-toluoyl-L-tartrate crystal form A of compound I;

[0022] FIG. 3 is a TGA chart of Di-p-toluoyl-L-tartrate crystal form A of compound I;

[0023] FIG. 4 is an HNMR chart of Di-p-toluoyl-L-tartrate crystal form A of compound I.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0024] The present disclosure is further explained by below specific embodiments, but it should not be concluded to limit the protective scope of the present disclosure. Those skilled in the art can make improvements on the preparation method and use of instruments within the scope of the claims. These improvements should also be considered as within the protection scope of the present disclosure. Therefore, the protection scope of the invention should be subject to the appended claims.

[0025] In the following embodiments, the test method is usually implemented according to conventional conditions or conditions recommended by the manufacturer; the compound I is prepared by the method of patent W02017066775.

[0026] The explanations of the abbreviations used in the present disclosure are as follows:

[0027] XRPD: X-ray powder diffraction

[0028] DSC: Differential Scanning calorimetry

[0029] TGA: Thermogravimetric Analysis

[0030] The X-ray powder diffraction pattern of the present invention is collected on the D2PHASER X-ray powder diffractometer of Bruker Company.

[0031] The XRPD method parameters of the present invention are as follows:

TABLE-US-00001 Step Size [°2Th.]: 0.0201 Scan Step Time [s]: 0.1 K-Alpha1 [Å]: 1.54060 K-Alpha2 [Å]: 1.54439 Generator Settings: 10 mA, 30 kV Scan Range [°2Th.]: 3-40

[0032] The differential scanning calorimetry (DSC) chart of the present invention is collected on a differential scanning calorimeter DSC2000 from TA Instruments.

[0033] The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

TABLE-US-00002 Sample tray Aluminum plate, gland Temperature range/° C. RT-250 Scanning rate/° C./min 10 Protective gas Nitrogen

[0034] The thermo-gravimetric analysis (TGA) graph of the present invention is collected on the TGA Q500 of TA Instruments' thermogravimetric analyzer. The method parameters of the thermo-gravimetric analysis (TGA) of the present invention are as follows:

TABLE-US-00003 Sample tray Aluminum plate, gland Temperature range/° C. RT-250 Scanning rate/° C./min 10 Protective gas Nitrogen

[0035] The high-performance liquid chromatography (HPLC) results of the present invention are collected on Waters 2695. The method parameters of the high-performance liquid chromatography (HPLC) of the present invention are as follows:

[0036] Liquid chromatography column: Agilent Zorbax Plus-C18, 4.6*100 mm, 3.5 um;

[0037] Mobile phase: water-acetonitrile-trifluoroacetic acid system;

[0038] Flow rate: 1 mL/min;

[0039] Column temperature: 40° C.;

[0040] Detection wavelength: 220 nm.

EXAMPLE 1

[0041] Preparation Method of Compound I Oxalate:

[0042] 380 mg of compound I was dissolved in 6 mL of isopropyl acetate, and 100 mg/2 mL of oxalic acid in isopropyl acetate was slowly added dropwise at 20° C., stirred at room temperature for 2 h, filtered, and sampled to test. The purity by HPLC was 99.51%.

EXAMPLE 2

[0043] Preparation Method of p-Toluenesulfonic Acid Salt of Compound I:

[0044] 380 mg of compound I was dissolved in 6 mL of isopropyl acetate, 360 mg/2 mL of p-toluenesulfonic acid in isopropyl acetate was slowly added dropwise at 20° C., stirred at room temperature for 2 hours, filtered, and sampled for test. The purity by HPLC was 98.73%.

EXAMPLE 3

[0045] The Preparation Method of Compound I Di-p-toluoyl-L-tartrate:

[0046] Dissolve 380 mg of compound I in 6 mL of isopropyl acetate, slowly add 390 mg/2 mL of Di-p-toluoyl-L-tartaric acid in isopropyl acetate solution dropwise at 20C, stir at room temperature for 2 h, filter, and sampled for test. The purity by HPLC was 99.32%.

EXAMPLE 4 (SUMMARY OF COMPARISON RESULTS)

[0047] Comparison of the Salt-Forming Purification Effect of Compound I:

TABLE-US-00004 Entry Acid HPLC 18603097-0 Free base (starting material for 84.58% salt formation) 18603097-22 oxalic acid 99.51% 18603097-23 p-Toluenesulfonic acid 98.73% 18603097-24 Di-p-toluoyl-L-tartaric acid 99.32% 18603099-24 L-tartaric acid 93.49%

EXAMPLE 5

[0048] Preparation Method of Di-p-toluoyl-L-tartrate Crystal Form A of Compound I:

[0049] Dissolve 390 mg of compound I in a mixed solution of 1 mL of isopropyl acetate, 0.5 mL of isopropanol and 0.3 mL of water, and slowly drop 400 mg/2 mL of Di-p-toluoyl-L-tartaric acid at 50° C. The isopropyl acetate solution was stirred at 50° C. for 2 hours, and then 5 mL of isopropyl acetate solution was added to slowly reduce to room temperature, filtered and drained 740 mg of solid. The HPLC purity of the sample was 99.78%.

[0050] HNMR data:

[0051] 1H-NMR (DMSO-d6, 400 MHz) δ: 12.29 (1H, s), 8.58 (1H, s), 7.89 (4H, d), 7.40-7.60 (2H, m), 7.38 (4H, d), 6.95 -7.06 (2H, m), 5.81 (2H, s), 4.35 (1H, dd), 5.65-5.93 (5H, m), 3.27 (1H, dd), 2.50-2.62 (1H, m), 2.40 (6H) , S), 1.05-1.15 (1H, m), 0.75-0.88 (1H, m), 0.64 (3H, t).

[0052] The Test XRPD Results are as Follows:

TABLE-US-00005 2theta d value Intensity %  3.88 22.80  41.36  7.47 11.83  33.28  7.70 11.48 100.00 10.40  8.50  62.44 13.03  6.80  22.55 13.40  6.61  79.74 15.26  5.81  40.57 16.46  5.39  24.26 18.40  4.82  32.10 19.32  4.60  46.82 19.98  4.44  49.06 23.13  3.85  25.62 23.44  3.79  42.78 23.96  3.71  24.54

EXAMPLE 6

[0053] Preparation Method of Di-p-toluoyl-L-tartrate Crystal Form A of Compound I:

[0054] Add 415 mg of compound I and 430 mg of Di-p-toluoyl-L-tartaric acid into the reaction flask, add a mixed solution of 8 mL isopropyl acetate, 0.5 mL isopropanol and 0.3 mL water, and stir at 50° C. for 2 hours, It was cooled to room temperature slowly, filtered and drained 755 mg of solid, and the HPLC purity of the sample was 99.79%.

[0055] HNMR data:

[0056] 1H-NMR (DMSO-d6, 400 MHz) δ: 12.29 (1H, s), 8.58 (1H, s), 7.89 (4H, d), 7.40-7.60 (2H, m), 7.38 (4H, d), 6.95 -7.06 (2H, m), 5.81 (2H, s), 4.35 (1H, dd), 5.65-5.93 (5H, m), 3.27 (1H, dd), 2.50-2.62 (1H, m), 2.40 (6H) , S), 1.05-1.15 (1H, m), 0.75-0.88 (1H, m), 0.64 (3H, t).

[0057] The Test XRPD Results are as Follows:

TABLE-US-00006 2theta d value Intensity %  3.87 22.81  43.59  7.48 11.82  52.26  7.69 11.50 100.00 10.37  8.53  70.43 13.28  6.66  60.79 15.00  5.91  20.68 15.24  5.81  60.49 16.39  5.41  24.30 18.27  4.86  30.15 19.21  4.62  28.37 19.97  4.45  32.89 23.12  3.85  22.23 23.36  3.81  58.03