| 46 % |
With trifluoroacetic acid at 90℃; Inert atmosphere; |
3 Method 1:
The reaction flask was charged with intermediate 5A2 (10 g, 1.00 eq.), hexamethylenetetramine (HMTA, 16.8 g, 4.00 eq.) and trifluoroacetic acid (500 mL) and heated at 90° C. for 1.5 hours under nitrogen atmosphere. The reaction was complete as detected by LC-MS. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent to obtain a residue. To the obtained residue was added water (30 mL). Neutralization was conducted with 10% sodium bicarbonate aqueous solution. Dichloromethane extraction (1000 mL×3). The organic phases were combined, dried over sodium sulfate, concentrated, and washed with acetonitrile and ethyl acetate respectively to obtain compound Orin1001 (yellow solid, 5 g). The yield was 46%. 1H NMR (TH03493-010-2M CDCl3, 400 MHz): δ 12.45 (s, 1H, OH), 10.59 (s, 1H, CHO), 7.24 (s, 1H, ArH), 3.95 (s, 3H, CH3), 3.78-3.62 (m, 10H, CH2), 2.46 (s, 3H, CH3). LC-MS [M+H]+=362.2. (0214) X-ray powder diffraction (XRPD) detection was performed on the finally obtained compound Orin1001. It was demonstrated to be in a crystalline state, and was named as crystal form I. (0215) The crystal form I was subjected to TGA, DSC, DVS and stability tests. The results are as follows. (0216) 1) XRPD Detection (0217) The XRPD of the crystal form I is substantially as shown in FIG. 1. The 2θ data sheet is shown in Table 1. (0218) 2) TGA Test (0219) According to the thermogravimetric analysis (TGA) results, when heated to 200° C., there was a weight loss gradient of about 0.017%, and the thermogravimetric analysis pattern is substantially as shown in FIG. 2. It can be seen from FIG. 2 that Orin1001 crystal form I is anhydrous. (0220) 3) DSC Test (0221) According to the results of differential scanning calorimetry (DSC), an endothermic peak begins to appear when heated to around 239.4° C., and the differential scanning calorimetry pattern is substantially as shown in FIG. 3. It can be seen from FIG. 3 that the onset temperature (Tonset) of Orin1001 crystal form I is about 239° C.±5° C., for example, 239° C.; the peak temperature (Tpeak) is about 242° C.±5° C., for example, 242° C. (0222) 4) DVS Test (0223) According to the results of dynamic vapor sorption (DVS), the crystal form I gained 0.34% in weight after equilibration at 90% relative humidity, demonstrating only slightly hygroscopic. (0224) The crystal form did not change after the DVS measurement. The DVS detection results are substantially as shown in FIG. 4, and the XRPD comparison charts before and after DVS detection are substantially as shown in FIG. 5. It can be seen from FIG. 4 and FIG. 5 that the Orin1001 crystal form I is slightly hygroscopic. (0225) 5) Stability Test (0226) Two samples of the crystal form I were placed under the conditions of 40° C./75% relative humidity (RH), and the temperature in the oven was 60° C. (with humidity not controlled) for 14 days. Samples were taken on the 0th, 7th and 14th days for HPLC purity detection and XRPD detection, and the results showed that Form I had good chemical and physical stability (Table 3, Table 4, FIG. 6, FIG. 7). [table-us-00003-en] TABLE 3 crystal form I stability test results (HPLC purity: peak area %)-the 7th day TO 40° C./75% RH 60° C. (in oven) Sample-1 99.60 99.62 99.64 Sample-2 99.58 99.54 99.58 [table-us-00004-en] TABLE 4 crystal form I stability test results (HPLC purity: peak area %)-the 14th day TO 40° C./75% RH 60° C. (in oven) Sample-1 99.53 99.54 99.52 Sample-2 99.54 99.56 99.54 (0227) It can be seen from Table 3, Table 4, FIG. 6 and FIG. 7 that Orin1001 crystal form I has excellent stability. |
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