Heterocyclic compound as well as preparation method and application thereof
A technology of heterocyclic compounds and compounds, applied in the field of heterocyclic compounds and their preparation and application, which can solve problems such as property differences, and achieve the effect of inhibiting cancer or related diseases, significant cancer or related diseases
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Embodiment 1
[0569] 1 free base amorphous
[0570] Prepare the compound of formula I (compound 45 in the patent) by referring to the method of Example 49 in the patent number CN113087700A
[0571] Synthesis of 2-((S)-4-((R)-4-chloro-2'-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3,5' ,8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile
[0572] 2-((S)-4-((R)-4-chloro-2'-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) -2,3,5',8'-tetrahydro-6'H-spiro[indene-1,7'-quinazoline]-4'-yl)piperazin-2-yl)acetonitrile (1.0g, 1.88 mmol), DMAP (0.23g, 1.88mmol), TEA i.e. triethylamine (0.57g, 5.63mmol) and 2-fluoroacrylic acid (0.51g, 5.63mmol) in dichloromethane (referred to as DCM, 20mL) in solution Join T 3 P was propylphosphoric anhydride (2.39 g, 3.75 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added and the resulting mixture was extracted three times with DCM. The combined organic layers were washed with brine and washed with ...
Embodiment 2
[0612] Embodiment 2 Preparation of hydrochloride crystal form
[0613] 1 Hydrochloride salt form A
[0614] Hydrochloride salt form A is composed of free base amorphous (compound of formula I prepared by the method in Example 1) dissolved in ethanol (referred to as EtOH) / n-heptane (1:4, v / v, weight to volume ratio of 40g / L), add hydrochloric acid (acid-base molar ratio 1:1), stir at room temperature for 3 days, centrifuge to remove the supernatant, and dry the obtained solid overnight at room temperature.
[0615] XRPD characterization results such as Figure 17 As shown, the diffraction data are shown in Table 7 below.
[0616] TGA results ( Figure 18 ) shows that the sample has a weight loss of 8.93% before heating from room temperature to 160 °C.
[0617] DSC results ( Figure 19 ) shows that the sample has an endothermic peak at 158.4 °C (peak temperature).
[0618] 1 H-NMR results ( Figure 20 ) shows that the molar ratio of residual EtOH to API in the sample is ...
Embodiment 3
[0647] Embodiment 3 Preparation of sulfate crystal form
[0648] 1 Sulfate crystal form A
[0649] Sulphate crystal form A is mixed with free base amorphous (such as the compound of formula I prepared by the method in Example 1) and acetone / n-heptane (1:1, v / v), adding sulfuric acid (acid-base feeding mole (ratio 1:1) was stirred at room temperature for about 3 days, centrifuged to remove the supernatant, and the obtained solid was dried overnight at room temperature.
[0650] The XRPD result of sulfate crystal form A is as follows Figure 33 As shown, the diffraction data are shown in Table 11 below.
[0651] TGA results ( Figure 34 ) shows that the sample has a weight loss of 6.52% when heated from room temperature to 150 °C.
[0652] DSC results ( Figure 35 ) showed two endothermic peaks at 108.7 and 148.3 °C (peak temperature).
[0653] 1 H-NMR results ( Figure 36 ) shows that the molar ratio of residual n-heptane to API in the sample is 0.05 (corresponding to a...
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