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Heterocyclic compounds and their preparation methods and applications

A compound and heterocyclic technology, applied in the field of heterocyclic compounds and their preparation and application, can solve problems such as property differences, and achieve the effect of inhibiting cancer or related diseases, significant cancer or related diseases

Active Publication Date: 2022-07-05
ASCENTAGE PHARMA SUZHOU CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, pharmaceutical active ingredients can exist in different crystal forms, and different crystal forms may have different properties

Method used

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  • Heterocyclic compounds and their preparation methods and applications
  • Heterocyclic compounds and their preparation methods and applications
  • Heterocyclic compounds and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0569] 1 Free base amorphous

[0570] The compound of formula I (compound 45 in the patent) was prepared by referring to the method of Example 49 in Patent No. CN113087700A

[0571] Synthesis of 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'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile

[0572] To 2-((S)-4-((R)-4-chloro-2'-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) under Ar at 0 °C -2,3,5',8'-Tetrahydro-6'H-spiro[indene-1,7'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile (1.0 g, 1.88 g mmol), DMAP (0.23 g, 1.88 mmol), TEA i.e. triethylamine (0.57 g, 5.63 mmol) and 2-fluoroacrylic acid (0.51 g, 5.63 mmol) in dichloromethane (DCM for short, 20 mL) join T 3 P is 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 organic layers were combined, washed with brine, washed ...

Embodiment 2

[0612] Example 2 Preparation of hydrochloride crystal form

[0613] 1 Hydrochloride Form A

[0614] The hydrochloride salt crystal form A is dissolved in ethanol (abbreviated as EtOH) / n-heptane (1:4, v / v by the free base amorphous (the compound of formula I obtained by the method in Example 1), and the weight to volume ratio is 40g / L), add hydrochloric acid (acid-base molar ratio 1:1), stir at room temperature for 3 days, remove the supernatant by centrifugation, 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 an 8.93% weight loss before being heated to 160°C at room temperature.

[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...

Embodiment 3

[0647] Example 3 Preparation of sulfate crystal form

[0648] 1 Sulfate Form A

[0649] Sulfate crystal form A is mixed with acetone / n-heptane (1:1, v / v) by the free base amorphous (the compound of formula I obtained by the method in Example 1), and then sulfuric acid (acid-base feeding molar) is added. Ratio 1:1) After stirring at room temperature for about 3 days, the supernatant was removed by centrifugation, and the obtained solid was dried at room temperature overnight.

[0650] The XRPD results of sulfate crystal form A are as follows Figure 33 As shown, the diffraction data are shown in Table 11 below.

[0651] TGA results ( Figure 34 ) shows a 6.52% weight loss when the sample is heated from room temperature to 150 °C.

[0652] DSC results ( Figure 35 ) showed 2 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 w...

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PUM

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Abstract

The invention discloses a heterocyclic compound and a preparation method and application thereof. Specifically provide a free base crystal form, hydrochloride salt crystal form, sulfate crystal form, maleate crystal form, phosphate crystal form, fumarate crystal form, Mesylate crystal form, oxalate crystal form and hydrobromide salt crystal form, as well as the preparation method of each crystal form and the application in the preparation of medicine. Wherein each crystal form has excellent physical and chemical properties, so that the crystal form of the compound is particularly suitable for formulation development, especially as a drug for treating cancer, and has a good drug prospect. .

Description

technical field [0001] The present invention relates to a heterocyclic compound and its preparation method and application. Background technique [0002] Patent CN113087700A discloses 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'-quinazolin]-4'-yl)piperazin-2-yl)acetonitrile (Compound 45 synthesized with reference to Example 49 ), also disclosed that the compound is effective in the treatment of cancer, such as lung cancer, pancreatic cancer or colorectal cancer. [0003] However, active pharmaceutical ingredients may exist in different crystal forms, which may have differences in properties. Changes in properties resulting from different crystal forms can also improve the final formulation, for example, such changes can increase solubility, which in turn increases bioavailability, or improve the stability of the active ingredient, or more unexpectedly, increase solubility while increasing solubility Ha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00A61K31/527C07C51/41C07C51/43C07C57/145C07C57/15C07C55/07C07C303/32C07C303/44C07C309/04
CPCC07D487/04A61P35/00C07C51/412C07C51/43C07C57/145C07C57/15C07C55/07C07C303/32C07C303/44C07C309/04C07B2200/07C07B2200/13
Inventor 温剑锋林艳琼冯建鹏李卫东李宗斌王传申
Owner ASCENTAGE PHARMA SUZHOU CO LTD
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