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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

Active Publication Date: 2022-05-06
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 compound as well as preparation method and application thereof
  • Heterocyclic compound as well as preparation method and application thereof
  • Heterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

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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Abstract

The invention discloses a heterocyclic compound as well as a preparation method and application thereof. Specifically, the invention provides a free alkali crystal form, a hydrochloride crystal form, a sulfate crystal form, a maleate crystal form, a phosphate crystal form, a fumarate crystal form, a mesylate crystal form, an oxalate crystal form and a hydrobromide crystal form of the heterocyclic compound as shown in a formula I, a preparation method of each crystal form and application of the crystal forms in preparation of drugs. Wherein each crystal form has excellent physicochemical properties, so that the compound crystal form is particularly suitable for preparation development, especially as a medicine for treating cancers, and has a good patent medicine prospect. .

Description

technical field [0001] The 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 ), which also discloses that the compound is effective in the treatment of cancer, such as lung cancer, pancreatic cancer or colorectal cancer. [0003] However, pharmaceutical active ingredients may exist in different crystal forms, and different crystal forms may have differences in properties. Changes in properties caused by different crystalline forms can also improve the final dosage form, for example, the change can increase solubility and thus bioavailability, or improve the stability of the active ingredient, or more surprisingly, increase solubility at the same time. Has good st...

Claims

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Application Information

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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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