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Di-hydroxyethyl sulfate of cell-cycle cyclin-dependent kinase inhibitor, as well as crystallization form and preparation method of di-hydroxyethyl sulfate

A technology of crystallization and crystal form, applied in the fields of organic chemistry, sexual diseases, organic chemistry, etc., can solve the problem that is inferior to mono-isethionate, and has not studied the properties of di-isethionate and its crystal form and other problems, to achieve the effect of good crystal stability, good stability and stable production process

Inactive Publication Date: 2016-11-16
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] CN1835951A discloses the monoisethionate of Palbociclib, and thinks that this compound is a dibasic base compound, which can also generate diisethionate, but not as good as mono-isethionate, and has not studied di-isethionate. Properties and Crystal Forms of Isethionate

Method used

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  • Di-hydroxyethyl sulfate of cell-cycle cyclin-dependent kinase inhibitor, as well as crystallization form and preparation method of di-hydroxyethyl sulfate
  • Di-hydroxyethyl sulfate of cell-cycle cyclin-dependent kinase inhibitor, as well as crystallization form and preparation method of di-hydroxyethyl sulfate
  • Di-hydroxyethyl sulfate of cell-cycle cyclin-dependent kinase inhibitor, as well as crystallization form and preparation method of di-hydroxyethyl sulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Take (1.0g, 1.43mmol) the compound shown in formula (I) (prepared according to the method disclosed in CN1835951A) and add it to a 25ml single-necked bottle, add 16ml 90% ethanol, heat to dissolve, then cool to room temperature to crystallize, suction filter, vacuum After drying, 0.71 g of solid was obtained, and the yield was 71.0%. The X-ray diffraction spectrum figure of this crystalline sample is shown in figure 1 . The crystallization at about 4.32 (20.44), 6.37 (13.86), 9.78 (9.04), 12.74 (6.94), 13.94 (6.35), 14.74 (6.00), 16.93 (5.23), 17.79 (4.98), 19.13 (4.64), 20.42 (4.34), 21.56(4.12), 22.26(3.99), 23.46(3.79), 24.29(3.66), 25.75(3.46), 26.49(3.36), 28.07(3.18) and 29.78(3.00). See the DSC spectrum figure 2 , there is a sharp endothermic peak around 275.69°C, which we define as I crystal form.

Embodiment 2

[0043] Take (1.0g, 1.43mmol) the compound shown in formula (I) (prepared according to the method disclosed in CN1835951A) and add it to a 50ml single-necked bottle, add 20ml 90% methanol, heat to dissolve, then cool to room temperature for crystallization, suction filtration, vacuum After drying, 0.28 g of solid was obtained, and the yield was 28.0%. The X-ray diffraction spectrum figure of this crystalline sample is shown in image 3 . The crystallization at about 4.31 (20.50), 5.45 (16.20), 6.72 (13.14), 7.87 (11.23), 9.59 (9.21), 11.59 (7.63), 13.07 (6.77), 13.46 (6.57), 13.94 (6.35), 16.14 (5.49), 16.30(5.41), 18.23(4.86), 19.30(4.60), 20.35(4.36), 20.91(4.24), 21.50(4.13), 23.16(3.84), 24.52(3.63), 25.01(3.56), 26.97 There are characteristic peaks at (3.30) and 28.19 (3.16). See the DSC spectrum Figure 4 , there is a sharp endothermic peak around 274.80 ° C, which we define as II crystal form.

Embodiment 3

[0045] Take (1.0g, 1.43mmol) the compound shown in formula (I) (prepared according to the method disclosed in CN1835951A) and add it to a 50ml single-necked bottle, add 35ml 90% isopropanol, heat to dissolve, then cool to room temperature for crystallization, and suction filter , dried in vacuo to obtain 0.83 g of solid with a yield of 83.0%. The X-ray diffraction spectrum figure of this crystalline sample is shown in Figure 5 . The crystallization at about 3.00 (29.40), 5.99 (14.74), 7.80 (11.32), 8.97 (9.85), 12.32 (7.18), 15.03 (5.89), 18.02 (4.92), 19.00 (4.67), 20.91 (4.24), 22.95 There are characteristic peaks at (3.87), 24.86(3.58), 27.20(3.28) and 30.24(2.95). See the DSC spectrum Figure 6 , there is a sharp endothermic peak around 277.16 ° C, which we define as the III crystal form.

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Abstract

The invention relates to di-hydroxyethyl sulfate of a cell-cycle cyclin-dependent kinase inhibitor, as well as a crystallization form and preparation method of the di-hydroxyethyl sulfate. Specifically, the invention relates to the di-hydroxyethyl sulfate (a compound as shown in a formula (I) of 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(1-piperazinyl) pyridine-2-amino] pyrido [2, 3-d] pyrimidine-7(8H)-ketone, and a I type crystal, a II type crystal, and a III type crystal thereof, as well as a preparation method of the di-hydroxyethyl sulfate. The I type crystal of the compound as shown in the formula (I) disclosed by the invention has favorable crystal form stability and chemical stability, besides, the used crystal solvent is low in toxins and low in residues, and the di-hydroxyethyl sulfate can be well used for clinical treatment.

Description

technical field [0001] The present invention relates to a crystalline form of the diisethionate salt of a highly selective cyclin-dependent kinase (CDK4 / 6) inhibitor, in particular 6-acetyl-8-cyclopentyl-5-methanol Diisethionate of base-2-[5-(1-piperazinyl)pyridine-2-amino]pyrido[2,3-d]pyrimidin-7(8H)-one (formula (I) Form I, II, and III crystals of compound). Background technique [0002] The global incidence of breast cancer has been on the rise since the late 1970s. 1 in 8 women in the U.S. will develop breast cancer in her lifetime. China is not a country with a high incidence of breast cancer, but it should not be optimistic. In recent years, the growth rate of the incidence of breast cancer in my country is 1 to 2 percentage points higher than that of countries with a high incidence. According to the 2009 breast cancer incidence data released by the National Cancer Center and the Ministry of Health's Bureau of Disease Control and Prevention in 2012, the incidence of...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/519A61P35/00A61P15/14
CPCC07D471/04C07B2200/13
Inventor 武乖利张全良郭昌山卢韵
Owner JIANGSU HENGRUI MEDICINE CO LTD