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New crystal form of istradefylline and preparation method thereof

A technology of istradefylline and crystal form, which is applied in the field of new crystal form of istradefylline and its preparation, can solve problems such as crystal aggregation and uneven dispersion, and achieve the effects of improving bioavailability, small particle size, and good properties

Active Publication Date: 2017-01-04
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The inventors of the present invention have conducted extensive research on the crystallization of istradefylline, and finally found a new crystal form that is thermodynamically stable, has significantly improved solubility in water, and can simultaneously solve the problems of crystal aggregation and uneven dispersion in the process-based operation of preparations.

Method used

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  • New crystal form of istradefylline and preparation method thereof
  • New crystal form of istradefylline and preparation method thereof
  • New crystal form of istradefylline and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0044] Preparation example 1: the preparation method of istradefylline crude product

[0045]

[0046] Under mechanical stirring, add intermediate II 50g (0.135mol), potassium carbonate 28g (0.203mol), N,N-dimethylformamide 550mL and methyl iodide 15mL (0.241mol) into a 3L reaction flask, heat to 50°C, The reaction was stirred for 5 h, cooled to 0°C, and 550 mL of purified water was added to the reaction solution. After filtering, the filter cake was washed with 1.1 L of purified water, and then vacuum-dried at 45° C. to obtain 51.3 g of a light yellow solid with a yield of 99% and a HPLC purity of 98.6%, which was used for the preparation of the following istradefylline A crystal form.

Embodiment 1

[0047] Embodiment 1: Preparation of istradefylline A crystal form

[0048] Add 3 g (7.8 mmol) of crude istradefylline to 60 mL of dichloromethane, stir to dissolve. At room temperature, add 60 mL of n-heptane, then cool to 0-10°C, stir and crystallize for 2 hours. Filtrate and dry under vacuum at 45°C to obtain 2.67g of light yellow-green solid powder, yield 89%, HPLC purity 99.8%, product particle size D 90 It is 40.231 μm. The obtained crystalline sample is subjected to powder X-ray powder diffraction, and the obtained collection of illustrative plates is shown in the attached figure 1 , and the spectral data are shown in Table 1.

[0049] Table 1 The characteristic peak data of istradefylline A crystal form powder X-ray diffraction obtained in Example 1

[0050] 2θ(°) Relative Strength(%) 6.0 14.4 7.1 22.1 9.5 16.1 10.4 46.6 11.2 100 12.5 26.7 14.1 24.3 15.8 64.7 19.7 20 21.6 25.2 24.6 38.2 25.2 45....

Embodiment 2～11

[0051] Examples 2-11: Investigation on preparation conditions of crystal form A of istradefylline

[0052] With reference to the preparation method of Example 1, only the corresponding preparation conditions are changed, and the experimental conditions and results are as follows:

[0053] Table 2 Experimental results of Examples 2 to 11

[0054]

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Abstract

The invention discloses a new crystal form of istradefylline and a preparation method thereof. The powder X-ray diffraction of the new crystal form of istradefylline has characteristic peaks where 2theta is equal to 10.4 + / -0.2 degrees, 11.2 + / -0.2 degrees, 15.8 + / -0.2 degrees, 24.6 + / -0.2 degrees, and 25.2 + / -0.2 degrees. The new crystal form of istradefylline is thermodynamically stable and has obviously improved solubility in water; the new crystal form of istradefylline, which is crystalline solid powder having a small particle size, is good in fluidity, so that the problem of non-uniform crystal condensation and dispersion in process operation of a preparation can be solved; the new crystal form of istradefylline is more suitable for storage and for use as a bulk pharmaceutical chemical; and a new way is provided for the preparation of istradefylline drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new crystal form of istradefylline and a preparation method thereof. Background technique [0002] Itradefylline (Istradefylline, trade name NOURIAST), chemical name is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-3, 7-dihydro-1H-purine-2,6-dione, the structural formula is as shown in formula I: [0003] [0004] Itraphylline is a selective adenosine A2A receptor antagonist developed by Japan Kyowa Hakko Kirin Co., Ltd. It can improve the motor function of patients with Parkinson's disease by changing the activity of neurons, and is clinically used to treat Parkinson's disease and Improvement of movement disorders in the early stages of Parkinson's disease. [0005] European patent EP0590919 discloses istradefylline and its preparation method. The crude istradefylline is recrystallized in isopropanol to obtain light yellow needle crystals with a melting po...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06A61K31/522A61P25/16
CPCC07B2200/13C07D473/06
Inventor 龚登凰王洁盖京华杨杰孙文娇杨敏杨春巧马玉秀
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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