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Preparation method of azelnidipine alpha crystal form

A technology of azeldipine and crystal form, which is applied in the field of raw material drug preparation, can solve the problems of high production cost, mixed crystals, difficult solvent selection, etc., and achieves the effects of convenient crystal transformation, stable quality and simple process operation.

Inactive Publication Date: 2017-09-22
WEIHAI DISU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In summary, the existing technology for preparing the α crystal form of azedipine has technical problems such as difficulty in solvent selection, mixed crystals, and high production costs.

Method used

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  • Preparation method of azelnidipine alpha crystal form
  • Preparation method of azelnidipine alpha crystal form
  • Preparation method of azelnidipine alpha crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of Azedipine Diisopropanolate and α Crystal Form

[0041] Add 500g of isopropanol to the crude product of Azedipine (converted to 100g of pure Azedipine), heat and reflux until it dissolves, cool down to 28°C to start crystallization, continue to cool down to -10°C and keep warm for 4 hours, and filter to obtain yellow The solid was dried at room temperature to obtain 108.9 g of azeldipine diisopropanolate. Yield 90.3%, HPLC purity 99.91%. As determined by gas phase, the content of isopropanol was 16.8% (theoretical amount was 17.1%). Its nuclear magnetic spectrum, crystal form determination and DSC are shown in the attached drawings (2, 4, 6)

[0042] Add 50 g of the obtained azelnidipine diisopropanolate to 300 g of cyclohexane, heat and reflux for 3 hours, cool down to 10-20°C and continue to keep warm for 2 hours, filter, and vacuum dry to obtain 39.2 g of yellow powder, yield 94.6% , HPLC purity 99.97%. . Its crystal form was determined t...

Embodiment 2

[0043] Example 2 Preparation of Azeldipine Diisopropanolate and α Crystal Form

[0044] Add 100g of Azedipine in the β crystal form into 1000g of isopropanol, heat to reflux to dissolve, cool down to 32°C, crystallization begins, continue to cool down to -10°C and keep warm for 4 hours, filter to obtain a yellow solid, and let it dry at room temperature After drying, 99.6 g of diisopropanolate was obtained, the yield was 82.6%, and the HPLC purity was 99.96%. The content of isopropanol was 17.3% (theoretical amount was 17.1%) as determined by gas phase. Its crystal form determination is consistent with Example 1.

[0045] Add 50 g of the obtained azelnidipine diisopropanolate to 400 g of cyclohexane, lower the temperature to 10-15 ° C and keep stirring for 6 hours, filter, and vacuum-dry to obtain 38.4 g of yellow powder, the yield is 92.6%, and the HPLC purity is 99.98% . The determination of its crystal form is completely consistent with Example 1.

example 3

[0046] Example 3 Preparation of Azeldipine Diisopropanolate and α Crystal Form

[0047] Add 100g of amorphous azedipine into 800g of isopropanol, heat to reflux to dissolve, cool down to 35°C, crystallization begins, continue to cool down to -10°C and keep warm for 4 hours, filter to obtain a yellow solid, and dry at room temperature , 104.8 g of diisopropanolate was obtained, the yield was 86.9%, and the HPLC purity was 99.93%. The content of isopropanol was 18.1% (theoretical amount was 17.1%) as determined by gas phase. Its crystal form determination is consistent with Example 1.

[0048] Add 50 g of the obtained azelnidipine diisopropanolate to 1000 g of cyclohexane, raise the temperature to 40-45°C and keep stirring for 4 hours, filter, and vacuum-dry to obtain 36.8 g of yellow powder with a yield of 88.8% and an HPLC purity of 100.0%. The determination of its crystal form is completely consistent with Example 1.

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Abstract

The invention relates to a preparation method of an azelnidipine alpha crystal form. According to the technical scheme, the preparation method comprises the following steps; I, adding non-alpha-crystal-form azelnidipine or crude azelnidipine of other forms into isopropanol of which the amount is not less than 5 times the mass of the non-alpha-crystal-form azelnidipine or the crude azelnidipine, heating for dissolved clarification, cooling to the temperature of 40 DEG C, observing whether crystallization occurs or not, if so, replenishing the isopropanol for dissolved clarification once again, cooling to the temperature of 40 DEG C or less for crystallization, preserving heat at the temperature of 10 DEG C below zero to 0 DEG C for 6 to 12 hours, and filtering to obtain an azelnidipine-diisopropanol compound; II, putting the azelnidipine-diisopropanol compound solid prepared by filtering in the step I into a crystal transformation kettle, adding cyclohexane in an amount which is not less than 6 times the mass of the azelnidipine-diisopropanol compound solid for crystal transformation with stirring, stirring for not less than 3 hours, finishing crystal transformation, filtering, and performing vacuum drying under a reduced pressure to obtain the azelnidipine alpha crystal form. By adopting the method, the crude azelnidipine and the non-alpha-crystal-form azelnidipine can be transformed into the azelnidipine alpha crystal form.

Description

technical field [0001] The invention relates to a method for preparing α-crystal form of azelnidipine, which belongs to the technical field of preparation of raw materials. Background technique [0002] Azelnidipine, English name: Azelnidipine, its structural formula is as follows: [0003] [0004] Azhedipine is a hypotensive drug jointly developed by Japan Sankyo Company and Ube Company. It is a third-generation long-acting dihydropyridine calcium channel blocker and was launched in Japan in 2003. It is well absorbed orally, and is widely used clinically in patients with mild or moderate symptoms of essential hypertension, hypertension with renal dysfunction, and severe hypertension. [0005] Azedipine is a polymorphic drug, including α, β, γ, ε and amorphous form, among which the medicinal crystal form is α crystal form because of its high bioavailability. [0006] The earliest report on the preparation of the α-crystal form of azedipine is the Japanese patent JPS632...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/13
Inventor 徐可岭吴荣贵崔仰仰薛复照门连彬
Owner WEIHAI DISU PHARMA CO LTD
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