Letrozole I-type crystal and preparation method thereof

A letrozole and crystallization technology, applied in the field of letrozole type I crystallization and its preparation, can solve the problems of inconsistent physical and chemical properties of active substances, uneven properties of final products of preparations, difficult preparation molding technology, etc., and it is easier to achieve quality The effect of control, rapid and complete crystallization, simple and practical process

Active Publication Date: 2011-05-25
SHENZHEN NEPTUNUS PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inconsistencies in the physical form and / or physicochemical properties of the active substance may lead to difficulties in the preparation technology of solid preparations or even liquid preparations, and may cause the final product of the preparation to be difficult to apply in clinical practice due to its inhomogeneous properties

Method used

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  • Letrozole I-type crystal and preparation method thereof
  • Letrozole I-type crystal and preparation method thereof
  • Letrozole I-type crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] [Example 1] Preparation of 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) control crystal form

[0044] The crude 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole compound of the control crystal form can be prepared by the method described in US Patent No. 20,070,100,149: add 20 g of the crude letrozole to 140 ml dichloromethane, and then 500 ml of methanol were added. Stir for 10 min, remove part of the solvent by rotary evaporation at a temperature below 40°C until 105-120ml of mixed solvent remains, add 350ml of water, and stir for 1h. A large amount of white solid formed and was filtered, washed with 140ml of water at the same time, and suction-filtered under reduced pressure at 55-60°C for 4 hours to obtain 15.2g of white crystalline powder with a yield of 76%. Its XRD spectrogram, DSC spectrogram refer to U.S. Patent US 20,070,100,149, see Figure 4 , Figure 5 .

Embodiment 2

[0045] [Example 2] Preparation of 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) type I crystal

[0046] Add anhydrous potassium carbonate to solvent acetone, shake well, reflux for 4 hours to distill, and put 4ALinde molecular sieves into the collection bottle at the same time to obtain anhydrous acetone solvent. Add 50g of letrozole crude product into about 1.5L of anhydrous acetone solvent, dissolve and filter, and concentrate the filtrate under reduced pressure (0.1Mpa, 50°C), concentrate and dry to constant weight (0.1Mpa, room temperature), and obtain 43g of white crystalline solid , yield 86%.

[0047] Its XRD spectrum is as figure 1 As shown, the DSC spectrum is as figure 2 As shown, the infrared spectrum as image 3 shown. The main diffraction peaks of the XRD spectrum are shown in Table 1.

[0048] Table 1

[0049] peak

Embodiment 3

[0050] [Example 3] Preparation of 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole (letrozole) type I crystal

[0051] Calcium oxide (200g / L) was added into the solvent isopropanol and refluxed for 3 hours, and then distilled, and the distillate was further distilled by adding calcium hydride to obtain anhydrous isopropanol solvent. Add 50g of letrozole crude product into about 1.5L of anhydrous isopropanol solvent, dissolve and filter, concentrate the filtrate under reduced pressure (0.1Mpa, 50°C), concentrate and dry to constant weight (0.1Mpa, room temperature), and obtain 40g of white Crystalline solid, yield 80%.

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Abstract

The invention relates to a letrozole I-type crystal and a preparation method thereof, in particular to an anhydrous letrozole crystal. The structure and characteristics of the anhydrous letrozole crystal are represented by X-radial powder diffraction, differential scanning calorimetry, infrared spectrum and the like. Characteristic diffraction peaks, which are positioned at the degrees 2theta of 13.08+ / -0.2, 14.06+ / -0.2, 17.04+ / -0.2, 21.44+ / -0.2 and 29.24+ / -0.2, are positioned in the X-radial powder diffraction pattern of the crystal powder. The anhydrous letrozole crystal is simple in preparation process, the yield and purity of the crystal are high, and the anhydrous letrozole crystal has good stability and is suitable for production of medicinal preparations. The invention also provides a method for preparing the anhydrous letrozole crystal by using an anhydrous and pure organic solvent as a crystallization solvent and application of the crystal in the medicinal preparations which are used for treating advanced breast cancer of a patient after menopause by antiestrogen.

Description

technical field [0001] The invention relates to letrozole type I crystals, a preparation method thereof, and a pharmaceutical composition containing letrozole type I crystals. Background technique [0002] Letrozole, English name Letrozole, chemical name 1-[bis(4-cyanophenyl)methyl]-1,2,4-triazole, is a new generation of aromatase inhibitor, which is a synthetic benzyl Triazole derivatives. Letrozole reduces the level of estrogen by inhibiting aromatase, thereby eliminating the stimulating effect of estrogen on tumor growth. The results of in vivo and in vitro studies show that letrozole can effectively inhibit the conversion of androgen to estrogen, and the estrogen in postmenopausal women mainly comes from the aromatization of androgen precursor substances in peripheral tissues, so it is especially suitable for the treatment of postmenopausal women. of breast cancer patients. [0003] Patents and documents (see the table below) etc. all describe its preparation. Howeve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08A61K31/4196A61P5/32A61P35/00
CPCC07D249/08A61K31/4196A61P5/32A61P35/00
Inventor 唐田王彦青马春铭陈佳陈学明李勇叶冠豪刘碧秀
Owner SHENZHEN NEPTUNUS PHARM CO LTD
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