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Preparation method of tamibarotene stable crystals

A tamibarotene and crystallization technology, which is applied in the field of compound crystal preparation, can solve the problems of strong irritating odor, easy residual solvent, strong corrosiveness, etc., and achieves a solution with no solvent residue, low reagent toxicity, and avoidance of degradation. Effect

Inactive Publication Date: 2011-04-27
深圳万乐药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] CN101200435A discloses a method for preparing Tamibarotene type II crystals by recrystallization of lower organic acid or aqueous solution of lower organic acid. The organic acid formic acid or acetic acid used in the method has a strong pungent smell and a high boiling point. Solvents are easy to remain. In addition, formic acid is also highly corrosive, and the impact on the environment and operational safety must be considered during industrial mass production.

Method used

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  • Preparation method of tamibarotene stable crystals
  • Preparation method of tamibarotene stable crystals
  • Preparation method of tamibarotene stable crystals

Examples

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Effect test

Embodiment 1

[0020] Add 2 g of tamibarotene into 60 ml of methanol-20 ml of water mixed solvent, reflux for 0.5 hours, let it stand and cool to room temperature, fully analyze the crystallization, filter and dry the crystals in vacuum at 80°C for 4 hours, and crush the dried needle crystals into In fine powder form, vacuum-dried at 140° C. for 24 hours to obtain 1.85 g of Tamibarotene crystals. The melting point measured by capillary method is 233-234°C. The purity detected by HPLC was 99.83%. Simple impurities are all below 0.1%.

Embodiment 2

[0022] Add 2 g of tamibarotene into 40 ml of methanol-20 ml of water mixed solvent, reflux for 0.5 hours, let it stand to cool to room temperature, fully analyze the crystallization, filter and dry the crystals in vacuum at 80°C for 4 hours, and crush the dried needle crystals into In fine powder form, vacuum-dried at 160° C. for 15 hours to obtain 1.79 g of Tamibarotene crystals. The melting point measured by capillary method is 233-234°C. The purity by HPLC was 99.85%. Simple impurities are all below 0.1%.

Embodiment 3

[0024] Add 2 g of tamibarotene into 40 ml of methanol-10 ml of water mixed solvent, reflux for 0.5 hours, let it stand and cool to room temperature, fully analyze the crystallization, filter and dry the crystals in vacuum at 80°C for 4 hours, and crush the dried needle crystals into In fine powder form, vacuum-dried at 170° C. for 10 hours to obtain 1.80 g of Tamibarotene crystals. The melting point measured by capillary method is 233-234°C. The purity detected by HPLC was 99.80%. Simple impurities are all below 0.1%.

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Abstract

The invention discloses a preparation method of tamibarotene stable crystals with an endothermic peak at the temperature of about 233 DEG C in differential scanning thermal analysis. The method comprises the following steps of: recrystallizing tamibarotene by using a methanol-water mixed solvent; and physically grinding the obtained crystals, heating the powder at the temperature of between 140 and 180 DEG C, drying and transforming so as to obtain the tamibarotene stable crystals. In the method, high-temperature heating and transformation are not needed, degradation is avoided and stable crystals with individual impurities of less than 0.1 percent and the purity of more than 99.8 percent can be obtained; moreover, the method is easy and convenient to operate, a used reagent has low toxicity, solvent residues and pungent smell are prevented and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a compound crystal form, in particular to a preparation method of a stable crystal form of tamibarotene. Background technique [0002] Tamibarotene is a retinoic acid compound discovered and synthesized for the first time by Professor Suto of the University of Tokyo. It is a RARα agonist, specifically for patients with acute promyelocytic leukemia (APL) for all-trans retinoic acid (ATRA) ) drug resistance or drug toxicity intolerance, and is suitable for the treatment of APL relapsed or refractory cases. Compared with other retinoic acid drugs for the treatment of APL, it has high curative effect and is not easy to produce drug resistance. Advantages such as small adverse reactions. The chemical name of tamibarotene is 4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)carbamoyl]benzoic acid, and its structural formula is as follows: [0003] [0004] Tamibarotene is a white crystalline powder, and ...

Claims

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Application Information

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IPC IPC(8): C07C233/65C07C231/24
Inventor 王建新张广明
Owner 深圳万乐药业有限公司
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