Tulobuterol crystal form and preparation method thereof

A technology of tulobuterol and crystal, applied in the field of medicinal chemistry synthesis

Active Publication Date: 2021-04-27
SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

After searching and consulting domestic and foreign literature, there is no report of tulobuterol crystal form

Method used

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  • Tulobuterol crystal form and preparation method thereof
  • Tulobuterol crystal form and preparation method thereof
  • Tulobuterol crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037](1) Synthesis of α-bromo-2-chlorophenyl (3)

[0038]230.0 g (1.5 mol) of o-chlorophenylideophenone and 1188 ml of water were added to the 3L three-necked bottle, 20 ° C, and 84 ml (1.6 mol) of broshor was added dropwise at 0.5 h, stirred for 15 min. With 400 ml of dichloromethane, the organic layer was washed with a water solution of 4.7 mol / L sodium carbonate, dried over anhydrous sodium sulfate. Filtration, evaporation of the solvent to evaporated, 346.3 g of light yellow oily liquid, yield 99%. ESI-MS M / Z: 234.0 [M + H]+139.1 [M-CH2BR]+111.1 [m-coch2BR]+.

[0039](2) Synthesis of 1- (2-chlorophenyl) -2-bromide ethanol (4)

[0040]347.4 g (1.5 mol) 3 was dissolved in 1126.9 ml of anhydrous ethanol, and 42.48 g (0.74 mol) of potassium borohydride was added dropwise under ice bath conditions, and the temperature of 244.6 ml was prepared, and the control temperature was below 20 ° C, drop Bi, continue to stir 15 min. The ethanol was evaporated under reduced pressure, and 760 mL of w...

Embodiment 2

[0054]50 g of Totorro was added to 100 mL of acetone, heated to 40 to 50 ° C to stir the dissolution. After dissolving, the acetone solution of Totorro was cooled to 30 to 40 ° C, and 300 ml of n-hexane was slowly added dropwise with the dropping rate of 4 ml / min, and the temperature was held at 30 to 40 ° C. The mixture was stirred for 8 hours or more, filtered crystals, and extract filtered cakes for 12 hours to give 43.2 grams, yield; 86.4%, HPLC purity 99.9%.

[0055]The XRD and structural confirmation results obtained by the product obtained in this embodiment were the same as in Example 1, and will not be described again.

Embodiment 3

[0057]50 g of Totoro was added to 200 ml of acetonitrile, heated to 40 to 50 ° C, stirred and dissolved. After dissolving, the acetone solution of the Totoro was cooled to 30 to 40 ° C, and 800 ml of cyclohexane was slowly added dropwise with a dropwise increase of 4 ml / min, and the temperature was held at 30 to 40 ° C. The mixture was stirred for 8 hours or more, filtered crystals, and dried into vacuum for 12 hours to obtain 47.2 grams of product, yield; 94.4%, HPLC purity 99.8%.

[0058]The XRD and structural confirmation results obtained by the product obtained in this embodiment were the same as in Example 1, and will not be described again.

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Abstract

The invention provides a tulobuterol crystal form and a preparation method thereof. The preparation method comprises the following steps of: dissolving tulobuterol in ethyl acetate and other good solvents, dropwisely adding n-heptane and other poor solvents into the system, filtering, taking the filter cake, and drying the filter cake to obtain the tulobuterol crystal form crystal. The crystal form is high in purity and good in stability, has superiority in process production, and is suitable for long-term storage in the preparation process.

Description

Technical field[0001]The present invention relates to the art of pharmaceutical synthesis, and involves a Totor Rootor, and the preparation method.Background technique[0002]Tulobuterol, is a selective β2 receptor agonist developed by Japan ABBOT, and in 1981, Japan was approved by Japan as an anti-asthma. In 1998, it was used to treat asthma and chronic obstructive disease (COPD). At present, many pants are used to treat children. The indications are used for the use of thousands of pneumatoids, acute bronchitis, chronic bronchitis, emphysema and other airways. Symptoms such as breathing caused by obstructive diseases. Totorro, the chemical name is a chemical name of 1- (2-chlorophenyl) -2-tert-buthamino ethanol, which is as follows:[0003][0004]There are many literatures in Totorro: German Patent DE2244737, published, 1973.3.22, disclosed, which discloses compound Totoro, which also discloses a synthetic process and a salt to form a salt from other pharmaceutically acceptable acids....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/30C07C213/10A61K31/137A61P11/06A61P11/08A61P11/00
CPCC07C215/30C07C213/10A61P11/06A61P11/08A61P11/00C07B2200/13C07B2200/07Y02P20/55
Inventor 郭伟杨杰何淑旺王文笙方亮蔡琨颜世强梁林解春文景亚军
Owner SHANDONG DYNE MARINE BIOTECHCAL PHARM HLDG CO LTD
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