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Preparation method of orlistat

A technology of orlistat and preparation column, which is applied in the direction of organic chemistry, can solve the problems of no significant breakthrough in the purification process, the simplicity of the operation steps, the linearity of amplification and the further improvement of the yield, etc., so as to reduce the consumption of solvent and facilitate The effect of production control and shortening the production cycle

Active Publication Date: 2011-05-25
ZHUHAI UNITED LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Chinese patent application with the publication number CN101948450A and the title of the invention "A Method for the Production and Preparation of Orlistat" still adopts the combination of ordinary silica gel column and repeated crystallization for purification. still need to be further improved
[0008] In addition, there are also preparation methods that combine extraction, cooling crystallization, extraction, adsorption filtration and vacuum drying, as described in patents such as WO2005 / 007639, WO2005 / 026140, and WO2009 / 040827. These patent applications are still in the Roche patent to a certain extent. Partial improvement on the basis of technology, no significant breakthrough in purification process

Method used

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  • Preparation method of orlistat
  • Preparation method of orlistat
  • Preparation method of orlistat

Examples

Experimental program
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Effect test

Embodiment 1

[0042] About 80Kg is adjusted to a particle size of 10μm and a pore size of 300 Pour the reversed-phase C18 spherical silica gel filler into about 150L isopropanol, stir evenly to make a filler slurry, remove the filler fragments and fine powder, quickly pour into the DAC preparation column cylinder with an inner diameter of φ800mm, set the column pressure to 20MPa , Open the pneumatic piston rod of the column packing machine for axial compression, and open the valve at the lower end of the DAC preparation column to discharge and recover the isopropanol. When the piston is compressed to the set pressure of 20MPa, the column is installed, the height of the column bed is 250mm, and the size of the column bed is φ800mm×250mm. The installed DAC preparation column has been tested for efficiency, and the theoretical plate number has reached 46812N / m.

[0043] The lipstatin (purity 87.46%, content 66.20%) is dissolved in 86% methanol solution, and the concentration of lipstatin is abou...

Embodiment 2

[0049] About 75Kg is adjusted to a particle size of 10μm and a pore size of 100 Pour the reversed-phase C8 spherical silica gel filler into about 150L isopropanol, stir evenly to make a filler slurry, remove the filler fragments and fine powder, quickly pour it into the DAC preparation column cylinder with an inner diameter of φ800mm, set the column pressure to 24MPa , Open the pneumatic piston rod of the column packing machine for axial compression, and open the valve at the lower end of the DAC preparation column to discharge and recover the isopropanol. When the piston is compressed to the set pressure of 24MPa, the column is installed, the height of the column bed is 250mm, and the size of the column bed is φ800mm×250mm. The installed DAC preparation column has been tested for efficiency, and the theoretical plate number is 42663N / m.

[0050] The lipstatin (purity 87.46%, content 66.20%) is dissolved in 85% methanol solution, and the concentration of lipstatin is about 3% af...

Embodiment 3

[0055] About 10Kg, the particle size is 15μm, the pore size is 100 Pour the polystyrene / divinylbenzene-based high-pressure inverse polymer resin filler into about 20L of isopropanol, stir evenly to make a filler slurry, after removing filler fragments and fine powder, quickly pour it to an inner diameter of φ300mm In the DAC preparation column cylinder, the pressure is set to 10MPa, the pneumatic piston rod of the column packing machine is turned on for axial compression, and the lower valve of the DAC preparation column is opened to discharge and recover isopropanol. When the piston is compressed to the set pressure of 10MPa, the column is installed, the height of the column bed is 300mm, and the size of the column bed is φ300mm×300mm. The installed DAC preparation column has been tested for efficiency and the theoretical plate number is 38764N / m.

[0056] The lipstatin (purity 89.17%, content 64.56%) is dissolved in 84% ethanol solution, and the concentration of lipstatin afte...

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Abstract

The invention discloses a preparation method of orlistat, which comprises the following steps: (1) using reverse phase silica gel or reverse phase polymer resin as a filler of a DAC (dynamic axial compression) preparative column, and uniformly mixing an organic solvent and the filler to prepare a slurry; (2) filling the filler slurry into a cylinder of the DAC preparative column, and starting a column packing machine to carry out axial compression; (3) pumping a mobile phase into the DAC preparative column by using a preparative pump, thereby carrying out displacement washing on the organic solvent in the column and balancing the preparative column; (4) injecting a crude orlistat product solution into the DAC preparative column by using a high-pressure preparative pump to carry out column adsorption; (5) after the column adsorption, analyzing the orlistat solution by using a mobile phase, and collecting the analytic liquid in multiple sections; and (6) merging samples with qualified purity, concentrating, crystallizing and drying to obtain the finished orlistat product. By using the purification and preparation method of orlistat researched and developed by the invention, the purification and preparation amount of orlistat per batch is up to several kilograms and even myriagrams, and the purification production cycle is shortened to about 1-2 hours from tens of hours in the past.

Description

Technical field [0001] The invention belongs to the field of chemical pharmacy, and relates to a purification preparation method of organic compounds. Specifically, the invention relates to a purification method for preparing high-purity lipase inhibitor orlistat. technical background [0002] Orlistat is a derivative of lipstatin, which is a secondary metabolite of the fermentation of Streptomyces Toxytricini, after catalytic hydrogenation, so it is also called tetrahydrolipstatin Statins (Tetrahydrolipstatin, THL), chemical name N-formyl-L-leucine (1S)-1-[[(2S,3S)-3-hexyl-4-oxo-oxetanyl]methyl] Dodecyl ester or (S)-2-carboxamido-4-methyl-pentanoic acid (S)-1-[[(2S,3S)-3-hexyl-4-oxo-oxetan Base]methyl]dodecyl ester. The chemical reaction formula of lipstatin to Orlistat after catalytic hydrogenation is as follows: [0003] [0004] Orlistat is a specific gastrointestinal lipase inhibitor, originally researched by Roche, first listed in New Zealand in 1998. The radioisotope C14...

Claims

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Application Information

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IPC IPC(8): C07D305/12
CPCC07D305/12
Inventor 许勇煌彭韪王德刚唐彬喜刘德富
Owner ZHUHAI UNITED LAB
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