Methods of making L-ornithine phenyl acetate

A technology of ornithine phenyl acetate and ornithine salt, which can be used in the fields of medicinal chemistry, biochemistry and medicine, and can solve problems such as excess body fluids

Active Publication Date: 2014-01-08
OCERA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For intravenous administration, high concentrations of excess salt may require substantial solution dilution, which results in fluid overload

Method used

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  • Methods of making L-ornithine phenyl acetate
  • Methods of making L-ornithine phenyl acetate
  • Methods of making L-ornithine phenyl acetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0181] Example 1: Small scale batch process for the preparation of L-ornithine phenyl acetate

[0182] About 8.4g (0.049mol) of L-ornithine hydrochloride were dissolved in 42mLH 2 O and dissolved approximately 11.4 g of silver benzoate in 57 mL of DMSO. Subsequently, the silver benzoate solution was added to the L-ornithine hydrochloride solution. Combining the two mixtures immediately resulted in the precipitation of an exothermic milky white solid (AgCl). The solids were removed by vacuum filtration and the filtrate was retained (with L-ornithine benzoate in solution). 200 mL of IPA was added to the filtrate and the mixture was cooled to 4°C. A crystalline solid (L-ornithine benzoate) precipitated after about 3 hours and was isolated by vacuum filtration. Yield: 60%.

[0183] Dissolve 7.6 g (0.03 mol) of L-ornithine benzoate in 38 mL of H 2 O and dissolved approximately 4.4 g sodium phenylacetate in 22 mL H 2 O middle. Subsequently, sodium phenylacetate was added t...

Embodiment 2

[0184] Example 2: Large scale batch process for the preparation of L-ornithine phenyl acetate

[0185] Two separate batches of L-ornithine phenylacetate were prepared as follows:

[0186] About 75 kg of L-ornithine monohydrochloride was dissolved in 227 kg of water. To the resulting solution was added 102 kg of silver benzoate dissolved in 266 kg of DMSO at room temperature within 2 hours. A strong exotherm was initially observed and silver chloride precipitated. The receiver containing the solution was then washed with 14 kg of DMSO added to the reaction mass. To remove the silver chloride formed, the reaction mass was filtered with a lens filter made of 10 kg Celite and a 1 mm GAF filter. After filtration, the filter was washed with an additional 75 kg of water. The reaction mass was placed in a separate tank after filtration to prevent contamination with residual silver chloride. The reaction mass was then heated at 35±2° C., and then 80 kg of sodium phenylacetate wa...

Embodiment 3

[0191] Embodiment 3: in-situ preparation sodium phenylacetate solution

[0192] Dissolve phenylacetic acid (PAA) in isopropanol solution. Add about 1 molar equivalent of sodium hydroxide to the solution and stir. The resulting solution was added dropwise to a solution containing about 1 molar equivalent of L-ornithine benzoate. The L-ornithine phenylacetate was precipitated from the solution using generally the same procedure as described in Example 2. Yield: 53.5%. The white powder was further characterized and summarized in Table 6 under the heading "Test A".

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Abstract

Disclosed herein are processes for making L-ornithine phenyl acetate. The process may include, for example, inter-mixing a halide salt of L-ornithine with silver phenyl acetate. The process may also include forming a phenyl acetate salt in situ. The present application also relates to various compositions obtained from these processes, including crystalline forms.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Application No. 61 / 390,585, filed October 6, 2010, which is incorporated by reference in its entirety. technical field [0003] This application relates to the fields of medicinal chemistry, biochemistry and medicine. In particular, it relates to a process for the preparation of L-ornithine phenylacetate. Background technique [0004] Hyperammonemia is a hallmark of liver disease and is characterized by excess ammonia in the bloodstream. Hepatic encephalopathy is the main clinical consequence of progressive hyperammonemia and is a complex neuropsychiatric syndrome that can worsen acute or chronic liver failure. Hepatic encephalopathy is characterized by changes in mental status (including a wide range of neuropsychiatric syndromes, ranging from mild symptoms of altered brain function to overt psychiatric and / or neurological symptoms, or even profound coma). Accumulation of unme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/26C07C57/46A61K31/198A61K31/192A61P1/16
CPCC07C51/412A61K31/192A61K31/198C07C227/18A61P1/16C07C229/26C07C57/32
Inventor K·H·安德森J·贝林C·H·杜根S·W·瓦特P·玛尼尼A·菲吉尼
Owner OCERA THERAPEUTICS INC
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