Processes of making l-ornithine phenylacetate

A technology of ornithine hydrochloride and phenylacetate, applied in the fields of medicinal chemistry, biochemistry and medicine, can solve the problems of danger, difficult intravenous administration, and undesired

Pending Publication Date: 2020-01-31
OCERA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Although salt forms may exhibit improved degradation properties, certain salts, especially sodium or chloride salts, may be undesirable when treating patients with conditions associated with liver disease such as hepatic encephalopathy
For example, high sodium intake can be dangerous in cirrhotic patients prone to ascites, fluid overload, and electrolyte imbalance
Similarly, certain salts are difficult to administer intravenously due to increased osmotic pressure (i.e., the solution is hypertonic)
High concentrations of excess salt may require dilution of large volumes of solution for intravenous administration, resulting in excessive fluid overload

Method used

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  • Processes of making l-ornithine phenylacetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Large scale batch process for the preparation of crude L-ornithine phenylacetate

[0063] Charge 4.05kg (61.38mol) KOH in the first reactor, dissolve it in 10.4L (10.4kg) H 2 O and stirred until a clear solution formed. Subsequently, 9.00 kg (53.37 mol) of L-ornithine hydrochloride was added to the KOH solution in two parts at about 15-25° C. to form a suspension. Subsequently, 45.0 L (35.5 kg) of ethanol was added to the suspension at 15-25 °C and stirred for about 15-20 min. The suspension is then cooled to about 0-5°C and stirred at this temperature for at least 60 min, but not more than 90 min. Separately, 8.72kg (64.05mol) of phenylacetic acid (PAA) was dissolved in 36.0L (28.4kg) of ethanol in a second reactor and stirred at 15-25°C until completely dissolved. The cold suspension from the first reactor was filtered by depth filtration into the PAA solution to remove precipitated KCl, and the filter cake was washed with about 18.0 L (14.2 kg) of eth...

Embodiment 2

[0065] Example 2: Improved large-scale batch process for the preparation of crude L-ornithine phenylacetate

[0066] Charge 4.05kg (61.38mol) KOH in the first reactor (100L), dissolve it in 10.4L (10.4kg) H 2 O and stirred until a clear solution formed. Subsequently, 9.00 kg (53.37 mol) of L-ornithine hydrochloride was added to the KOH solution in two parts at about 15-25° C. to form a suspension. Subsequently, 45.0 L (35.5 kg) of ethanol was added to the suspension at 15-25° C., and stirred for about 15-20 min. The suspension is then cooled to about 0-5°C and stirred at this temperature for at least 60 min, but not more than 90 min. Separately, 8.72kg (64.05mol) of phenylacetic acid (PAA) was dissolved in 36.0L (28.4kg) of ethanol in a second reactor (450L) and stirred at 15-25°C until completely dissolved. The cold suspension from the first reactor was filtered by depth filtration into the PAA solution to remove precipitated KCl, and the filter cake was washed with abou...

Embodiment 3

[0069] Example 3: Recrystallization of L-ornithine phenylacetate

[0070] In the first container, add the crude product L-ornithine phenylacetate of 13.12kg (48.89mol) embodiment 2, then add 32.8L (32.8kg) H 2 O, and stirred at 15-25°C for about 15-30min until completely dissolved. The resulting solution was then filtered through a particle filter (0.2 μm) into a second container. The particle filter was washed with 262.4 L (207.8 kg) methanol into a second vessel and a suspension formed. The suspension was cooled to 0-5°C and stirred at 0-5°C for about 60 min, but not more than 90 min. A crystalline solid (L-ornithine phenylacetate) precipitated after cooling. The precipitate was separated by centrifugation and washed with 52.5 L (42.6 kg) of methanol. The final product was vacuum dried at about 50 °C for at least 10 h. The dried product was delumped by grinding (1.0 mm sieve). Yield: Overall 70.5% (9.72 kg) (74.1% yield from recrystallization only). The recrystalliz...

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Abstract

Embodiments of the present disclosure are related to improved processes for making L-ornithine phenylacetate without using any silver salts or forming any L-ornithine intermediate salts, such as a benzoate salt. The present processes may be used in the commercial scale manufacturing of L-ornithine phenylacetate with high yields and low impurities.

Description

technical field [0001] The present disclosure relates to the fields of medicinal chemistry, biochemistry and medicine. In particular, the present disclosure relates to methods of making L-ornithine phenylacetate, compositions and methods of using the same. Background technique [0002] Hyperammonemia is a hallmark of liver disease 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 be complicated by acute or chronic liver failure. It is characterized by changes in mental status, including a wide range of neuropsychiatric symptoms, ranging from mild signs of altered brain function to overt mental and / or neurological symptoms, or even profound coma. Accumulation of unmetabolized ammonia has been implicated as a major factor in the pathogenesis of hepatic encephalopathy, but other mechanisms may also be involved. [0003] L-ornithine monoh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/16C07C227/40C07C227/42C07C229/26C07C57/46
CPCC07C227/16C07C227/40C07C227/42C07C229/26C07C57/32C07B2200/13C07C51/43
Inventor L·皮尔索G·温克勒F·德马丁V·埃利辛
Owner OCERA THERAPEUTICS INC
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