Background and overview[1][2]
The urea cycle is a metabolic process through which the body’s nitrogen is excreted. Six enzymes participate in this process. A defect in any of the enzymes will disrupt the metabolic process, resulting in excess nitrogen (in the form of ammonia). Retention in the body. The six urea cycle disorders are: carbamoyl phosphate synthetase deficiency disease; N-acetylglutamate synthetase deficiency disease; ornithine carbamoyltransferase deficiency disease; argininosuccinate synthase deficiency disease; Argininosuccinate lyase deficiency disease and arginase deficiency. If a newborn baby is deficient in one of these rare enzymes in the urea cycle, and the enzyme deficiency is severe, it can cause the baby to become comatose or die within a few days of birth.
Sodium Phenylbutyrate can be rapidly metabolized into phenylacetate in the body, and can combine with glutamate and ammonia to form phenylacetyl glutamine, which is excreted through the kidneys and is a pathway for the excretion of nitrogen-containing waste. It can reduce excessive blood ammonia levels and blood glutamate concentrations to form phenylacetyl glutamine, indicating increased excretion of nitrogenous waste products. On May 13, 1996, the U.S. FDA approved it through fast track for use as an adjuvant treatment for carbamoyl phosphate synthase (CPS), ornithine carbamoyltransferase (OTC) or argininosuccinate synthetase (AS). Hyperammonemia caused by chronic uric acid cycle disorders caused by deficiency, the trade name is Buphenyl, and it has also been granted orphan drug status by the FDA.
Sodium phenylbutyrate is originally developed and produced by Ucyclyd Pharma in the United States. The dosage form is tablets and granules. It is widely used in the United States, the European Union and other countries for the treatment of urea cycle disorders in newborns, infants, children and adults. In addition, sodium phenylbutyrate is being studied abroad as a new drug that induces the differentiation of malignant tumors. Research shows that it has a significant effect on glioma, prostate cancer, melanoma, leukemia, lymphoma, and chemoprevention. It is a potential new drug with high efficiency, low toxicity and broad spectrum to induce differentiation.
Up to now, the approved dosage forms and indications of sodium phenylbutyrate are still tablets and granules, which are used for the auxiliary treatment of urea cycle disorders. Sodium phenylbutyrate is prepared by reacting phenylbutyric acid with sodium hydroxide in water or an organic solvent to form a sodium salt. It can be seen that the difficulty in the preparation of sodium phenylbutyrate is to obtain a high purity (99.9%) product. It is best to Does not contain impurities other than those specified in the standard. The recrystallization of sodium phenylbutyrate itself is not effective in removing impurities. It is necessary to use high-purity phenylbutyric acid (99.9%) to form a sodium salt to obtain high-purity sodium phenylbutyrate. Therefore, in order to obtain high-purity sodium phenylbutyrate, it is necessary to provide high-purity raw material phenylbutyric acid.
Structure
Apply[2]
4-phenylbutyric acid (4-PBA) is a low molecular weight fatty acid composed of aromatic rings and butyric acid. Existing research has reported some application methods of 4-phenylbutyric acid, such as: (1) As an ammonia chelator, its tablets or powder are used in the clinical treatment of urea cycle disorders through oral administration or nasogastric tube intubation; (2) Due to its ability to activate embryonic hemoglobin transcription, it is used to treat sickle cell anemia and thalassemia; (3) It also has beneficial effects in patients with spinal muscular atrophy; (4) It can be used in certain diseases related to neuroinflammatory reactions (such as multiple sclerosis and ischemia); (5) It can alleviate cognitive defects in Alzheimer’s disease mice.
In addition, 4-PBA is effective in preventing the transition from AKI to CKD and is used to prepare drugs for the treatment of acute kidney injury. After acute kidney injury has occurred, administration of 4-PBA can restore part of the renal function damaged after acute kidney injury; improve renal tubular atrophy, renal interstitial fibrosis, chronic renal inflammation, and tubular cell death after acute kidney injury. Animal model studies have confirmed that 4-PBA can effectively alleviate the further deterioration of acute kidney injury to CKD.
For example, the 4-phenylbutyric acid can be administered under the following symptoms: (1) The ratio of kidney weight/body weight on the ischemic side increases significantly, the kidneys are enlarged and pale to the naked eye, and the cut cortex is pale and the medulla is pale. Dark red in color. Or the kidneys are enlarged under B-ultrasound. (2) The contralateral kidney weight/body weight ratio has not changed significantly, indicating that the contralateral kidney has not yet undergone compensatory hypertrophy; (3) Serum creatinine (Sc)r) increased significantly, indicating renal function damage; (4) HE staining showed extensive damage and necrosis of renal tubular cells.
Preparation [3-4]
Method 1: Purification method of phenylbutyric acid, including the following steps:
1) Under the catalysis of a catalyst, industrial grade phenylbutyric acid is reacted in an alcoholic solvent. The reacted system is processed to obtain 4-phenylbutyrate; the processing steps are as follows: 1) Remove the The solvent in the reacted system obtains a residue; 2) Place the residue in water, and adjust its pH value to 7.5-10, stir and let stand for layering, collect the organic phase, and record it as organic phase I; 3) Wash the organic phase I with sodium carbonate aqueous solution, and after letting it stand for stratification, collect the organic phase, which is recorded as organic phase II; 4) Wash the organic phase II with water, let it stand for stratification, and collect the organic phase Phase, recorded as organic phase III, is the 4-phenylbutyrate.
2) In the presence of an alkaline catalyst or an acidic catalyst, the 4-phenylbutyrate undergoes a hydrolysis reaction in a solvent to obtain purified phenylbutyric acid, that is, the industrial grade phenylbutyrate is achieved. Purification of acids.
Method 2: Add powdered aluminum chloride (200g) to benzene (400g) and stir at 50°C for 10 min. Butyrolactone (86g) was added in portions. The temperature was maintained at 50 to 60°C for 90 min, and then the reaction mixture was added to a mixture of ice and 5% sodium hydroxide while stirring. The temperature is below 35°C and the pH value is maintained between 9 and 9.5 for 2 hours. The mixture was filtered under vacuum. Precipitate the phenylbutyric acid from the aqueous portion by adding ice and hydrochloric acid. Crude (93.7%-94.3%) 4-phenylbutyric acid was isolated by vacuum filtration.
Crude 4-phenylbutyric acid is purified by vacuum distillation (120-125℃, 1mm Hg). The acid was dissolved in 5% sodium hydroxide and stirred. The acid was dissolved in 5% sodium hydroxide and stirred with carbon tetrachloride for 15 minutes. The carbon tetrachloride was removed and the phenylbutyric acid solution was mixed with acetone, methanol and a small amount of activated carbon for 15 minutes at room temperature. The mixture was filtered and acidified by adding HCl. 4-Phenylbutyric acid crystals (yield 81.15%) were isolated and dried by freeze-drying. HPLC analysis showed the final product to be 99.87% pure.
Main reference materials
[1] CN201610594728.0 Sodium phenylbutyrate tablet and preparation method thereof
[2] CN201810851301.3 Application of 4-phenylbutyric acid
[3] CN201610459879.5 A purification method of phenylbutyric acid
[4] CN02810264.9 Synthesis of 4-phenylbutyric acid
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