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Levodopa crystalline powder and preparation method thereof

A technology of crystalline powder and manufacturing method, applied in the directions of organic chemistry method, chemical instrument and method, cyanide reaction preparation, etc., can solve the problems of rare levodopa, long reaction time, many by-products, etc., to avoid appearance Effects of browning, improving moisture uniformity, and improving yield

Active Publication Date: 2016-11-16
CHANGXING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few reports on the industrialization of levodopa prepared by biological methods
The existing biological method for preparing levodopa has a series of problems such as long reaction time, many by-products, low conversion rate, high residual substrate concentration, poor color of the finished product, low crystallinity, and high impurity content.

Method used

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  • Levodopa crystalline powder and preparation method thereof
  • Levodopa crystalline powder and preparation method thereof
  • Levodopa crystalline powder and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1 tyrosine phenol lyase biocatalytic process

[0033]Put initial pyruvate into the water, control the pH at 7.0-9.0 with concentrated ammonia water; then add antioxidants, chelating agents, ammonium salts, pyridoxal 5-phosphate in sequence, and control the pH at 7.0-9.0 with concentrated ammonia water again, add The enzyme solution of recombinant tyrosine phenol lyase with a concentration of 80-200g / L is passed through nitrogen, the temperature is adjusted to the reaction temperature, the pH is adjusted to 7.0-9.0 with ammonia water, and catechol is added to start the reaction; the initial basic substrate o The molar ratio of hydroquinone to pyruvic acid and its sodium salt is 1:1-1.5. Afterwards, add the substrates catechol and pyruvate (or ammonium pyruvate, only pyruvate unless otherwise specified) at 2 g / L every 10 minutes, and the final concentration of catechol is 50-70 g / L (calculated based on the initial volume), the final concentration of pyruvic a...

Embodiment 2650

[0038] Example 2 650L conversion system

[0039] Take the levodopa conversion solution obtained in Example 1, add concentrated hydrochloric acid to adjust the pH to 5.1, and obtain a levodopa mixed solution with a total volume of 650 L and a concentration of 110 g / L. The temperature is reduced to 6 ° C. After standing for 4 hours, Use a centrifuge to filter and rinse with a small amount of drinking water. The crude product of levodopa can be collected if no obvious liquid flows out from the material outlet of the centrifuge. The total weight of the crude levodopa collected was 97.5kg, and the levodopa content calculated as dry product was 67.5kg, and the yield of levodopa obtained by centrifuging the crude product was 94.4%.

[0040] Put 97.5kg of crude levodopa obtained by centrifugation into an enamel reaction kettle, add 570L of drinking water, and control the temperature at 30-35°C. Start stirring, add concentrated hydrochloric acid, adjust the pH to 0.97, the amount of c...

Embodiment 36500

[0048] Example 3 6500L conversion system

[0049] Take the levodopa conversion solution obtained in Example 1, add concentrated sulfuric acid with a mass volume ratio of 50% to adjust the pH to 5.4, obtain a total volume of 6500L, and a concentration of levodopa mixed solution of 104g / L, and the temperature drops to 9°C After standing still for 4 hours, press filter with a plate filter, and top wash with a small amount of purified water, and the crude product of levodopa can be collected without obvious liquid flowing out at the outlet of the clear liquid. The total weight of the crude levodopa collected was 858kg, the levodopa content calculated as dry product was 643.6kg, and the yield of levodopa obtained by the plate filter was 95.2%.

[0050] Put 858kg of levodopa crude product obtained by the plate filter into the enamel reaction kettle, add 5700L of drinking water, and control the temperature at 30-35°C. Start stirring, add concentrated hydrochloric acid, adjust the pH...

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Abstract

The invention discloses levodopa crystalline powder and a preparation method thereof. The preparation method includes: obtaining a mixed solution containing levodopa through tyrosine phenol lyase biotransformation; using acidic liquid to adjust pH of the mixed solution to be on the acidic side; centrifuging or filtering and collecting coarse crystal; continuing acid adjusting and redissolving; adding activated carbon, and heating and stirring for decoloring; filtering clean liquid, performing adjusting alkali and crystallizing, filtering, and drying to obtain the levodopa crystalline powder. By using the method, on the basis that industrial production is realized, and residual substrate, protein and pigment in the process of transformation are filtered away effectively; vacuum microwave drying technology is adopted, so that product loss caused by exogenic action of hot air blowing and material turning during conventional drying is reduced, product appearance browning caused after levodopa is damaged or decomposed through high-temperature oxidation is avoided, and moisture uniformity of the crystalline powder after being dried. The crystalline powder obtained by the method is high in quality, total impurities calculated by HPLC peak appearing area percentage is not more than 0.05%, and crystallinity of the crystalline powder is higher than 90%.

Description

technical field [0001] The invention relates to the field of biochemical industry and separation and purification, in particular to a levodopa crystalline powder and a manufacturing method thereof. Background technique [0002] Levodopa (3,4-dihydroxylphenylalanine, Levodopa), also known as L-dopa, chemical name is 3,4-dihydroxyphenylalanine, CAS: 59-92-7; white crystalline powder, odorless Odorless; it is an important biologically active substance in organisms and an important intermediate product in the biochemical metabolic pathway from L-tyrosine to catechol or melanin. Its structural formula is as follows: [0003] [0004] Levodopa and compound levodopa (such as Madopar) have been used for more than 40 years in the treatment of Parkinson's disease, a common senile disease. They are still the most effective drugs for Parkinson's disease, and they are well tolerated. Slowing of movement, relief of major symptoms, and prolongation of life in patients with Parkinson's...

Claims

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Application Information

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IPC IPC(8): C07C227/42C07C229/36
CPCC07B2200/07C07B2200/13C07C227/42C07C229/36
Inventor 肖延铭杨卫华陈明亮龚彬成严燕兵谈聪
Owner CHANGXING PHARMA
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