Process for preparing cytidine diphosphate choline

A technology for citicoline and choline, applied in the field of biopharmaceuticals, can solve the problems of high price and high cost

Active Publication Date: 2012-07-18
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The starting materials such as orotic acid or uracil or cytidylic ac

Method used

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  • Process for preparing cytidine diphosphate choline

Examples

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preparation example Construction

[0016] A preparation method of citicoline based on the de novo synthesis of pyrimidine. The method includes: in the presence of a culture solution of microorganism A, or in the presence of a culture solution or treatment of microorganism B, The choline raw material is reacted for 10 to 72 hours at a reaction temperature of 20 to 38°C, and the pH is controlled to be 5 to 7.5 to accumulate citicoline.

[0017] The choline material is selected from choline, choline chloride, choline phosphate, choline iodide or choline bromide.

[0018] The microorganism A is selected from one or two of the genus Corynebacterium, Brevibacterium, Bacillus, Rseudomonas, and Saccharomyces cerevisiae Strains of the above genus. The strain used has the following characteristics:

[0019] (1) It can be metabolized to produce cytosine nucleoside products;

[0020] (2) It is resistant to structural analogues of pyrimidine and can relieve the feedback inhibition of UMP and CTP products;

[0021] (3) The cytidine...

specific Embodiment approach

[0078] The following examples further illustrate the present invention, and these examples should not be regarded as a limitation of the present invention. Unless otherwise specified, the amount of each component in the examples is mass percentage.

[0079] The sources of microorganisms in the examples are as follows:

[0080] Industrial beer yeast wet cells were purchased from Jinan Brewery.

[0081] D-Biotin was purchased from Shanghai Shenggong Biological Engineering Co., Ltd.

[0082] Corynebacterium glutamicum deposit number ATCC No. 13032, Pseudomonas cepacia deposit number ATCC No. 25416, Arthrobacter citrinum deposit number ATCC No. 11624, Corynebacterium glutamicum deposit number ATCC No. 13287, Escherichia coli deposit number ATCC No. 21148, etc. were purchased from the American Standard Biological Products Collection Center. Bacillus subtilis (Bacillus subtilis) QL28001 is preserved by the General Microbiology Center of the China Microbial Culture Collection Management Co...

Embodiment 1

[0085] A. Inoculate Bacillus subtilis QL28001 in a culture solution containing 0.5% glucose, 0.5% beef extract, 1% peptone, 0.5% yeast powder, and 0.5% sodium chloride, and cultivate it at 32°C until the sugar is exhausted to obtain subtilis Bacillus culture;

[0086] B. Inoculate the obtained culture of Bacillus subtilis QL28001 in a culture solution containing 20% ​​glucose, 5% yeast powder, 0.5% magnesium sulfate, and 1% potassium dihydrogen phosphate at an inoculum of 5%, and cultivate at 32°C 6h; Obtain the culture solution of Bacillus subtilis QL28001;

[0087] C. The obtained culture solution of Bacillus subtilis QL28001 was continuously added with 1% choline phosphate, and the reaction was continued for 30 hours. During the process, the pH was adjusted to 6.8 with concentrated ammonia water, and the obtained culture solution contained citicoline 5.7 g / L.

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Abstract

The invention relates to a process for preparing cytidine diphosphate choline. According to the method, denovo synthesis of pyrimidine is utilized as a basic reaction and choline materials are subjected to a reaction at the reaction temperature ranging from 20 DEG C to 38 DEG C for 10 to 72 hours with pH controlled at 5 to 7.5 in the presence of culture solution of microorganism A or further in the presence of culture solution of microorganism B or treatment so as to accumulatively produce cytidine diphosphate choline. Simple starting materials of carbon and nitrogen sources are utilized, in culture solution containing the choline materials, precursor of the cytidine diphosphate choline, namely cytidine monophosphate is synthesized by means of metabolic process, and cytidine diphosphate choline is cumulatively produced in the reaction solution. According to the method, expensive cytidine monophosphate or the precursor materials are avoided so that the preparing cost of the cytidine diphosphate choline is greatly reduced.

Description

Technical field [0001] The invention relates to a preparation method of citicoline, in particular to the preparation of citicoline by a fermentation method, and belongs to the technical field of biological pharmacy. Background technique [0002] Citicoline (CDPC) is the precursor of the phospholipid phosphatidylcholine and a necessary coenzyme for the synthesis of lecithin. Citicoline is widely used clinically in the treatment of cerebral ischemia, brain injury, Alzheimer's disease, Parkinson's disease and senile dementia. Citicoline is also known as citicoline, cytidine diphosphate choline. The known preparation methods of citicoline include chemical synthesis, enzymatic methods using microorganisms such as yeast, and enzymatic methods using genetically recombinant microorganisms for transformation. [0003] The common point in these preparation methods is the use of expensive cytidine monophosphate (CMP), cytidine diphosphate (CDP), cytidine triphosphate (CTP), cytosine and oth...

Claims

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Application Information

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IPC IPC(8): C12P39/00C12P19/30C12R1/125C12R1/13C12R1/15C12R1/07C12R1/38C12R1/865C12R1/19
Inventor 王晶翼潘怀明孙英侠毕晓峰薛永玲
Owner QILU PHARMA HAINAN
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