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Bio-preparation method for pseudoephedrine

A technique for pseudoephedrine and biological preparation, applied in the field of biological preparation of pseudoephedrine, can solve problems such as cost and environmental protection, unfavorable actual production, high cost, low yield and the like

Inactive Publication Date: 2018-01-26
武汉茵茂特生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This traditional process is cumbersome and labor-intensive; the production cost is high, and it directly depends on the resources of ephedra grass, and the output is small and unstable
In addition, the production of ephedrine in a German company directly uses chemical synthesis, and the racemate of pseudoephedrine is first produced, which requires further resolution. The resolution reagents are expensive and costly
There are many advantages in the production of ephedrine by biotransformation. A semi-biological transformation method for producing ephedrine is reported at home and abroad. First, phenylacetone synthase is used to convert benzaldehyde into R-phenylacetyl carbinol, and then further chemically synthesize ephedrine. , but the yield is not high
Still will carry out isomer resolution in the chemical synthesis, consider unfavorable for actual production from cost and environmental protection, and the method that utilizes enzymatic catalyzed direct biotransformation to produce ephedrine has not yet been reported both at home and abroad

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The genetic engineering bacteria derived from the phenylacetone synthase of Acetobacter pasteurii, the specific preparation method is:

[0061] (1) construct the expression vector that contains phenylacetone synthase gene:

[0062] The genomic DNA of the phenylacetone synthase of Acetobacter pasteurii was extracted as a template, and the following nucleotide sequences containing NdeI and XhoI restriction sites were used as primers for PCR amplification:

[0063] Primer 1:5'—GAATT CATATG ACCTATACCGTGGGCATG—3’

[0064] Primer 2:5' - GCC CTCGAG TTACGCCAGGGTGGTT—3’

[0065] The NdeI restriction site and the XhoI restriction site were introduced into the underlined portion of the 5' end of the above primers, respectively.

[0066] The PCR amplification system is: genomic DNA 2uL, primer 1 and primer 2 each 2uL, dNTP 4uL, 10×Taq buffer 5uL, Taq enzyme 1uL, ddH 2 O 34uL;

[0067] The PCR reaction program was as follows: pre-denaturation at 94 °C for 2 min; denaturation ...

Embodiment 2

[0091] The compound of formula I, benzaldehyde, and the compound of formula IV are reacted in a buffer solution under the catalysis of biological enzymes, and purified to obtain optically pure compound of formula II (S)-1-phenyl-2-carbonyl-3-propanol;

[0092] The specific reaction process is as follows: the reaction is carried out in a 1L shake flask, the reaction system is controlled to 300mL, and the compound of formula I benzaldehyde (30g, 0.28mol) and the compound of formula IV pyruvic acid (35.2g, 0.4mol) are used as substrates, and lemon is used as the substrate. The acid-sodium citrate buffer solution is used as a solvent, and the whole cell of genetically engineered bacteria derived from the phenylacetone synthase of Acetobacter pasteurii is used as a catalyst, and coenzyme thiamine pyrophosphate is added. The concentration of the whole cell of the genetically engineered bacteria that controls the phenylacetone synthase derived from Acetobacter pasteurii is 70 g / L, and...

Embodiment 3

[0096] Optically pure compound of formula II (S)-1-phenyl-2-carbonyl-3-propanol reacts with methylamine in a buffer solution under the catalysis of biological enzymes to generate pseudoephedrine;

[0097] The reaction was carried out in a 1L shake flask, the reaction system was controlled to 300mL, and the compound of formula II (S)-1-phenyl-2-carbonyl-3-propanol (30g, 0.2mol) and methylammonium (15.5g, 0.5mol) were mixed with ) as a substrate, adding glucose (45g, 0.25mol), using phosphate buffer solution as a solvent, using the genetically engineered bacteria whole cell and glucose dehydrogenase derived from the N-methyl amino acid dehydrogenase of Pseudomonas putida ATCC12633 as catalysts , add the coenzyme NAD+. The whole cell concentration of the genetically engineered bacteria controlling N-methyl amino acid dehydrogenase derived from Pseudomonas putida ATCC12633 was 28 g / L, and the concentration of the control coenzyme NAD+ was 0.4 g / L. The pH value of the transformati...

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Abstract

The invention discloses a bio-preparation method for pseudoephedrine. The bio-preparation method comprises the following steps: reacting benzaldehyde with ethylene, pyruvic acid or pyruvate in a buffer solution under the catalysis of bio-enzymes and carrying out purification so as to obtain optically pure (S)-1-phenyl-2-carbonyl-3-propanol; reacting the optically pure (S)-1-phenyl-2-carbonyl-3-propanol with methylamine in a buffer solution under the catalysis of bio-enzymes so as to produce (1S,2S)-2-methylamino-phenylpropan-1-ol, i.e., pseudoephedrine. According to the invention, raw materials are widely available and cheap and do not need to prepare separately; used reagents are low in cost; the prepared pseudoephedrine is easy to recrystallize and purify and has low cost; enzymatic direct biotransformation is employed for production of pseudoephedrine, reaction conditions are mild, and the method is suitable for industrial production; reaction conditions are easy to control; operation is simple; process flow is easy; and the method has no special requirements on equipment and is suitable for large-scale production.

Description

technical field [0001] The present invention relates to the preparation method of raw material medicine and medicine intermediate, specifically refers to a kind of biological preparation method of pseudoephedrine. Background technique [0002] The herbal ephedra has good medicinal value, and has the advantages of safe and reliable medication, strong tolerance and small side effects. Its main active ingredients are ephedrine and pseudoephedrine. Pseudoephedrine is a sympathomimetic drug, which has vasoconstriction and pressure-boosting effects on the mucosa of the upper respiratory tract, a significant diuretic effect, and an anti-inflammatory effect. Compared with ephedrine, it has less side effects, and when used for treatment, it has less adverse reactions such as increasing heart rate, increasing blood pressure, and central excitation, and has the advantages of significant diuresis and good drug tolerance. Clinically, it is mainly used to treat colds, hay fever, hypoten...

Claims

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Application Information

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IPC IPC(8): C12P13/00C07C213/10C07C215/30
Inventor 胡磊奚超群曾超
Owner 武汉茵茂特生物技术有限公司
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