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Preparation method of (R)-chloromandelic acid

A technology of o-chloromandelic acid and reaction buffer, which is applied in the direction of fermentation, can solve environmental hazards, waste liquid discharge and other problems, and achieve the effects of reducing emissions, reducing production costs and improving utilization

Pending Publication Date: 2019-08-30
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, producing (R)-o-chloromandelic acid at an industrial level will produce a large amount of waste liquid discharge, which will cause certain harm to the environment

Method used

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  • Preparation method of (R)-chloromandelic acid
  • Preparation method of (R)-chloromandelic acid
  • Preparation method of (R)-chloromandelic acid

Examples

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preparation example Construction

[0034] Specifically, the preparation method of the embodiment of the present invention at least includes the following steps:

[0035] (1) cultivating Escherichia coli engineering bacteria expressing nitrilase;

[0036] (2) adopting the engineered bacterium that cultivates to obtain as catalyst, o-chloromandelonitrile as substrate, and reaction buffer as reaction medium to react;

[0037] (3) After the reaction finishes, separate and collect the supernatant;

[0038] (4) After extracting (R)-o-chloromandelic acid in the supernatant, a flow-through is obtained, and the flow-through is recycled at least once in step (2) as the reaction buffer.

[0039] Specifically, the engineered Escherichia coli bacteria expressing nitrilase used in step (1) can be commercially available strains, and preferably engineered bacteria constructed in the method disclosed in Application No. 201510978973.7.

[0040] Optionally, the culturing in step (1) includes culturing in shake flasks or ferment...

Embodiment 1

[0067] 1. Add 100ml of phosphate buffer (NaH 2 PO 4 / Na 2 HPO 4 Buffer), pH 7.5~8.5, add 1.5g of engineered bacteria cells, 30mM substrate o-chloromandelonitrile and cosolvent (methanol, the amount added is 1% of the volume of the reaction system), react in a shaker at 220rpm, The substrate was fed in batches for 6 times, and the substrate concentration was 25 mM each time, and the end point of the reaction was monitored by thin-layer chromatography. After the substrate has reacted, the insolubles are removed by centrifugation, and the supernatant is transferred to an activated weak base anion resin, the product (R)-o-chloromandelic acid in the adsorption supernatant is collected, and the flow-through is recorded as Reaction solution 1; then use 50ml 2M HCl to elute the product on the resin, collect the eluent, and record it as eluent 1.

[0068] 2. Transfer reaction solution 1 to a 250ml Erlenmeyer flask, add 1.5g of engineering bacteria cells, 30mM substrate o-chloromand...

Embodiment 2

[0076] Embodiment 2 only replenishes the lost volume after each measurement of the collected reaction solution volume, and other implementations are the same as in Example 1, and the resulting eluate product results are shown in Table 2:

[0077] Table 2:

[0078]

[0079]

[0080] Note 1 : The substrate is o-chloromandelonitrile racemate.

[0081] Note 2 : Add new reaction buffer after the volume of the reaction solution decreases.

[0082] Note 3 : Cycle 10 times, and the concentration of substrate catalyzed is equivalent to 1500mM.

[0083] From the experimental results of this example, it can be seen that the yield of the product can be further significantly improved by adding new reaction buffer.

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Abstract

The invention belongs to the field of pharmaceutical chemistry and particularly relates to a preparation method of (R)-chloromandelic acid. The preparation method at least comprises the following steps: culturing engineered escherichia coli expressing nitrilase, taking the engineered escherichia coli as a catalyst, chloromandelonitrile as a substrate and a reaction buffer as a reaction medium forreaction, separating and collecting supernate after the reaction is finished, obtaining flow-through liquid after extracting (R)-chloromandelic acid from the supernate, and recycling the flow-throughliquid as a reaction buffer for at least one time. According to the preparation method, a utilization ratio of the reaction buffer is increased, so that the production cost of (R)-chloromandelic acidis lowered; the emission of waste liquid is significantly reduced; and green and environment-friendly production of (R)-chloromandelic acid is achieved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of (R)-o-chloromandelic acid. Background technique [0002] (R)-o-chloromandelic acid is a white crystalline powder with the chemical formula C 8 h 7 ClO 3 , with a molecular weight of 186.59 and a melting point of 86-92°C, is an important pharmaceutical intermediate and fine chemical product, and is a raw material for the synthesis of a new safe and effective anti-platelet aggregation drug, clopidogrel. As a global blockbuster drug, clopidogrel is currently the best-selling drug on the market. With the expiry of the patent of clopidogrel, a global upsurge of imitation has been set off, so the demand for (R)-o-chloromandelic acid, which is an important intermediate, continues to grow at home and abroad. Therefore, how to efficiently and cheaply prepare a large amount of high-purity (R)-o-chloromandelic acid will have important market value. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/42
CPCC12P7/42
Inventor 赵涛涛韩瑞张伟王成李文强张琦谢国范吴鸣
Owner WUHAN WUYAO PHARMA
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