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Separation extraction method for (R)-2-chloromandelic acid

A technology of o-chloromandelic acid and extraction method, applied in the separation/purification of carboxylic acid compounds, organic chemistry, etc., can solve the problems of high market price and unsatisfied market demand, and achieve simple operation, simple equipment and long service life long lasting effect

Active Publication Date: 2019-08-27
WUHAN WUYAO PHARMA
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  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

Clopidogrel was developed in 1996 by Sanofi of France and Spirulina of the United States, and was approved by the FDA in the following year. It was officially launched in the United States in March 1998. Its trade name was "Plavix". According to statistics, the sales volume of clopidogrel is 9.4 billion US dollars, and the single-drug sales revenue ranks second among all drugs in the world. With the success of clopidogrel, its demand is also continuously increasing. An important intermediate, with the gradual expansion of clopidogrel in the field of generic drugs in China, the demand for o-chloromandelic acid is also expanding. Not only that, the further development of other uses of o-chloromandelic acid is also increasing its market demand , and the market price is high, and the market demand cannot be met. Therefore, further research and development of o-chloromandelic acid will have good economic and social benefits, especially a series of technologies for extracting optically pure o-chloromandelic acid.

Method used

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  • Separation extraction method for (R)-2-chloromandelic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] The pH=7.58, (R)-o-chloromandelic acid content of 143mmol / L water-phase immobilized bacteria catalytic reaction liquid is the liquid to be treated, using HZ-202 type resin.

[0089] 1. Pretreatment under the conditions of 25°C and 220rpm shaker: first soak and wash with 1M NaOH solution, the ratio of the volume of NaOH solution (in ml) to the mass of strongly basic anion resin (in g) is 3: 1. Then soak and wash with 1M dilute hydrochloric acid. The ratio of the volume of dilute hydrochloric acid (unit: ml) to the mass (unit: g) of strong basic anion resin is 3:1. washing;

[0090] 2. Soak the treated resin with a buffer solution of pH=8, extract the product o-chloromandelic acid from the reaction solution by static adsorption, hang the column for a certain period of time (2-6 hours), and separate the liquid from the resin;

[0091] 3. Elute the adsorbed resin with 1M dilute hydrochloric acid 5 times the mass volume of the resin at a flow rate of 2.5ml / min;

[0092] 4....

Embodiment 2

[0094] pH = 4.3, (R)-o-chloromandelic acid content of 140mmol / L water-phase immobilized bacteria catalytic reaction liquid is the liquid to be treated, using HZ-202 resin.

[0095] 1. Pretreatment at room temperature: first soak and wash with 1M NaOH solution, the ratio of the volume of NaOH solution (in ml) to the mass of strongly basic anion resin (in g) is 3:1, and then use 1M dilute hydrochloric acid For soaking and washing, the ratio of the volume of dilute hydrochloric acid (in ml) to the mass of strongly basic anion resin (in g) is 3:1, soak for 15 minutes, and wash at a speed of 2 ml / min;

[0096] 2. Soak the treated resin with a buffer solution of pH=8, extract the product o-chloromandelic acid from the reaction solution by means of dynamic adsorption, and after hanging on the column for 15 minutes, separate the liquid from the resin at a rate of 2.5ml / min;

[0097] 3. Elute the adsorbed resin with 1M dilute hydrochloric acid 5 times the mass volume of the resin at a ...

Embodiment 3

[0100] The water-phase free bacteria catalyzed reaction liquid with pH=7.2 and (R)-o-chloromandelic acid content of 156mmol / L is the liquid to be treated, and HZ 202 resin is used.

[0101] 1. In the exchange column at room temperature, the resin that has been recycled once is used for adsorption, and the product o-chloromandelic acid is extracted by dynamic adsorption. After hanging on the column for 15 minutes, the liquid is separated from the resin at a speed of 2.5ml / min;

[0102] 2. Elute the adsorbed resin with 1M dilute hydrochloric acid 5 times the mass volume of the resin at a flow rate of 2.5ml / min;

[0103] 3. The collected desorption solution is extracted with ethyl acetate of 0.3 times the volume of the eluent, and the extracted organic phase is distilled under reduced pressure (50°C-60°C, 0.09MPa), and the obtained solid is vacuum-dried to obtain (R )-o-chloromandelic acid crude product. The experimental results are shown in Table 1.

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Abstract

The invention relates to an extraction method for a chiral medical intermediate, in particular to a separation extraction method for (R)-2-chloromandelic acid. The method at least comprises the following steps that strongly-alkaline anion resin is pretreated, wherein pretreatment comprises the steps of alkaline washing and acid washing in sequence, and quaternary ammonium salt strongly-alkaline anion resin is preferably selected as the strongly-alkaline anion resin; the treated strongly-alkaline anion resin is adopted for adsorbing a to-be-treated solution of the (R)-2-chloromandelic acid; anelution agent is adopted for elution, an eluent is obtained, extracted and concentrated, and the (R)-2-chloromandelic acid is obtained. The separation extraction method has a good separation effect and is high in yield, the adopted strongly-alkaline anion resin is long in service life, the separated water-phase system can continue to provide the reaction system for the next biological catalysis, the production cost is reduced, and discharge of waste water is reduced.

Description

technical field [0001] The invention relates to a method for extracting chiral pharmaceutical intermediates, in particular to a method for separating and extracting (R)-o-chloromandelic acid. Background technique [0002] The synthesis and development technology of chiral drugs has become a research hotspot and commanding height in the field of pharmaceuticals in today's society. The development of chiral drugs and the improvement of related technologies have also greatly promoted the exploration of extraction methods for related drugs. [0003] O-chloromandelic acid, also known as α-hydroxy o-chlorophenylacetic acid, has the molecular formula C 8 h 7 o 3 Cl, with a relative molecular mass of 186.5, has two enantiomeric configurations, R-type and S-type, and is widely used in many fields such as pharmaceutical production, asymmetric synthesis, and optical resolution, and the (R) -O-chloromandelic acid can synthesize a new type of safe and efficient anti-platelet aggregati...

Claims

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Application Information

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IPC IPC(8): C07C51/47C07C59/56C07C51/42
CPCC07C51/47C07C51/42C07C59/56
Inventor 赵涛涛汪兆谱张伟王成韩瑞张琦谢国范吴鸣
Owner WUHAN WUYAO PHARMA
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