Preparation method of novel chiral resolving agent and (R)-chloromandelic acid

A chiral separation technology of o-chloromandelic acid, applied in the field of medicine and chemical industry, can solve the problems of difficult industrial production of separation efficiency, and achieve the effects of environmental protection and safe production, easy separation and recovery, and cost reduction

Active Publication Date: 2014-05-21
SOUTHWEST RES & DESIGN INST OF CHEM IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many kinds of resolution methods for (RS)-o-chloromandelic acid, among which electrochemical method, extraction resolution method, chromatographic resolution method, electrophoretic resolution method, and enzymatic resolution method are due to the resolution scale, resolution efficiency and other reasons. Difficult to achieve industrial production

Method used

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  • Preparation method of novel chiral resolving agent and (R)-chloromandelic acid
  • Preparation method of novel chiral resolving agent and (R)-chloromandelic acid
  • Preparation method of novel chiral resolving agent and (R)-chloromandelic acid

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Effect test

Embodiment 1

[0047] The chiral resolving agent S-(1) of this embodiment is R in general formula I 1 =Cl, the substitution position is ortho, R 2 =H, the specific structure of (S)-1 in this embodiment is as follows:

[0048]

[0049] A preparation method of (R)-o-chloromandelic acid, the specific steps are as follows:

[0050] Fill the reaction vessel with nitrogen in advance for replacement, weigh 18.6g (0.1mol) of racemic (RS)-o-chloromandelic acid and completely dissolve it in 69g (1.5mol) of absolute ethanol, stir and cool down to 15°C, slowly Slowly add the same amount of (S)-1, after the addition is complete, there will be a large amount of white precipitate in the solution, heat up to 80°C, keep warm and continue to stir for 0.5 hours, keep stirring and naturally cool down to 20°C, place Filter after 10 hours, wash the filtered white needle-like solid with absolute ethanol that has been cooled to 0°C in advance, and dry it in a vacuum oven at 60°C to constant weight. The white n...

Embodiment 2

[0052] The chiral resolving agent S-(1) of this embodiment is R in general formula I 1 =Cl, the substitution position is para, R 2 =NO 2 , the substitution position is the para position, and the specific structure of (S)-1 is as follows:

[0053]

[0054] A preparation method of (R)-o-chloromandelic acid, the specific steps are as follows:

[0055] Fill the reaction vessel with nitrogen in advance for replacement, weigh 558g (3mol) of racemic (RS)-o-chloromandelic acid and completely dissolve it in 1334g (18mol) of tert-butanol, stir and cool down to 15°C, and slowly add 644g (2.1mol) of (S)-1, from the addition of (S)-1, there is a white precipitate in the solution, heat up to 120°C, keep warm and continue to stir for 2 hours, when the temperature is lowered to 80°C, add a small amount of ( R)-o-chloromandelic acid·(S)-1 diastereoisomeric salt as seed crystal, keep stirring and cool down naturally to lower the temperature to 18°C, let stand for 5 hours and then filter, ...

Embodiment 3

[0058] The chiral resolving agent S-(1) of this embodiment is R in general formula I 1 = H, R 2 =NO 2 , the substitution position is the para position, and the specific structure of (S)-1 is as follows:

[0059]

[0060] A preparation method of (R)-o-chloromandelic acid, the specific steps are as follows:

[0061] Fill the reaction vessel with argon in advance for replacement, weigh 186g (1mol) of racemic (RS)-o-chloromandelic acid and completely dissolve it in 300g (5mol) of isopropanol, stir and cool down to 15°C, slowly Add 109g (0.4mol) (S)-1, a large amount of white precipitates are produced in the solution during the addition process, heat up to 70°C, keep warm and continue to stir for 1 hour, keep stirring and naturally cool down to 10°C, place for 12 After 1 hour, filter, and the filtered white needle-shaped solid is washed with isopropanol that has been cooled to 0°C in advance, and dried in a vacuum oven to constant weight. The obtained white needle-shaped soli...

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Abstract

The invention discloses a novel chiral resolving agent S-(1) which is used for chemically resolving (RS)-chloromandelic acid to prepare the (R)-chloromandelic acid. The invention further discloses a preparation method of the (R)-chloromandelic acid. The preparation method comprises the following steps: making the resolving agent S-(1) react with the (RS)-chloromandelic acid to obtain a (R)-chloromandelic acid and resolving agent diastereomer salt, decomposing the (R)-chloromandelic acid and resolving agent diastereomer salt to obtain the (R)-chloromandelic acid, and optionally recovering the S-(1). The preparation method has the beneficial effects that (1), the chiral resolving agent (S)-1 is high in resolving efficiency, stable in chemical property, and easy to separate and recycle, and the recycling purity is more than 99 percent; (2), an industrial line of the preparation method is developed, the process condition is mild, and industrialized production is facilitated; (3), the content of the prepared (R)-chloromandelic acid is more than 99 percent, and the ee value is more than 99 percent; (4), the used organic solvent can be recycled, and no special and toxic reagents are used.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new chiral resolving agent and a method for preparing a pharmaceutical intermediate using the chiral resolving agent, especially a chiral resolving agent and a chiral resolving agent for amino alcohol derivatives. A method for preparing a clopidogrel intermediate (R)-o-chloromandelic acid using the chiral resolving agent. Background technique [0002] Clopidogrel is a platelet aggregation inhibitor, which is widely used clinically to prevent cardiovascular and cerebrovascular diseases such as myocardial infarction, stroke, arteriosclerosis, etc. Compared with other platelet inhibitors, it has strong effect, good tolerance and small side effects, etc. advantage. It was launched in the United States and the United Kingdom in 1998, and in China in August 2001. It is currently the antithrombotic drug with the highest market share. [0003] Studies have shown that (S)-c...

Claims

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Application Information

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IPC IPC(8): C07C59/56C07C51/487
CPCC07B57/00C07B2200/07C07C51/487C07C59/56
Inventor 卢乔森黄超明李毅肖英陈春玉谢辉辉姚雄生
Owner SOUTHWEST RES & DESIGN INST OF CHEM IND
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