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Preparation method of L-chloperastine fendizoic acid

A technology of levocloperastine and oxalate, which is applied in the field of chemical drug synthesis, can solve the problems of low product yield, high production cost, unqualified product quality, etc., achieve high stereoselectivity and reduce production cost , the effect of shortening the reaction cycle

Active Publication Date: 2013-06-12
CHONGQING WORLD HAORUI PHARM CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The first synthetic method uses strychnine and dimethyl strychnine which are extremely poisonous in the resolution reagents, which are plant extracts, which are expensive and difficult to obtain. In addition, the resolution yield is only about 20%, resulting in high product costs. Not suitable for industrial production
The second route uses D-tartaric acid to directly split racemic cloperastine to obtain optically pure L-cloperastine. are not conducive to the industrial production of products;
[0012] All of the above methods have limitations to varying degrees. The main disadvantage is that to obtain optically pure L-cloperastine, it is necessary to rely on resolution methods, resulting in low total product yield, high production costs, and serious waste pollution and difficult product production. issues of industrial production

Method used

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  • Preparation method of L-chloperastine fendizoic acid
  • Preparation method of L-chloperastine fendizoic acid
  • Preparation method of L-chloperastine fendizoic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0046] (1)(R)-DPP-H 8 - Preparation of binol (IV). Add (R)-binol 50g (0.175mol), absolute ethanol 600ml, 5% Pd / Cl 10g in a dry and clean 1000ml autoclave successively, keep the reaction at 60°C for 8.0 hours under 2.5MPa pressure, filter, and concentrate to obtain white crystals. Add the above white crystals to a 1000ml reaction flask, then add 96.6g potassium carbonate, 49g dimethyl carbonate, and 500ml acetone to reflux for 6h, filter, and concentrate to obtain an off-white solid. Add 300ml of dichloromethane directly to the above system, add 22.1g of bromine dropwise under cooling in an ice-water bath, after the addition is complete, keep the reaction for 20min, wash with water, dry and concentrate to obtain a light yellow solid. Suspend the light yellow solid obtained above in a mixed solution of dioxane and water, then add 45 g of 3,5-diphenylphenylboronic acid, 60.9 g of barium hydroxide octahydrate, and 20.3 g of palladium tetrakistriphenylphosphine, Reflux at 110°C f...

Embodiment 2

[0054] The whole process and the added reaction materials are all the same as in Example 1, and the difference in step (1) is that the molar ratio of the brominated product and 3,5-diphenylboronic acid reacts is 1: 1; the step (2) The difference is 4-chlorobenzaldehyde: phenyl Grignard reagent: isopropyl titanate: chiral ligand (R)-DPP-H 8 The molar ratio of -binol1 is 0.01: 0.01: 1, and the reaction temperature is -80°C; the difference in step (3) is that left-handed 4-chlorobenzhydryl alcohol: N-(2-chloroethyl)-piperidine hydrochloride mole The ratio is 1:1.0; the molar ratio of L-4-chlorobenzhydryl alcohol: fendyzalic acid is 1.0:0.95, and the reaction temperature is 0° C.; the final yield of L-cloperastine fendyzaic acid is 95.4%.

Embodiment 3

[0056] The whole process and the added reaction materials are all the same as in Example 1, and the difference in step (1) is that the molar ratio of the brominated product and 3,5-diphenylboronic acid reaction is 1: 3; the step (2) The difference is 4-chlorobenzaldehyde: phenyl Grignard reagent: isopropyl titanate: chiral ligand (R)-DPP-H 8 The molar ratio of -binol1 is 0.1, and the reaction temperature is 50°C: 1:2; the difference in step (3) is that the molar ratio of L-4-chlorobenzhydryl alcohol: N-(2-chloroethyl)-piperidine hydrochloride It is 1:1.5; the molar ratio of L-4-chlorobenzhydryl alcohol: fendizac acid is 1.0:1.1, and the reaction temperature is 85°C. The final yield of levocloperastine fendisate: 96.4%.

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Abstract

The invention discloses a preparation method of L-chloperastine fendizoic acid, which comprises the following steps: directly carrying out asymmetric synthesis to obtain L-4-chlorobenzhydrol without resolution, reacting the L-4-chlorobenzhydrol with N-(2-chloroethyl)-piperidine hydrochlorate to obtain L-chloperastine, and finally, salifying with fendizoic acid to obtain the target compound. Sincethe asymmetric synthesis is basically orientation reaction, the theoretical yield is up to 100%, the actual yield is up to higher than 95%, while the theoretical yield by resolution is only 50%, and the actual yield is only 30% or so. The optical purity e.e% is up to higher than 99%. The obtained chiral ligand can be used repeatedly, so that the chiral ligand is needed once for all, thereby simplifying the operation, greatly lowering the cost and reducing the pollution of three wastes. The invention protects the health of operating personnel, avoids environmental pollution, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical drug synthesis, and in particular relates to a preparation method of the compound L-cloperastine fendizaic acid. Background technique [0002] Racemic cloperastine itself has good biological activity and drug activity. It is a central antitussive drug, which mainly inhibits the cough center and antitussive. It also has a weak antihistamine effect, and has no addiction and tolerance , Clinically used for cough caused by upper respiratory tract infection. However, levocloperastine fendecic acid has higher clinical drug activity, and its curative effect is many times that of racemic cloperastine. It basically has no side effects, and it can be used as a medicine for children, so the market demand for this product is large. , the outlook is good. [0003] At present, the known preparation methods of L-cloperastine fendizaic acid mainly include: [0004] 1) Use racemic 4-chlorobenzhydryl alcohol as the start...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/088C07C65/40C07C51/41
Inventor 颜伟伟舒坤陈晓朋林国跃
Owner CHONGQING WORLD HAORUI PHARM CHEM