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Preparation method of tetrahydrobenzyl isoquinoline compound

A compound and mixture technology, which is applied in the field of preparation of tetrahydrobenzylisoquinoline compounds, can solve the problems affecting the total yield and quality of mivacurium chloride finished products, many impurities in the product, low chemical purity and optical purity, etc.

Pending Publication Date: 2022-07-08
SICHUAN CREDIT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0009] The yield of this step hydrogenation reduction reaction reported in the prior art is low, the product has many impurities, and the chemical purity and optical purity are all low, which then affects the yield and purity of the follow-up reaction, and finally affects the total yield of mivacurium chloride finished product. rate and quality
The literature (Tetrahedron: Asymmetry, 2013, 24, 50) reports the preparation method of the compound of formula (I-1). After post-treatment and purification, a viscous target substance is obtained. The optical purity of the viscous substance is not ideal. The highest ee value is only 95%, that is to say, at least 2.5% of the S-configuration compound is contained, which cannot meet the requirements of clinical use at all; The chemical purity is very low, which not only increases the difficulty of subsequent synthesis and purification of mivacurium chloride, but also greatly affects the safety and effectiveness of clinical medication

Method used

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  • Preparation method of tetrahydrobenzyl isoquinoline compound
  • Preparation method of tetrahydrobenzyl isoquinoline compound
  • Preparation method of tetrahydrobenzyl isoquinoline compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: Weigh 2.6 g of catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-cumene) ruthenium (II) chloride, add 100 mL A mixture of dichloromethane and 400 mL of formic acid / triethylamine (5:2) was prepared as a standby solution. Weigh 150.0 g of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline, dissolve it in 200 mL of dichloromethane, and add the above-mentioned standby solution , the reaction was complete at room temperature. Aqueous sodium hydroxide solution was added to the reaction solution to quench the reaction, the layers were allowed to stand, and the organic phase was concentrated.

[0068] Add ethanol to dissolve, then add 55 g of D-tartaric acid, and reflux under stirring until the reaction is complete. Stir to cool and crystallize, and filter. The filter cake was dissolved in water, stirred with activated carbon, and filtered. The filtrate was added with aqueous sodium hydroxide solution to adjust pH to 10, extracted wi...

Embodiment 2

[0069] Example 2: Weigh 1.3 g of catalyst (S, S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-cumene) ruthenium (II) chloride, add 300 mL of N , N-dimethylformamide and 150 mL of formic acid / triethylamine (5:2) mixed solution to prepare a standby solution. Weigh 150.0g of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline and dissolve it in 300mL of N,N-dimethylformamide , add the above-mentioned stock solution, and react at room temperature until the reaction is complete. Aqueous potassium hydroxide solution was added to the reaction solution to quench the reaction, extracted with ethyl acetate, the ethyl acetate layer was washed with water and saturated brine, respectively, the layers were separated, and the organic phase was concentrated.

[0070] Add methanol to dissolve, then add 50 g of D-malic acid, and reflux with stirring until the reaction is complete. Stir to cool and crystallize, and filter. The filter cake was dissolved in water, stirred wit...

Embodiment 3

[0071] Example 3: Weigh 20g catalyst (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-cumene) ruthenium(II) chloride, add 3000mL acetonitrile and 4500mL formic acid / triethylamine (5:2) mixed solution to prepare a standby solution. Weigh 1500g of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline, dissolve it in 3000mL of acetonitrile, add the above-mentioned stock solution, and at room temperature React until the reaction is complete. The reaction solution was concentrated, an aqueous sodium hydroxide solution was added to quench the reaction, extracted with dichloromethane, the dichloromethane layer was washed with water and saturated brine respectively, the layers were separated, and the organic phase was concentrated to dryness.

[0072] Add isopropanol to dissolve, then add 600 g of D-mandelic acid, and reflux under stirring until the reaction is complete. Stir to cool and crystallize, and filter. The filter cake was dissolved in water, stirred wit...

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Abstract

The invention relates to a preparation method of a tetrahydrobenzyl isoquinoline compound, which is characterized in that the method comprises the step of adding a specific chiral organic acid into a mixture containing a compound shown as a formula (I) to form a salt, and the chemical purity and optical purity of the prepared product of the compound shown as the formula (I) are greatly improved while the high yield is ensured. The method is favorable for improving the total yield and controlling the product quality in the synthesis process of the mivacurium chloride or cisatracurium besylate finished product, provides a powerful guarantee for improving the safety and effectiveness of the finished product medicine, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of tetrahydrobenzyl isoquinoline compounds. Background technique [0002] Neuromuscular blocking agents have been widely used in clinical surgery since 1942, disrupting chemical signaling at the neuromuscular junction by inhibiting the interaction between acetylcholine released by autonomic nerve fibers and nicotinic acetylcholine receptors on skeletal muscle cell membranes Transmission, play the role of muscle relaxation. According to the different pharmacological mechanisms of action, neuromuscular blocking agents can be divided into depolarizing and non-depolarizing types. The duration of action of depolarizing muscle relaxants is shorter than that of non-depolarizing muscle relaxants, but the selectivity is poor and the side effects are more obvious; non-depolarizing muscle relaxants themselves have no biological activity, and can be rescued by neostigmine in overdose Therefore, it is easy to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20
CPCC07D217/20C07B2200/07
Inventor 秦勇傅霖宿磊陈刚李晓莉
Owner SICHUAN CREDIT PHARMA
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