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Synthesis method of (R)-5'-methoxyl laudanosine

A technology of methoxylabadenin and synthesis method, applied in the directions of organic chemistry, organic chemistry, etc., can solve the problems of genotoxic impurity residue, low catalyst selectivity, etc., and achieves easy large-scale production, and the technological operation process is not harsh. , the effect of high optical purity

Pending Publication Date: 2021-10-08
GUANGDONG JIABO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Although the method mentioned in this patent has a high yield and the optical purity of the obtained product is also high, the catalyst used contains p-toluenesulfonyl, which is prone to genotoxic impurity residues. In this method, various D- In order to obtain the required high optical purity product, the selectivity of the catalyst used is still not very high. In addition, the obtained high optical purity compound must be subjected to N-methylation reaction in order to obtain the required high optical purity product. Obtain the target product (R)-5'-methoxylaudansu

Method used

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  • Synthesis method of (R)-5'-methoxyl laudanosine
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  • Synthesis method of (R)-5'-methoxyl laudanosine

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Embodiment 1

[0050] A kind of synthetic method of (R)-5'-methoxylaudansu in the embodiment of the present invention: the reagents of N-formylation reaction are formic acid and zinc powder, and the product purification solvent of N-formylation reaction is ethanol ; The asymmetric hydrogenation reduction reaction adopted methanol-dichloromethane mixed solvent; the formyl reduction adopted lithium aluminum hydride as a reducing agent; the total yield of the reaction route was 45.86%, and the obtained (R)-5'-methoxy The optical purity of baudansu is 99.79%; the specific synthesis method is as follows:

[0051] (1) Synthesis of (Z)-N-formyl-6,7-dimethoxy-1-(3,4,5-trimethoxybenzylidene)-3,4-dihydroisoquinoline :

[0052] Weigh 37.2g (0.1mol) of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline into a three-necked flask, add 151g of formic acid (3.28mol), after stirring and dissolving, add 0.66g (0.01mol) of zinc powder, use a 500W tungsten lamp to irradiate and heat, stir and re...

Embodiment 2

[0059]A kind of synthetic method of (R)-5'-methoxylaudansu in the embodiment of the present invention: the reagent of N-formylation reaction is formic acetic anhydride, the product purification solvent of N-formylation reaction is methanol; Symmetric hydrogenation reduction reaction adopted methanol-dichloromethane mixed solvent; formyl reduction adopted rhodium chloride trihydrate-diphenylsilane as reducing agent; reaction route total yield was 59.78%, obtained (R)- The optical purity of 5'-methoxylaudansin is 99.80%; the specific synthesis method is as follows:

[0060] (1) Synthesis of (Z)-N-formyl-6,7-dimethoxy-1-(3,4,5-trimethoxybenzylidene)-3,4-dihydroisoquinoline :

[0061] Weigh 37.2g (0.1mol) of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline into a three-necked flask, add formic acetic anhydride 22g (0.25mol), tetrahydrofuran 100mL, triethylamine 50.1g (0.5mol), use 500W tungsten lamp to irradiate and heat, stir and react at 70-75°C for 2.0-2.5 hou...

Embodiment 3

[0067] A kind of synthetic method of (R)-5'-methoxylaudansu in the embodiment of the present invention: the reagent of N-formylation reaction is 2,2-dimethylpropionic formic anhydride, N-formylation The product purification solvent of reaction is ethanol; What asymmetric hydrogenation reduction reaction adopts is ethanol-dichloromethane mixed solvent; What formyl reduction adopts is rhodium chloride trihydrate-diphenylsilane as reducing agent; Reaction route total yield is 81.9%, the optical purity of (R)-5'-methoxylaudansin obtained is 99.82%; the specific synthesis method is as follows:

[0068] (1) Synthesis of (Z)-N-formyl-6,7-dimethoxy-1-(3,4,5-trimethoxybenzylidene)-3,4-dihydroisoquinoline :

[0069] Weigh 37.2 g (0.1 mol) of 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline into a three-necked flask, add 2, 27.5g (0.21mol) of 2-dimethylpropionic formic anhydride, 150mL of dichloromethane, and 34.6mLg (0.43mol) of pyridine were stirred and reacted at 23-...

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Abstract

The invention discloses a synthesis method of (R)-5'-methoxyl laudanosine, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: by taking 6,7-dimethoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinoline as a raw material, sequentially carrying out N-formylation, asymmetric hydrogenation reduction and formyl reduction to obtain (R)-5'-methoxy laudanosine. According to the technical scheme, the yield of (R)-5'-methoxyl laudanosine directly prepared is high, the total yield of the three-step reaction can reach up to 81.9%, the optical purity is 99.79% or above, and after refining, the optical purity is larger than 99.98%, and the chemical purity is larger than 99.93%. Besides, according to the technical scheme, the chiral selective catalyst Ru(CH3COO)2(R)-BINAP without genotoxicity is adopted, the defect that genotoxic impurities containing p-toluenesulfonyl and the like are prone to remaining is overcome, the Ru(CH3COO)2(R)-BINAP is an industrial mature catalyst, the technological operation process is not harsh, and large-scale production is easy to achieve.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a synthetic method of (R)-5'-methoxylaudansin. Background technique [0002] Mivacurium chloride was approved by the U.S. FDA in January 1992. It is currently the non-depolarizing muscle relaxant with the shortest action time and fastest recovery. It has no effect on the cardiovascular system, intracranial pressure and intraocular pressure when used routinely. It is used for endotracheal intubation and maintenance of muscle relaxation. Because of its short action time and no accumulation, flexible intravenous administration can be used to flexibly block and relax neuromuscular muscles during surgery. It is very suitable for children to use in anesthesia operations, so it has received more and more applications and attention in clinical anesthesia operations. Mivacurium chloride belongs to benzyl isoquinoline compounds, and its chemical structure is shown in the followin...

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 袁民政周林波徐礼锋
Owner GUANGDONG JIABO PHARM CO LTD
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