A kind of preparation method of chiral α-methyl arylethylamine

A methyl arylethylamine and chirality technology, which is applied in the field of preparation of chiral α-methyl arylethylamine, can solve the problems of being unsuitable for large-scale industrial production, low atom utilization rate and high production cost, and can avoid a large number of The generation of solid waste and isomers, the effect of overcoming the problem of column chromatography separation, and reducing the hidden danger of production safety

Active Publication Date: 2022-07-01
暨明医药科技(苏州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] (1) High production cost and great potential safety hazard
Need to use palladium to catalyze the high-pressure hydrogenation reaction, which is costly and has potential safety hazards; the use of non-natural chiral raw materials is expensive, resulting in a further increase in costs
[0018] (2) Low yield and low atom utilization
The method of column chromatography separation can only obtain part of the target configuration products, and the unnecessary isomers are discarded to cause pollution and waste; the selectivity of the products obtained by the chiral induction method is poor, and multiple crystallizations are required to improve the chiral purity of the product
[0019] (3) The operation process is complex and not suitable for large-scale industrial production

Method used

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  • A kind of preparation method of chiral α-methyl arylethylamine
  • A kind of preparation method of chiral α-methyl arylethylamine
  • A kind of preparation method of chiral α-methyl arylethylamine

Examples

Experimental program
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Effect test

Embodiment 1

[0054] (1) Boc-L-tryptophan methyl ester (318.4g, 1.0mol) was added into a 5L three-necked flask, ethanol (2.5L) was added, and sodium borohydride (95.1g, 2.5mol) was added under temperature control at 0-10°C , and react at 30°C for 10h after the addition. Saturated ammonium chloride solution (1.5L) was added dropwise under temperature control at 0-5°C, and the ethanol was evaporated under reduced pressure. Extracted twice with ethyl acetate (2 L). The organic phases were combined, dried over sodium sulfate, concentrated under reduced pressure, and slurried with n-heptane to obtain 275.7 g of the product Boc-L-tryptophanol with a yield of 95% and a purity of 99.1%.

[0055] (2) Boc-L-tryptophanol (145.0g, 0.5mol) obtained in step (1) was added in a 5L there-necked flask, and dichloromethane (1.5L), triethylamine (111.0g, 1.1mol), Imidazole (102.0 g, 1.5 mol) was added dropwise to thionyl chloride (65.5 g, 0.55 mol) under temperature control at 0-5 °C, and the reaction was in...

Embodiment 2

[0060] The difference from Example 1 is that in step (3), anhydrous lithium chloride is replaced with anhydrous zinc chloride, and the rest are the same.

[0061] The reaction finally obtained 27.1 g of the product with a yield of 78% and a purity of 99.2%.

Embodiment 3

[0063] Different from Example 1, step (3) was changed to add the sulfonamide compound (70.5g, 0.2mol) obtained in step (2) in a 2L there-neck flask, and diethylene glycol dimethyl ether (1L) was added. , sodium borohydride (15.2g, 0.4mol), anhydrous lithium chloride (54.4g, 0.4mol), react at 80°C for 24h. The reaction solution was added to a 4M hydrogen chloride-ethyl acetate solution (150 mL) at a temperature of 5-10 °C, and the reaction was carried out at 30 °C for 12 h. After precipitation under reduced pressure, saturated sodium bicarbonate solution was added, extracted twice with ethyl acetate (400 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was recrystallized from ethyl acetate and n-heptane. The rest are the same.

[0064] The reaction finally obtained 23.8 g of product with a yield of 68% and a purity of 98.9%.

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Abstract

The invention provides a preparation method of chiral α-methylarylethylamine, and relates to the technical field of organic synthetic medicines. In the present invention, Boc-amino acid methyl ester is used as a starting material, and Boc-amino alcohol is obtained by reduction, reacted with thionyl chloride, oxidized by sodium periodate to obtain a sulfonamide compound, and then reduced by sodium borohydride promoted by Lewis acid , acid conditions to remove the protective group to obtain the target compound. The method has cheap and easy-to-obtain raw materials, uses chiral raw materials to obtain a single optical isomer product, overcomes the problem of column chromatography separation, avoids the generation of a large amount of solid waste and isomers, improves atom economy, and has high product purity and yield. High rate, effectively reducing production costs. Moreover, the present invention uses a mild reduction system to replace the original high-pressure hydrogenation reaction, the process operation is relatively simple, and is more suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthetic medicines, and relates to a preparation method of chiral α-methylarylethylamine. Background technique [0002] Chiral α-methylarylethylamine is an important fragment of many drugs. For example, (R)-α-methyl-4-methoxyphenethylamine is an important intermediate of asthma treatment drugs Formoterol and Carmoterol. Another example is (R)-3-(2-aminopropyl)-1H-indole is a key fragment of AZD9496 for the treatment of breast cancer (De Savi, C. et al. reported, "Optimization of a Novel Binding Motif to ( E)-3-(3,5Difluoro-4-((1R,3R)2-(2-fluoro-2-methylpropy 1)-3-meth yl-2,3,4,9-tetrahydro-1H-pyrido[ 3,4b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable SelectiveEstrogen Receptor Downregulator and Antagonist", J. Med. Chem., 58, 8128-8140 (2015); and HUANG PETER Its analogs reported by QINHUA et al., "Estrogen receptormodulators", WO2017172957). [0003] [0004] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C209/00C07C211/27
CPCC07C209/00C07C269/06C07D291/04C07C211/27C07C271/12Y02P20/55
Inventor 陈剑戈苑可
Owner 暨明医药科技(苏州)有限公司
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