Preparation method of chiral alpha-methyl arylethylamine

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

Active Publication Date: 2021-06-08
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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  • Preparation method of chiral alpha-methyl arylethylamine
  • Preparation method of chiral alpha-methyl arylethylamine
  • Preparation method of chiral alpha-methyl arylethylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] (1) Add Boc-L-tryptophan methyl ester (318.4g, 1.0mol) into a 5L three-necked flask, add ethanol (2.5L), and add sodium borohydride (95.1g, 2.5mol) at a temperature of 0-10°C , Reaction at 30°C for 10h after addition. Saturated ammonium chloride solution (1.5 L) was added dropwise at 0-5°C under temperature control, and ethanol was distilled off under reduced pressure. Ethyl acetate (2 L) extracted 2 times. The combined organic phases were dried with 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 into a 5L three-necked flask, and dichloromethane (1.5L), triethylamine (111.0g, 1.1mol), Imidazole (102.0 g, 1.5 mol) was added dropwise with thionyl chloride (65.5 g, 0.55 mol) under temperature control at 0-5°C, and the reaction was kept for 4 hours after the addition...

Embodiment 2

[0060] Different from Example 1, in step (3), Lithium Chloride Anhydrous is changed into Zinc Chloride Anhydrous, and all the other are the same.

[0061] The reaction finally yielded 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-necked 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 4M hydrogen chloride-ethyl acetate solution (150 mL) under temperature control at 5-10°C, and reacted at 30°C for 12h. 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 a crude product, which was recrystallized from ethyl acetate and n-heptane. Everything else is the same.

[0064] The reaction finally yielded 23.8 g of the 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 alpha-methyl arylethylamine, and relates to the technical field of organic synthesis medicines. Boc-amino acid methyl ester is used as an initial raw material, Boc-amino alcohol is obtained through reduction, Boc-amino alcohol reacts with thionyl chloride and is oxidized through sodium periodate to obtain a sulfonamide compound, and then the sulfonamide compound is reduced through sodium borohydride promoted by lewis acid and a protecting group is removed under the acidic condition to obtain a target compound. According to the method, raw materials are cheap and easy to obtain, a single optical isomer product is obtained by using chiral raw materials, the problem of column chromatography resolution is solved, generation of a large amount of solid wastes and isomers is avoided, atom economy is improved, the product purity is high, the yield is high, and the production cost is effectively reduced. In addition, the mild reduction system is used for replacing the original high-pressure hydrogenation reaction, the process operation is relatively simple, and the method 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 medicines Formoterol and Carmoterol. Another example is that (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-methyl-2,3,4,9-tetrahydro-1H-pyrido[ 3,4b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Or ally Bioavailable SelectiveEstrogen Receptor Downregulator and Antagonist”, J.Med.Chem., 58, 8128-8140 (2015); and HUANG PETER Its analog reported by QINHUA et al., "Estrogen receptor modulators", WO2017172957). [0003] [0004] For...

Claims

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Application Information

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Patent Type & Authority Applications(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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