Preparation method of (S)-5-bromo-1, 2, 3, 4-tetrahydro-N-Boc-isoquinoline-1-carboxylic acid

A technology of tetrahydroisoquinoline and isoquinoline, which is applied in the fields of organic chemistry, organic chemistry, etc., can solve the problems of no synthetic method, etc., and achieve the effects of easy-to-obtain raw materials, mild reaction conditions, and reasonable and effective synthetic routes

Active Publication Date: 2021-04-30
CHEMVON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no effective synthetic method in the current literature, so it is necessary to s

Method used

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  • Preparation method of (S)-5-bromo-1, 2, 3, 4-tetrahydro-N-Boc-isoquinoline-1-carboxylic acid
  • Preparation method of (S)-5-bromo-1, 2, 3, 4-tetrahydro-N-Boc-isoquinoline-1-carboxylic acid
  • Preparation method of (S)-5-bromo-1, 2, 3, 4-tetrahydro-N-Boc-isoquinoline-1-carboxylic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0026] The first step: the synthesis of benzyl o-bromophenethylamine formate.

[0027]

[0028] Add o-bromophenethylamine (360g, 1.8mol), diisopropylethylamine (581.6g, 4.5mol) and 1800g of dichloromethane into a 3L jacketed reaction flask, lower the temperature and control it at -2-2°C, add dropwise Benzyl chloroformate (307g, 1.8mol), after dropping, slowly raise the temperature to 20°C, react for 2 hours, GC detects 0.5% of the raw material, add 0.2M hydrochloric acid to adjust pH=4, separate layers, wash the organic phase with water, and wash with saturated saline Once, the organic phase was concentrated until it was stagnant, and n-heptane was added to make a slurry to obtain 547.2 g of benzyl o-bromophenethylamine formate, with a yield of 91%, and GC: 97.3%. 1 HNMR (400MHz, CDCl 3 )δ:7.55-7.01(m,9H),4.75(s,1H),4.11(m,2H),3.48-3.40(m,2H),2.96(m,2H),1.23(m,3H).

[0029]

[0030] Add o-bromophenethylamine (360g, 1.8mol), triethylamine (400.7g, 3.96mol) and 1800g dic...

Embodiment 2

[0032] The second step: the synthesis of 5-bromo-2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid.

[0033]

[0034] Add concentrated sulfuric acid / acetic acid = 1:3 (700mL), 50% glyoxylic acid (666.4g, 4.5mol) and 2.5L toluene into a 5L jacketed reaction flask, raise the temperature to 30-35°C, and slowly add o-bromophenethylamine Benzyl formate (501.3g, 1.5mol), dropwise, react at 30-35°C for 8 hours, HPLC detects 0.5% of the raw material, separate layers, extract the acidic aqueous layer with toluene once, combine the organic phases, adjust with sodium bicarbonate aqueous solution pH=2-3, separate layers, and concentrate the organic phase until stagnant to obtain 541.4g of 5-bromo-2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid , yield 92.5%, GC: 94.9%. 1 HNMR (400MHz, CDCl 3 )δ:10.4(s,1H),7.55-7.01(m,8H),5.61(d,1H),4.26-3.86(m,3H),3.68-3.61(m,1H),2.95(m,2H) ,1.33-1.20(m,3H).

[0035]

[0036] Add glyoxylic acid (144.4g...

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Abstract

The invention discloses a preparation method for synthesizing (S)-5-bromo-1, 2, 3, 4-tetrahydro-N-Boc-isoquinoline-1-carboxylic acid, and belongs to the technical field of medical intermediates. The method comprises the following steps: reacting o-bromophenylethylamine serving as a raw material with benzyl chloroformate in an alkaline environment to obtain benzyl o-bromophenylethylamine formate; then carrying out cyclization reaction with glyoxylic acid under the catalysis of acid; then carrying out palladium-carbon catalytic hydrogenation to remove protection, so as to obtain 5-bromo-1, 2, 3, 4-tetrahydroisoquinoline-1-carboxylic acid; finally, obtaining the (S)-5-bromo-1, 2, 3, 4-tetrahydro-N-Boc-isoquinoline-1-carboxylic acid through induced resolution and Boc protection. The method is simple, convenient and stable in process operation, high in yield, environmentally friendly, cheap and easily available in raw materials and beneficial to industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a preparation method of (S)-5-bromo-1,2,3,4-tetrahydro-N-Boc-isoquinoline-1-carboxylic acid. Background technique [0002] Organic compounds of tetrahydroisoquinoline derivatives have attracted extensive attention in chemical and medical research in recent years, which may be due to the diversity of their pharmacological effects. Its alkaloids are an important class of biologically active ingredients in biological medicines. The artificially synthesized Yijing, a natural product with biological activity, has become the focus of attention. Tetrahydroisoquinoline derivatives alkaloids are the most important components in the genus Xiaoju. The main alkaloid has a similar mother nucleus structure and has various activities, such as antibacterial, antitumor, analgesic, antiplatelet aggregation, antiarrhythmia, etc. Tetrahydroisoquinoline derivatives al...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26C07B2200/07
Inventor 薛峰刘洪强高峰
Owner CHEMVON BIOTECH CO LTD
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