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Preparation method for unnatural amino acids

A technology of unnatural amino acid and adamantyl glycine, which is applied in the chemical pharmaceutical field of pharmaceutical intermediates, can solve problems such as unfavorable safety and environmental protection, complicated reagent application, and increased production costs, achieving excellent quality, short routes, and reduced production costs Effect

Inactive Publication Date: 2015-08-05
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many reaction steps in this route, and the application of reagents is complicated. The highly toxic substance sodium cyanide is used in the process, which is not conducive to safety and environmental protection. The yield of hydroxyl groups in the last step is only 40%, which wastes a lot of intermediates and increases production costs.

Method used

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  • Preparation method for unnatural amino acids
  • Preparation method for unnatural amino acids
  • Preparation method for unnatural amino acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Preparation of 3-hydroxy-1-adamantanecarboxylic acid (B)

[0058] Add 10g (0.056mol) adamantanecarboxylic acid (A), 2.5gKOH (0.045mol), 126ml water, 2ml tert-butanol into a 250ml three-necked flask, heat to 45°C, add 10.6g (0.067mol) in batches within half an hour mol) potassium permanganate, after the addition, the temperature was raised to 60° C. and kept at this temperature for eight hours, and 20 ml of 10% sodium sulfite solution was added to quench unreacted potassium permanganate. Filtrate while hot to obtain a white clear liquid, cool the filtrate to room temperature, adjust to pH = 1 with concentrated hydrochloric acid, obtain a white turbid liquid, stir overnight, filter to obtain a white powdery solid 3-hydroxy-1-adamantanecarboxylic acid (B) 9.36 g, yield 86%.

Embodiment 2

[0060] Preparation of 3-Hydroxy-1-adamantanylmethylketone (C)

[0061] Add 15g (0.076mol) compound (B) and 30ml thionyl chloride to a 100ml round bottom flask, heat and reflux for 6 hours, remove excess thionyl chloride by distillation under reduced pressure, cool to obtain a white solid, add 50ml petroleum ether Dissolve and set aside.

[0062] Add 3.0g (0.130mol) sodium metal and 100mL petroleum ether into a 500mL three-necked flask, and slowly add a mixed solution of 30ml (0.192mol) diethyl malonate and 50mL petroleum ether dropwise at room temperature until the sodium metal reacts completely Afterwards, the above-mentioned 50 ml petroleum ether solution in which adamantanecarbonyl chloride was dissolved was added dropwise, and stirred overnight at room temperature. Add 200ml of distilled water, separate the organic layer, concentrate the solvent to obtain a light yellow oil, add 6mL of concentrated sulfuric acid, 18mL of distilled water, 60mL of glacial acetic acid, stir ...

Embodiment 3

[0064] Preparation of 2-(3-hydroxy-1-adamantyl)glyoxylic acid (D)

[0065] Add 3.0g (0.015mol) compound C, 100ml 2% KOH solution, 12ml tert-butanol in a 250ml three-necked flask, heat to 40°C, add 4.3g (0.027mol) potassium permanganate in batches within 1 hour, keep After reacting at 40°C for 4 hours, 20 mL of 10% sodium sulfite solution was added to quench unreacted potassium permanganate. Suction filtration while hot, and the filter cake was washed with 10ml hot water. The filtrate was cooled to room temperature, adjusted to pH = 1 with concentrated hydrochloric acid, extracted three times with ethyl acetate, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to an oil, and washed with ethyl acetate:petroleum ether ( 1:1) to obtain 3.12 g of white solid, yield 90%. mp 162-163°C; 1 H-NMR (400 MHz, DMSO-d6) 6: 3.32 (br s, 1H), 2.16 (s, 2H), 1.74-1.42 (m, 12H).

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Abstract

The invention relates to a preparation and chiral resolution method for unnatural amino acids. The method comprises the following steps: with adamantanecarboxylic acid as a raw material, preparing 3-hydroxy-adamantanecarboxylic acid; carrying out chlorination, oxidation and the like so as to obtain 2-(3-hydroxy-1-adamantyl)glyoxalic acid; reacting 2-(3-hydroxy-1-adamantyl)glyoxalic acid with hydroxylamine hydrochloride so as to obtain 3-hydroxyadamantyl-glyoxalic acid oxime; carrying out reduction with a reducing agent and protection with Boc acid anhydride so as to obtain N-tertbutyloxycarbonyl-3-hydroxyadamantylglycine; and carrying out resolution with organic base so as to obtain two unnatural amino acids, i.e., (S)-N-tertbutyloxycarbonyl-3-hydroxyadamantylglycine and (R)-N-tertbutyloxycarbonyl-3-hydroxyadamantylglycine. Compared with the prior art, the method provided by the invention has the following advantages: improved synthesis technology; mild reaction conditions; small environmental pollution; and applicability to industrial production.

Description

technical field [0001] A method for preparing unnatural amino acid N-tert-butoxycarbonyl-3-hydroxyl-1-adamantylglycine and its chiral resolution. The invention belongs to the chemical pharmaceutical field of pharmaceutical intermediates. Background technique [0002] The unnatural amino acid N-tert-butoxycarbonyl-3-hydroxy-1-adamantylglycine is an important pharmaceutical intermediate, such as used in the preparation of dipeptidyl peptidase IV (DPP-IV) inhibitor antidiabetic drug Saxaglidex Ting et al. [0003] Saxagliptin is a new type of dipeptidyl peptidase IV (DPP-IV) inhibitor antidiabetic drug jointly developed by Bristol-Myers Squibb and AstraZeneca. The second anti-type II diabetes DPP-IV inhibitor drug approved by the U.S. FDA after Tingting was launched in Europe in the same year and entered the Chinese market in May 2011 under the trade name "Angliza". Saxagliptin is a highly selective and reversible competitive dipeptidyl peptidase IV (DPP-IV) inhibitor, which...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/08C07C269/00C07B57/00
Inventor 胡湘南潘辛梅李杰甘润朱兴欣袁月谢江龙曹艳芳
Owner CHONGQING MEDICAL UNIVERSITY
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