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A Synthetic Method of Highly Optically Active Chiral Marine Natural Products

A technology of optical activity and synthetic method, which is applied in the field of synthesis of chiral marine natural products, can solve the problems of complex process, cumbersome route steps, difficult mass production, etc., and achieve wide application prospects, simple synthetic steps, and mild reaction conditions Effect

Active Publication Date: 2017-03-22
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The structure of this compound is relatively novel and unique, and it has a chiral center. However, the chemical extraction and separation of natural products involves complex processes, low yield and large waste, resulting in high cost of the extract and difficult to produce in large quantities. Since then, people have continued to try And successfully carried out its total synthesis research
The synthetic method of this compound that has been reported is as follows: Thomas Lindel and his colleague first reported the total synthesis of natural product midpacamide (Lindel, T.and H.Hoffmann, Liebigs Annalen, 1997,1997 (7), 1525-1528.) , however, the reagents used in these processes are rare, expensive, and cannot solve the problem of racemization
In 2001, Pilar M etc. used a new method to re-synthesize midpacamide (Fresneda, P.M., P.Molina, and M.A.Sanz, Tetrahedron letters, 2001, 42(5), 851-854.), this method is easy to get raw materials , but did not solve the problem of racemization
In 2004, Pilar M et al. tried a new method for the total synthesis of midpacamide (Fresneda, P.M., Tetrahedron letters, 2004, 45(8), 1655-1657.). This method is difficult to synthesize some reagents, and racemization has not yet been resolved. question
The steps of the above synthetic schemes are relatively cumbersome, and the most important thing is that the problem of racemization is not solved. All the routes available in the prior art have not realized that the obtained product is a single configuration product

Method used

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  • A Synthetic Method of Highly Optically Active Chiral Marine Natural Products
  • A Synthetic Method of Highly Optically Active Chiral Marine Natural Products
  • A Synthetic Method of Highly Optically Active Chiral Marine Natural Products

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of 2-amino-5-(((benzyloxy)carbonyl)amino)pentanoic acid

[0056] Dissolve 7.5g of L-ornithine hydrochloride in 89ml of 0.5mol / L sodium hydroxide solution, add 5.55g of anhydrous copper sulfate, react for 15min, then add 6.15g of anhydrous potassium carbonate and 8.2ml of benzyl chloroformate in turn , reacted overnight, filtered and washed to obtain a blue solid, then added saturated EDTA disodium solution, heated to reflux for 2 h, then at room temperature overnight, filtered, washed and dried to obtain a white solid with a yield of 83%.

Embodiment 2

[0057] Example 2: Preparation of methyl 2-amino-5-(((benzyloxy)carbonyl)amino)valerate

[0058] 8.5 ml of acetyl chloride was added dropwise to methanol under ice bath conditions, and the reaction was carried out at room temperature for 10 min. 10.6 g of compound 1 was added to the reaction solution, refluxed for 5 hours, and then the solvent was evaporated, ethyl acetate was added, and after washing and drying, the solvent was evaporated to obtain a light yellow solid with a yield of 85%. 1 H-NMR (300MHz, CDCl 3 ):δ1.36-1.61(m,2H),1.74-1.82(m,2H),2.97-3.03(q,2H),3.74(s,3H),4.05(s,1H),δ5.01(s ,2H),δ7.28-7.40(m,6H),δ8.51(s,3H); 13 C-NMR (100MHz, CDCl 3 ):δ25.3,27.4,40.1,52.9,53.3,66.5,128.0,128.5,128.6,136.7,156.8,170.2.

Embodiment 3

[0059] Example 3: Preparation of methyl 5-(((benzyloxy)carbonyl)amino)-2-(3-methylureido)pentanoate

[0060] Under ice bath conditions, 11.2 g of compound 2 was dissolved in a mixed solution of dichloromethane and saturated sodium bicarbonate, and 5.29 g of triphosgene was added, reacted for 15 min, and then rapidly extracted. The organic phase was dried to obtain a dichloromethane solution of isocyanate. In an ice bath, the dichloromethane solution of isocyanate was dropped into the dichloromethane solution containing methylamine and triethylamine, and the reaction was carried out at room temperature for 1 hour after the drop was completed. After the solvent was evaporated, ethyl acetate was added, the organic phase was washed and dried, and then the solvent was evaporated. Recrystallization gave a white solid with a yield of 78% and a melting point of 114-117°C. 1 H-NMR (300MHz, DMSO-d 6 ):δ1.38-1.49(m,2H),δ1.52-1.69(m,2H),δ2.51-2.54(d,3H),2.95-3.01(q,2H),δ3.60(s, 3H),δ4....

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Abstract

The invention discloses a synthetic method for a chiral marine natural product with high optical activity. According to the method, a marine natural product with the high optical activity is prepared by adopting chiral amino acid. The method specifically comprises the following steps: first, using L-ornithine monohydrochloride and D-ornithine monohydrochloride as starting raw materials, and performing copper ion complexing, amino protecting, esterifying, urea forming and cyclizing to obtain an intermediate 5; then, using N-methylpyrrole as a raw material, and performing electrophilic reaction, hydrolyzing, acidizing and acylating in sequence to obtain an intermediate 9; finally, enabling the intermediate 5 and the intermediate 9 to react to prepare corresponding chiral natural products, namely (S)-midpacamide or (R)-midpacamide. According to the synthetic method, synthetic steps are simple; the operation is simple and convenient; reaction conditions are mild; the original structure of the product prepared by the provided synthetic route is kept; the optical purity of the obtained marine natural product is greater than 99 percent; the marine natural product has a wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a method for synthesizing a chiral marine natural product with high optical activity. Background technique [0002] In recent years, marine natural products have become the research focus of scientists, midpacamide is a marine natural product with antibacterial activity (Triana Hertiani, RuAngelie Edrada-Ebel, Sofia Ortlepp, Rob W.M. Van Soest, Nicole J. de Voogd Bioorganic & Medicinal Chemistry 2010, 18, 1297–1311) in 1977 Lionel Chevolot first reported the marine natural product midpacamide, which was isolated and extracted from an unnamed sponge in the waters near the Marshall Islands in the western Pacific Ocean. ,5-disubstituted imidazoline-2,4-dione marine alkaloids. The compound has a relatively novel and unique structure and has a chiral center. However, the chemical extraction and separation of natural products involves complex processes, low yield and large ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12
CPCY02P20/55
Inventor 方浩肖云丁胜勇宿莉杨新颖陈禹
Owner SHANDONG UNIV
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