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Synthesis of optically-pure sulfur-containing quaternary heterocyclic drug intermediate

A compound, a sulfolane-based technology, is applied in the synthesis of sulfur-containing four-membered heterocyclic drug intermediates, which can solve the problems of danger, difficulty in operability, low overall synthesis yield, harsh reaction conditions, etc., and achieve optical purity of the product Good, simple equipment and process, high overall yield

Active Publication Date: 2018-08-03
富乐马鸿凯(大连)医药有限公司
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AI Technical Summary

Problems solved by technology

Obviously, in these known methods, the synthesis route is long, resulting in low overall synthesis yield, and the use of azide compounds leads to harsh reaction conditions, which is dangerous and difficult to operate
Therefore, the known method is difficult to carry out on a kilogram scale, and then it is difficult to apply industrially

Method used

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  • Synthesis of optically-pure sulfur-containing quaternary heterocyclic drug intermediate
  • Synthesis of optically-pure sulfur-containing quaternary heterocyclic drug intermediate
  • Synthesis of optically-pure sulfur-containing quaternary heterocyclic drug intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0054] Synthesis of Embodiment 1 Compound II

Embodiment 1

[0056] Under stirring, 152 g of DBU was completely dissolved in 400 mL of dichloromethane to prepare an alkaline solution. And the alkali solution was cooled to 0°C in an ice-water bath for use.

[0057] 23.4 g of (±)-BOC-A-phosphonoglycine trimethyl ester was dissolved in 100 mL of dichloromethane, and then the above alkali solution was added dropwise at 0° C. to form a phosphorus ylide solution.

[0058] Next, 5.4 g of thietanone was dissolved in 100 mL of dichloromethane, and then, this solution was added dropwise to the above-mentioned phosphorus ylide solution. At this time, the reaction solution changed from yellow to brown, and then the reaction mixture was warmed to room temperature and reacted overnight. The progress of the reaction was monitored by TLC. After the reaction was completed, dilute hydrochloric acid was added to quench the reaction. The organic phase was obtained after standing for separation. Subsequently, the organic phase was successively washed wi...

Embodiment 2

[0060] Example 2 was carried out in the same manner as in Example 1 above, except that the base used was triethylamine. The product was confirmed by nuclear magnetic resonance spectrum, and the yield was 23%.

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Abstract

The invention provides a novel method for synthesizing an optically-pure sulfur-containing quaternary heterocyclic drug intermediate which is (S)-2-[(tert-butyloxycarboryl)-amino]-2-[3-(3-methoxy)-1-cyclopropylsulfonyl]-acetic acid. The method comprises the following steps: taking thietanone as a starting raw material, carrying out Wittig-horner reaction, methoxylation, oxidization and enzymatic catalysis hydrolytic resolution to prepare an optically-pure target compound. The method is easily available in raw materials, simple in requirements on equipment and efficient in synthesis of chiral compounds; the steps can be enlarged to kilogram scale for production; the method is a novel method suitable for industrial application.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a synthesis method of a sulfur-containing four-membered heterocyclic drug intermediate of a deacetylase inhibitor. Background technique [0002] In recent years, enzyme-inhibitor antimicrobials have attracted extensive attention due to their broad-spectrum and high-efficiency. Among them, the deacetylase (LpxC) enzyme inhibitor (as shown in the following formula) has been confirmed as a broad-spectrum antibacterial agent (Curr.Med.Chem.2012,19,2038-2050; mBio.2014,5, 01551-14; Bioorg. Med. Chem. 201119, 852-860). Through in-depth research on such inhibitors, it is expected to design an ideal drug against endotoxin infection with obvious curative effect, low side effects and low price. [0003] [0004] LpxC enzyme inhibitor [0005] In the study on the synthesis of LpxC enzyme inhibitors, it was found that one of the potentially important synthetic units is a chiral drug in...

Claims

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Application Information

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IPC IPC(8): C07D331/04C12P17/00
CPCC07B2200/07C07D331/04C12P17/00
Inventor 于洋赫巍赵新俊高汉荣冯言枢
Owner 富乐马鸿凯(大连)医药有限公司
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