Method for preparing chiral tert-butyl sulfinamide

A technology of tert-butylsulfinamide and chirality, which is applied in the field of preparation of tert-butylsulfinamide, can solve the problems of high cost, long overall steps, unfavorable industrial production, etc., and achieve the effect of cheap price

Inactive Publication Date: 2021-01-29
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In this process, although tert-butyl mercaptan with foul smell is not used, the cost of other materials used in this process is relatively high, and the overall steps are long, which is not conducive to industrial production

Method used

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  • Method for preparing chiral tert-butyl sulfinamide
  • Method for preparing chiral tert-butyl sulfinamide
  • Method for preparing chiral tert-butyl sulfinamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Preparation of Compound 2

[0039]

[0040] In a dry glass reaction kettle under nitrogen protection, magnesium chips (24g, 1.0eq) were added and heated to 45-55°C. Take another preparation bottle, add tert-butyl bromide (177g, 1.3eq) and 2-methyltetrahydrofuran MeTHF (500g), mix well, add part of the mixture dropwise into the reaction bottle to form a Grignard reaction system, and cool down to 40 -50°C, drop the mixed solution of tert-butyl bromide, after the dropwise addition, stir the reaction for more than 5 hours, cool down the Grignard reaction solution to -5 to 5°C, feed sulfur dioxide into the reaction kettle, the sulfur dioxide The weight is (171g, 2.5eq). After insulated reaction at around 0°C for 1 hour, add concentrated sulfuric acid dropwise to the reaction kettle to quench the reaction, distill under reduced pressure, control the temperature at 30-45°C, distill under reduced pressure to dry to viscous liquid (remove excess sulfur dioxide), then add Te...

Embodiment 2

[0054] Preparation of Compound 2

[0055]

[0056] In a dry glass reaction kettle under nitrogen protection, add magnesium chips (10g, 1.0eq), heat to 45-55°C, take another preparation bottle, add tert-butyl iodide (98g, 1.3eq), methyl tert-butyl Ether (300g), mix well, drop the mixed solution into the reaction flask to form a Grignard reaction system, cool down to 40-50°C, continue to drop the mixed solution of tert-butyl bromide, after the dropwise addition, stir and react for more than 5h , the temperature of the Grignard reaction solution was lowered to -5 to 5°C, and sulfur dioxide was introduced into the reaction kettle, and the weight of the sulfur dioxide introduced was (60g, 2.3eq). After insulated reaction at around 0°C for 1 hour, add concentrated sulfuric acid dropwise to the reaction kettle to quench the reaction, distill under reduced pressure, control the temperature at 30-45°C, distill under reduced pressure to dry to viscous liquid (remove excess sulfur dio...

Embodiment 3

[0070] In this example, other steps are the same as in Example 1, the difference is that compound 4-3 is prepared by the following method.

[0071] Preparation of compound 4-3 (isobutyl ester)

[0072]

[0073] Dissolve 2g (14.2 mmol, 1.0eq) of compound 3 in 6ml of methyl tert-butyl ether for use; in a 200mL three-necked flask, add 3.2g of isobutanol (42.6 mmol, 3.0eq), 5.07g of quinidine g (15.6 mmol, 1.1 eq) and 60ml methyl tert-butyl ether, under nitrogen protection, lower the temperature to -50°C±5°C, add the methyl tert-butyl ether solution of compound 3 dropwise, and control the temperature at - Below 30°C (±5°C); after dripping, keep the reaction at -35°C for 2 hours. It is found that the reaction system becomes viscous and cannot continue to stir. The temperature of the reaction system was raised to -25°C, and the reaction was continued for two hours, and the reaction of the raw materials was detected to be complete.

[0074] Post-treatment: add ice water, add 10%...

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Abstract

The invention belongs to the technical field of chemical synthesis, and provides a method for preparing (R)-tert-butyl sulfinamide. The method comprises the following steps: (1) preparing a Grignard compound by using halogenated tert-butane as an initial raw material through a Grignard reaction, introducing sulfur dioxide gas into the Grignard reaction solution, and reacting to obtain tert-butyl sulfinic acid; (2) converting tert-butyl sulfinic acid into tert-butyl sulfinyl chloride by adopting thionyl chloride; (3) converting tert-butyl sulfinyl chloride into tert-butyl sulfinate through an alcohol reagent and an alkaloid compound; and (4) converting tert-butyl sulfinate into chiral (R)-tert-butyl sulfinate amine in the presence of ferric nitrate, lithium metal or sodium metal. Accordingto the method, the defects of an existing process are overcome, foul tert-butyl mercaptan is not used, used halogenated tert-butane and the like are common and cheap materials, alkaloid compounds canbe recycled, and the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, in particular to a preparation ( R )-tert-butylsulfinamide method. Background technique [0002] Chiral amine compounds have important application value in the synthesis of drugs and natural products. More than 75% of drugs and candidate drugs have amine functional groups, so compounds containing amine groups have attracted the attention of many pharmacologists and synthetic chemists in recent years. Tert-butylsulfinamide is a new type of chiral compound designed and synthesized by Ellman in 1997. It is used as a class of chiral auxiliary reagents in many asymmetric synthesis reactions and shows good induction (references: Ellman, J.A. ; owens, T.D.: Tang, T .P . Acc. Chem. Res., 2002, 35, 984.), better achieved the synthesis of highly active chiral amine compounds. [0003] Chiral tert-butylsulfinamides include R Type and S-type two chiral configurations, the synthetic route is ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C313/06C07C313/04C07B53/00
CPCC07B53/00C07B2200/07C07C313/02C07C313/04C07C313/06
Inventor 李文森张文琦田雷
Owner HEADING NANJING PHARMTECH CO LTD
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