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Purification method of cis-2,6-dimethylmorpholine

A technology of dimethylmorpholine and dimethylmorpholine carboxylate, which is applied in the chemical field, can solve the problems of unavailable raw materials, high cost, and inaccessibility, and achieves wide application range of the process, low industrialization cost, and controlled production cost effect

Active Publication Date: 2021-12-28
ZHEJIANG HISOAR PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventor of the present application repeated the preparation method and found that its disadvantages are: (1) the reaction temperature of 200° C. is too high and easy to carbonize, and the reaction temperature of about 180° C. is more suitable; The product of formula -2,6-dimethylmorpholine and trans-2,6-dimethylmorpholine, the actual product obtained is a mixture of complex dimethylmorpholine isomers, except that the content is ≥80 Mole % of cis-2,6-dimethylmorpholine, also contains trans-2,6-dimethylmorpholine, cis-2,5-dimethylmorpholine and trans-2, 5-Dimethylmorpholine
But there are many deficiencies in this method: the raw material is limited to the mixture of cis-2,6-dimethylmorpholine and trans-2,6-dimethylmorpholine and the content of the cis component needs to reach 91% Above, and its source is not disclosed, such raw materials are not easy to get, and the cost is high; Salt formation in toluene, xylene, chloroform, dichloromethane, solvent toxicity is relatively large; The inventor of the application repeats this preparation method and also finds that When forming a salt in methyl chloride or chloroform, no salt-separated solid can be seen, and the product cannot be obtained; the organic acids used, such as phenylglycic acid, o-chlorobenzoic acid, m-chlorophenylglycic acid, etc., are more expensive, and the production cost is high

Method used

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  • Purification method of cis-2,6-dimethylmorpholine
  • Purification method of cis-2,6-dimethylmorpholine
  • Purification method of cis-2,6-dimethylmorpholine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] In a 5L four-neck flask, add 816.0 g of concentrated sulfuric acid and 46.8 g of water. 426.2 g of diisopropanolamine were added in portions with stirring. After the addition is complete, heat up to 178-183°C, and add a water separator to separate the water. Keep stirring for 4.5-5h. After keeping warm, cool down in ice water; add 640ml of water to dilute. Then 33.3% sodium hydroxide solution was added dropwise to adjust the pH to 14. Separate the liquid to obtain a black oily substance in the upper layer. The black oil was distilled under reduced pressure, and the light yellow fraction was collected. After the distillation, add 240.0g of solid NaOH to the distillate, dissolve it under stirring, and make the system layered. Separate the liquids, add 35.0 g of solid NaOH to the upper product layer, and dissolve part of the solids under stirring. After liquid separation, 308.2 g of the product was obtained, with a yield of 83.63%. According to gas chromatography (G...

Embodiment 2

[0057] In a 5L four-neck flask, add 816.0 g of concentrated sulfuric acid and 46.8 g of water. 426.2 g of diisopropanolamine were added in portions with stirring. After the addition is complete, heat up to 178-183°C, and add a water separator to separate the water. Keep stirring for 4.5-5h. After keeping warm, cool down in ice water; add 640ml of water to dilute. Then 33.3% sodium hydroxide solution was added dropwise to adjust the pH to 14. Separate the liquid to obtain a black oily substance in the upper layer. The black oil was distilled under reduced pressure, and the light yellow fraction was collected. After the distillation, add 240.0g of solid NaOH to the distillate, dissolve it under stirring, and make the system layered. Separate the liquids, add 35.0 g of solid NaOH to the upper product layer, and dissolve part of the solids under stirring. After liquid separation, 312.5 g of the product was obtained, with a yield of 84.79%.

[0058] Transfer the material to ...

Embodiment 3

[0060] In the reaction flask, add 46.07g (0.4mol) of the product of Example 1, and then add 165ml of ethyl acetate. The temperature was raised to 30° C. under stirring, and 26.18 g (0.44 mol) of acetic acid was added dropwise. After dropping, slowly cool to 20-25°C, stir and crystallize for 2-3h, then cool to 0-10°C, stir and crystallize for 2.5-3.0h. After suction filtration and drying of the filter cake, 53.29 g of cis-2,6-dimethylmorpholine acetate crystals were obtained (the yield of salt formation was 76.03%). The above crystals were hydrolyzed to pH=14 with 33.3% (w / w) sodium hydroxide solution, extracted twice with 40ml chloroform, the chloroform layer was dried with anhydrous potassium carbonate, filtered to remove potassium carbonate, concentrated under reduced pressure to obtain cis- 34.50 g of 2,6-dimethylmorpholine, the gas chromatography (GC) purity was 99.20%, and the yield was 74.88%.

[0061] The NMR data of cis-2,6-dimethylmorpholine acetate are as follows: ...

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Abstract

The present application discloses a method for purifying cis-2,6-dimethylmorpholine, including providing cis-2,6-dimethylmorpholine, trans-2,6-dimethylmorpholine, A mixture of cis-2,5-dimethylmorpholine and trans-2,5-dimethylmorpholine, reacting the mixture with carboxylic acid in an ester solvent, and crystallizing to obtain cis-2 , 6-dimethylmorpholine carboxylate, wherein the content of cis-2,6-dimethylmorpholine in the mixture is ≥80 mole%, and the cis-2,6-di The methylmorpholine carboxylate is hydrolyzed with an alkaline substance to obtain cis-2,6-dimethylmorpholine. The raw materials of the method of the application are easy to obtain, the selection range of raw materials is wider, the process is simple, the cost is low, the reagents used are environmentally friendly, and the finished product has high purity, which can meet the requirements for use in medicine and other fields.

Description

technical field [0001] The application belongs to the field of chemistry, and in particular relates to a purification method for obtaining high-purity cis-2,6-dimethylmorpholine. Background technique [0002] 2,6-Dimethylmorpholine is an important pesticide and pharmaceutical intermediate. It is indispensable in the synthesis of pesticide fungicides cloxacillin, morphazoline, propaphenoline, and fenfenmorph. The key intermediate of the fungal drug amorolfine hydrochloride. [0003] For propacloline, the antibacterial activity of the cis isomer is significantly higher than that of the trans isomer, while the activity of the mixture of cis and trans isomers is lower, so the molecular structure of propacloline usually refers to its cis isomer. [0004] Amorolfine hydrochloride, the chemical name is (±)-cis-4{3-[4-(1,1-dimethylpropyl)phenyl]-2-methylpropane}-2,6-di Methylmorpholine hydrochloride, the structural formula is as follows [0005] [0006] In terms of clinical...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/30
CPCC07D265/30
Inventor 何敏焕石岳崚黄光东徐定洪徐丹萍赵富录李洪明
Owner ZHEJIANG HISOAR PHARMA