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Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof

A technology of propanolacetamide and compounds, which is applied in the field of medicinal chemistry, can solve problems such as difficulties, instability, and difficulty in ensuring product quality control, and achieve the effect of improving stability and inhibiting degradation

Inactive Publication Date: 2014-01-01
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the preparative impurity (9) and impurity (2) disclosed in the prior art were separated from linezolid injection by semi-preparative HPLC (Hadden, CE .; Bowman, PB.; Duholke, WH. et al. A long-range 15N-NMR study of the oxazolidinone antibiotic Zyvox and the major thermal degradation products. Journal of Heterocyclic Chemistry i> (2000), 37(6), 1623-1627), due to the large number of impurities in linezolid injection, the retention time of each impurity is very close, and a single impurity with high purity and relatively large amount can be obtained by chromatography It is very difficult, and the purity of the impurity (9) separated by the existing technology is only 91%, which cannot meet the requirements as a reference substance or standard substance for related substances
For this reason, in our further research on the above separation method, we found that the low purity of the isolated impurity (9) was not due to the fact that the many impurities in linezolid injection affected the separation from each other, but was related to the impurity (9) The compound itself is unstable at room temperature or low temperature (-20~-80°C), and is easily degraded (the content is reduced to about 80% at -20°C for 24 hours)
When studying the influence of impurities in linezolid injection on the stability and efficacy of the drug, it is necessary to use high-purity impurities (9) as reference substances or standards for related substances, otherwise the safety and effectiveness of the drug will be lacking. Reliable basis, it is difficult to guarantee the quality control of the product

Method used

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  • Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof
  • Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof
  • Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (2 S )-1-amino-3-[[3-fluoro-4-(4-morpholinyl)phenyl]amino]-2-propanol (6a)

[0030]

[0031] Add linezolid (0.06 mol), 150 ml of methanol, 50 ml of deionized water and lithium hydroxide (0.3 mol) into the reaction flask, heat up to reflux and stir for 8 hours, after the reaction, evaporate the solvent under reduced pressure, and the residue Dissolved with 150 ml of dichloromethane, washed with deionized water and saturated NaCl aqueous solution successively, and the organic layer was washed with anhydrous NaCl 2 SO 4 After drying, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a white solid, m.p. 99.5-100.5°C, yield 82.6%, purity 99.8%; 1 H NMR (DMSO- d 6 , 400MHz) δ: 6.81(t, J = 9.6Hz, 1H, Ar-H), 6.41(dd, J = 2.4, 15.2Hz, 1H, Ar-H), 6.34(dd, J = 2.4, 8.8Hz, 1H, Ar-H), 5.46(t, J = 5.2Hz, 1H, Ar-NH), 4.72(brs, 1H, OH), 3.69(t, J = 4.4Hz, 4H, 2×CH 2 O), 3.49(m, 1H, CHOH), 3....

Embodiment 2

[0033] (2 R )-1-amino-3-[[3-fluoro-4-(4-morpholinyl)phenyl]amino]-2-propanol (6b)

[0034] Operation method is the same as embodiment 1 , just use linezolid with ( R )-configuration of linezolid, methyl alcohol was replaced by tetrahydrofuran, lithium hydroxide was replaced by potassium hydroxide, and the temperature was raised and refluxed for 12 hours to obtain (2 R )-1-amino-3-[[3-fluoro-4-(4-morpholinyl)phenyl]amino]-2-propanol, m.p. 99.2-100.5°C, yield 80.0%, purity 99.5%; its The structure was verified by HRMS-ESI, 1 Confirmed by H-NMR.

Embodiment 3

[0036] ( dl )-1-amino-3-[[3-fluoro-4-(4-morpholinyl)phenyl]amino]-2-propanol (6c)

[0037] Operation method is the same as embodiment 1 , just use linezolid with ( dl )-configuration of linezolid, methyl alcohol was replaced by deionized water, lithium hydroxide was replaced by sodium hydroxide, and the temperature was raised and refluxed for 10 hours to obtain ( dl )-1-amino-3-[[3-fluoro-4-(4-morpholinyl)phenyl]amino]-2-propanol, yield 88.2%, purity 99.5%; its structure was confirmed by HRMS-ESI, 1 Confirmed by H-NMR.

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Abstract

The invention discloses a salt (I) of a 3-amino-2-propanol acetamide compound, and also discloses a preparation method of the salt, and use of the salt as a reference substance or a standard substance of related substance in quality control of a linezolid preparation. In a formula, A represents boric acid, phosphoric acid, C1-8 fatty acid, trifluoroacetic acid, benzoic acid, salicylic acid, phthalic acid, mandelic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; n represents 1 / 2 or 1; the compound is a racemate, an (S)-optical isomer or an (R)-optical isomer.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a salt (I) of a class of 3-amino-2-propanolacetamide compounds, a preparation method thereof, and a reference substance or a standard substance used as a reference substance or a standard substance of related substances, which are used in linezolid preparations For use in quality control, the structural formula of the salt (I) of the 3-amino-2-propanolacetamide compound is as follows: [0002] [0003] In the formula: A represents boric acid, phosphoric acid, C 1-8 Fatty acids, trifluoroacetic acid, benzoic acid, salicylic acid, phthalic acid, mandelic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, ethylsulfonic acid, benzene Sulfonic acid, p-toluenesulfonic acid, n represents 1 / 2 or 1; the compound is a racemate, (S) - optical isomers, or (R) - optical isomers. Background technique [0004] Linezolid (linezol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/135
CPCY02P20/55C07D295/135
Inventor 邓勇晁若冰桑志培曹海彦李岩何洪光
Owner SICHUAN UNIV
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