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Oxazolidinone derivative and preparation method and application thereof

A technology of oxazolidine and medicine, which is applied in the field of blood coagulation, can solve the problems such as difficult purification of rivaroxaban, and achieve the effect of low price, easy preparation and easy purification

Active Publication Date: 2012-05-23
天津药业集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Wherein, the yield of the first step reaction (preparation of 4-(4-morpholin-3-one) nitrobenzene) is only 17.6%, and rivaroxaban is difficult to purify

Method used

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  • Oxazolidinone derivative and preparation method and application thereof
  • Oxazolidinone derivative and preparation method and application thereof
  • Oxazolidinone derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] (S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine-5- (Yl)methyl)thiophene-2-carboxamide (I-1)

[0047]

[0048] A. Synthesis of 1-(4-aminophenyl)-1H-pyridin-2-one (Compound VII)

[0049] Add 104g pyridine-2(1H)-one (compound IX), 200g p-iodoaniline (compound VIII), 26gCuI, 151g potassium carbonate, 18g8-hydroxyquinoline, 500ml DMF, nitrogen protection, heating and refluxing, heat preservation and stirring to the reaction flask. 10h. Filter while hot, take the filtrate, evaporate the solvent under reduced pressure, add 1L ethyl acetate to the residue, keep stirring at 0°C for 1h, filter, dry the solid, and refine with 2L acetonitrile to obtain 98g dark red solid. The refined mother liquor was concentrated to 500ml, stirred in an ice bath for 1h, and filtered to obtain 19g of dark red solid. A total of 117 g of product was obtained, with a yield of 68.9%.

[0050] 1 H-NMR(DMSO-d 6 ), δ (ppm): 5.306 (s, 2H), 6.236 (d, 1H), 6.406 (d, 1H), 6.601 (d, 2H)...

Embodiment 2

[0074] (S)-5-Bromo-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine-5- (Yl)methyl)thiophene-2-carboxamide (I-2)

[0075]

[0076] Melting point: 200.8~201.8℃;

[0077] 1 H-NMR(DMSO-d 6 ), δ (ppm): 3.580 (t, 2H), 3.902 (m, 1H), 4.221 (t, 1H), 4.849 (m, 1H), 6.308 (t, 1H), 6.468 (d, 1H), 7.193 (d, 1H), 7.426 (m, 2H), 7.500 (m, 1H), 7.637 (m, 4H), 8.967 (t, 1H);

[0078] MS(ESI): m / z=474(M+H);

[0079] HPLC: rt(%)=13.44(99.55);

[0080] [α] 20 D = -32.9° (c 0.3010, DMSO);

Embodiment 3

[0082] (S)-5-methyl-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine-5 -Yl)methyl)thiophene-2-carboxamide (I-3)

[0083]

[0084] 1 H-NMR(DMSO-d 6 ), δ (ppm): 3.457 (s, 3H), 3.600 (t, 2H), 3.897 (m, 1H), 4.224 (t, 1H), 4.860 (m, 1H), 6.314 (t, 1H), 6.468 (d, 1H), 6.842 (d, 1H), 7.419 (d, 2H), 7.499 (m, 1H), 7.622 (m, 4H), 8.724 (t, 1H).

[0085] MS(ESI): m / z=410(M+H);

[0086] In the HPLC data given in the above examples, the unit of retention time rt is minutes, and the HPLC parameters are:

[0087] Instrument: Waters 996-717-600 liquid chromatograph; Column: GL Science C18 column; Column temperature: 45°C; Eluent: Phase A is potassium dihydrogen phosphate solution, Phase B is potassium dihydrogen phosphate solution-acetonitrile ( 20:80); detection wavelength: 233nm; flow rate: 1.2ml / ml; gradient: 0.0min 55%A→5min 55%A→10min 40%A→20min 0%A→35min 0%A→36min 55%A.

[0088] In order to more fully explain the implementation of the present invention, the following pharmacolog...

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Abstract

The invention relates to the field of blood coagulation, in particular to a novel oxazolidinone chiral compound with the structure of a general formula (1), a preparation method of the oxazolidinone chiral compound and a medicine combination containing the oxazolidinone chiral compound as well as an application of the oxazolidinone chiral compound serving as a bioactive substance to the prevention and / or treatment of diseases, wherein the definition of R is stated in the specification.

Description

Technical field [0001] The present invention relates to the field of blood coagulation. Specifically, the present invention relates to a new oxazolidinone derivative, its preparation method and its use as a biologically active substance in medicine. Background technique [0002] In the cardiovascular system of a living body, blood coagulation occurs, or certain processes in the blood are formed, analyzed, and aggregated to form solid masses, which is called thrombosis, and the solid masses formed are called thrombus. Thrombosis is the abnormal coagulation of blood in the flowing state due to activation of platelets and activation of coagulation factors. [0003] Blood coagulation is originally a protective mechanism of organisms. There are antagonistic coagulation system and anticoagulation system in the blood. Under physiological conditions, the coagulation factors in the blood are continuously activated, thereby producing thrombin, forming trace fibrin, and depositing on the vas...

Claims

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Application Information

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IPC IPC(8): C07D413/14A61K31/4439A61P7/02
Inventor 黄长江袁静张士俊商倩刘鹏付晓丽蔡志强龚珉汤立达徐为人
Owner 天津药业集团有限公司
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