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Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative

The technology of rivaroxaban and hydroxymethyl is applied in the field of synthesis of intermediates of anticoagulant drug rivaroxaban, can solve the problems of unsuitability for industrial production, low yield and high raw material cost, and achieves low production cost, high yield effect

Inactive Publication Date: 2016-08-03
CHANGZHOU FANGNAN MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the yield of compound (I) from compound (II) through compound (VII) is low, and the yields of the two-step reactions are 86% and 80% respectively, which ultimately leads to high raw material costs of the entire synthetic route. Suitable for industrial production

Method used

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  • Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative
  • Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative
  • Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] step 1)

[0038] Add compound II (15.0g, 78.0mmol), water (200ml) and sodium bicarbonate (13.1g, 156mmol) into a 250ml three-neck round bottom flask, cool down to 0~5°C, and control the temperature at 5~10°C. Compound IIIa (10.0 g, 82.8 mmol) was slowly added dropwise. After dropping, warm up to room temperature and continue stirring for 3-4 hours. After the reaction was completed by HPLC tracking, it was filtered, and the filter cake was washed with water and dried to obtain 20.7 g of compound (IVa), with a yield of 96.1%.

[0039] 1HNMR (400MHz, d6-DMSO):9.78(s,1H),7.40(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),6.05-5.86(s,1H),5.35 -5.31(m,1H),5.23-5.18(m,1H),4.64-4.56(m,2H),4.15(s,2H),3.96-3.87(m,2H),3.68-3.62(m,2H) .LC-MS(ESI):m / z277.

[0040] step 2)

[0041] Add compound IVa (20.2g, 73.0mmol), (R)-glycidyl butyrate (11.6g, 80.3mmol) and tetrahydrofuran (190ml) into a 250ml three-neck round bottom flask and, at 20~30℃ Slowly add lithium tert-butoxide (11.7...

Embodiment 2

[0043]

[0044] step 1)

[0045] Add compound II (15.0g, 78.0mmol), triethylamine (8.68g, 85.8mmol) and dichloromethane (150ml) into a 250ml three-neck round bottom flask, cool to 0~5°C, and control the temperature for 5~ At 10°C, compound IIIb (12.75 g, 85.8 mmol) was slowly added dropwise. After dropping, warm up to room temperature and continue stirring for 3-4 hours. After the completion of the reaction was followed by HPLC, it was filtered, and the filter cake was washed with water and dried to obtain 22.5 g of compound (IVb), with a yield of 94.8%.

[0046] 1HNMR (400MHz, d6-DMSO):9.78(s,1H),7.40(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),6.05-5.86(s,1H),4.64 LC-MS (ESI):m / z305.

[0047] step 2)

[0048] Add compound IVa (22.0g, 72.3mmol), (R)-glycidyl butyrate (11.5g, 79.5mmol) and tetrahydrofuran (190ml) to a 250ml three-neck round bottom flask and, at -80~-70 Slowly add 2.5 mol / L n-butyllithium n-hexane solution (34.7ml, 86.8mmol) dropwise at ℃, after the drop is complet...

Embodiment 3

[0050]

[0051] step 1)

[0052] Add compound II (15.0g, 78.0mmol), compound IIIc (15.3g, 89.7mmol), triethylamine (9.47g, 93.6mmol), 4-(N,N-di methylamino)pyridine (0.5g) and dichloromethane (150ml). The temperature was raised to reflux, and the stirring was continued for 3-4 hours. After the reaction was completed by HPLC tracking, it was filtered, and the filter cake was washed with water and ethanol, and dried to obtain 21.2 g of compound (IVc), with a yield of 93.7%.

[0053] 1HNMR (400MHz, d6-DMSO):9.78(s,1H),7.40(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H),5.35-5.31(m,1H),5.23 LC -MS(ESI):m / z291.

[0054] step 2)

[0055] Add compound IVa (20.0g, 68.9mmol), (R)-glycidyl butyrate (10.9g, 75.8mmol) and tetrahydrofuran (190ml) into a 250ml three-necked round bottom flask and, at 0~10℃ Slowly add 1 mol / L tetrahydrofuran solution of lithium hexamethylsilylamide (82.7ml, 82.7mmol) dropwise, after the dropwise completion, slowly raise the temperature to room temperature, and rea...

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Abstract

The invention provides a synthetic method of a rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative, and concretely provides a method for preparing a rivaroxaban intermediate (I). The synthetic method comprises the following steps: 1) a compound (II) and a compound (III) are subjected to a reaction in the presence of alkali to obtain a compound (IV); and 2) the compound (IV) and (R)-glycidyl butyrate are subjected to a reaction in the presence of alkali to obtain the rivaroxaban intermediate (I), which is 4-(4-((5S)-5-(hydroxy methyl)-2-oxo-1, 3-oxazolidine-3-yl)phenyl)morpholine-3-ketone. The provided novel method has the advantages of mild reaction condition, simple operation, convenient purification, and low production cost, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the synthetic method of anticoagulant drug rivaroxaban intermediate, specifically relates to rivaroxaban intermediate 4-(4-((5S)-5-(hydroxymethyl)-2-oxo-1 , The synthetic method of 3-oxazolidin-3-yl) phenyl) morpholin-3-one. Background technique [0002] Rivaroxaban, chemical name 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxo-4-morpholinyl)phenyl)-1 , 3-oxazolidin-5-yl) methyl-2-thiophenecarboxamide, its structure is as shown in formula (I): [0003] [0004] Rivaroxaban (Rivaroxaban) is a new type of highly selective anticoagulant drug developed by Bayer AG of Germany. Its English name is Xarelto?, and it was approved by the European Commission in September 2008. Rivaroxaban competitively inhibits free and bound factor Xa and prothrombin activity, prolongs prothrombin time (PT) and activated partial thromboplastin time (APTT) in a dose-dependent manner, and is used to prevent hip and knee Formation of deep vein thrombosis ...

Claims

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Application Information

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IPC IPC(8): C07D413/10C07D265/32
Inventor 张席妮资春鹏熊志刚王颖奇
Owner CHANGZHOU FANGNAN MEDICINE TECH CO LTD
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