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Synthesis method of rivaroxaban

A technology of rivaroxaban and a synthetic method, which is applied in the field of synthesis of small-molecule drug rivaroxaban, can solve problems such as difficult removal of by-products, low synthesis yield, and unsuitable synthetic routes for industrial scale-up production, etc. Production cost, simple reaction conditions, and the effect of improving the total yield

Active Publication Date: 2012-10-03
ARROMAX PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] In the synthetic methods of rivaroxaban in the prior art, some use highly toxic reagents (such as phosgene, etc.) and other more expensive reagents, and most of the methods have relatively long reaction steps, and the synthetic routes are mostly in 6 steps Above, the overall yield of the synthesis of the linear route is low; in addition, there are also disadvantages such as difficult removal of by-products during the deprotection of the hydrazinolysis amino group. These problems have caused most of the existing synthetic routes to be unsuitable for industrial scale-up production.

Method used

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  • Synthesis method of rivaroxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Synthesis of the compound of embodiment 1 formula (II)

[0048]

[0049]Dissolve sodium azide (3.00 g, 46.1 mmol) and compound of formula (I) (1.00 mg, 10.8 mmol) in water (10 mL), cool to 0 °C, add acetic acid (5 mL), and stir at 0 °C After 1 hour, rise to room temperature and stir overnight; after the reaction is complete, extract three times with dichloromethane, wash the organic phase twice with saturated aqueous sodium bicarbonate, dry over anhydrous sodium sulfate, filter and concentrate to the compound of formula (II) (1.20 g, the yield was 83%). Repeat the reaction steps in this example to prepare more compound of formula (II) for use in subsequent examples.

[0050] 1 H-NMR (CDCl 3 , 400MHz, δppm): 2.81(d, 1H, J=5.6Hz), 3.41(d, 2H, J=5.6Hz), 3.54(m, 2H), 3.92(m, 1H).

Embodiment 2

[0051] Synthesis of the compound of embodiment 2 formula (III)

[0052]

[0053] Dissolve the compound of formula (II) (2g, 14.8mmol) and acetic anhydride (3g, 29.6mmol) in dichloromethane (30mL), heat to 30°C, add pyridine (2.34g, 29.6mmol), and stir at the same temperature overnight; after the reaction was complete, it was concentrated and subjected to column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1) to obtain the compound of formula (III) (1.5 g, yield 58%).

[0054] 1 H-NMR (CDCl 3 , 400MHz, δppm): 2.12(s, 3H), 3.56(m, 2H), 3.66(m, 2H), 5.10(m, 1H).

Embodiment 3

[0055] Synthesis of the compound of embodiment 3 formula (VI)

[0056]

[0057] Dissolve the compound of formula (IV) (500mg, 2.60mmol) in acetone (10mL), add sodium bicarbonate (241mg, 2.86mmol) and water (13mL), cool to 0°C, add dropwise the compound of formula (V) The compound (299 mg, 2.76 mmol) was stirred overnight; after the reaction, water (20 mL) was added, filtered, washed with water, and dried to obtain the compound of formula (VI) (637 mg, yield 93%).

[0058] 1 H-NMR (CDCl 3 , 400MHz, δppm): 1.31(t, 3H, J=7.2Hz), 3.73(t, 2H, J=5.2Hz), 4.02(t, 2H, J=5.2Hz), 4.22(dd, 2H), 4.33 (s, 2H), 6.79 (s, 1H), 7.25 (d, 2H, J=3.2Hz), 7.40 (d, 2H, J=4.8Hz).

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Abstract

The invention provides a synthesis method of rivaroxaban. The synthesis method comprises the following steps of: (a) reacting a compound shown as a formula (I) with sodium azide to obtain a compound shown as a formula (II), and reacting the compound shown as the formula (II) with acetic anhydride to produce a compound shown as a formula (III); (b) reacting a compound shown as a formula (IV) and a compound shown as a formula (V) to obtain a compound shown as a formula (VI); (c) reacting the compound shown as the formula (VI) with the compound shown as the formula (II) or the compound shown as the formula (III) under the action of an alkali to obtain a compound shown as a formula (VII); (d) reacting the compound shown as the formula (VII) with hydrazine hydrate to obtain a compound shown as a formula (VIII); and (e) reacting the compound shown as the formula (VIII) with a compound shown as a formula (IX) to obtain the compound rivaroxaban shown as a formula (X). The synthesis method has the advantages of fewer reaction steps, mild reaction conditions, simpleness for post-treatment, and suitability for industrial mass production.

Description

technical field [0001] The present invention relates to the field of chemical medicine, and more particularly relates to a method for synthesizing small molecule drug rivaroxaban. Background technique [0002] Rivaroxaban (Rivaroxaban), the chemical name is 5-chloro-N-(((5s)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)- 1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide is the world's first oral direct factor Xa inhibitor developed by Bayer / Johnson & Johnson. In October 2008, it was approved for marketing in Canada and the European Union under the product name Xarelto. In March 2009, the US FDA Advisory Committee agreed that the clinical data of rivaroxaban has a good benefit-risk ratio. At present, rivaroxaban has been registered and approved in Canada, the European Union, South America, China, Australia and other countries and regions. In the second half of 2009, a launch conference was held in China, and the product name is Xarelto. [0003] As a new type of oral anticoagulan...

Claims

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Application Information

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IPC IPC(8): C07D413/14
Inventor 洪健张宗华李建王景炳
Owner ARROMAX PHARMATECH
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