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4-(4-amion phenyl)-3-morpholone intermediate amide and synthesis method and application thereof

A technology of aminophenyl and synthetic method, which is applied in the field of drug synthesis, can solve the problems of severe reaction conditions, difficult to obtain raw materials, poor environmental friendliness, etc., and achieve the effect of mild reaction conditions, easy to obtain raw materials, and cheap raw materials

Inactive Publication Date: 2012-01-18
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Analysis of the various synthetic routes of existing 4-(4-aminophenyl)-3-morpholinone (1) shows that these routes have problems such as low yield, difficult or expensive raw materials, severe or harsh reaction conditions, Disadvantages such as high requirements for reaction equipment and poor environmental friendliness

Method used

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  • 4-(4-amion phenyl)-3-morpholone intermediate amide and synthesis method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Example 1 Preparation of 2-(4-nitrophenyl)aminoethanol (10)

[0030] Add 2.02g (0.010mol) p-nitrobromobenzene, 920uL (0.015mol) aminoethanol, and 10mL DMF into a 25mL flask, then add 6.90g (0.05mol) anhydrous potassium carbonate, and heat at 120°C for 24 hours. Solid potassium carbonate was removed by filtration, rinsing with ethyl acetate. The system was spin-dried, and put on the column (silica gel) by dry method, and the P / E (petroleum ether / ethyl acetate) = 1:1 was passed through the column. 229 mg of starting material were recovered. A small amount of column chromatography was used for analysis, and the remaining crude product was directly used for the next reaction.

[0031] 1 H NMR (CDCl 3 , 400MHz): δ8.07(d, 2H), 6.61(d, 2H), 3.88(t, 2H), 3.37(t, 2H).

Embodiment 2

[0032] Example 2 Preparation of 2-(4-aminophenyl)aminoethanol (11)

[0033]Using methanol as a solvent, the compound of Example 1 was hydrogenated overnight at room temperature and pressure with 10% Pd / C. Pd-C was filtered off with celite, spin-dried, and column chromatography (silica gel) yielded 0.778 g of the product. The two-step yield was 59%.

[0034] 1 H NMR (CDCl 3 , 400MHz): δ6.60(d, 2H), 6.54(d, 2H), 3.76(t, 2H), 3.19(t, 2H).

Embodiment 3

[0035] Example 3 Preparation of N-chloroacetyl-N-(4-(N-chloroacetyl)-N-phenyl)aminoethanol (2a)

[0036] Under nitrogen protection, 0.778 g of substrate 11 was dissolved in 5 mL of THF. And add 2.30mL triethylamine to the system and stir at 0°C. Under nitrogen protection, dissolve 0.82mL of chloroacetyl chloride in 5mL of THF, cool to 0°C, and slowly drop into the system. React at 0°C for 4 to 5 hours. The reaction solution was filtered with anhydrous sodium sulfate and rinsed with ethyl acetate. After being spin-dried, it was applied to the column (silica gel) by dry method, P / E (petroleum ether / ethyl acetate) = 4:1 to 2:1, and 539 mg of the product was obtained with a yield of 68%.

[0037] 1 H NMR (CDCl 3 , 400MHz): δ7.67(d, 2H), 7.31(d, 2H), 4.22(s, 2H), 3.90(t, 2H), 3.86(s, 2H), 3.80(t, 2H).

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Abstract

The invention relates to a 4-(4-amion phenyl)-3-morpholone intermediate amide and a synthesis method and application. The method has the advantages of cheap and readily available raw materials, mild reaction condition and high yield; and intermediate amide can be used for synthesizing 4-(4-amion phenyl)-3-morpholone and further synthesizing a rivaroxaban medicament.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to the key intermediate 4-(4-aminophenyl)-3-morpholinone amide in the chemical synthesis of oral anticoagulant drug rivaroxaban, a synthesis method and a method for synthesizing 4- Use of (4-aminophenyl)-3-morpholinone and rivaroxaban. Background technique [0002] Rivaroxaban, English name Rivaroxaban, is an oral antithrombotic drug developed by Bayer, which was approved for marketing in Canada and the European Union on September 15, 2008 and October 1, 2008, and its trade name is Xarelto. In China, rivaroxaban was officially launched on June 18, 2009 under the product name Xarelto. So far, rivaroxaban has been approved for registration in Canada, the European Union, South America, Australia, China and other countries and regions. [0003] [0004] Rivaroxaban is the first oral direct inhibitor of factor Xa, which can directly inhibit factor Xa in free o...

Claims

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Application Information

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IPC IPC(8): C07C233/43C07C231/02C07D265/32C07D413/14
Inventor 孙炳峰林国强
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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