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Preparation of (5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide

IP.com Disclosure Number: IPCOM000200951D
Publication Date: 2010-Nov-01
Document File: 9 page(s) / 46K

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Preparation of (5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-
5-yl}-methyl)-2-thiophenecarboxamide

(5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)- 2-thiophenecarboxamide, ("referred as RVB") of the following formula;

N

O

O

N O

   O N

H

O

S

Cl

is used for the prophylaxis of venous thromboembolism (Cardiovascular Drugs) in patients undergoing hip or knee replacement surgery.

A process for preparing "RVB" was found and is described herein below.

N N O

O

O

O

O

   O N

   O N

H2

O

N N O

(II) (III)

(IV)

or actived

O

Cl

O

O

H

O

S Cl

S Cl

(V)

O

O

OH

O

O

O

O

H

N N

OH

H

N N O

Cl

N

S

Cl

N

S

O

(VI)

O

(I)

Preparation of 4-{4-[5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]pheneyl} morpholine-3-one
(III) Example 1:
3.00 g of 2-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-1H- isoindole-1,3(2H)dione (II) was suspended in 9 mL of ethanol and 3.5 mL of 33% solution of methylamine in ethanol was added in. The reaction mixture was warmed to 50 °C and stirred at this temperature for 28 h. The reaction mixture was diluted with 18 mL of heptane and the obtained mixture was stirred at 50 °C for additional 2 hours, then it was spontaneously cooled


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to room temperature and stirred overnight at room temperature. Unsoluble part was separated by filtration, washed with heptane and dried to give 3.31 g of product III in the mixture with N,N'-dimethylphthalic diamide.

Example 2:
9.10 g of 2-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-1H- isoindole-1,3(2H)dione (II) was suspended in 91 mL of ethanol and 3.0 mL of hydrazine hydrate was added in. The reaction mixture was warmed to 55 °C and stirred at this temperature for 3.5 hours. The reaction mixture was cooled to 40 °C and then diluted with 100 mL of hexane. The reaction vessel was extended by azeotropical adapter. The mixture was warmed to reflux and aqueous phase was azeotropicaly removed from the mixture. The mixture was cooled to room temperature and then stirred at this temperature for 1 hour. Insoluble part was separated by filtration, washed with hexane and dried to give 9.92 g of product III in the mixture with phthalhydrazide.

Example 3:
3.00 g of 2-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-1H- isoindole-1,3(2H)dione (II) was suspended in 9 mL of ethanol and 4.5 mL of propylamine was added in. The reaction mixture was warmed to 50 °C and stirred at this temperature for 25 h. The reaction mixture was diluted with 15 mL of hexane and the obtained mixture was stirred at 50 °C for additional 1 hour, then the mixture was spontaneously cooled to room temperature and stirred overnight at room temperature. Insoluble part was separated by filtration, washed with hexane and dried to give 3.02 g of crude product III.

Example 4:
3.00 g of 2-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-1H- isoindole-1,3(2H)dione (II) was suspended in 12...