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Improved process for the preparation of 2-Thiophenecarboxamide, 5-chloro-N- [[(5S)-2-oxo-3-[4-(3-oxo-4morpholinyl)phenyl]-5-oxazolidinyl]methyl] intermediate

IP.com Disclosure Number: IPCOM000180805D
Publication Date: 2009-Mar-17
Document File: 5 page(s) / 32K

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Improved process for the preparation of 2-Thiophenecarboxamide, 5-chloro-N- [[(5S)-2-oxo-3-[4-(3-oxo-4morpholinyl)phenyl]-5-oxazolidinyl]methyl] intermediate

    2-Thiophenecarboxamide, 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4morpholinyl)phenyl]- 5-oxazolidinyl]methyl] is known as RVRX. RVRX, having the following chemical structure:

is an orally administered anticoagulation agent that is effective in inhibiting the effects of the activated serine protease Factor Xa. RVRX drug was developed by Bayer HeathCare AG and is co-marked with Ortho-McNeil Pharmaceutical under the trade name Xarelto®.

    US patent no. 7,157,456 ("US '456") discloses a process for preparing RVRX according to the following scheme:

O

NH

OXA-2

O

O

O

N

OXA-5

2

O

N NO2

H2, Pd/C

O

N NH2

O

NO2

F NaH, NMP

EtOH

O

O

1

3 4

5

OXA-4

O

O

O

O

N NH OH N

CDI, DMAP MeNH2

O

N N O

N

O

OXA-6 OXA-7

O

O

6 7

O

Cl

O

Cl

S

O

9

N N O

O

N N O

O

O

H

N

Cl

NH2

S

O

O

OXA-8

8

R

i

b

O

    In the above process 4-(3-oxo-morpholin-4-yl)phenylamine of formula OXA-4 is prepared using 4-halonitrobenzene (4-Fluoronitrobenzene) for the coupling reaction with 3- Morpholinone of formula OXA-2 under basic conditions. The reported yield for preparing the compound of formula OXA-4 according to US '456 is 17.6%.

Described is a 7 step improved process for preparing an intermediate of RVRX of

formula OXA-8:

1

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O

O

N N O

NH2

O

OXA-8

    In the improved process described below, 4-Bromoaniline or 4-iodoaniline is used in the preparation of the compound of formula OXA-4, instead of 4-halonitrobenzene (4- Fluoronitrobenzene) used in US '456, to obtain a much higher yield of 85%.

The 7 step process may be illustrated by the following scheme:

O

Cl

O

H

N

O

Cl

+

OH

H2N

DCM t-BuOK

t-BuOH

OXA-2

O

NH

OH

O

Chloroacetyl chloride

Ethanolamine

Cl

OXA-A-1

O

HN

O

Cl + t-BuOK

OXA-5-0a OXA-5-0b

O

O

O

N

O

OXA-5

OXA-5

O

X NH2

OXA-2

O

N NH2

O

N NH OH N

EtOH

O

O

O

OXA-01-b

OXA-4

OXA-6

O

O

O

CDI, DMAP MeNH2

N N O

N N O

O

NH2

N

O

O

OXA-7 OXA-8

O

Step 1: The compound of formula OXA-A-1 is prepared by a process comprising: combining ethanolamine with dichloromethane ("DCM") to obtain a solution; adding a solution of chloroacetyl chloride in DCM; and recovering.

Preferably, prior to the addition of chloroacetyl chloride in DCM, the solution is stirred and cooled. Preferably, the addition of the chloroacetyl chloride in DCM is done drop-wise. Preferably, the temperature of the reaction mixture during the addition of chloroacetyl chloride in DCM, is not higher than about -10˚C.Preferably, prior to the recovery, the temperature is raised from about 10˚C to about 15˚C. Preferably, prior to the recovery, a stirring step is performed.

  Step 2: The compound of formula OXA-2 is prepared by a process comprising: combining tetrahydrofuran ("THF") with t-BuOH; adding t-BuOK; a...