METHOD FOR PRODUCING 5-CLORO-N-(METHYL)-2-THIOPHENECARBOXAMIDE

• US 20100081807A1
• Filed: 09/09/2009
• Published: 04/01/2010
• Est. Priority Date: 01/07/2003
• Status: Active Grant

• Current Assignee: Bayer Intellectual Property GmbH (Bayer AG)
• Original Assignee: Bayer Healthcare AG (Bayer AG)
• Inventors: Thomas, Christian R.
• Granted Patent: US 8,106,192 B2
• Time in Patent Office: Days
• US Class Current: 544/137
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The invention relates to a method for producing 5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide starting from 5-chlorothiophene-2-carbonyl chloride, (2S)-3-amino-propane-1,2-diol and 4-(4-aminophenyl)-3-morpholinone.

Claims

1-13. -13. (canceled)

14. A process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of the formula (I)

comprising preparing 5-chlorothiophene-2-carbonyl chloride (IV) in a first step by chlorinating 5-chlorothiophene-2-carboxylic acid;

reacting said 5-chlorothiophene-2-carbonyl chloride (IV) in a second step with (2S)-3-aminopropane-1,2-diol hydrochloride (VII) to give N—

((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII);

converting said N—

((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) in a third step to N—

((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX);

converting said N—

((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) in a fourth step by reacting with 4-(4-aminophenyl)-3-morpholinone (III) to N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X); and

reacting said N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) in a fifth step with phosgene or a phosgene equivalent.

15. A process for preparing N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X), comprising reacting N—

((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) with 4-(4-aminophenyl)-3-morpholinone (III).

23. N-{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide of the formula (X)

produced in accordance with the process of claim 15.

16. A process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of the formula (I), comprising reacting N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) with phosgene or a phosgene equivalent and further comprising preparing said N-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) by reacting N—

((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) with 4-(4-aminophenyl)-3-moxpholinone (III).

17. The process as claimed in claim 16, characterized in that the phosgene equivalent is N,N-carbonyldiimidazole.

18. The process as claimed in claim 17, characterized in that from 1.1 to 1.3 equivalents of N,N-carbonyldiimidazole are used.

19. The process of claim 16, wherein the reaction takes place in a solvent mixture of 1-methyl-2-pyrrolidone and toluene.

20. The process of claim 16, further comprising preparing the N—

((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) by reacting N—

((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) with hydrobromic acid in acetic acid.

21. The process of claim 20, further comprising preparing said N—

((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) by reacting 5-chlorothiophene-2-carbonyl chloride (IV) with (2S)-3-aminopropane-1,2-diol hydrochloride (VII).

22. N—

((S)-3-Bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide of the formula (IX)