| Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide -> Monitor Keywords |
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Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamideRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered And Includes At Least Nitrogen And Oxygen As Ring Hetero Atoms (e.g., Monocyclic 1,2- And 1,3-oxazines, Etc.), Morpholines (i.e., Fully Hydrogenated 1,4- Oxazines), Additional Hetero Ring Attached Directly Or Indirectly To The Morpholine Ring By Nonionic Bonding, Polycyclo Ring System Having The Additional Hetero Ring As One Of The Cyclos, ,Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070149522, Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to a process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-- 5-yl}methyl)-2-thiophene-carboxamide starting from 5-chlorothiophene-2-carbonyl chloride, (2S)-3-aminopropane-1,2-diol and 4-(4-aminophenyl)-3-morpholinone. [0002] The compound 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-- 5-yl}methyl)-2-thiophenecarboxamide is known from WO-A 01/47919 and corresponds to the formula (I) [0003] The compound of the formula (I) acts as an inhibitor of clotting factor Xa and may be used as an agent for the prophylaxis and/or treatment of thromboembolic disorders, especially myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses. [0004] WO-A 01/47919 also describes a method for preparing the compound of the formula (I) starting from 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (II), 4-(4-aminophenyl)-3-morpholinone (III) and 5-chlorothiophene-2-carbonyl chloride (IV): [0005] In this method, the epoxyphthalimide (II) is prepared by reacting (2S)-1-chloropropane-2,3-diol (V) with potassium carbonate via the stage of (S)-glycidol (VI) and subsequent Mitsunobu reaction with phthalimide: [0006] The process known from WO-A 01/47919 has various disadvantages which have a particularly unfavorable effect when the compound of the formula (I) is prepared on the industrial scale: [0007] For instance, the glycidol (VI), especially in relatively large amounts, is polymerization-sensitive and thus not storage-stable, additionally toxic and potentially carcinogenic. The Mitsunobu reaction in the preparation of compound (II) is technically costly and inconvenient, one reason being that racemization occurs readily in relatively large batches. Another reason is that the atom economy is extremely unsatisfactory, since triphenylphosphine oxide and diisopropyl azodicarboxylate hydrazide are generated in stoichiometric amounts as waste materials. In addition, the nitrogen atom in the oxazolidinone ring of the target molecule (I) is introduced in phthalimide-protected form. However, the phthalic acid radical as a protecting group has to be removed in the further course of the synthesis, which means an increase in the number of stages and additional waste. [0008] It is thus an object of the present invention to provide a simplified process for preparing the compound of the formula (I) in large amounts. [0009] It has been found that, surprisingly, the compound of the formula (I) can be prepared in improved yield in a shortened reaction sequence using storage-stable and less toxic starting materials, starting from 5-chlorothiophene-2-carbonyl chloride (IV), (2S)-3-aminopropane-1,2-diol hydrochloride (VII) and 4-(4-aminophenyl)-3-morpholinone (III). In this reaction sequence, the use of protecting groups is also avoided, which reduces the number of stages and thus shortens the reaction time. [0010] In the first step of the process according to the invention, 5-chlorothiophene-2-carbonyl chloride (IV) is prepared from 5-chlorothiophene-2-carboxylic acid. [0011] Compound (IV) may be prepared under the customary reaction conditions for the preparation of carbonyl chlorides from the corresponding carboxylic acids. Preference is given to the reaction of 5-chlorothiophene-2-carboxylic acid with thionyl chloride as the chlorinating reagent in toluene as the solvent. [0012] In the second step of the process according to the invention, 5-chlorothiophene-2-carbonyl chloride (IV) is reacted with (2S)-3-aminopropane-1,2-diol hydrochloride (VII) to give N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) [0013] The reaction (IV)+(VII).fwdarw.(VIII) may be effected under the reaction conditions customary for the formation of amide bonds from the appropriate carbonyl chlorides and amines. Preference is given to a biphasic system composed of aqueous sodium hydrogencarbonate solution and 2-methyltetrahydrofuran as the organic solvent. (2S)-3-Aminopropane-1,2-diol is used in the form of the free base or in the form of the acid addition salt. Preference is given to the hydrochloride (VII) which crystallizes better than the free base and can therefore be handled readily. To increase the reaction yield, optionally either an excess of amine is used or an auxiliary base is added. The addition of from 1 to 3, preferably 2, equivalents of an auxiliary base such as sodium hydrogencarbonate is preferred. The reaction is effected generally within a temperature range of from 0.degree. C. to 40.degree. C., preferably of from 5.degree. C. to 30.degree. C. [0014] In the third step of the process according to the invention, N--((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) is converted to N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) [0015] The reaction (VIII).fwdarw.(IX) is carried out with from 1 to 5, preferably from 3 to 5, in particular 4, equivalents of a solution of hydrobromic acid in acetic acid, optionally in the presence of acetic anhydride. The reaction temperature is between 20.degree. C. and 80.degree. C., preferably between 60 and 65.degree. C. The amount of methanol added may be varied over a wide range; preference is given to using from 40 to 80 mol, in particular from 50 to 60 mol, of methanol per mole of (VIII). For the workup, the solvents are distilled off, preferably under reduced pressure. The remaining distillation residue is optionally also neutralized before the filtration of the product. [0016] In the fourth step of the process according to the invention, N--((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) is reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot- hiophene-2-carboxamide (X) [0017] The solvent for the reaction (IX)+(III).fwdarw.(X) may be varied widely; preference is given to toluene. The reaction temperature is between 80.degree. C. and 200.degree. C.; preference is given to a range between 90.degree. C. and 110.degree. C. The reaction is effected optionally in the presence of an auxiliary base, for example triethylamine, diisopropylethylamine or collidine; preference is given to using collidine. The stoichiometry of the reaction and the reaction time are variable over a wide range; preference is given to a ratio of compound (IX) to compound (III) to collidine of 1.2 to 1.0 to 1.0 and a reaction time of from 4 to 8 hours, especially of from 5 to 6 hours. [0018] In the fifth step of the process according to the invention, N--{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorot- hiophene-2-carboxamide (X) is reacted with phosgene or a phosgene equivalent to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-- 5-yl}methyl)-2-thiophene-carboxamide (I). [0019] In the reaction (X).fwdarw.(I), one or more equivalents of phosgene or phosgene equivalents are used in the presence of inert solvents or solvent mixtures. Phosgene equivalents are, for example, phosgene replacements such as di- or triphosgene, or carbon monoxide equivalents, for example N,N-carbonylbisimidazole. Preference is given to using from 1 to 2 equivalents, in particular from 1.1 to 1.3 equivalents, of N,N-carbonylbisimidazole in a solvent mixture of 1-methyl-2-pyrrolidone and toluene. For purification of the product, a clarifying filtration and/or a recrystallization optionally follows. The reaction is effected generally within a temperature range of from 20.degree. C. to 150.degree. C., preferably of from 30.degree. C. to 110.degree. C., in particular of from 75.degree. C. to 85.degree. C. [0020] The individual stages of the process according to the invention may be carried out at standard, elevated or at reduced pressure (for example of from 0.5 to 5 bar). In general, standard pressure is used. [0021] The following scheme summarizes the synthesis: [0022] The invention is illustrated in detail below by a preferred working example, to which it is not, however, restricted. Unless stated otherwise, all quantitative data relates to percentages by weight. Synthesis of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-- 5-yl}methyl)-2-thiophenecarboxamide (I) 1st Step Continue reading about Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide... Full patent description for Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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