MXPA06007902A - Production method - Google Patents

Abstract

The invention relates to a method for producing 5-chloro-N -({(5S)-2-oxo -3-[4-(3-oxo- 4-morpholinyl) -phenyl]-1, 3-oxazolidine -5-yl}-methyl) -2-thiophene carboxamide from 2-[(2S)-2 -oxiranylmethyl]-1H-isoindol-1, 3(2H)-dione, 4-(4-aminophenyl) -3-morpholinone, and 5-chlorothiophene -2-carbonyl chloride.

Description

PREPARATION PROCEDURE DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of 5-chloro-lv- ( { (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1, 3-oxazolidin-5-yl.} Methyl) -2-thiophenecarboxamide from 2- [(2S) -2-oxiranylmethyl] -1H-isoindole-1,3 (2H) -dione, 4- ( 4-aminophenyl) -3-morpholinone and 5-chlorothiophene-2-carbonyl chloride. 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 formula (I) The compound of formula (I) acts as an inhibitor of blood coagulation factor Xa and can be used as an agent for. prophylaxis and / or treatment of thromboembolic diseases, especially myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary emboli or thrombosis deep veins REF.:174168 In WO-A 01/47919 there is also described a process for the preparation of the compound of formula (I) - in the range of grams, from the same starting compounds 2- [. { 2S) -2-oxiranylmethyl] -lH-isoindol-1,3 (2H) -dione (II), 4- (4-aminophenyl) -3-morpholinone (III) and 5-chlorothiophene-2-carbonyl chloride (IV ): In this regard, 2- [(2S) -2- 'oxiranylmethyl] -l-isoindol-1,3 (2H) -dione (II) is reacted with 4- (4- to inophenyl) -3-morpholinone (III ) to 2- ((2i?) -2-hydroxy-3 { [4- (3-oxo-4-morpholinyl) phenyl] amino.}. propyl) -lH-isoindol-1, 3 (2H) ) -diona (V). It is then transformed (V) with a phosgene equivalent to 2- ( { (5S) -2-oxo-3- [4- (3-oxo-4 ~ morpholinyl) phenyl] -1,3-oxazolidin -5-yl.) Methyl) -Iff-isoindol-1,3 (2H) -dione (VI). Cleavage of the phthalimido protecting group provides 4-. { 4- [(55) -5- (aminomethyl) -2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (VII), which is finally reacted with 5-chlorothiophene-2-carbonyl (IV) chloride to 5-chloro-JV- ( { (5S) -2-oxo-3- [4 - (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5-yl.} Methyl) -2-thiophenecarboxamide (I). This process known from WO-A-01/047919, however, presents different disadvantages in carrying out the reaction, which particularly unfavorably affect the preparation of the compound of formula (I) on an industrial scale. An alternative process for the synthesis of the compound of formula (I) from 5-chlorothiophene-2-carbonyl chloride is disclosed in DE 10300111.5.

(IV), (2S) -3-aminopropane-l, 2-diol (VIII) hydrochloride and 4- (4-aminophenyl) -3-morpholinone (III): In this case, 5-chlorothiophene-2-carbonyl (IV) chloride is reacted with (25) -3-aminopropane-1,2-diol (VIII) hydrochloride to ((5) -2, 3-dihydroxypropyl) 5-chlorothiophene-2-carboxylic acid amide (IX). Next, (IX) is converted to 5-chlorothiophene-2-carboxylic acid ((5) -3-bromo-2-hydroxypropyl) amide (X), which is then reacted with 4- (4-aminophenyl) -3-morpholinone (III) to. { (R) -2-hydroxy-3- [4- (3-oxomorpholin-4-yl) phenylamino] propyl} 5-chlorothiophene-2-carboxylic acid amide (XI). Finally, it is reacted (XI) with phosgene or an equivalent of phosgene to 5-chloro-iv "- ( { (55) -2- oxo-3- [4- (3-oxo-4-morpholinyl) phenyl) ] -1, 3-oxazolidin-5-yl.] Methyl) -2-thiophene-carboxamide (I) This alternative synthesis allows an industrial-scale embodiment, however solvents or partially toxic reagents are used. In addition, these toxic substances must be separated from the final product (I) to below the upper limits permitted respectively for regulatory reasons in the product, which means an additional expense.Thus, the objective of the present invention arises, to provide a simplified procedure for the preparation of compound (I) on an industrial scale avoiding solvents or toxic reagents, especially in the last stages of the procedure. Surprisingly, it has now been found that by modifying reaction parameters determined in the synthesis known from WO-A 01/47919, the compound of formula (I) can also be prepared in larger amounts in good yield and purity. The subject of the present invention is therefore a process for the preparation of 5-chloro-V- ( { (55) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1 , 3-oxazolidin-5-yl.} Methyl) -2-thiophenecarboxamide of formula (I) by reaction of 4- hydrochloride. { 4- [(55) -5- (aminomethyl) -2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (VII) with 5-chlorothiophene-2-carbonyl chloride (IV), characterized in that the reaction is carried out in a solvent selected from the group of ether, alcohol, ketone or water or in a mixture of the using an inorganic base. Suitable solvents are, for example, and preferably: - ethers such as tetrahydrofuran, dioxane, diisopropyl ether - or methyl ether-ether; alcohols such as "methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol or tert-butanol, ketones such as methyl ethyl ketone, methyl isobutyl ketone or acetone, or water or mixtures of two or more of the solvents mentioned. Preferred as solvent are ketones or mixtures of ketones with water, especially acetone or preferably mixtures of acetone with water, Suitable alkali metal hydroxides (for example sodium and potassium) and alkaline earth metal hydroxides (for example calcium) are mentioned as suitable inorganic bases. and magnesium), alkali metal and alkaline earth metal carbonates or alkali metal and alkaline earth metal carbonates Especially preferred as inorganic bases are sodium hydroxide, sodium carbonate or sodium hydrogencarbonate, especially sodium carbonate The reaction of aminomethyloxazolidinone hydrochloride (VII) with acid chloride chlorothiophenecarboxylic (IV) is preferably carried out in a mixture of acetone / water as a solvent, using sodium carbonate as a base. In this regard, the acetone / water ratio is variable over a wide range, preferably amounts to 0.5 to 1.5 (v / v), especially 0.9 to 1.1 (v / v). In this way, on the one hand, the carcinogenic pyridine, which is used in the process described in WO-A 01/47919 as solvent and base, can be avoided. In addition, the technically expensive chromatographic purification of the product (I) can be avoided according to the invention. In carrying out the process according to the invention, an aqueous solution of sodium carbonate is preferably provided, to which acetone is first incorporated, then aminomethyloxazolidinone hydrochloride.

(VII) and then chlorothiophenecarboxylic acid chloride (IV). The addition of the reactants is preferably carried out at a temperature between 0 and 202 C, especially between 10 and 152 C. After the addition is made, the reaction mixture is then stirred at a temperature between 40 and 55 ° C, preferably at about 50 ° C. After cooling to room temperature, the product can then be isolated easily by filtration. In a preferred embodiment of the present invention, the crude product obtained by the above-described filtration of the compound of formula (I) is recrystallized with acetic acid in a subsequent step for further purification. The preparation of aminomethyloxazolidinone (VII) is carried out, as already disclosed in WO-A 01/47919, by cleavage of the phthalimide protecting group of oxadolidinonemethylphthalate (VI) with methylamine in ethanol as solvent. After carrying out the reaction, however, in a manner different from that described in WO-A 01/47919, aqueous hydrochloric acid is added at elevated temperature to the reaction mixture up to a pH value between 1 and 4, preferably between 2 and 3. The addition is carried out at elevated temperature, preferably at a temperature between 50 and 60 ° C. In this way, pure aminomethyloxazolidinone (VII) is isolated simply in the form of its hydrochloride, which thus precipitates crystalline and well filterable. The process according to WO-A 01/47919, in which the crude product aminomethyloxazolidinone (VII), obtained after the concentration of the reaction mixture, is used directly in the subsequent reaction with chlorothiophenecarboxylic acid chloride (IV ), has the disadvantage that the secondary components of this reaction, which are contained in the crude product of aminomethyloxazolidinone (VII), hinder the subsequent preparation of the final product (I) and further impurify the product (I). In contrast to this, the use according to the invention of aminomethyloxazolidinone (VII) as the hydrochloride in pure form isolated as substance in the following reaction with chlorothiophenecarboxylic acid chloride (IV), enables a better performance of the reaction, avoiding side reactions undesired and obtaining a purer product, so that expensive chromatographic purification can be avoided. The preparation of oxazolidinonmethylphthalimide (VI) is carried out, as already disclosed in WO-A 01/47919, by cyclization of the hydroxyamino compound (V) with one equivalent of phosgene, for example and preferably, with N / iV-carbonyldiimidazole. In contrast to the reaction conditions disclosed in WO-A 01/47919, the reaction is carried out according to the invention without a catalyst in IV-methylpyrrolidone or toluene, preferably in toluene as solvent, instead of in presence of dimethylaminopyridine as catalyst and tetrahydrofuran as solvent. Thus it is also possible to isolate the oxazolidinonemethylphthalimide (VI) formed by a. simple filtration, rather than by expensive chromatographic purification.

The preparation of hydroxyamine (V) is carried out, as already disclosed in WO-A 01/47919, by reacting (5) -epoxyphthalimide (II) with anilinomorpholinone (III) in aqueous ethanol as a solvent a reaction temperature of 602C. In a manner different from that disclosed in WO-A 01/47919, the ratio of ethanol / water (v / v), however, amounts according to the invention to 1: 1 to 1: 3, preferably 1. : 2 (v / v), instead of 9: 1, and it is no longer necessary to dose the reactant (II) later. ' Instead, the reaction mixture is stirred between 24 and 48 hours, preferably about 36 hours, at a temperature between 55 and 652C. In a preferred embodiment of the present invention, the reaction mixture is mixed after one to two hours of reaction with seed crystals of the reaction product (V), so that the crystallization of the reaction product begins. In a particularly preferred embodiment of the present invention, the reaction mixture is heated to reflux towards the end of the reaction time, whereby the suspension obtained remains, and then the reaction temperature is again cooled to between 55 and 50 ° C. 652C. This heating to reflux is repeated if necessary, preferably heated twice in total. The synthesis of the starting compound (S) - epoxy f talimide (II) is described, for example, in [A. Gutcait et al. , Tetrahedron Asym. 1996, 1_, 1641]. In addition, the substance is commercially available, for example in the company Daiso Ltd., Japan. The synthesis of the starting compound anilinomorf olinone (III) is described in detail, for example, in WO-A 01/47919, pages 55 to 57, or in DE 10342570.5. The individual steps of the process according to the invention can be carried out at normal, high or reduced pressure (for example, 50 to 500 kPa). Unless otherwise indicated, it is generally operated at normal pressure. The invention is illustrated in detail below by means of a preferred embodiment, to which, however, it is not limited. Unless otherwise indicated, the quantity data refer to percentage by weight. Synthesis of 5-chloro-iV- ( { (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -l, 3-oxazolidin-5-yl} methyl. ) -2-thiophenecarboxamide (I) a) 2 - ((2l?) -2-Hydroxy-3 { [4- (3-oxo-4-orpholinyl) phenyl] amino.}. Propyl) -lH- isoindol-1,3 (2H) -dione (V) 1,173 g of 2- [(25) -2-oxiranylmethyl] -lfi-isoindol-y, 3- (2H) -dione and 4- (4-aminophenyl) are mixed. -3-morpholinone (III) to 202C with 6.7 1 of water and 14.4 1 of ethanol. The suspension is heated at 58 to 60 ° C. and the formed solution is stirred for 36 hours. After 2 hours, the reaction mixture is mixed with 5 g of 2- ((2R) -2-hydroxy-3 { [4- (3-oxo-4-morpholinyl) phenyl] amino. .propyl) -lH-isoindol-1,3 (2J?) -dione (V), after which the crystallization of the product begins. After cooling to 26 ° C, the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 1.522 g, corresponds to 81.4% of theory. Melting point: 2152C. b) 2- ( { (5S) -2-0x0-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-co? azolidin-5-yl.} methyl) -lH-isoindol-1,3 (213) -dione (VT) 2.641 g of 2- ((2H) -2-hydroxy-3 { [4- (3-oxo-4-orf-olinyl) are suspended. ferj? l] ap no.} propyl) -lH-isoindol-l, 3 (2fi) -dione (V) in 221 toluene and are mixed at 192C with 1300 g of ^ N-carbonyldiimidazole. The reaction mixture is then heated to reflux and then mixed at 60 = C with 4.51 ethanol. After cooling to 25 to 30 ° C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 2,756 g, corresponds to 97.9% of theory. Melting point: 220, 52C. c) 4-. { 4- [(5S) - (Aminomethyl) -2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (VII) 1,360 g of 2- ( { (55) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin are suspended. -5-yl.) Methyl) -lif-isoindol-1,3 (2if) -dione (VI) at 22aC in 10.2 1 of ethanol, and mixed with 1,103 g of methylamine solution (40% strength). Water) . The reaction mixture is heated to 60 to 63 SC, and the formed solution is stirred for 2 hours at this temperature. After cooling to 55 to 60 aC, 2,348 g of hydrochloric acid solution (20% in water) are added in total to a pH value of 2.7, whereupon crystallization of the product begins. After cooling to 202 C, the precipitated reaction product is filtered off with suction, washed with methanol and then dried Yield: 875 g corresponds to 82.7% of the theoretical melting point: Decomposition above 2802C NMR-1H (300 MHz, d6-DMS0): 3.25 (m, 2H), 3.72 (m, 2H), 3.98 (m, 3H), 4.42 (m, 3H), 4.97 (m, 1H), 7.42 (d, 2H, J = 9.0 Hz), 7.57 (d, 2H, J = 9.0 Hz), 8.44 (sa, 3H) ppm d) 5-Chloro-1H- ( { (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -l, 3-oxazolidin-5-yl}. methyl) -2-thiophenecarboxamide (I) 1 = stage: 5-chlorothiophene-2-carbonyl chloride (IV) 3.00 kg of 5-chlorothiophene-2-carboxylic acid (commercially available) is suspended in 8.48 kg of toluene and heated to 75 to 80 ° C. 2.63 kg of thionyl chloride are added dropwise at this temperature over a time interval of 85 minutes, then stirring is continued for 30 minutes at 75 to 80 ° C. and then at room temperature Reflux until completion of the gas evolution. After cooling, the reaction mixture of excess thienyl chloride and toluene is distilled off under reduced pressure and successively increasing internal temperature (up to 60 ° C. maximum), until a solution of approx. 30% of the acid chloride in toluene. 2 = step: 5-Chloro-iV- ( { (5 _?) - 2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -l, 3-oxazolidin-5-yl} methyl) -2-thiophenecarboxamide (I), crude product 10,100 g of 4- hydrochloride are successively added to 10SC. { 4- [(55) -5- (aminomethyl) -2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (VII), 350 ml of water and 2.7 g of acetone to a solution of 464 g of sodium carbonate in 5.95 l of water. To 8 to 122C are added 2,535 g of 5-chlorothiophene-2-carbonyl chloride (IV) (30% solution in toluene) and another 517 ml of toluene. The reaction mixture is then heated at 50 ° C., mixed with 2,700 ml of acetone and stirred for a further 30 minutes at 50 to 53 aC. After cooling to 26 ° C, the precipitated reaction product is filtered off with suction and washed with water and acetone. Yield: 1,998 g of crude product containing solvent.

The residual moisture determined amounts to 24.3%, which corresponds to a calculated dry weight of 1,505 g or 98.7% of the d.t. 3rd step: 5-Chloro-jW- ( { (5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -l, 3-oxazolidin-5-yl}. methyl) -2-thiophenecarboxa ida (I), recrystallization 2.120 g of crude product containing solvent (remanent moisture 9.4%) are suspended in 12 kg of acetic acid, and heated to 110 to 1152C. The formed solution is continued to stir for 10 minutes at this temperature and, after clarification, cooled to 202 ° C. The precipitated product is filtered off with suction, washed with acetic acid and water and then dried. Yield: 1.818 g, corresponds to 94.7% of theory (based on the dry weight of the crude product). Melting point: 2302C. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (15)

1. CLAIMS Having described the invention as above, the property is claimed as contained in the following claims: 1. Procedure for the preparation of 5-chloro-iv- ( { (55) -2-oxo-3 - [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5-yl} methyl) -2-thiophene carboxamide of formula (I) by reaction of 4- hydrochloride. { 4- [(55) -5- (aminomethyl) -2 -oxo-1, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (VII) with 5-chlorothiophene-2-carbonyl chloride (IV), characterized in that the reaction is carried out in a solvent selected from the group of ether, alcohol, ketone and water or in a mixture of the using an inorganic base.
2. 2. Process according to claim 1, characterized in that the reaction is carried out in a ketone or a mixture of ketone and water as solvent.
3. 3. Method according to claim 1 or 2, characterized in that the reaction is carried out with sodium hydroxide, sodium carbonate or sodium hydrogencarbonate as the inorganic base. Four . Process according to one of claims 1 to 3, characterized in that the reaction is carried out in a mixture of acetone / water as solvent using sodium carbonate as the base. 5 . Process according to one of claims 1 to 4, characterized in that an aqueous solution of sodium carbonate is placed and the addition of the reactants is carried out at a temperature between 10 and 152 ° C., and the reaction mixture is then stirred at 50 ° C. . 6 Process according to one of claims 1 to 5, characterized in that the crude product thus obtained of the compound of formula (I) is recrystallized with acetic acid in a subsequent step. 7 The method according to claim 1, wherein aminomethyloxazolidinone hydrochloride (VII) is prepared by cleavage of the protective group fimide of oxazolidinonmethylfimide (VI) with methylapdine in ethanol as solvent, characterized in that the aminomethyloxazolidinone (VII) it is isolated as a substance in the form of a hydrochloride. 8. Process according to claim 7, characterized in that after the reaction of oxazolidinonmethylfimideimide (VI) with methylamine, aqueous hydrochloric acid is added at a temperature between 50 and 60 ° C to the reaction mixture to a pH value between 2. and 3. The method according to claim 7 or 8, wherein oxazolidinonmethylphthalimide is prepared (VI) by cyclization of the droxyamino compound (V) with a phosgene equivalent, characterized in that the reaction is carried out in toluene as solvent. 10 Process according to claim 9, characterized in that the oxazolidinonmethylfimide (VI) is isolated by filtration. eleven . Procedure of conformity with one of. claims 9 or 10, in which the hydroxyamine (V) is prepared by reacting (5) -epoxif tal ida (II) with anilinomorph olinone (III) in aqueous ethanol as a solvent, characterized in that the ethanol / water ratio amounts to 1: 2 12 Procedure in accordance with the claim 11, characterized in that the reaction mixture is mixed after one to two hours of reaction with seed crystals of the reaction product (V). 13 Procedure in accordance with the claim 12, characterized in that the reaction mixture is heated to reflux or towards the end of the reaction time twice, and then the reaction temperature is again cooled to between 55 and 65 SC respectively. 14 5-Chloro-N- ( { (55) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5-yl.} Methyl) - 2-thiophenecarboxamide of formula (I), obtainable by the process according to one of claims 1 to 13. 15. Use of 5-chloro-N- ( { (55) -2-oxo-3 - [4- (3-oxo-4-morpholinyl) phenyl] -l, 3-oxazolidin-5-yl}. methyl) -2-thiophenecarboxamide of formula (I), obtainable by the process according to one of claims 1 to 13, for the preparation of a medicament for the prophylaxis and / or treatment of thromboembolic diseases.