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    • 专利摘要:
    PROCESS FOR THE PRODUCTION OF DABIGATRAN ETEXYLATE. The present invention relates to an improved process for the production of dabigatran etexilate as well as analogous compounds of formula (7).
    公开号:BR112012011689B1
    申请号:R112012011689-4
    申请日:2010-11-06
    公开日:2021-05-04
    发明作者:Frieder GNAD；Rolf Dach；Ingo Heddesheimer；Helmut Heitger；Siegfried Meineck；Hermann Mueller-Boetticher；Stefan Schmitt
    申请人:Boehringer Ingelheim Interantional Gmbh；
    IPC主号:
    专利说明:

    BACKGROUND OF THE INVENTION
    Substituted (4-benzimidazol-2-ylmethylamino)-benzamidines, especially dabigatran etexilate (CAS 593282-20-3), are already known from the international patent application WO 98/37075, published as active substances with an inhibitory effect. thrombin and thrombin time extender. The main fields of indication for the compound of chemical formula I are postoperative prophylaxis of deep vein thrombosis and stroke prophylaxis (prevention of stroke due to atrial fibrillation, abbreviated SPAF).
    In WO 98/37075 it is proposed to produce the substituted (4-benzimidazol-2-ylmethylamino)-benzamidines by reacting correspondingly substituted (4-benzimidazol-2-ylmethylamino)-benzonitriles with ammonia. This process is very expensive according to the production technique and leads to a high load of acids to be discarded (see also WO 2007/071743, WO 2007/071742).
    The following describes an improved process for the production of dabigatran etexilate, as well as analogous compounds thereof. By switching to new starting materials, the application of phase transfer catalysis and the formation of benzimidazole without the use of copulation reagents, a significantly more efficient synthesis of dabigatran ethoxylate is obtained. The high selectivity in the copulation of intermediate products (step 2) contributes, in this case, essentially to the economy of the new synthesis route. DETAILED DESCRIPTION OF THE INVENTION
    em que R1, R2 e R3, aqui e a seguir, cada um independentemente um do outro, representa Ci.6-alquila e Hal representa cloro ou bromo, preferencialmente cloro, para 5 podem ser usados de acordo com a invenção, anidrido 5 de ácido halogenoacético 5b-1, ácido halogenoacético 5b-2, ortoésteres do ácido halogenoacético 5b-3 ou cloreto de halogenoacetila 5b-4, preferencialmente para 5 são usados anidrido de ácido halogenoacético 5b-1 ou orto- éster de ácido halogenoacético 5b-3.The present invention describes a process for the preparation of compounds of the formula 7: wherein R 1 , R 2 and R 3 , here and hereinafter, each independently of the other, represents C 1-6 -alkyl and Hal represents chlorine or bromine, preferably chlorine, for 5 can be used according to the invention, anhydride 5 of halogenoacetic acid 5b-1, halogenoacetic acid 5b-2, halogenoacetic acid orthoesters 5b-3 or halogenoacetyl chloride 5b-4, preferably for 5 halogenoacetic acid anhydride 5b-1 or halogenoacetic acid orthoester 5b-3 are used.
    Preferably, R 1 , R 2 and R 3 hereinafter each independently represent methyl, ethyl, propyl, butyl or hexyl, particularly preferably methyl, ethyl or hexyl, especially R 1 represents hexyl; R2 represents methyl and R3 represents ethyl.
    In step 1a, p-aminobenzamidine 1 and C1-6 alkyl chloroformate 2 react to form intermediate product 3 (4-aminobenzamidin-15C1-6 alkyl-carbamate).
    To that end, aminobenzamidine 1, preferably as the hydrochloride, particularly preferably as the dihydrochloride, is cooled in a polar solvent selected from the group consisting of acetone, ethyl acetate and butyl acetate, preferably acetone, to less than 40°C preferably 10 to 35°C, particularly preferably 15 to 25°C, especially 18 to 22°C. Then NaOH or a comparable base and a chloroformate 2 (R1 = C1-6-alkyl) are added. After a reaction time of about 5 to 30 minutes, preferably 10 to 20 minutes, the phases are separated.
    The mixture is concentrated and diluted with a polar solvent selected from the group consisting of butyl acetate and ethyl acetate, preferably butyl acetate, and purified with water by means of extraction.
    Then, the product is precipitated with an acetone cyanhydrin S selected from the group consisting of hydrochloric acid, oxalic acid and methanesulfonic acid, preferably hydrochloric acid and optionally washed with organic solvents selected from the group consisting of acetone, butyl acetate and ethyl acetate or mixtures thereof, preferably a mixture of acetone and butyl acetate. The preferred mixing ratio of acetone to butyl acetate is 1:1. Compound 3 is obtained as the corresponding salt of the acid S mentioned above.
    In a parallel step 1b, compound 4 is reacted with compound 5 to form intermediate product 6.
    The synthesis of benzimidazoles with activated carboxylic acids or acid chlorides by copulation reagents is known, so far, however, it has not been described with α-monochloroacetic acid anhydrides. In that case, for 5, according to the invention, the following compounds can be used: • variant 1 b-1: haloacetic acid anhydride 5b-1; • variant 1b-2: haloacetic acid 5b-2; • variant 1b-3: 5b-3 haloacetic acid orthoester, preferably of the formula Hal-CH3-C(OR4)3 (R4, independently of one another, is C1-6-alkyl, preferably, independently of one another, is methyl or ethyl), for example 2,2,2-triethoxychlorethane is mentioned; • variant 1b-4: haloacetyl chloride 5b-4.
    Where halogen (Hal) represents bromine or chlorine, this preferably represents chlorine. In all variants 1b-1, 1b-2, 1b-3 and 1b-4, previous isolation of diamine 4 (R273 = C1-6-alkyl) is not necessary. Likewise, the product solution of a reduction reaction of the nitro compound as described in the prior art (see WO 98/37075, WO 2007/071743, WO 2007/071742) can be reacted.
    For variant 1b-1, compound 4 is suspended in a cooled solvent, in which the solvent is selected from the group consisting of ethyl acetate, butyl acetate and tetrahydrofuran, preferably ethyl acetate and the temperature is less than 50° C, preferably 0 to 30°C, particularly preferably 5 to 25°C, especially 18 to 22°C. To the suspension, for example, 5b-T chloroacetic acid anhydride is added and then heated to 50 to 80°C, preferably to 55 to 75°C, particularly preferably to 60 to 70°C, especially at 65°C. After a period of 1 to 6 hours, preferably 1 to 4 hours, particularly preferably 1 to 3 hours, especially 2 hours, a weak base selected from the group consisting of potassium carbonate, sodium carbonate and is added. sodium bicarbonate, preferably potassium carbonate, at a temperature of 20 to 60°C, preferably 30 to 50°C, particularly preferably at 35 to 45°C, especially 40°C and stirred for a further 30 to 60 minutes, preferably 40 to 50 minutes, particularly preferably 45 minutes. After filtration, the filtrate is washed with a solvent selected from the group consisting of ethyl acetate, butyl acetate and tetrahydrofuran, preferably ethyl acetate, concentrated and precipitated at a temperature of 25 to 65°C, preferably 35 to 55 °C, particularly preferably at 40 to 50 °C, especially 45 °C by addition of another solvent selected from the group consisting of MTBE and tetrahydrofuran, preferably MTBE. By cooling the mixture, precipitation can be improved. The product thus obtained is washed with organic solvents selected from the group consisting of ethyl acetate, butyl acetate, MTBE and tetrahydrofuran or mixtures thereof, preferably a mixture of ethyl acetate and MTBE. After drying the filter cake, product 6 is obtained.
    Variant 1b-2: Compound 4 is added to toluene with a molecular sieve (4 Angstroms) and, for example, chloracetic acid. The mixture is heated to at most 60°C, preferably to 30 to 55°C, particularly preferably to 35 to 55°C, especially to 50°C and stirred. After a period of 1 to 8 hours, preferably 1 to 6 hours, particularly preferably 1 to 4 hours, especially 3 hours, the mixture is cooled to a maximum of 20°C and the product is precipitated. The product thus obtained is washed with toluene. After drying the filter cake, product 6 is obtained.
    For variant 1b-3, compound 4 is suspended in the polar solvent selected from the group consisting of ethyl acetate, butyl acetate and tetrahydrofuran, preferably ethyl acetate, for example, 5b-3' chloroacetic acid orthoester is added as well as optionally p-toluenesulfonic acid and then heated to 40 to 80°C, preferably to 50 to 70°C, particularly preferably to 55 to 65°C, especially to 60°C. 1 to 6 hours, preferably 2 to 5 hours, particularly preferably 2.5 to 3.5 hours, especially 3 hours, the reaction mixture is concentrated in vacuo, the residue is precipitated with a solvent selected from the group consisting of MTBE and tetrahydrofuran, preferably MTBE. By cooling the mixture, precipitation can be improved. The product thus obtained is washed with organic solvents selected from the group consisting of ethyl acetate, MTBE and tetrahydrofuran or mixtures thereof, preferably a mixture of ethyl acetate and MTBE. After drying the filter cake, product 6 is obtained.
    For variant 1b-4, compound 4 is suspended in a solvent selected from the group consisting of ethyl acetate, THF and dioxane, eg chloroacetyl chloride 5b-4' is added within 3 hours at 50°C and it is then alkalized with NaOH or a comparable base. Then, the aqueous phase is separated and the organic phase is concentrated, selected with a solvent and taken from the group consisting of butyl acetate and ethyl acetate, the phases are separated and the organic phase is concentrated again. The residue is precipitated with a solvent selected from the group consisting of MTBE and tetrahydrofuran. By cooling the mixture, precipitation can be improved. The product thus obtained is washed with organic solvents selected from the group consisting of butyl acetate, ethyl acetate, MTBE and tetrahydrofuran or mixtures thereof. After drying the filter cake, product 6 is obtained.
    Intermediate products 3 and 6 are reacted in step 2 under phase transfer catalysis and activation with iodide to form compound 7.
    The coupling of alkyl chlorides and amidines under catalysis of iodide ions is known, however, so far no selectivity of this coupling reaction has been revealed, which is why also the prior art syntheses have deviated from doubly protected amidines. Surprisingly, according to the pr°C described below, a copulation reaction can be carried out with uniquely protected p-aminobenzamidine (3) with high regioselectivity (>99.7%).
    For this, compound 3, as well as a base selected from the group consisting of NaOH, potassium carbonate and sodium carbonate preferably NaOH, are previously introduced into a mixture of an organic solvent selected from the group consisting of toluene, tetrahydrofuran, 2 -methyltetrahydrofuran, butyl acetate and ethyl acetate, preferably butyl acetate and water and heated to 30 to 65°C, preferably 40 to 60°C, particularly preferably to 45 to 55°C , especially at 50°C. Then the phases are separated and optionally the organic phase is extracted once more with water.
    The organic phase is mixed with compound 6, as well as with sodium iodide, sodium bicarbonate, tetrabutylammonium iodide, in cyclohexane and water and then heated to 30 to 60°C, preferably to 35 to 50° C, particularly preferably at 35 to 45°C, especially at 40°C. After a period of 1 to 6 hours, preferably 1 to 4 hours, particularly preferably 1 to 3 hours, especially 2 hours, the cyclohexane is distilled and butyl acetate is added and again heated to 50 to 90°C. °C, preferably at 60 to 80 °C, particularly preferably at 65 to 75 °C, especially at 70 °C for a period of 1 to 6 hours, preferably 1 to 4 hours, particularly preferably 1 to 3 hours, especially 2 hours. Then the phases are separated and optionally the organic phase is extracted with water. The organic phase is concentrated, cooled and filtered. The product thus obtained is washed with organic solvents selected from the group consisting of butyl acetate and MTBE, preferably butyl acetate or mixtures thereof. After drying the filter cake, product 7 is obtained (R1/2/3 = C1-6-alkyl).
    The selectivity and reaction rate are considerably influenced by the solvent system mentioned above. Especially when using a two-phase system of water and two different polar organic solvents, such as butyl acetate / cyclohexane, conversion is possible with excellent reaction time and corresponding product purity.
    Optionally, the compound of formula 7 can be transformed in a third step into the mesylate 8 in a manner analogous to the prior art by reacting 7 with methanesulfonic acid 9.
    na qual o radical R1 representa Ci-6-alquila, preferencialmente metila, etila, propila, butila ou hexila, de modo particularmente preferido, metila, etila ou hexila, especialmente n-hexila.Another aspect of the invention is the new intermediate products of the above process. This comprises compounds of formula 3 in which the radical R 1 represents C 1-6 -alkyl, preferably methyl, ethyl, propyl, butyl or hexyl, particularly preferably methyl, ethyl or hexyl, especially n-hexyl.
    na qual os radicais R2 e R3 cada um independentemente, representa Ci-6- alquila, preferencialmente independentemente uns dos outros, metila, etila, propila, butila ou hexila, de modo particularmente preferido metila, etila ou hexila e especialmente R2 representa metila e R3 representa etila, bem como Hal tem o significado de cloro ou bromo, preferencialmente cloro.Furthermore, the compounds of formula 6 are object of the invention. in which the radicals R2 and R3 each independently represent C1-6-alkyl, preferably independently of one another, methyl, ethyl, propyl, butyl or hexyl, particularly preferably methyl, ethyl or hexyl and especially R2 represents methyl and R3 represents ethyl and Hal has the meaning of chlorine or bromine, preferably chlorine. DEFINITIONS
    By the term "C1-6-alkyl" (also provided that they are a component of other radicals) is meant branched and unbranched alkyl groups having 1 to 6 carbon atoms and by the term "CM-alkyl" is meant branched and unbranched alkyl groups with 1 to 4 carbon atoms. To that end, there are mentioned, for example: methyl, ethyl, n-propyl, iso-propyl, n-butyl, /so-butyl, sec-butyl, fert-butyl, n-pentyl, /so-pentyl, neo- pentyl or n-hexyl. Optionally, also the abbreviations Me, Et, n-Pr, /-Pr, n-Bu, /-Bu, FBu and so on are used for the groups mentioned above. Unless otherwise described, the definitions propyl, butyl, pentyl and hexyl comprise all conceivable isomeric forms of the respective radicals. Thus, for example, propyl comprises n-propyl and /so-propyl, butyl comprises /so-butyl, sec-butyl and tert-butyl and so on.
    By an "organic solvent" in the context of the invention is meant an organic substance, of low molecular weight, which can physically bring other organic substances into solution. The condition for suitability as a solvent is that in the dissolution procedure, neither the dissolved substance nor the dissolved substance changes chemically, that therefore the solution components can be re-obtained through physical separation processes, such as distillation, crystallization, sublimation, evaporation, adsorption on the original structure. For various reasons, not only pure solvents can be used, but mixtures, which unite the solvent properties, can be used. For example, the following are mentioned: • alcohols, preferably methanol, ethanol, propanol, butanol, octanol, cyclohexanol; • glycols, preferably ethylene glycol, diethylene glycol; • glycol ethers/ethers, preferably diethyl ether, tert-butyl methyl ether, dibutyl ether, anisole, dioxane, tetrahydrofuran, mono-, di-, tri-, polyethylene glycol ether; • ketones, preferably acetone, butanone, cyclohexanone; • esters, preferably acetic acid ethyl ester, glycol ester; • amides, among others, nitrogen compounds, preferably dimethylformamide, pyridine, N-methylpyrrolidone, acetonitrile; • sulfur compounds, preferably carbon sulphide, dimethyl sulphoxide, sulfolane; • nitro compounds, preferably nitrobenzene; • halogenated hydrocarbons, preferably dichloromethane, chloroform, tetrachloromethane, tri-, tetrachloroethane, 1,2-dichloroethane, chlorofluorocarbons; • aliphatic or alicyclic hydrocarbons, preferably benzene, petroleum ether, cyclohexane, methylcyclohexane, decalin, terpene-L; or • aromatic hydrocarbons, preferably benzene, toluene, o-xylene, m-xylene, o-xylene; or corresponding mixtures. EXAMPLES
    STEP 1A: SYNTHESIS OF 4-AMINOBENZAMIDIN-N-HEXYLCARBAMATE
    Aminobenzamidine * 2 HCI (21.2 g) is dissolved in acetone (150 ml), warmed to 20°C and added with caustic soda dropwise (80 ml, 4M). At 20°C, n-hexyl chloroformate (16.5 g) is added per dosage. After re-rinsing with acetone (20 ml) stir at 5-10°C for a further 15 minutes. Then the phases are separated. The organic phase is concentrated under vacuum, diluted with butyl acetate (150 ml) and the phases are again separated. Extract again with water (40 ml) and add hydrochloric acid (9.84 ml, 32%). Waste water is distilled in the water separator and then concentrated. At 45°C, the suspension is added to acetone (150 ml), cooled to 20°C and aspirated. This is washed with a mixture of butyl acetate and acetone (100 ml). The filter cake is dried in a vacuum and 29.2 g of product 3 are obtained (97.2% of theory).
    pode ser, dependendo da variante da síntese, anidrido de ácido cloroacético 5b-T, ácido cloroacético 5b-2' ou um ortoéster de ácido clo- roacético 5b-3' ou cloreto de cloroacetila 5b-4'.STEP 1B: ESTER 6 SYNTHESIS (β-ALANINE-N-ff1-METHYL-1H-BENZIMI-DAZOL-2-CHLOROMETHYL1-5-CARBONYL1-N-2-PYRIDINYL-ETHYL it can be, depending on the synthetic variant, chloroacetic acid anhydride 5b-T, chloroacetic acid 5b-2' or an orthoester of chloroacetic acid 5b-3' or chloroacetyl chloride 5b-4'.
    Variant 1b-1: Compound 4 (28.0 g) is suspended in ethyl acetate (120 ml) at 20°C. Then, a mixture of ethyl acetate (50 ml) and 5b-1" chloroacetic acid anhydride (14.5 g) is slowly added at 20°C and then heated to 65°C. for 2 hours, potassium carbonate (15.0 g) is added at 40°C and filtered after 45 minutes.The filter residue is washed with ethyl acetate (8.0 ml) The filtrate is concentrated in vacuo and precipitated at 45°C with MTBE (150 ml).This is cooled to -2°C and filtered.The product is washed with a mixture of ethyl acetate and tert-butylmethyl ether (MTBE) (50 ml). The filter cake is dried in a vacuum and 29.6 g of product 6 are obtained (90.3% of theory).
    Variant 1b-2: Compound 4 (2 g) is mixed in toluene (20 ml) with molecular sieve (4A, 2 g) and chloroacetic acid (2.08 g). The mixture is heated to 50°C and stirred. After a period of approximately 3 hours, the mixture is cooled to less than 20°C and the product is precipitated. The product thus obtained is washed with toluene. After drying the filter cake, product 6 is obtained (30% of theory).
    Variant 1b-3: Compound 4 (4.28 g) is suspended in ethyl acetate (26 ml) at room temperature and mixed with 5b-3' chloroacetic acid orthoester (2.79 g) and acid p -toluenesulfonic acid (0.02 g) and then heated to 60°C. After stirring for 3 hours, the reaction mixture is concentrated in vacuo, the residue is crystallized from MTBE (25 ml) and filtered.
    The product is washed with MTBE (25 ml). The filter cake is dried in vacuum and 4.77 g of product 6 is obtained (95.2% of theory).
    Variant 1b-4: Compound 4 (28.0 g) is suspended in THF (80 ml). Then, within 2.5 hours, a mixture of THF (200 ml) and chloracetyl chloride 5b-4' (10.0 g) is added at 50°C and then alkalized with NaOH (2 mols/l, 50 ml). Then, the aqueous phase is separated and the organic phase is concentrated and taken up in butyl acetate. The phases are again separated, the organic phase is concentrated in vacuo and precipitated with MTBE (240 ml) at 45°C. Cool to -2°C and filter. The product is washed with a mixture of butyl acetate and tert-butyl methyl ether (MTBE) (50 ml). The filter cake is dried in vacuum and 23.3 g of product 6 are obtained (71% of theory).
    STEP 2: SYNTHESIS OF THE β-ALANIN-N-ff2fff4fff(HEXYL0XI) ESTER CARB-NYL14-AMINO1-IMINOMETYL1PHENYL1AMINO1METHYL1-1-METHYL-1H-BENZIMI-DAZOL-5-YL1CARBONYL1-N-2-PYRYDINIL
    Compound 3 (7.7 g) is previously introduced into butyl acetate (65 ml), caustic soda (25 ml, 45%) and water (25 ml) and heated to 50°C. Then the phases are separated and the organic phases are again extracted with water (30 ml). The organic phase is mixed with sodium iodide (1.54 g), sodium bicarbonate (4.00 g), tetrabutylammonium iodide (0.75 g), compound 6 (10.0 g), cyclohexane (65 ml) and water (30 ml) and stirred for 2 hours at 40°C. Then, cyclohexane is distilled under vacuum, butyl acetate (95 ml) is added and stirred at 70°C for 2 hours. Then the phases are separated and the organic phase is extracted twice with water (10 ml). The organic phase is concentrated under vacuum, the solution is cooled to 50°C and filtered. The product is washed with butyl acetate (30 ml). The filter cake is dried in vacuum and 13.8 g of product 7 is obtained (87.8% of theory). STAGE 3: β-ALANIN-N-ri2-if[4-rrr(HEXY-LOXY)-CARBONYL ESTER METANQSULFQNATQ-4-AMINO]IMINQ-METHYLlPHENYLAMINOlMETHYL-1-METHYL-1H-BENZIMIDAZOL-5-YL1CARBONYL-1 2-PYRIDINYL-ETHYL
    Compound 7 (20 g) is suspended in acetone (238 ml) at room temperature and heated to reflux. The solution is filtered to clear and rinsed with acetone (20 ml). The filtrate is cooled to 33°C and a 0°C cooled solution of methanesulfonic acid (3.0 g) in acetone (34 ml) is dosedly increased and rinsed with acetone (5.0 ml). It is then filtered by cooling to 20°C. The product is washed with acetone (54 ml). The filter cake is dried under vacuum and 22.2 g of product 8 (96.3% of theory) are obtained.
    权利要求:
    Claims (12)
    [0001]
    caracterizado pelo fato de que um composto da fórmula 6 é reagido com um composto da fórmula 3 em que nos compostos 7, 6 e 3 acima, os radicais R1, R2 e R3 cada um in-dependentemente um do outro, representa C1-6-alquila e Hal representa clo-ro ou bromo.1. Process for preparing compounds of formula 7 characterized by the fact that a compound of the formula 6 is reacted with a compound of formula 3 wherein in the above compounds 7, 6 and 3, the radicals R 1 , R 2 and R 3 each independently of the other represents C 1-6 -alkyl and Hal represents chloro or bromo.
    [0002]
    é preparado por meio da reação de um composto da fórmula 4 com um composto da fórmula 5, selecionado do grupo consistindo em ani- drido de ácido halogenoacético 5b-1, ácido halogenoacético 5b-2, orto halo- genoacetato 5b-3 ou cloreto de halogenoacetila 5b-4, em que halogênio (Hal) pode representar cloro ou bromo, em que nos compostos 4 e 6 acima os radicais R1, R2 e R3 cada um independentemente um do outro, represen-tam C1-6-alquila.2. Process according to claim 1, characterized in that the compound of formula 6 is prepared by reacting a compound of formula 4 with a compound of formula 5 selected from the group consisting of halogenoacetic acid anhydride 5b-1, halogenoacetic acid 5b-2, ortho halogenacetate 5b-3 or halogenoacetyl chloride 5b-4, wherein halogen (Hal) may represent chlorine or bromine, in which in the above compounds 4 and 6 the radicals R 1 , R 2 and R 3 each independently of one another, represent C 1-6 -alkyl.
    [0003]
    com um composto da fórmula 2 em que nos compostos 3 e 2 acima os radicais R1, R2 e R3 cada um inde-pendentemente um do outro, representam C1-6-alquila.3. Process according to claim 1 or 2, characterized in that the compound of formula 3 is prepared by reacting a compound of formula 1 with a compound of formula 2 wherein in the above compounds 3 and 2 the radicals R 1 , R 2 and R 3 each independently of one another represent C 1-6 -alkyl.
    [0004]
    4. Process according to any one of claims 1 to 3, characterized in that the radicals R1, R2 and R3 each independently of the other, represent methyl, ethyl, propyl, butyl or hexyl.
    [0005]
    5. Process according to any one of claims 1 to 4, characterized in that the radical R1 represents hexyl; the radical R2 represents methyl and the radical R3 represents ethyl.
    [0006]
    6. Process according to any one of claims 1 to 5, characterized in that the compound of formula 5 is selected from chloroacetic acid anhydride 5b-1', chloroacetic acid 5b-2', chloroacetic acid orthoester 5b -3' or chloroacetyl chloride 5b-4'.
    [0007]
    7. Process according to any one of claims 1 to 5, characterized in that the compound of formula 5 is selected from chloroacetic acid anhydride 5b-1' or chloroacetic acid orthoester 5b-3'.
    [0008]
    8. Process according to any one of claims 1 to 7, characterized in that the reaction of the intermediate product 6 is carried out with a compound of formula 3 in a two-phase solvent system consisting of water and an organic, non-miscible solvent with this one.
    [0009]
    9. Process according to claim 8, characterized in that the reaction of intermediate product 6 is carried out with a compound of formula 3 in a two-phase solvent system consisting of water and one or more solvents selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran, butyl acetate, cyclohexane and ethyl acetate.
    [0010]
    10. Process according to any one of claims 1 to 9, characterized in that compound 7 is reacted with methanesulfonic acid 9 to form a compound of formula 8
    [0011]
    em que os radicais R2 e R3 cada um independentemente um do outro, repre-senta C1-6-alquila e Hal representa cloro ou bromo.11. Compound, characterized in that it has the formula 6 wherein the radicals R2 and R3 each independently of the other represent C1-6-alkyl and Hal represents chlorine or bromine.
    [0012]
    12. Compound according to claim 11, characterized in that R2 represents methyl, R3 represents ethyl and Hal represents chlorine.
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    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-12-04| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2020-06-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |
    2020-11-17| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: C07D 401/12 , C07C 257/20 Ipc: C07D 401/12 (2006.01), C07C 257/20 (2006.01), A61P |
    2021-03-09| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2021-03-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-05-04| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 06/11/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME MEDIDA CAUTELAR DE 07/04/2021 - ADI 5.529/DF |
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    优先权:
    申请号 | 申请日 | 专利标题
    EP09176369.8|2009-11-18|
    EP09176369|2009-11-18|
    PCT/EP2010/066959|WO2011061080A1|2009-11-18|2010-11-06|Method for producing dabigatran etexilate|
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