TW200413329A - (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole, the monohydrochloride thereof, preparation thereof and the use as pharmaceutical composition - Google Patents

Abstract

The present invention relates to the crystalline forms of the compounds (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole and the monohydrochloride thereof, processes for the preparation thereof and the use thereof as pharmaceutical compositions.

Description

200413329 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to the compound (r) _2- (4-fluorenylphenylaminomethyl)-: 1-methyl_5_ [1β (& methylamino Biharanyl) _ethyl] -benzobenzoic crystalline form, and its monohydrochloride, its preparation method and its use as a pharmaceutical composition. [Prior art] Many benzimidazole derivatives are known in the prior art. Thus, for example, international patent case WO 00/01704 discloses benzimidazole derivatives, which have valuable pharmacological properties, especially antithrombotic activity, which are based on, for example, thrombin_inhibition or factor Xa-inhibitory activity. Through its pharmacological properties, the compound (R) -2- (4_ 脒 phenylaminemethyl) _ 丨 _methylcarboxamido 丨-(pyrrolidinylcarbonyl) _ethyl] _benzimidazole and its monomers Hydrochloride for the prevention and treatment of venous thrombosis in various vascular regions, including deep and superficial leg venous thrombosis, vena cava thrombosis, renal and hepatic venous thrombosis, including venous-occlusive disease, and prevention and treatment of pulmonary embolism Can treat patients with various types of transient heart disease, including acute types, such as unstable angina pectoris or acute myocardial infarction, and chronic types, such as stable angina pectoris, or patients with myocardial infarction, can prevent all vascular area circuit surgery Acute and chronic reocclusion after posterior and angioplasty (PT (C) A), and can prevent occlusion in patients with peripheral arterial disease, can treat acute stroke, chronic type of stroke in patients with post-stroke condition, and can prevent transmission Into patients with cerebral arterial stenosis. The above-mentioned benzimidazoles can also be used to treat patients undergoing renal replacement therapy. This includes anticoagulant effects during renal replacement therapy to keep the system open, and // spinal block system activation, such as those that occur in renal replacement therapy 85873 200413329 people 'in patients undergoing long-term hemodialysis, and in ongoing Vein _ Vein or Artery · Patients with chronic infiltration of veins. Therefore, patients with chronic renal failure and patients with acute renal failure can be treated regardless of the cause of renal failure. This also includes prevention and treatment of dialysis shunt blockage. The benzimidazole derivatives disclosed in the prior art have the above-mentioned pharmacological properties of the fluorene compound, which are basic prerequisites for effective use of pharmaceutical compositions. However, the license for use as a pharmaceutical product is that the active ingredient must meet further requirements. Most of these variables are about the materialized nature of the active substance. Without intending to be limited, examples of these variables are the stability of the starting material's action under various environmental conditions, the stability of pharmaceutical blending products, and the stability of the drug in the final composition. Therefore, the pharmaceutically active substance used for preparing the pharmaceutical composition has great stability ', which can be ensured even at various ambient temperatures. It is absolutely necessary for the medicinal composition used, in addition to the active substance itself, to avoid disintegration products. In this example, the content of the active substance present in the pharmaceutical blend may be lower than stated. The absorption of water vapor will reduce the content of pharmaceutically active substances due to the increase in weight caused by water absorption. Pharmaceutical compositions with a tendency to absorb water need to be protected from water during storage. If a suitable tincture is added, it must be stored in a water-resistant environment. In addition, if the music is exposed to the environment without any fumigation furnace, the content of pharmaceutically active substances will be reduced due to water absorption during manufacture. The better pharmaceutically active substance in the mouth should only be slightly hygroscopic. Because the crystal modification of the active substance Tian 3 τ is 10,000; it is very important that the preparation 芡 reproducible active substance contains guest 疋, so any polymorphism of the active substance in the crystal form 85873 200413329 should be clarified as much as possible. If there are different polymorphic modification of active substance f, care should be taken to ensure that the crystal modification of the substance will not be changed in the pharmaceutical preparation made by him. In addition, this has a deleterious effect on the reproducible strength of the drug. For comparison with the background, active substances characterized by only slightly polymorphisms are preferred. Depending on the blend used or the manufacturing process selected, another important rate under certain conditions is the solubility of the active substance. For example, if a pharmaceutical solution is preferred (e.g., for infusion), the active substance should be substantially soluble in a reasonably acceptable solvent. If the drug is to be taken orally, it is also important that the active substance is sufficiently soluble. The problem of the present invention is to propose a pharmaceutically active substance, which not only has high pharmacological strength characteristics, but also meets the above-mentioned physicochemical requirements as much as possible. [Summary of the Invention] Surprisingly, it has been found that the problems listed above can be solved by the compound of formula (R) _2_ (4-fluorenylanilinemethyl) 4-methyl_5-1 > (carboxymethylamino) _i_ (pyrrole Burning carbonyl) _ethyl] -benzimid.

The monohydrochloride according to the present invention is characterized by a high degree of stability in a physiologically acceptable solvent and a high solubility. 85873 200413329 according to the compound (R) _2_ (4_ 脒 anilinemethyl group) according to the present invention ―methyl-5_ Π- (¾methylamino) -1- (pyrrolidinylcarbonyl > ethyl) mono salt Acid salt crystal form, characterized by having a melting point of Tm.p 222 ° c and 5 ° c (determined by DSO differential scanning calorimetry 'depends on the beginning; heating rate: 〇. 0 / min). Values shown

DSC% 21 by Messrs Mettler Toledo decided. Therefore, a subject of the present invention is the compound (R) _2_ (4-fluorenylanilinemethyl) -1-methyl-5- [1- (retylamino) -1- (pyrrolidinylcarbonyl) _ethyl ] _ Benzomidol crystalline monohydrochloride: characterized by having a melting point of Tmp = 22: rc ± 5t: i. (R) -2- (4-Amanilidenimethylmethyl) -methylmethyl · tl_ (carboxymethylamino) -1- (pyrrolidinylcarbonyl) -ethyl] -benzimidazole monosalt according to the present invention The crystal form of the acid salt is examined more closely with χ_ ray powder diffraction. The resulting pattern is shown in Figure 1. Table 1 summarizes the data obtained in this analysis: Table 1: (R) -2- (4-fluoranilidine (Methyl) -1_methyl ^-[丨 ((carboxymethylamino) __ (pyrrolidinylcarbonyl) -ethyl] -benzimidazole-monohydrochloride 1-ray powder reflection and intensity (standardized ) Is

200413329 On the table! In ,,, 2Θ [. ] " value represents the diffraction angle in degrees, and "'[A] " value represents the detailed distance between the lattice planes in A. Within the scope of the present invention, the X-ray powder map is used This "d8 advanced diffractometer to record, it is equipped with a sensitive detector (OED) for its location, and has a copper anode as the source of X-rays (^ dagger radiation, input = 1.5418 A, 30 kV, 40 mA). According to the data shown in Table 1, it is found that the present invention is related to the crystalline form of () 1) _2_ (4_fluorenylphenylmethyl) The benzimid 4 · monohydrochloride 'is characterized by χ-ray powder diagrams, and particularly has the characteristic data of .31, 6.07, 5.14 and 3.72. Compound (R) _2_ (4_ 脒 phenylaminomethyl) _ 丨 _methyl-5 · [W jimethylaminoΗdecapyrrolidine ethyl] _Benzimid crystalline single Hydrochloride occurs in a hydrate type, which depends on the relative humidity and contains about 3.0% to 6.5% of water. Through its structure, the compound can absorb crystal water and can be released again, and the crystal structure is substantially unchanged. Furthermore, the monohydrochloride according to the present invention may form a solvate with an organic solvent such as ethanol. The two themes of S invented by the invention are the preparation of (r) _2 | methylbenzyl) small methylimidoamine) "debihalolyl) · ethyl] benzom! | Salt salt method of crystallizing salt, the method includes the following steps. The starting material is (R) -2- (4_m! 个 妆 τ 暴) _ 丨 _ τ 丞 基] 七 比 钱 裂 基) -Ethyl] -benzimidazole, formula (π), described 00/01704: '85873 200413329

The free-state primary amine group is, for example, equivalent; preferably about 12 equivalents, the compound of the following formula is calcined

r ~ KX OR, (III) where R represents not a Cw alkyl group, and χ represents a leaving group, such as a halogen atom, such as chlorine, bromine, or moth atom, p-toluenesulfonyl or methanesulfonyl, where Ethyl bromoacetate or n-propionic acid bromoacetate is preferred, and it is present in organic solvents or solvent mixtures. Suitable solvents in accordance with the present invention include ethyl acetate, 'Ethyl n-propyl ester', N-methyl p-bilonidone, dimethylformamide, dimethylacetamide, or mixtures thereof. According to the invention, a solvent mixture consisting of N-methylpyrrolidone and ethyl acetate or n-propyl acetate! Is used. Suitable bases include, for example, tertiary amines, such as diliter propylethylamine (Htinig base) or triethylamine, in an amount of 1 to 2.5 equivalents. The reaction is better. (: Mixed with the solvent at the boiling point of the poplar, such as between 0C and 150 ° C, preferably between 10.0 and 30 ° C. The reaction mixture is purified by aqueous extraction and evaporated in the organic solvent part After the formation of crude (R) -2- (4-cyanoanilidemethyl) -1-methyl-5- [l- (n-Cu-alkoxycarbonylmethylamino) -i_ (pyrrolidine Carbonyl) _ethyl] -benzimidazole concentrated solution-11-85873 200413329

, (ιν). wherein R represents Cu alkyl. Step (b): The concentrated solution of the crude compound of formula (IV) obtained in step (a) is dissolved in Ci-3 · alcohol as a solvent, and hydrogen chloride gas is pipetted, and the reaction is carried out under cooling (better temperature) Below about 20 ° C, an intermediate imine ester can be produced. According to the present invention, 'methanol is preferred' or n-propanol is the alcohol, and the choice of solvent depends on the ester of formula (IV) used Once, all the hydrogen chloride gas is sucked into the reaction mixture 'stir it until the reaction is completely between 0 and 30, preferably at about 20 C. Imine conversion-or-under "Formula- m— ~~ ------------------

Where R represents Cu · sintered group, which is carried out under cooling, preferably at a temperature between 0 ° C and 4 (rc, preferably between 15 and 40 ° C, and is reacted with ammonia in Ci · 3 · alcohol, preferably It is methanol, ethanol, n-propanol ... Once the reaction is over, it is necessary to dechlorinate it as needed to obtain it. This is after the solvent is partially distilled. Compound (V) can be in the form of a hydrochloride in the middle of the process. 85873 -12 -200413329-toluene sulfonate is directly separated. (See: see step-off, or general formula (IV) vs. C). Step (c) Intermediate compound (R) -2- (4-Phenylphenylamine) Methyl (n-Ci3-koxy ^ ylmethylamino) (pyrrolidinylcarbonyl) _ethyl] _benzimidazole, formula (V) 'Acid according to the present invention in the form of a sulfonate, such as benzene -, Para-toluene_ 'para-chlorobenzene-, 1- or 2-fluorene sulfonate, preferably of the general formula (VI)

Where R represents Ci · 3 · carbon, which allows the compound to be easily separated from the aqueous medium. 'The further purification of the para-toluenesulfonate of the compound of the general formula (VI) is carried out by dissolving and immersing the salt in an aqueous medium under pH control, or by suspending it in water. Step House X ^ · In order to prepare the free-form base (R) -2- (4-fluorenylphenylaminomethyl) ^-5 _ [[1- (carboxymethylH) -M-pyrrolidinylcarbonyl) _ Ethyl] _benzene

85873 -13. (VII) 200413329 In organic solvents, isopropyl alcohol, or, preferably, the para-toluene salt corresponding to the general formula (VI), is dissolved in suitable organic solvents including, for example, alcohols, Such as methanol, ethanol, polar solvents' such as Nm phases or dimethylformamide or ethanol. "After adding h5_3 equivalents, preferably 2_2.5 equivalents to the solution, suitable tests in the scope of the invention include steel hydroxide, hydrogen, and tests. Chemical bell and barium hydroxide. The reaction mixture can be reheated and the milking process can be accelerated. Preferably, the reaction mixture is added with 1 to 3% under full mixing, and the degree of recovery is determined by the boiling point of the solvent used. The preferred temperature is 30 ° C and 80 ° C. 〇between. After that, 0.5 to 2 equivalents, preferably 5 equivalents of acid, and more preferably para-toluene acid are added. If sodium hydroxide is used as the test, the product of formula (VII) can be obtained directly by crystallization. In the case of unloading with hydroxide, the p-toluton's unloading salt can be crystallized and unfolded first. The desired product of formula (νπ) is then crystallized. Step [eh] In order to prepare the crystalline monohydrochloride according to the general formula ⑴ according to the present invention, the test (VII) in step ⑷ is performed or dissolved in a suitable organic solvent or solvent mixture. Tejiaxin solvent 'according to the present invention includes methanol, ethanol, n-propanol, propylpropanol, acetone, metformamidine or N-methylpyrrolidone. A certain amount of water can be added as a latent solvent. The reaction mixture is then heated to between 201 and the reflux temperature of the solvent, preferably between 30 c and 80 c. According to the present invention, chlorinated rat or rat murine fel dissolved in an organic solvent is added to a solution or suspension. 85873 -14- 200413329 In accordance with the present invention, 0.8-1.2 mol, preferably about 1 mol of hydrogen chloride is added per mol base. Once the acid has been added, the suspension is cooled to between 0 ° C and 40 ° C, preferably between 20 ° C and 25 ° C, and the product is filtered off. The second subject of the present invention is related. The method described above can be obtained as a crystalline (R) _ 2- (4-fluoranilinomethyl · methyl_5_tl_ (carboxymethylamino) _ 丨 _ (pyrrolidinecarbonyl group). ) -Ethyl] -benzimidazole-monohydrochloride. The fourth subject of the present invention is the compound (R) _2_ (4-fluorenylphenylaminomethyl) methyl_5_ [1 carboxymethylamino)- ^ (Pyrrolidylcarbonyl) -ethyl] -benzimidazole is a crystalline monohydrochloride, which is used as a pharmaceutical composition based on its pharmacological activity. The para-toluenesulfonic acid of formula (VI) obtained as an intermediate in the above method is used to prepare a crystalline form of formula (I) (R) -2- (4-fluorenylphenylmethylmethyl) -methyl ^- [BU 丨 Carboxymethylamino) 1 (Erocarbon) -ethylbenzobenzyl mono-hydrochloride, a very valuable intermediate product. Therefore, the fifth subject of the present invention includes the para-toluenesulfonate of the general formula (VI): ⑴ (R) -2- (4- 脒 phenylaminemethylmethyl (Pyrrolidinylcarbonyl) -ethyl] -benzimidazole_p-toluenesulfonate (2) (R) -2_ (4_adenophenylaminemethyl)] _ methylquintas- (ethoxy A few methylamino groups) _ 1_ (pyrrolidinylcarbonyl) -ethyl] -benzimidazole-p-toluenesulfonate, and (3) (R) _2- (4-fluorenylphenylamine methyl H • Methyl (n-propoxymethylamino) -1- (pyrrolidinylcarbonyl) -ethyl] • benzimidazole_p-toluenesulfonate. Free base (R) -2- (4- 脒The crystalline form of phenylaminofluorenylmethyl _5_π_ (carboxymethylamino carbonyl) · ethyl] benzimidazole is a direct precursor of the preparation hydrazone monohydrochloride, and also has the pharmacological activity described above. The sixth subject is the free state test (R) _2_ (4-Phenylaminemethyl) i_methyl85873-15-200413329yl-5- [l- (carboxymethylamino) -1- (pyrrolidinylcarbonyl) -Ethyl] -benzimidazole crystal form, characterized by melting point Tm.p = 241 ° C ± 5 ° C (by DSC = differential scanning: tracing calorimetry; determined by the beginning; heating rate = 10 ° C / Minutes). Shown The value given is determined by D $ C 821 produced by Messrs Mettler Toledo. The free state base (R) -2- (4-fluorenylphenylmethyl) -1-methyl-5- [1- The crystalline form of (carboxymethylamino) -1- (pyrrolidinylcarbonyl) -ethyl] -benzimidazole was examined in more detail by X-ray powder diffraction. The resulting pattern is shown in Figure 2. Table 2 is shown below To sum up the data obtained in this analysis: Table 2: (R) -2- (4-fluorenylphenylmethyl) -1-methyl-5- [l-carboxymethylamino] -1- ( X-ray diffraction and intensity (standardized) of pyrrolidinecarbonyl) -ethyl] -benzimidazole ¢ .- 2 Θ [°] dhkl [A]: intensity 1/1 10 [%] 2Θ [.] Dhkl [ A] 丨 Intensity I / Iq [%] 7.331 12.04817 11.9 21.500 4.12969 15.8 10.804 8.18223 7.5 22.240 3.99395 7.9 11.572, 7,64093 12.3 23.308 3.81335 '19.4 12.312 7.18300 4.2 23.738 3.74525 9.4 12.976 6.81712 7.6 24.308 3.65862: 8.2 13.726 6.44632 5.9 24.890744 8.3 14.295 6.19076 17.9 25.131 3.54076 7.9 14.726 6.01067 100.0 26.503 3.36044 4.7 15.365 5.76201 6.7 27.204 3.27547 7.3 17.168 5.16080 29.4 27.786 3.20815 9.6 18.014 4.92041 11. 3: 28.530 (3.12608 7.5 18.309 4.84161 1 9.2 29.678 3.00774 6.3 19.168 4.62671 7.1 30.962 2.88589 5.0 20.224 4.38744 8.8, 32.412 2.76004 4.3 In Table 2 above, "2 Θ [° Γ indicates the diffraction angle in degrees, and" "dhkl [A]" indicates the detailed distance in A between the lattice planes. -16-85873 200413329 The recorded X-ray diffraction powder map is made using Bruker, which is equipped with a sensitive detector that is sensitive to the position. D8 advanced diffractometer () within the scope of the present invention and can be an x-ray source Steel positive electrode (CuKa radiation, Λ = 1.5418 30kV, 40 mA). According to the findings in Table 2, the present invention relates to the crystalline form (R) _2_ (4_fluorenylaminomethyl) 1methyl-5- [1- (carboxymethylamino) _b (pyrrolidinecarbonyl) _ Ethyl] -benzimidazole, which has the characteristics of & ^ Α, 6 〇1 Α '5 · 1 6 A, 4 · 1 3 A, and 3 · 8 1 A in the X-ray powder chart. Value. The present invention further relates to the crystalline form (R) _2_ (succinylphenylaminemethylbumethyl-5- [1- (carboxymethylamino)-丨-(pyrrolidinecarbonyl > ethyl) -benzimidazole, based on The invention can be used as a pharmaceutical composition because of its pharmaceutical activity. Free state test and equivalent g hydrochloride stress condition state stress stability data stress variable temperature temperature and relative humidity light storage method open glass dish open Glass m open glass dish 105 ° C 70 ° C; about 90% relative humidity solar tester 氤 lamp storage time 24 hours 3 days 22-24 hours Decomposition (&1; 1%) About 4% decomposition-about 1% decomposition [Performance method] The HPLC data shown in the experimental part is measured under the following variables, unless there is another column: Prontosil 120-5- C18AQ, 5 micron, 125x4 ^; Do, solvent A · 0.2% aqueous solution of K 2 PO 4, adjusted with 1M NaOH to PΗ = 5 5 · a ^ ·), each agent B: acetonitrile; column temperature: 45 ° C; flow rate: 1 ml / min, gradient system silk ^ ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Gradient to 60% solvent B in 14 minutes, 80% solvent B in 4 minutes; concentration of sample solution j mg / ml in acetonitrile / water = 7: 3; injection volume: 1 μl; at 220 nm Measurements: Example 1: (R) -2- (4-fluorenylphenylaminomethyl) -1-methyl-5- [1- (n-propoxycarbonylmethylamino)-1-〇biloryl carbonyl) _Ethyl] -benzimidazine-p-toluate 442 g (2.09 mmol) n-propyl bromoacetate was poured into 700 g (1.74 Mol) (R) _2- (4-cyano Phenylamine methyl) · 1-methylamino (pyrrolidinylcarbonyl) -ethyl] -benzimidazole and 700 ml of diisopropylethylamine in 4 liters of N-methylexordinone and 1.4 liters of n-propyl acetate solution within 15 minutes at 20 ° C. The reaction mixture was stirred at 20 ° C for 14 hours. Add 2.1 liters of n-propyl ester and 5.6 liters of water. The mixture was cooled to 20 ° C and the aqueous phase was separated. 3.5 liters of water was added to the organic phase, and 30% hydrochloric acid was added to make ρΗ = 5.8. The aqueous phase was separated, and 3.5 liters of water and 105 g of sodium chloride were added to the organic phase with stirring. The water phase was separated again. The organic phase was concentrated by evaporation under reduced pressure using a rotary evaporator. To the resulting oil, 0.9 liters of n-propyl acetate and 3.5 liters of n-propanol were added. The other 3 liters of solvent were distilled off under reduced pressure. Add 3.5 liters of n-propanol to the residue and cool to -15 ° C. Inhale 1.92 A kg of chlorinated gas into this solution so that the temperature does not exceed 8. Once the introduction of the gas was completed, the reaction mixture was stirred at 20 ° C for 20 hours. The post-cardiac reaction solution was cooled to 10 t again. The reaction solution was stirred to 4 53 liters 25 /. Ammonia solution in 7 liters of n-propanol solution was cooled to -20. 〇, while maintaining the temperature at 20 ° C. The reaction mixture was stirred at 24 ° C for 16 hours 85873 -18- 200413329. 5.8 liters of the solvent were removed by distillation under reduced pressure. The reaction mixture was cooled at ° c 'and filtered under pressure. Pressurized filter with 3.5 liters of hot n-diol, priority. uL of solvent was removed from the filtrate by evaporation in a rotary evaporator under reduced pressure: the remaining residue was suspended in 7L of acetone while heating and refluxing. The suspension was cooled to o ° C and stirred at this temperature for i hours. The suspension was evacuated and washed with v2 · 8 liters of acetone. The filter block is dried under a circulating air dryer of 5 (rc.% 1.23 kg of (R) -2- (4-fluorenylphenylmethylmethyl-5_ [η 『_propoxycarbonylmethylamino) -1 -(, Bicylcarbonyl) _ethyl] benzimidazole-hydrochloride., HPLC: Rf = 9.9 min (product)

Rf = 12.9 minutes (dialkylated agent product) in the para position_toluene acid 骧 increased to avoid 1. 2 2 kg of the above crude hydrochloride dissolved in stirring 丨 〇5 liters of n-propanol and 5.6 liters of water and heat to 55 ° C. To this solution was added a solution of 53 g of para-mesymesulfonic acid monohydrochloride and 146 ml of 50% sodium hydroxide in 4.2 liters of water. The resulting mixture was cooled to 0 ° C and stirred at this temperature for 30 minutes. Suspend was suction-filtered and washed with 3.5 liters of water. The filter block was dried under circulating air at 5 ° C. 0.70 kg of the title compound para-methyl salt was obtained as a crude product. ^ HPIX: H 6 minutes (para-toluenesulfonic acid)-~ 9 · 9 minutes (product)

Rf 2.9 minutes (byproduct of double-baking) from the mother liquor to 25. /. Adjusting the pH of ammonia to 7.5 can separate 0.19 kg of product. Total yield _ · 0 · 89 kg (73% of theoretical value) 85873 -19- 200413329 The p-toluate salt of the above-mentioned M kg of crude product was dissolved in 2 Mg, and the amount was less than moderate. Add 151 grams of fresh_toluene acid and milliliter of Zhejiang acid. At this time, the solid is dissolved in the solution, and the pw4 gas p is added to 25% ammonia solution to make the pH #) to 4 (about 170%). Rise). The resulting suspension was stirred at 20 ° C and filtered out at 9 ° C / 12 ° C (a by-product of double burning). The filter block is washed with 2.2 litres of water. Add 1.54 liters of n-propanol to the filtrate, and pump 13 () ml of aqueous ammonia solution. The suspension was stirred overnight at 20 ° C. The Shen Dianwu was vacuum filtered, and it was washed with 3.3 liters of water. Filter block at 50. . Dry in a circulating air dryer. &Quot; 3 kg (76 ° / 〇theoretical) of the title compound. HPLC: R 3.6 min (para-toluenesulfonic acid)

Rf = 9.9 minutes (product) by the method of preparing free state test, & hydroxide dissociation, starting from the para-toluenesulfonate (R) -2- (4-fluorenylphenylamine) of n-propyl ester Group) + methyl_5_π_ (carboxymethylamino) small (pyrrole carbonyl) -ethyl] -benzimidazoline

To 27.7 g (40 mmol) (R > 2- (4 ^ phenylaminemethyl) -1_methyl-5- [l- (n-propoxycarbonylmethylamino) ·: [_ (pyrrolidine Carbonyl-ethyl) _benzimidazole_para-toluenesulfonate in 134 ml of methanol solution, 3.36 g (84 mmol) of sodium oxide was added, and the mixture was refluxed for 3 hours. Add $ 37 g (44 millimolar) of para-toluenesulfonic acid-hydrate, and the mixture was refluxed for another 5 hours. The valley liquid & but soil 4 0 C 'was passed through (clear filtration). 170 ml of methanol was added and re-planted. The resulting suspension was stirred overnight at 20 ° C. Suspended 85873-20-200413329 was suction-filtered and the filter cake was washed with 60 ml of methanol. 〇t drying in a circulating air drying oven. The title compound was obtained as a crystalline solid. Yield: 13.8 g (72% of theory) Melting point: Tm.P = 249 ° C ± 5 ° C (decomposition, DSC, use Evaluation started, heating rate: 10 ° C / min) t Example 3: Method for preparing free state from esters, using sodium hydroxide dissociation, starting from n-propyl ester hydrochloride phenylamine methyl) -1 · Methyl-5 1_ (Carboxymethyl, some chlorhexylcarbonyl, ethyl, 1-benzimidium to 93.9 g (0.15 mole), (R) -2- (4-fluorenylphenylamine methyl pi-methyl_5_ [1- (Positive " 'propoxy and methylamino) -1- (0 than glutamyl) -ethyl] -benzoyl η-salt edge salt X 1 equivalent of n-propanol in 470 ml of methanol To the solution, 13.3 g (0.33 ng) of sodium oxidized solid was added, and the mixture was refluxed under inert gas pressure for 1.5 hours. It was allowed to cool to 5 rc, and 22.8 was added dropwise over 10 minutes. Mao liter (0.18 mol) of chlorotrimethyl sulfite. The mixture was diluted with 470 ml of dimethyl sulfoxide, and then 370 ml of methanol was distilled off at 300 mbar / 8 (rc). To eliminate sodium chloride, The suspension was filtered while hot. The filtrate was cooled to 20 t: and stirred at 20 C for 3 hours. The resulting suspension was vacuum filtered and the filter cake was washed with 50 mL of sulfoxide and 100 mL of acetone. The filter block was dried in a circulating air drying cabinet at 5 ° C. The title compound was obtained as a colorless solid. Yield: 58.8 g (81% of theory) For further purification, the product thus obtained can be crystallized from methanol. Melting point · Tm .P = 24rC ± 5 ° C (decomposition, DSC, evaluated from the beginning, heating rate: 10 ° C / min) 85873 -21- 200413329 _ [Example 4: Method for precipitating monohydrochloride from free state alkali ( R) -2- (4-fluorenylphenylaminemethyl)-; 1-methyl-5- [1_ (carboxymethylaminob (pyrrolidinecarboxyl) -ethyl] -benzimidazole-monohydrochloride Salt 11 g (23 pen moles) (r) -2- (4-Phenylaminemethyl) _ 丨 _methyl_5_ [丨 _ (carboxymethylamino) -1- (pyrrolidinyl) A suspension of _ethyl] _benzimidazole in 88 ml of methanol was heated to 35 C-40 ° C. To this suspension was added 8.4 ml of a solution of 2.75 moles of hydrogen chloride (23 mmol) in ethyl acetate. The starting material was dissolved and the hydrochloride began to crystallize out. The suspension was cooled to 20 ° C. 〇Re-vacuate and filter. Filter block at 35. (: Dry in a vacuum drying cabinet. 92 g (78% of theory) of the title compound can be obtained as a crystalline solid. In order to eliminate trace amounts of methanol, 4 g of the above was obtained; ^ Vietnam compounds were suspended in milliliters Stir in ethanol for 30 minutes at μ. The suspension is cooled to 2nd generation, and then filtered under vacuum. The nuggets are washed with ethanol and dried in a 35 ° C vacuum drying cabinet. Yield: 7.3 g (Based on the hydrochloride used, 91% of the theoretical value) Less points: Tm.p = 222 ° C ± 5 ° C (decomposition, DSC, after evaluation, heating rate: 10 ° c / min ): (R) -2- (4-fluorenylphenylaminomethyl) -1-methyl (ethoxycarbonylmethylamino (t-tolylcarbonyl) -ethyl) -benzimidazole-para-toluene Acid salt 4-22 kg (10 · 5 mol) (R) -2- (4-cyanoanilinemethyl) _methylamino- (pyrrolidinecarbonyl) -ethyl] -benzimidazole and 311 kg ( 241 mol) Diisopropylethylamine is dissolved in a mixture of 8.4 liters of N-methylpyrrolidone and 8.4 liters of ethyl acetate at 22-85873 200413329. Measure 2 ·! Kg (12.6 mol Ethyl bromoacetate, and the mixture was stirred at 2 (TC for 15 hours) Add 34 liters of water. Separate the aqueous phase. Add η liters of water to the organic phase, and adjust the pH to 孓 7 from the addition of hydrochloric acid (30%). Separate the aqueous phase and the organic phase with 0.42 kg of sodium chloride. The solution was washed with 21 liters of water. The organic phase was concentrated under reduced pressure (distilled off 10.6 liters of ethyl acetate). The concentrate was diluted with 42 liters of ethanol and concentrated under reduced pressure (distilled off) at π C Then, 15 kg (411 moles) of hydrochloric acid gas was sucked into the resulting solution, and stirred at 20 ° C until the reaction was completed (the reaction to obtain the imide ester was tracked by HPLC). The amine ester solution was diluted with liters of ethanol. 37.8 kg (555 mol) of ammonia solution (25%) was added to the solution so that the temperature did not exceed 40 ° C. The solution was stirred for another 2 hours. The ammonium chloride formed was passed through Add to a filter and filter, and filter the material with 30 liters of ethanol. Remove 42 liters of ethanol from the filtrate and remove it under reduced pressure. Add 3 86 kg (20-3 mol) of para-toluenesulfonic acid to the filtrate. A solution of the hydrochloride in 17 liters of water. Add another 20 liters of water. Adjust the pH to 8 with sodium hydroxide solution. Leaving the

The ethanol was removed under reduced pressure. Yu steamed out the crystallizable product. The pH was adjusted to 7.5 with a sodium hydroxide solution (50%), and the resulting suspension was cooled to 3 c. The product was centrifuged out and washed with 13 liters of water. The product was at 50. 〇The drying in the cabinet. This gave 4.89 kg (69% of theory) of the title compound as a crude product. 4.75 kg of the crude product of p-gallate was suspended in liter of water. The suspension was at 20 ° C. 〇 Stir for 2.5 hours. The suspension was centrifuged and washed with 19 liters of water. The product was dried in a drying cabinet at 50 ° C. The title compound was obtained in an amount of 3 · kg (81% of theory). 85873 -23- 200413329 HPLC: Rf = 3.6 minutes (para-toluenesulfonic acid) Rf = 17.6 minutes (product) Solvent A: 0 · 3% Column: Inertsil 〇DS_2, 5 microns, 125 × 4 · 6 mm ΚΗ2ρ〇4 Aqueous solution, adjusted with 1M NaOH to ρM = 50. Solvent acetonitrile; column temperature value; flow rate = 1ml / min; gradient system: start to pass through solvent B; gradient to 25% solvent β within 20 minutes, β. Gradient to 50% solvent B within 1 minute; concentration of sample solution: 2 mg / ml at 2 g / ml = 7: 3; injection volume · 3 microliters; detection at 2 17 nm. Gallium: A method for preparing a free-state base from vinegar, dissociating with potassium hydroxide and starting from the para-toluenesulfonate of ethyl ester (R) -2- (4- 脒 phenylaminemethylΗmethyl) _5_π_ (Carboxymethylamino) small (errocenyl) -ethyl] -benzoyl TJ sits 3.7 kg (5.49 moles) (feet) _2- (4_fluorenylaminomethyl) _1_form _5_ [1_ (ethoxycarbonylmethylamino) _1decylpyrrolidinecarbonyl) _ethyl] _benzimidazole_para-toluate is dissolved in 7.4 liters of TC. To this solution was added a solution of 0795 kg (12.8 mol) of hydroxide powder in 5.6 liters of methanol, and then rinsed with 1.8 liters of methanol. The mixture was stirred at 4 ° C for 2.5 hours. Para- The potassium salt of toluene j acid crystallized out. 137 kg (7.2 moles) of para-toluenesulfonic acid in a solution of early hydrate in 2.8 liters of methanol was added to the suspension, which was then rinsed with 18 liters: alcohol 'And cooled to 22t. Use a pressure filter and a filter to separate the para-methyl benzoic acid " L gas potassium salt' and the filter block was washed with 7.4 liters of methanol. The filtrate was seeded into the title mouthpiece and 彳See overnight. The precipitated product was filtered under vacuum under argon, washed with 3.7 liters of methanol, and recycled. Into the reactor while still moist. Add 85873 -24- 200413329 1 8_5 liters of methanol, and the suspension was refluxed for 1 hour and cooled to 22.0. The product was vacuum filtered under argon, washed with 3.7 liters of methanol, And dried in a circulating air drying oven at 30 ° C. 2.22 kg (85% of theoretical value) of the title compound can be obtained. Melting point: Tm.P = 241 ° C ± 5 ° C (decomposition, DSC, use the start to evaluate Addition or rate -10 C / min, as measured by Messrs Netzsch-Geratebau GmbH of DSC 204) Example 7: Method for Precipitation of Monohydrochloride from Ethanol (R) -2- (4-Aminophenylaminemethylmethyl) _5_π- (Carboxymethylamino) _ 丨 _ (Pyrrolidinyl) -ethyl] -Benzotoxin_monohydrochloride ------------ 5.0 g (R) _2- (4-Fluorophenylaminemethylmethyl · (carboxymethylaminobubyl (pyrrolidinecarbonyl) -ethyl] -benzimidazole) is refluxed in 25 ml of ethanol. It can be obtained by adding 2 liters of water The solution. The solution was clarified by filtration (the filtrate was rinsed with 25 ml of ethanol. The filtrate was heated to 70 ° C. A solution of 0.802 ml of concentrated hydrochloric acid in 25 ml of ethanol was added, and another 25 ml of ethanol was added. The mixture was cooled to 25, and at this temperature The mixture was stirred for 1 hour. The product was filtered off, washed with 5 ml of ethanol, and dried in a circulating air drying oven. It can be reduced to 4.95 g (92% of theory) of the title compound as a crystalline solid. Melting point ·· Tm.p = 220 ° C ± 5 ° C (decomposition, DSC, start evaluation, heating rate = 10 ° C / min) [Simplified illustration of the figure] Figure 1 shows compound (R) -2- ( 4-Aminophenylamine methyl) _1_methyl-5_ [丨 _ (retylamino) -1- (pyrrolidinecarbonyl) · ethyl] _x-ray powder of benzimidazole crystalline monohydrochloride Diffraction map. 85873 -25- 200413329 Figure 2 shows the compound (R) -2- (4-fluorenylphenylmethyl) -1-methyl-5- [l- (carboxymethylamino) -1- (pyrrolidinecarbonyl) X-ray powder diffraction pattern of) -ethyl] -benzimidazole crystalline compound. 26- 85873

Claims (1)

200413329 The scope of patent application: K A kind of crystalline (to) -2- (4-fluorenylphenylaminomethylbenzene-methyl-5_ [1- (carboxymethylamino) -1- (P ratio P Each ethyl group) -ethyl] -benzimidazole-monohydrochloride, the specific purpose of which is the melting transition of Tm p = 222 + 5 C, and its hydrate and solvating agent. 2. According to the patent application Crystalline (R) -2- (4-fluorenylphenylaminomethyl) _ ^ methyl-5- [1- (carboxymethylamino) -1- (pyrrolidinylcarbonyl) _ethyl Bubenzimidamidine-monohydrochloride is characterized in that it has characteristic values of d = 6.31 A, 6.07 A, 5.14 A, and 3.72 A in the X-ray powder chart. 3. One (R) -2 -(4-fluorenylphenylaminomethyl) _1-methyl (carboxymethylaminomethyl; μ «Biol carbonyl) -ethyl] -benzimidazole-monohydrochloride, comprising: The following steps: (,), (a) calcining the compound of formula 111 (R) -2- (4 • cyanoanilinemethyl) · 1-methyl-5- [1- (amino-1--1- ( Pyrrolidine carbonyl) "ethyl) _free benzimidazole: r 1 " ---------------, one h3c, νη2 h3c , (III) where R represents a Cw alkyl group, and χ represents a centrifugal group, so that the general compound 85873 ^ u ^ 13329 can be obtained. R y wherein R represents CK3_alkyl; (ιν) (b) the compound of formula (IV) obtained in (a) will be converted to — — ------------------ s formula , (V) where R represents Cli3 • alkyl; (c) the intermediate compound of general formula (V) is precipitated in the para-position of the general formula 卞 toluenesulfonate 〇 〇R, (V!) Where R represents a Cy alkyl group; (d) convert the compound obtained according to (c) into the test (νπ), and then precipitate the free-form test (R) _2- (4 · benzene Methylaminomethyl) _1-methylcarboxamido > 丨-(pyrrolidinylcarbonyl) -ethyl] -benzimidazole 85873 and (VII) 1. '1,. (E) Shen · Yodo (I ) Of the monohydrochloride, the base obtained in (d) is suspended in a solvent or solvent mixture, and if necessary, the reaction mixture is heated to between 20 ° C and the reflux temperature of the solvent or solvent mixture, and hydrogen chloride . 4. Crystalline (R) -2- (4-fluorenylphenylmethyl) -1-methylcarboxymethylamino) -1- (pyrrolidinecarbonyl)-according to item 1 or 2 of the scope of the patent application- Ethyl] -benzimidazole_monophosphonate, for use as a pharmaceutical composition. 5 · —Seed crystal (R) -2- (4-fluorenylphenylaminomethyl) -1_methyl-5- [1- (retylamino) -1- (pyrrolidinecarbonyl) -ethyl ] -Benzimidazole-monohydrochloride is obtained from the method according to item 3 of the scope of patent application. 6. · A kind of medicinal concoction, which is characterized by containing a crystalline (R) _2- (4-methylimidoaminomethyl) -1 • fluorenyl_5- according to one of the items 1 to 3 of the scope of patent application. [1. (Carboxymethylamino) -1- (pyrrole.carbonyl) -ethyl] -benzimidazole-monohydrochloride. 7. — a para-methanesulfonate with the formula Where R represents (^ .3-alkyl. 8 · — seed crystal form (R) _2- (4-fluorenylphenylaminomethyl) -1-methyl-5- [N (carboxymethylamine 85873 and its (Pyrrolidinecarbonyl) _ethyl] -benzimidazole, characterized by a melting point of τ = 24ΐ ± 5 ° C. According to the crystalline form (R) -2- (4-fluorenylphenylamine) of item 8 in the scope of patent application Methyl) _methyl-5- [l- (carboxymethylamino) _ 丨 _ (pyrrolidinylcarbonyl) _ethylbenzimidazole 'is characterized by its X-ray powder pattern, which in particular has d = Characteristic values of 619 A, 6.01 Α, 5_1ό A, 4.13 A, and 3.81 A. 1 10. According to the crystal form (R) -2- (4-fluorene) of item 8 or 9 of the scope of patent application Aminomethyl) _1_methyl-5- [1- (carboxymethylamino) _ 丨 _ (pyrrolidinylcarbonyl) _ethylbenzamidone 'is used as a medical music composition. 11 · A medicine The blend is characterized by containing the crystalline form (r) _2- (4-fluorenylphenylaminomethyl) -bumethyl-5- [l- (carboxymethylamino) according to one of the items 8 or 9 of the scope of the patent application. -1- (pyrrolidinylcarbonyl) _ethyl] -benzimidazole. 85873