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    • 专利摘要:
    method for preparing a crystalline form of 1-chloro-4- (beta-d-glycopyran-1-yl) -2- (4 - ((s) -tetrahydrofuran-3-yloxy) benzyl) benzene. the present invention relates to a method for the preparation of a crystalline form of 1-chloro-4- (bd-glycopyran-1-1yl) -2- [4 - (((s) -tetrai-drofuran-3- iloxy) -benzyl] -benzene, moreover, the invention relates to a crystalline form obtainable by this method, to a pharmaceutical composition and to its use for preparing medicaments.
    公开号:BR112012007092B1
    申请号:R112012007092-4
    申请日:2010-09-24
    公开日:2020-03-31
    发明作者:Dirk Weber；Svenja Renner；Tobias FIEDLER；Simone Orlich
    申请人:Boehringer Ingelheim International Gmbh；
    IPC主号:
    专利说明:

    Invention Patent Specification Report for METHOD FOR PREPARING A CRYSTALLINE FORM OF A COMPOUND 1 -CHLORINE-4- (BETA-D-GLYCOPYRANES-1 -IL) -2- [4 - ((S) TETRAHYDROFURAN-3-ILOXY) - BENZIL] -BENZENE.
    [0001] The present invention relates to a method for preparing a crystalline form of 1-chloro-4- (3-D-glycopyran-1-yl) -2 [4 - ((S) -tetrahydrofuran-3 -yloxy) -benzyl] -benzene. In addition, the invention relates to a crystalline form obtainable by such a method and the use of the crystalline form to prepare medicaments.
    Background of the invention [0002] The compound 1-chloro-4- (3-D-glycopyran-1-yl) -2- [4 - ((S) tetrahydrofuran-3-yloxy) -benzyl] -benzene (as regards below, referred to as compound A) is described in international patent application WO 2005/092877 and has the chemical structure according to formula A
    CjO
    A [0003] The compounds described therein have a valuable inhibitory effect on the SGLT sodium-dependent glucose cotransporter, particularly SGLT2.
    [0004] International patent application WO 2006/120208 describes several methods of synthesizing SGLT2 inhibitors, inter alia, compound A.
    [0005] A crystalline form of compound A and a method for its preparation are described in international application WO 2006/117359. As preferred solvents, for example, methanol, ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, water and mixtures thereof are described for the crystallization process.
    Petition 870190121128, of 11/21/2019, p. 14/86
    2/35 [0006] In the synthesis of compound A, for example, according to the
    WO 2006/120208, it is observed that certain impurities can be found in the final substance. Furthermore, it appears that the crystallization processes, as described in WO 2006/117359, decrease the content of impurities and increase the purity of the compound, but not in a totally satisfactory way.
    [0007] It is well known to someone skilled in the art that, in the pharmaceutical field, highly pure compounds are desired. Very high purity can improve stability in long-term storage. On the other hand, impurities can be attributed to unwanted physicochemical properties, for example, hygroscopicity, or pharmacological side effects.
    Purpose of the invention [0008] The purpose of the present invention is to find an advantageous method for preparing a crystalline form of a compound 1-chloro4- (3-D-glycopyranes-1-yl) -2- [4 - ((S) - tetrahydrofuran-3-yloxy) -benzyl] benzene; in particular, a powerful method with which the crystalline form can be obtained in a high purity, with a low content of certain impurities, and / or that allows the manufacture of the crystalline form on a commercial scale with a low technical cost and a high performance by space / time.
    [0009] Another objective of the present invention is to provide a crystalline form of 1-chloro-4- (3-D-glycopyran-1-yl) -2- [4 - ((S) tetrahydrofuran-3-yloxy) -benzyl] -benzene, in particular, in a high purity.
    [00010] A further object of the present invention is to provide a pharmaceutical composition comprising the crystalline form.
    [00011] Another objective of the present invention is to provide a use of the crystalline form.
    [00012] The other objectives of the present invention will become
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    3/35 points for the technician versed directly from the preceding and following description.
    Purpose of the invention [00013] In a first aspect, the present invention relates to a method for preparing a crystalline form of a compound 1chloro-4- (3-D-glycopyranes-1-yl) -2- [4- ( (S) -tetrahydrofuran-3-yloxy) -benzyl] benzene, comprising the following steps:
    (a) dissolving the compound in a mixture of at least two solvents to form a solution, where the first solvent is selected from the group of solvents consisting of toluene and tetrahydrofuran, and the second solvent is selected from the group of solvents which consists of methanol, ethanol, 1-propanol and 2propanol, or the first solvent is ethanol and the second solvent is selected from the group of solvents consisting of ethyl acetate, n-propyl acetate and methyl ethyl ketone;
    (b) storing the solution to precipitate the crystalline form of the compound from the solution;
    (c) isolating the crystalline form of the compound from the solution. [00014] It is found that, with the method according to this invention, the crystalline form can be obtained in a high purity and in a high yield, in particular in commercially viable scales. The method shows a low technical cost and a high performance for space / time. Despite possible variations in the purity of the starting material, the method produces the crystalline form in a high purity. In particular, the following impurities in formulas IMP.1 and IMP.2 can be removed to a high degree:
    Petition 870190121128, of 11/21/2019, p. 16/86
    4/35

    IMP.1

    IMP.2 [00015] In another aspect, the present invention relates to the crystalline form of a compound 1-chloro-4- (3-D-glycopyran-1-yl) -2- [4 - ((S) tetrahydrofuran -3-yloxy) -benzyl] -benzene, obtainable by a process as described above and below.
    [00016] In another aspect, the present invention relates to the crystalline form of a compound 1-chloro-4- (3-D-glycopyran-1-yl) -2- [4 - ((S) tetrahydrofuran-3- iloxy) -benzyl] -benzene having a powder X-ray diffraction pattern comprising peaks at 18.84, 20.36 and 25.21 degrees 2Θ (± 0.1 degree 2Θ), where said diffraction pattern of Powder X-rays are made using CuK «1 radiation, characterized by a purity above 99%, as measured by HPLC.
    [00017] In yet another aspect, the present invention relates to a pharmaceutical composition comprising the crystalline form as described above and below.
    [00018] In yet another aspect, the present invention relates to a use of the crystalline form, as described above and below, to prepare a pharmaceutical composition that is suitable for the treatment or prevention of metabolic disorders, in particular of a metabolic disorder selected from the group consisting of di
    Petition 870190121128, of 11/21/2019, p. 17/86
    5/35 type 1 and type 2 diabetes, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricemia.
    [00019] The additional aspects of the present invention become apparent to someone skilled in the art from the following detailed description of the invention and the examples.
    Brief Description of the Figures [00020] Figure 1 shows an X-ray powder diffractogram corrected at the bottom of the crystalline form of compound A.
    [00021] Figure 2 shows the thermal analysis by means of DSC of the crystalline form of compound A.
    Detailed description of the invention [00022] This crystalline form of compound A can be identified by means of its characteristic powder X-ray diffraction (XRPD) patterns, in particular as described in WO 2006/117359.
    [00023] The crystalline form is characterized by a powder X-ray diffraction pattern comprising peaks at 18.84, 20.36 and 25.21 degrees 2Θ (± 0.1 degree 2Θ), where said diffraction pattern X-ray powder is made using CuK «1 radiation.
    [00024] In particular, said powder X-ray diffraction pattern comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Θ (± 0.1 degree 2Θ), where the said powder X-ray diffraction pattern is made using CuK «1 radiation.
    [00025] The said powder X-ray diffraction pattern is further characterized by peaks and comprises peaks at 14.69, 17.95, 18.84,
    19.16, 19.50, 20.36, 22.71, 23.44, 24.81 and 25.21 degrees 2Θ (± 0.1 degree 2Θ), where the said powder X-ray diffraction pattern is done using the
    Petition 870190121128, of 11/21/2019, p. 18/86
    6/35 radiation CuK i.
    [00026] More specifically, the crystalline form of compound A is characterized by a powder X-ray diffraction pattern, made using CuK «1 radiation, which comprises peaks in degrees 2Θ (± 0.1 degree 2Θ), as contained in Table 1 of WO 2006/117359 or as contained in Table 1 of Experiment A of the present application or as shown in Figure 1 of WO 2006/117359 or as shown in Figure 1 of the present application.
    [00027] In addition, the crystalline form of compound A is characterized by a melting point of about 151 ° C ± 5 ° C (determined by means of DSC; rated as the starting temperature; heating rate 10 K / min ).
    [00028] The powder X-ray diffraction patterns are recorded, within the scope of the present invention, using a STOE - STADI P diffractometer in transmission mode, adapted with a position sensitive detector (OED) and a Cu anode as the X-ray source (CuKa radiation, λ = 1.54056 Â, 40 kV, 40 mA).
    [00029] To allow the experimental error, the values of 2Θ described above must be considered to have a margin of error of ± 0.1 degree 2Θ, in particular ± 0.05 degree 2Θ. That is, when evaluating whether a given sample of crystals of compound A is the crystalline form according to the invention, a value of 2 Θ that is experimentally observed for the sample would be considered identical to a characteristic value described above if it falls on ± 0.1 degree 2Θ, in particular ± 0.05 degree 2Θ of the characteristic value.
    [00030] The melting point is determined by DSC (Differential Scanning Calorimetry) using a DSC 821 (Mettler Toledo).
    [00031] The present invention relates to a method for preparing a crystalline form of compound A, comprising the following steps:
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    7/35 (a) dissolve compound A in a mixture of at least two solvents to form a solution, where the first solvent is selected from the group of solvents consisting of toluene and tetrahydrofuran, and the second solvent is selected from from the group of solvents consisting of methanol, ethanol, 1-propanol and 2propanol, or the first solvent is ethanol and the second solvent is selected from the group of solvents consisting of ethyl acetate, n-propyl acetate and methyl ethyl ketone ;
    (b) storing the solution to precipitate the crystalline form of compound A from the solution;
    (c) isolating the crystalline form of compound A from the solution. [00032] The first solvent is preferably selected from the group of solvents consisting of toluene and tetrahydrofuran. [00033] The second solvent is preferably selected from the group of solvents consisting of methanol, ethanol, 1-propanol and 2-propanol; even more preferably from the group of solvents consisting of ethanol, 1-propanol and 2-propanol.
    [00034] According to a preferred alternative, the first solvent is ethanol and the second solvent is n-propyl acetate or ethyl acetate.
    [00035] Examples of mixtures of at least two solvents are toluene / methanol, toluene / ethanol, toluene / 1-propanol, toluene / 2propanol, tetrahydrofuran / methanol, tetrahydrofuran / ethanol, tetrahydrofuran / 1-propanol, tetrahydrofuran / 2-propanol , ethanol / n-propyl acetate, ethanol / ethyl acetate, ethanol / methyl ethyl ketone.
    [00036] Preferred examples of mixtures of at least two solvents are toluene / ethanol, toluene / 1-propanol, toluene / 2-propanol, tetrahydrofuran / ethanol, tetrahydrofuran / 1-propanol, tetrahydrofuran / 2propanol, ethanol / n-acetate propyl, ethanol / ethyl acetate.
    [00037] The weight ratio of the first solvent to the second sol
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    8/35 is preferably in the range of about 1: 10 to 10: 1, more preferably about 1: 5 to 5: 1, even more preferably about 1: 2 to 2: 1, most preferably of all about 1: 1.
    [00038] With respect to the preferred examples toluene / ethanol, toluene / 1-propanol, toluene / 2-propanol, ethanol / n-propyl acetate, ethanol / ethyl acetate, the weight ratio of the first solvent to the second solvent is preferably in the range of about 1: 5 to 5: 1, more preferably about 1: 2 to 2: 1, most preferably of all about 1: 1.
    [00039] With respect to the preferred examples tetrahydrofuran / ethanol, tetrahydrofuran / 1-propanol, tetrahydrofuran / 2-propanol, the weight ratio of the first solvent to the second solvent is preferably in the range of about 1: 10 to 2: 1, more preferably from about 1: 5 to 1: 1, even more preferably from about 1: 4 to 1: 2.
    [00040] In step (a), compound A can be used in an amorphous or crystalline form or as a solution, for example, obtained in the synthesis of compound A.
    [00041] Preferably, the solution obtained in step (a) is a saturated or almost saturated solution, at the given temperature.
    [00042] The terms saturated or near saturated are related to the starting material of compound A as used in step (a). For example, a solution that is saturated with respect to the starting material of compound A may be supersaturated with respect to its crystalline form.
    [00043] The weight ratio of compound A to the solvent mixture is preferably in the range 1: 8 to 1: 2, more preferably 1: 6 to 1: 3, even more preferably 1: 5 to 1: 4.
    [00044] In step (a), the solution can be heated to the boiling temperature of the solution or to a temperature in the range of about 60 ° C to 120 ° C, for example, about 100 ° C. The solution obtained
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    9/35 step (a) can be filtered, for example, over charcoal.
    [00045] At the beginning of step (b), the seeding crystals of compound A are preferably added to the solution obtained in step (a), optionally after a filtration step. The amount of the seeding crystals in relation to the total amount of compound A can be in the range of up to about 5% by weight, more preferably from about 0.001 to 1% by weight. Seeding crystals can be obtained, for example, by a process as described in WO 2006/117359. The seeding crystals are preferably added at a temperature in the range of about 30 ° C to 80 ° C, more preferably about 60 to 75 ° C. Alternatively, crystallization can be induced by methods as known in the art, for example, by scraping or rubbing.
    [00046] In step (b), the temperature is preferably lowered to obtain a high yield of the precipitated crystalline form of compound A. The temperature can be lowered continuously or by means of a predefined cooling ramp. An example of a cooling ramp is within about 30 min to 60 ± 5 ° C, then within about 90 min to 50 ± 5 ° C, then within about 60 min to 40 ± 5 ° C, then within about 60 min to 25 ± 5 ° C. A preferred final temperature at the end of step (b) is in the range of about -10 ° C to 40 ° C, more preferably about 0 ° C to 35 ° C, more preferably about 10 ° C to 30 ° C ° C.
    [00047] The duration of step (b) can range from about 30 min to 48 hours, preferably from about 3 to 6 hours.
    [00048] Step (b) can be performed with or without agitation. As known to someone skilled in the art, for the length of time and the temperature difference in step (b), the size, shape and quality of the crystals obtained can be varied.
    [00049] In step (c), the crystals obtained are isolated, for example,
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    10/35 by means of centrifugation or filtration. The crystals obtained are preferably washed with a solvent or a mixture of solvents, where the solvent is preferably selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol or tert.butyl methyl ether. The most preferred solvent is ethanol. Preferably, the remaining solvent (s) is (are) advantageously removed from the crystals in a drying step, preferably at a temperature in the range of about 0 ° C to 100 ° C, for example for example, from about 50 ° C to 80 ° C. The temperature, pressure and duration of this drying step can be chosen to decrease the content of one or more solvents below a given value. For example, the content of toluene in crystalline form can be chosen to be equal to or below 890 ppm, preferably below 500 ppm, even more preferably below 300 ppm. The content of ethanol in crystalline form can be chosen to be equal to or below 5000 ppm, preferably below 2000 ppm, even more preferably below 1000 ppm.
    [00050] Compound A can be synthesized by methods as specific and / or generally described or cited in international application WO 2005/092877. In addition, the biological properties of compound A can be investigated as described in international application WO 2005/092877, which, in its entirety, is incorporated herein by reference.
    [00051] The crystalline form according to the invention is preferably employed as a drug active substance in substantially pure form, that is, essentially free of other crystalline forms of compound A. However, the invention also includes the crystalline form as defined herein. document mixed with another form, or forms, crystalline. If the active drug substance is a mixture of crystalline forms, it is preferred that the substance comprises at least 50% of the crystalline form as described in this document.
    Petition 870190121128, of 11/21/2019, p. 23/86
    11/35 [00052] According to another aspect of the present invention, the crystalline form of compound A having a powder X-ray diffraction pattern comprising peaks at 18.84, 20.36 and 25.21 degrees 2Θ (± 0.1 degree 2Θ), where said powder X-ray diffraction pattern is made using CuK «1 radiation, is characterized by a purity above 99%, as measured by HPLC. Preferably, the purity is above 99.5%, even more preferably above 99.7%, more preferably still above 99.8%.
    [00053] In a preferred embodiment, the crystalline form, as defined above, is characterized by a content of the compound of the formula IMP.1
    Cl
    HO
    THE,,
    IMP.1
    OH equal to or below 1.00%, as measured by HPLC. Preferably, the content of the compound of the formula IMP.1 is equal to or below 0.15%, even more preferably equal to or below 0.05%, as measured by HPLC.
    [00054] In another preferred embodiment, the crystalline form, as defined above, is characterized by a content of the compound of the formula IMP.2
    Cl
    THE",
    IMP.2
    HO
    HO equal to or below 0.15%, as measured by HPLC. Preferably, the content of the compound of the formula IMP.2 is equal to or below
    0.05%, as measured by HPLC.
    [00055] According to a more preferred modality, the form
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    Crystalline 12/35 is characterized by a content of the compounds of the formulas IMP.1 and IMP.2 as defined above.
    [00056] The purity and impurity mentioned above and below can be determined with methods known to someone skilled in the art. Preferably, purity and impurity are measured using HPLC. Purity is preferably determined to be 100% minus the sum of all quantified impurities.
    [00057] Preferably, the HPLC device is equipped with a C18 column, in particular a column with microparticulate C18 packaging, used for reverse phase HPLC, for example, prepared by chemically linking a sterically protected C18 stationary phase (e.g., diisobutyl noctadecylsilane) to porous silica microspheres (e.g., with a pore size of about 80 A). The advantageous dimensions of the column and microspheres are 4.6 mm (internal dimension) x 50 mm and 1.8 pm column. UV detection is preferred, for example, at 224 nm.
    [00058] Typical parameters for such an HPLC are:
    Device: HPLC with UV detection
    Column: C18, 1.8 pm, 50 * 4.6 mm
    Column temperature: 20 ° C
    Gradient: time (min) eluent A (%) eluent B (%)0 100 01 70 304 70 308 5 9512 5 95
    Flow rate: 1.5 mL / min
    Analysis time: 12 min
    Balance time: 4 min
    Injection volume: 8 pl
    Petition 870190121128, of 11/21/2019, p. 25/86
    13/35
    Detection: 224 nm
    Preferred eluents are:
    Eluent A: water + 0.1% trifluoroacetic acid
    Eluent B: acetonitrile + 0.1% trifluoroacetic acid [00059] A preferred solvent for the samples or as a blank solution is a 50/50 (v / v) mixture of acetonitrile / water. Preferably, all solvents, including water, are HPLC grade.
    [00060] In view of its ability to inhibit SGLT activity, the crystalline form according to the invention is suitable for the preparation of pharmaceutical compositions for the treatment and / or preventive treatment of all these conditions or diseases that may be affected by inhibiting SGLT activity, particularly SGLT-2 activity. Therefore, the crystalline form is particularly suitable for the preparation of pharmaceutical compositions for the prevention or treatment of diseases, particularly metabolic disorders, or conditions, such as type 1 and type 2 diabetes mellitus, diabetes complications (such as, for example, retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidemias of different origins, atherosclerosis and related diseases, obesity, high pressure blood pressure, chronic heart failure, edema and hyperuricemia. The crystalline form is also suitable for the preparation of pharmaceutical compositions to prevent degeneration of beta cells, such as, for example, apoptosis or necrosis of pancreatic beta cells. The crystalline form is also suitable for the preparation of pharmaceutical compositions to improve or restore the functionality of pancreatic cells, and also to increase the number and size of pancreatic beta cells. The crystalline form according to the invention can also be used for the
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    14/35 preparation of pharmaceutical compositions useful as diuretics or antihypertensives, and suitable for the prevention and treatment of acute renal failure.
    [00061] By administering the crystalline form according to this invention, an abnormal accumulation of fat in the liver can be reduced or inhibited. Therefore, according to another aspect of the present invention, a method is provided to prevent, decrease, delay or treat diseases or conditions attributed to an abnormal accumulation of fat in the liver in a patient who needs it, characterized by the fact that it is administered a pharmaceutical composition according to the present invention. The diseases or conditions that are attributed to an abnormal accumulation of fat in the liver are particularly selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), non-alcoholic steatoepatitis (NASH), fatty liver induced by hyperalimentation , diabetic fatty liver, alcohol-induced fatty liver or toxic fatty liver.
    [00062] In particular, the crystalline form according to the invention is suitable for the preparation of pharmaceutical compositions for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and / or diabetic complications.
    [00063] In addition, the crystalline form according to the invention is particularly suitable for the prevention or treatment of overweight, obesity (including class I, class II and / or class III obesity), visceral obesity and / or obesity abdominal.
    [00064] The dosage required to obtain the corresponding activity for treatment or prevention usually depends on the patient, the nature and severity of the disease or condition and the method and frequency of administration and is for the patient's doctor to decide. Conveniently, the dosage can be from 1 to 100 mg per oral route, in
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    15/35 each case administered 1 to 4 times a day. For this purpose, the pharmaceutical compositions according to this invention preferably comprise the crystalline form together with one or more conventional inert carriers and / or diluents. Such pharmaceutical compositions can be formulated as conventional galenical preparations, such as single or coated tablets, capsules, powders, suspensions or suppositories.
    [00065] The following example of synthesis serves to illustrate a method of preparing compound A and its crystalline form. It is to be considered only as a possible method, described as an example, without restricting the invention to its contents.
    Determination of purity or impurity by means of HPLC:
    [00066] This method is used for the determination of organic impurities in compound A. Quantification is performed by means of external standard solutions. The reagents (acetonitrile, water, trifluoroacetic acid (TFA)) are used in the HPLC grade. The term compound Axx means the crystalline form of compound A, as obtained with a method according to this invention.
    Mobile Phase
    Eluent A: water + 0.1% TFA
    Eluent B: acetonitrile + 0.1% TFA
    Solutions
    Solvent: acetonitrile / water (50/50 (v / v))
    Blank solution: solvent
    Solution 1 [00067] Prepare a solution with a concentration of 0.5 mg / ml of compound IMP.2; for example, 25 mg of the substance is weighed, dissolved in 2 ml of methanol and diluted with solvent to a total volume of 50 ml.
    System suitability solution (SST)
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    16/35 [00068] A solution with a concentration of 0.5 mg / ml of compound Axx, containing approx. 0.5% of IMP.2; for example, 25 mg of compound Axx are weighed, dissolved in 2 ml of methanol (by means of ultrasound) and, after adding 250 μL of solution 1, diluted with solvent to a total volume of 50 ml. Optional, approx. 0.5% of the following possible impurities: IMP.1 Registration limit (0.05%) [00069] A solution with 0.05% of the nominal concentration is prepared. Therefore, 50 μl of a base solution is diluted with solvent to a total volume of 100 ml.
    Sample Solutions [00070] A solution of the substance to be analyzed with a concentration of 0.8 mg / mL is prepared. Therefore, for example, 40 mg of the substance are weighed, dissolved in 2 ml of methanol and diluted with solvent to a total volume of 50 ml. This solution is prepared twice.
    Base Solutions [00071] A solution of compound Axx with a concentration of 0.8 mg / ml is prepared. Therefore, for example, 40 mg of the substance are weighed, dissolved with 2 ml of methanol and diluted with solvent to a total volume of 50 ml. This solution is prepared twice.
    Reference Solutions (0.5%) [00072] A solution of compound Axx with a concentration of 4 μg / ml is prepared in comparison with the nominal heavy sample. Therefore, for example, 250 μl of the base solution is diluted with 50 ml. This solution is prepared twice (once from each base solution).
    Chromatographic Parameters:
    Device: HPLC with UV detection
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    17/35
    Column: Zorbax SB-C18, 1.8 pm, 50 * 4.6 mm, (manufacturer: Agilent)
    Column temperature: 20 ° C
    Gradient: time (min) eluent A (%) eluent B (%)0 100 01 70 304 70 308 5 9512 5 95 Flow rate: 1.5 mL / min
    Analysis time: 12 min
    Balance time: 4 min
    Injection volume: 8 pl
    Detection: 224 nm
    Injections:
    Solutions Injections Blank solution n> 1 Record limit 1 Reference solution 1 2 Reference solution 2 2 SST 1 Blind solution n> 1 Sample 1, Solution 1 2 Sample 1, Solution 2 2 Sample 2, Solution 1 2 Sample 2, Solution 2 2 Additional samples 2 each SST 1
    Typical Retention Times:
    [00073] The order of elution of the peaks in the chromatogram of the SST solution must correspond to an example chromatogram. The designation of the peak is carried out with an example chromatogram or by means of the relative retention times (TRRs).
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    18/35
    Substance TR (approx. Min) TRR IMP.1 3.35 0.84 Axx Compound 3.97 1.00 IMP.2 Isomer 1 4.97 1.25 IMP.2 Isomer 2 5.19 1.31
    Evaluation
    The impurity content is calculated according to the following formula.
    PF Sample * V Sample E ^ V Base Solution * Power Substance of
    Impurity% Reference ---------------- * - * 100
    EW Sample PF 0.5% Comparison * V Base Solution * VF
    PFx: Peak areas
    EWX: weighing
    Vx: volume up to which dilution is performed
    VF: dilution factor
    Potency: known potency in% of the reference substance of compound Axx [00074] The purity of a sample of compound A is calculated as
    100% less the sum of all quantified impurities.
    Preparation of compound A:
    [00075] The term room temperature means a temperature of about 20 ° C.
    GC gas chromatography hours ago i-Pr iso-propyl
    Me methyl min minute (s)
    THF tetrahydrofuran
    Petition 870190121128, of 11/21/2019, p. 31/86
    19/35
    Cl O
    I (COCl) 2
    IX.1 cat. DMF fluorbenzene
    F

    VIII.1 „o„ -o urY r
    TMSCl, NMM, DMAP / • X- O, O
    TMSO ^ V V
    HO
    tBuOK / THF
    2-Propanol
    HO OH
    Oh
    THF n-Heptane
    TMSO 'OTMS
    Otms
    IVa.1
    IV.1
    TMDS,AlCl3, Toluene, EtOH Cl IIiPrMgCl / LiCl Ά THF.n _________I V.1 aq. citric acid.
    Cl O.
    I
    VII.1
    EtjSiH / AlCl 3
    CH 2 Cl 2 / MeCN
    THE
    HO
    HO ’
    OH
    OH
    II.1
    Example 1: Synthesis of fluoride VIII.1 [00076] Oxalyl chloride (176 kg; 1386 moles; 1.14 eq) is added to a mixture of 2-chloro-5-benzoic acid (343 kg; 1214 moles) (compound IX.1), fluorbenzene (858 kg) and N, N-dimethylformamide (2 kg), within 3 hours, at a temperature in the range of about 25 to 30 ° C (gas formation). After the addition is complete, the reaction mixture is stirred for an additional 2 hours at a temperature of about
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    20/35 from 25 to 30 ° C. The solvent (291 kg) is distilled at a temperature between 40 and 45 ° C (p = 20 kPa (200 mbar)). Then, the reaction solution (911 kg) is added to aluminum chloride AlCh (181 kg) and fluorbenzene (192 kg), at a temperature between about 25 and 30 ° C, within 2 hours. The reaction solution is stirred at the same temperature for an additional hour. Then, the reaction mixture is added to an amount of 570 kg of water, within about 2 hours, at a temperature between about 20 and 30 ° C, and stirred for an additional hour. After phase separation, the organic phase (1200 kg) is separated into two halves (600 kg each). From the first half of the organic phase, the solvent (172 kg) is distilled at a temperature of about 40 to 50 ° C (p = 20 kPa (200 mbar)). Then, 2propanol (640 kg) is added. The solution is heated to about 50 ° C and then filtered through a charcoal cartridge (clear filtration). The cartridge can be changed during filtration and washed with a fluorbenzene / 2-propanol mixture (1: 4; 40 kg) after filtration. The solvent (721 kg) is distilled at a temperature of about 40 to 50 ° C and p = 20 kPa (200 mbar). Then, 2-propanol (240 kg) is added at a temperature in the range between about 40 to 50 ° C. If the fluorbenzene content is greater than 1%, as determined by means of GC, another 140 kg of solvent is distilled and 2-propanol (140 kg) is added. Then, the solution is cooled from about 50 ° C to 40 ° C, within an hour, and the seeding crystals (50 g) are added. The solution is further cooled from about 40 ° C to 20 ° C, within 2 hours. Water (450 kg) is added at around 20 ° C within 1 hour, and the suspension is stirred at around 20 ° C for an additional hour, before the suspension is filtered. The filter cake is washed with 2-propanol / water (1: 1; 800 kg). The product is dried until a water level of <0.06% w / w is obtained. The second half of the organic phase is processed identically. A total of
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    410 kg (94% yield) of product, which has a white to not entirely white crystalline appearance. The identity of the product is determined by means of infrared spectrometry.
    Example 2: Synthesis of ketone VII.1 [00077] To a solution of fluoride VIII.1 (208 kg), tetrahydrofuran (407 kg) and (S) -3-hydroxytetrahydrofuran (56 kg) is added to the solution of fer-butanolate potassium (20%), in tetrahydrofuran (388 kg), within 3 h, at a temperature of 16 to 25 ° C. After the end of the addition, the mixture is stirred for 60 min, at a temperature of 20 ° C. Then, the conversion is determined by means of HPLC analysis. Water (355 kg) is added within 20 min, at a temperature of 21 ° C (sudden aqueous cooling). The reaction mixture is stirred for 30 min (temperature: 20 ° C). The stirrer is turned off and the mixture is left to stand for 60 min (temperature: 20 ° C). The phases are separated and the solvent is distilled from the organic phase at a temperature of 19 to 45 ° C, under reduced pressure. 2-Propanol (703 kg) is added to the residue, at a temperature of 40 to 46 ° C, and the solvent is distilled at a temperature of 41 to 50 ° C, under reduced pressure. 2-Propanol (162 kg) is added to the residue, at a temperature of 47 ° C, and the solvent is distilled at a temperature of 40 to 47 ° C, under reduced pressure. Then, the mixture is cooled to 0 ° C within 1 h and 55 min. The product is collected in a centrifuge, washed with a mixture of 2-propanol (158 kg) and subsequently with ferric-butyl methyl ether (88 kg) and dried at 19 to 43 ° C, under reduced pressure. 227 kg (91.8%) of product are obtained as a colorless solid. The identity of the product is determined by means of infrared spectrometry.
    Example 3: Synthesis of iodide V.1 [00078] To a solution of ketone VII.1 (217.4 kg) and aluminum chloride (AlCh; 81.5 kg) in toluene (366.8 kg) is added 1 , 1,3,3 tetramethyldisiloxane (TMDS, 82.5 kg) within 1 h and 30 min (tempera
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    22/35 ture: 18-26 ° C). After the addition is complete, the mixture is stirred for an additional 1 h at a temperature of 24 ° C. Then, the conversion is determined by means of HPLC analysis. Subsequently, the reaction mixture is treated with acetone (15.0 kg), stirred for 1 h and 5 min, at a temperature of 27 ° C, and the residual TMDS content is analyzed by GC. Then, a mixture of water (573 kg) and concentrated HCl (34 kg) is added to the reaction mixture, at a temperature of 20 to 51 ° C (sudden aqueous cooling). The reaction mixture is stirred for 30 min (temperature: 51 ° C). The stirrer is turned off and the mixture is left to stand for 20 min (temperature: 52 ° C). The phases are separated and the solvent is distilled from the organic phase at a temperature of 53-73 ° C, under reduced pressure. Toluene (52.8 kg) and ethanol (435.7 kg) are added to the residue, at a temperature of 61 to 70 ° C. The reaction mixture is cooled to a temperature of 36 ° C and the seeding crystals (0.25 kg) are added. Stirring is continued at this temperature for 35 min. Then, the mixture is cooled to 0 to 5 ° C and stirred for an additional 30 min. The product is collected in a centrifuge, washed with ethanol (157 kg) and dried at 15 to 37 ° C, under reduced pressure. 181 kg (82.6%) of the product are obtained as a colorless solid. The identity of the product is determined through the HPLC retention time.
    Example 4: Synthesis of lactone IV.1 [00079] A suspension of D - (+) - glyconic acid-delta-lactone IVa.1 (42.0 kg), tetrahydrofuran (277.2 kg), 4-methylmorpholine (NMM ;
    152.4 kg) and 4-dimethylaminopyridine (DMAP; 1.44 kg) is treated with chlorotrimethylsilane (TMSCl; 130.8 kg), within 50 min, at 13 to 19 ° C. After completion of the addition, stirring is continued for 1 h and 30 min, at 20 to 22 ° C, and the conversion is determined by means of HPLC analysis. Then, n-heptane (216.4 kg) is added and the mixture is cooled to 5 ° C. Water (143 kg) is added at 3 to 5 ° C, within 15 min. after the
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    At the end of the addition, the mixture is heated to 15 ° C and stirred for 15 min. The stirrer is turned off and the mixture is left to stand for 15 min. Then, the phases are separated and the organic layer is washed in succession twice with water (143 kg each). Then, the solvent is distilled at 38 ° C, under reduced pressure, and n-heptane (130 kg) is added to the residue. The resulting solution is filtered and the filter is rinsed with n-heptane (63 kg) (the filter solution and the product solution are combined). Then, the solvent is distilled at 39 to 40 ° C, under reduced pressure. The water content of the residue is determined by Karl-Fischer analysis (result: 0.0%). 112.4 kg of the product are obtained as an oil (containing residual n-heptane, which explains the yield of> 100%). The identity of the product is determined by means of infrared spectrometry.
    Example 5a: Synthesis of glycoside II.1 [00080] To a solution of iodide V.1 (267 kg) in tetrahydrofuran (429 kg) is added the solution of Turbogrignard (isopropylmagnesium chloride / lithium chloride solution, 14% in weight of iPrMgCl in THF, molar ratio of LiCl: iPrMgCl = 0.9 - 1.1 mol / mol) (472 kg) at a temperature of -21 to -15 ° C, within 1 h and 50 min. At the end of the addition, the conversion is determined by means of HPLC analysis. The reaction is considered completed when the peak area corresponding to iodide V.1 is less than 5.0% of the total area of both peaks, iodide V.1 and the corresponding diode compound of iodide V.1. If the reaction is not completed, the additional Turbogrignard solution is added until the criterion is met. In this particular case, the result is 3.45%. Then, the IV.1 lactate (320 kg) is added at a temperature of -25 to -18 ° C, within 1 h and 25 min. The resulting mixture is stirred for 1 h and 30 min more, at -13 to -18 ° C. At the end of the addition, the conversion is determined by means of HPLC analysis (for information). At the end, a solution of citric acid in water (938 L;
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    24/35 centering: 10% by weight) is added to the reaction mixture of a volume of about 2500 L, at -13 to 19 ° C, within 1 h and 25 min. The solvent is partially distilled from the reaction mixture (residual volume: 1816-1905 L), at 20 to 30 ° C, under reduced pressure, and 2methyltetrahydrofuran (532 kg) is added. Then, the stirrer is turned off and the phases are separated at 29 ° C. After phase separation, the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with the pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel ). The measured pH value is 2 to 3. Then, the solvent is distilled from the organic phase at 30 to 33 ° C, under reduced pressure, and methanol (1202 kg) is added, followed by the addition of a 1 HCl solution. , 25 N in methanol (75 kg), at 20 ° C (pH = 0). The total conversion to acetate III.1 is obtained by subsequent distillation at 20 to 32 ° C, under reduced pressure, and addition of methanol (409 kg).
    [00081] The reaction is completed when two criteria are met:
    1) The ratio of the sum of the HPLC area of the alpha + beta form of intermediate III.1 to the area of intermediate IIIa.1 is greater than or equal to 96.0%: 4.0%.
    2) The HPLC area ratio of the alpha form of the intermediate
    III.1 for the beta form of III.1 is greater than or equal to 97.0% for 3.0%. [00082] In this particular case, both criteria are met. Triethylamine (14 kg) is added (pH = 7.4) and the solvent is distilled under reduced pressure, acetonitrile (835 kg) is added and further distilled under reduced pressure. This procedure is repeated (addition of acetonitrile: 694 kg) and methylene chloride (640 kg) is added to the resulting mixture to produce a mixture of acetate III.1 in acetonitrile and methylene chloride. The water content of the mixture is determined by Karl Fischer titration (result: 0.27%). THE
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    25/35 reaction mixture is then added within 1 h and 40 min, at 10 to 19 ° C, to a preformed mixture of AlCh (176 kg), methylene chloride (474 kg), acetonitrile (340 kg), and triethylsilane (205 kg). The resulting mixture is stirred at 18 to 20 ° C for 70 min. After the end of the reaction, water (1263 L) is added at 20 to 30 ° C, within 1 h and 30 min, and the mixture is partially distilled at 30 to 53 ° C, under atmospheric pressure, and the phases are separated . Toluene (698 kg) is added to the organic phase and the solvent is distilled off under reduced pressure, at 22 to 33 ° C. The product is then crystallized by adding seeding crystals (0.5 kg) at 31 ° C, and water (267 kg) added after cooling to 20 ° C. The reaction mixture is cooled to 5 ° C within 55 min and stirred at 3 to 5 ° C for 12 h. Finally, the product is collected in a centrifuge as a colorless, crystalline solid, washed with toluene (348 kg) and dried at 22 to 58 ° C. 211 kg (73%) of the product is obtained. The identity of the product is determined through the HPLC retention time.
    Example 5b: Synthesis of glycoside II.1 [00083] To a solution of iodide V.1 (30 g), in tetrahydrofuran (55 ml), is added the solution of Turbogrignard (isopropylmagnesium chloride / lithium chloride solution, 14 % by weight of iPrMgCl in THF, molar ratio of LiCl: iPrMgCl = 0.9 - 1.1 mol / mol) (53 g), at the temperature of -14 to -13 ° C, within 35 min. At the end of the addition, the conversion is determined by means of HPLC analysis. The reaction is considered complete when the peak area corresponding to iodide V.1 is less than 5.0% of the total area of both peaks, iodide V.1 and the corresponding diode compound of iodide V.1 If the reaction is not completed, the additional Turbogrignard solution is added until the criterion is met. In this particular case, the result is 0.35%. Then, lactone IV.1 (36 g) is added, at a temperature of -15 to -6 ° C, within 15 min. The resulting mixture is stirred for an additional 1 h at -6 to -7 ° C. At the end, the conversion is determined through
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    26/35 HPLC analysis (for information). At the end, a solution of citric acid in water (105 mL; concentration: 10% by weight) is added to the reaction mixture, at -15 to 10 ° C, within 30 min.
    [00084] The solvent is partially distilled from the reaction mixture (residual volume: 200 ml), at 20 to 35 ° C, under reduced pressure, and 2methyltetrahydrofuran (71 ml) is added. Then, the mixture is stirred for 25 min, at 30 ° C. Then, the stirrer is turned off and the phases are separated at 30 ° C. After phase separation, the pH value of the organic phase is measured with a pH electrode (Mettler Toledo MT HA 405 DPA SC) or alternatively with the pH indicator paper (such as pH-Fix 0-14, Macherey and Nagel ). The measured pH value is 3. Then, the solvent is distilled from the organic phase at 35 ° C, under reduced pressure, and methanol (126 mL) is added, followed by the addition of a 1.25 N HCl solution in methanol (10.1 ml), at 25 ° C (pH = 1-2). The total conversion to acetate III.1 is obtained by subsequent distillation at 35 ° C, under reduced pressure, and addition of methanol (47 mL).
    [00085] The reaction is completed when two criteria are met:
    1) The ratio of the sum of the HPLC area of the alpha + beta form of intermediate III.1 to the area of intermediate IIIa.1 is greater than or equal to 96.0%: 4.0%. In this particular case, the ratio is 99.6%: 0.43%.
    2) The HPLC area ratio of the alpha form of the intermediate
    III.1 for the beta form of III.1 is greater than or equal to 97.0% for 3.0%. In this particular case, the ratio is 98.7%: 1.3%.
    [00086] Triethylamine (2.1 ml) is added (pH = 9) and the solvent is distilled at 35 ° C, under reduced pressure, acetonitrile (120 ml) is added and further distilled under reduced pressure, at 30 to 35 ° C. This procedure is repeated (addition of acetonitrile: 102 ml) and methylene chloride (55 ml) is added to the resulting mixture to produce
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    27/35 mix a mixture of acetate III.1 in acetonitrile and methylene chloride. The water content of the mixture is determined by Karl Fischer titration (result: 0.04%). The reaction mixture is then added within 1 h and 5 min, at 20 ° C, to a preformed mixture of AlCl3 (19.8 g), methylene chloride (49 ml), acetonitrile (51 ml), and triethylsilane (23 g). The resulting mixture is stirred at 20 to 30 ° C for 60 min. After the end of the reaction, water (156 mL) is added at 20 ° C, within 25 min, and the mixture is partially distilled at 55 ° C, under atmospheric pressure, and the phases are separated at 33 ° C. The mixture is heated to 43 ° C and toluene (90 ml) is added and the solvent is distilled off under reduced pressure, at 41 to 43 ° C. Then, acetonitrile (10 mL) is added at 41 ° C and the percentage of acetonitrile is determined by means of GC measurement. In this particular case, the percentage of acetonitrile is 27% by weight. The product is then crystallized by adding seeding crystals (0.1 g) at 44 ° C and the mixture is further stirred at 44 ° C for 15 min. The mixture is then cooled to 20 ° C within 60 min and water (142 ml) is added to 20 ° C within 30 min. The reaction mixture is cooled to 0 to 5 ° C within 60 min and stirred at 3 ° C for 16 h. Finally, the product is collected on a filter as a colorless, crystalline solid, washed with toluene (80 mL) and dried at 20 to 70 ° C. 20.4 g (62.6%) of the product are obtained. The identity of the product is determined through the HPLC retention time.
    Preparation of the crystalline form:
    Experiment A:
    [00087] A solution of compound A (79.0 kg) in a mixture of toluene (186.6 kg) and ethanol (187.2 kg) is heated to reflux until complete dissolution and filtered (hot filtration). The filter is washed with toluene (19.6 kg) and the washing solution is combined with the product solution. The product solution is then cooled to 66 ° C and the seeding crystals (0.1 kg) are added. The product solution is
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    28/35 then cooled to 22 ° C using a defined cooling ramp: within 30 min to 57 ° C, then within 90 min to 50 ° C, then within 60 min to 41 ° C, then within 60 min to 22 ° C. Then, the suspension is further stirred at 21 ° C for 1 h, collected in a centrifuge and washed with ethanol (124.8 kg) and dried at around 70 ° C. 65.5 kg (82.95) of the product are obtained as white crystals with an HPLC purity of 99.9%.
    [00088] By means of differential scanning calorimetry (DSC), as described above, a melting point of 151 ° C is determined (Figure 2).
    [00089] By powder diffraction X-ray as described above, using CuK radiation 1, characterized in that the crystalline form is obtained and a pattern as shown in Figure 1. The intensity shown in Figure 1 it is given in units of cps (counts per second) and is corrected in the background.
    [00090] In addition, the crystalline form is characterized by the following structure parameters: orthorhombic symmetry, spatial group P2i2i2i with cell parameters, a = 5.70 (1) A, b = 9.25 (2) A, c = 39.83 (1) A, and the cell volume = 2101 (1) A3, which can be obtained by indexing the X-ray powder diagram to be measured at room temperature, using CuK «1 radiation, which comprises peaks in degrees 2Θ (± 0.1 degree 2Θ) as contained in Table 1. In Table 1 above, the values 2Θ [°] mean the diffraction angle in degrees and the d [A] values mean the distances specified in A between the planes of the structures. In addition, the h, k, l indices are provided and the difference between the experimental d values and those calculated in A.
    Table 1: X-ray diffraction pattern of indexed powder * of crystalline form (only peaks up to 30 ° in 2 Θ are listed):
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    2 © [°] d value[THE] I / Io intensity [%] Indexing dexp-calc[THE] H k l 4.43 19.93 10 0 0 2 -0.003 8.86 9.97 3 0 0 4 -0.010 9.82 9.00 3 0 1 1 0.014 11.63 7.60 2 0 1 3 -0.020 13.32 6.64 22 0 0 6 -0.001 14.66 6.04 36 0 1 5 -0.005 15.69 5.64 50 1 0 1 -0.001 16.16 5.48 16 1 0 2 -0.006 17.92 4.95 71 1 0 4 -0.001 18.30 4.84 24 0 1 7 0.011 18.40 4.82 26 1 1 1 -0.002 18.81 4.71 100 1 1 2 0.000 19.13 4.64 67 1 0 5 0.000 19.46 4.56 31 1 1 3 -0.002 20.34 4.36 67 1 1 4 -0.005 20.52 4.33 25 1 0 6 -0.003 21.15 4.20 7 0 2 4 -0.006 21.43 4.14 13 1 1 5 0.003 22.06 4.03 35 1 0 7 0.002 22.68 3.92 30 1 1 6 0.001 23.42 3.80 20 0 2 6 0.006 23.71 3.75 8 1 0 8 0.003 24.08 3.69 5 1 1 7 0.003 24.31 3.66 9 0 1 10 0.007 24.77 3.59 14 1 2 0 0.007 25.18 3.53 30 1 2 2 0.004 25.62 3.47 29 1 1 8 0.007 26.36 3.38 3 1 2 4 0.003 26.84 3.32 16 0 0 12 0.003 27.24 3.27 16 1 1 9 -0.010 27.87 3.20 2 0 2 9 0.001 28.22 3.16 2 1 2 6 -0.002 28.98 3.08 5 1 1 10 0.001 29.39 3.04 15 1 2 7 0.010 29.55 3.02 3 0 2 10 -0.016
    * For indexing, the structure parameters from the analysis of
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    30/35 individual crystal are used as starting values.
    Refined cell parameters from the XRPD standard:
    all peaks (35) up to 30 ° Θ indexed symmetry: orthorhombic spatial group: P2i2i2i a = 5.70 (1) A b = 9.25 (2) A c = 39.83 (1) A α = β = γ = 90 °
    V = 2101 (1) A 3
    Merit number: 118
    Experiment B:
    [00091] In the following experiment, it is investigated how the method according to this invention is able to reduce an impurity of the formula IMP.1, as described above.
    [00092] The compound of the formula IMP.1 is added to the crystalline form of compound A, as obtained according to Experiment A, in such a way that the amounts are obtained according to Table 2. For example, to obtain the mixture at 0.5% by weight, 6.96 g of the crystalline form of compound A, as obtained according to Experiment A, and 0.04 g of the compound IMP.1 are combined.
    [00093] After that, half of this mixture of compounds is recrystallized according to the procedure of Experiment A on a laboratory scale. The crystalline form of compound A is obtained as a white crystalline material. The content of the compound of the formula IMP.1 is analyzed using HPLC.
    [00094] The other half of this mixture of compounds is recrystallized using a mixture of methanol and water, according to the following procedure:
    [00095] About 7 g of a mixture of the crystalline form of with
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    31/35 station A, as obtained according to Experiment A, and the compound IMP.1 are added to a mixture of methanol (7.1 g) and water (7.3 g) and are heated to 60 ° C until complete dissolution. The clear solution is stirred for 15 min. Then the water (11.9 g) is added to the solution and, after completion of the addition, the solution is cooled to 57 ° C and the seeding crystals are added. The solution is then further stirred at 57 ° C for 30 min. The product solution is then cooled to 25 ° C within 2 h and 20 min. Then, the suspension is further stirred at 25 ° C for 15 min, collected over a filter and washed with a mixture of methanol (1.66 g) and water (9.5 g) and dried at around 45 ° C. 6.5 g (93.1%) of the product are obtained as white crystals.
    [00096] Compound A is obtained as a white crystalline material. The content of the compound of the formula IMP.1 is analyzed using HPLC.
    Table 2
    Impurity amount IMP.1 in compound A Before recrystallization (% by weight) After recrystallization using toluene / ethanol (HPLC-%) After recrystallization using methanol / water (HPLC-%) 0.5% 0.07% 0.07% 1.0% 0.06% 0.12% 1.5% 0.07% 0.85% 2.0% 0.09% 0.67% 3.0% 0.14% 1.68% 5.0% 0.34% 3.05%
    [00097] It has been observed that using a crystallization process with a mixture of toluene and ethanol, a better reduction of impurity IMP.1 can be obtained than with a process using a mixture of methanol / water.
    Experiment C:
    [00098] In the following experiment, it is investigated how the method according to this invention is able to reduce an impurity of the formula IMP.2, as described above.
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    32/35 [00099] The different raw material samples of compound A, for example, as obtained from a non-optimized laboratory scale procedure, according to Example 5a or 5b, are analyzed by means of HPLC in relation to its content of IMP.2.
    [000100] After that, each sample is recrystallized according to the procedure of Experiment A, on a laboratory scale, using a mixture of toluene and ethanol, to obtain the crystalline form of compound A. The content of IMP.2 and the The overall purity of the crystalline form of compound A is analyzed using HPLC.
    Table 3
    IMP.2 content before recrystallization (HPLC-%) IMP.2 content after recrystallization (HPLC-%) Overall purity after recrystallization using toluene / ethanol (HPLC-%) Yield 0.89% 0.05% 99.95% 90.1% 1.26% 0.14% 99.86% 89.3% 1.75% 0.13% 99.82% 87.1% 2.75% 0.17% 99.72% 86.1% 3.94% 0.29% 99.61% 79.1% 7.30% 0.51% 99.21% 73.3%
    Experiment D:
    [000101] In the following experiment, it is investigated how the method according to this invention is able to purify the raw material of compound A.
    [000102] The different raw material samples of compound A, for example, as obtained from a non-optimized laboratory scale procedure, according to Example 5a or 5b, are analyzed by means of HPLC in relation to its purity.
    [000103] After that, each sample is recrystallized according to the procedure of Experiment A, on a laboratory scale, using a mixture of toluene and ethanol, to obtain the crystalline form of compound A. The overall purity of the crystalline form of the compound A is analyzed using HPLC.
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    33/35 [000104] The other half of each sample is recrystallized using a mixture of methanol and water, according to the procedure as described in Experiment B.
    [000105] The purities of the raw material and crystallized material samples are given in Table 4.
    Table 4
    Purity before recirculationtalization (HPLC-%) Purity after recrystallization using toluene / ethanol (HPLC%) Purity after recrystallization using methanol / water (HPLC%) 96.17% 99.82% 98.25% 96.74% 99.84% 99.64% 97.09% 99.80% 99.26% 97.43% 99.81% 99.54% 95.60% 99.75% 98.63%
    [000106] It is observed that, using a crystallization process with a mixture of toluene and ethanol, greater purity of compound A can be obtained than with a process using a mixture of methanol / water.
    Experiment E:
    [000107] In the following experiment, the influence of the mixture and the solvent ratio on the purity and yield of the recrystallization procedure according to Experiment A is investigated.
    [000108] Therefore, a sample of the raw material of compound A, for example, as obtained according to Example 5a or 5b, is analyzed by means of HPLC for its purity and the result is found to be 95.16% . Then, this sample is recrystallized according to the procedure of Experiment A, on a laboratory scale (compound A: 35 g; sum of the first and second solvents: 162 g), with the modification that the two solvents, ethanol and toluene , are substituted against the solvent mixtures given in Table 5, to obtain the crystalline form of compound A. The overall purity of the crystalline form of
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    34/35 compound A is analyzed using HPLC.
    Table 5
    Solvent system (weight: weight ratio) Overall purity after recirculationtalization (HPLC-%) Yield Ethanol / Toluene = 1: 1 99.72% 80.8% 1-Propanol / Toluene = 1: 1 99.80% 82.2% 2-Propanol / Toluene = 1: 1 99.72% 72.0% Methanol / Toluene = 1: 4 99.69% 54.6% Ethanol / T etrahydrofuran = 4: 1 99.62% 82.9% 2-Propanol / Tetrahydrofuran = 2: 1 99.67% 67.9% Ethanol / n-propyl acetate = 1: 1 99.68% 79.1% Ethanol / Methyl ethyl ketone = 1: 1 99.61% 67.1% Ethanol / ethyl acetate = 1: 1 99.70% 78.4%
    Experiment F:
    [000109] In the following experiment, it is investigated how the method according to this invention is able to purify the raw material of compound A, in comparison with a procedure using a mixture of ethanol and water (see, for example, the Variant 2 experiment in WO 2006/117359).
    [000110] A sample of the raw material of compound A, for example, as obtained from a laboratory scale procedure, not optimized, according to Example 5a or 5b, is analyzed by means of HPLC in relation to its purity.
    [000111] After that, the sample is recrystallized according to the procedure of Experiment A, on a laboratory scale, using a mixture of toluene and ethanol, to obtain the crystalline form of compound A. The overall purity of the crystalline form of the compound A is analyzed using HPLC.
    [000112] The other half of the sample is recrystallized using a mixture of ethanol and water, according to the following procedure: [000113] 40 g of compound A are dissolved in 200 ml of a
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    35/35 water / ethanol mixture (volume ratio 2: 3) with heating to about 50 ° C. 320 mL of water is added over a temperature range of 45 to 50 ° C and the solution is allowed to cool to about 20 ° C in 1 to 3 h. After 16 h, the crystalline form is isolated as beige crystals, by filtration. The product is dried at an elevated temperature (40 to 50 ° C) for about 4 to 6 h.
    [000114] The purities of the raw material and crystallized material samples are given in Table 6.
    Purity before recrystallization (HPLC-%) Purity after recrystallization using toluene / ethanol (HPLC-%) Purity after recrystallization using ethanol / water (HPLC-%) 96.14% 99.74% 97.4%
    It is observed that, using a crystallization process with a mixture of toluene and ethanol, greater purity of compound A can be obtained than with a process using an ethanol / water mixture.
    权利要求:
    Claims (3)
    [1]
    1. Method for preparing a crystalline form of a 1-chloro-4- (3-D-glycopyran-1-yl) -2- [4 - ((S) -tetrahydrofuran-3-yloxy) benzyl] -benzene compound, characterized by the fact that it comprises the following steps:
    (a) dissolving the compound in a mixture of two solvents to form a solution, where the first solvent is toluene, and the second solvent is ethanol, where the weight ratio of the first solvent to the second solvent is in the range 1: 5 to 5: 1;
    (b) storing the solution to precipitate the crystalline form of the compound from the solution;
    (c) isolating the crystalline form of the compound from the solution;
    wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks at 18.84; 20.36 and 25.21 degrees 2Θ (± 0.1 degree 2Θ), in which the said powder X-ray diffraction pattern is made using CuK «1 radiation.
    [2]
    2. Method according to claim 1, characterized by the fact that the weight ratio of the first solvent to the second solvent is in the range of 1: 2 to 2: 1.
    [3]
    3. Method according to claim 1, characterized by the fact that the powder X-ray diffraction pattern still comprises peaks at 14.69; 19.16 and 19.50 degrees 2Θ (± 0.1 degree 2Θ), in which the said powder X-ray diffraction pattern is made using CuK radiation at 1.
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    公开号 | 公开日
    DK2483286T3|2016-09-19|
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    IL218102D0|2012-04-30|
    AR078475A1|2011-11-09|
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    EA201200506A1|2012-11-30|
    TW201127849A|2011-08-16|
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    US20110237526A1|2011-09-29|
    WO2011039107A1|2011-04-07|
    IN2012DN02756A|2015-09-18|
    PL2483286T3|2017-04-28|
    NZ598318A|2014-02-28|
    JP2013505974A|2013-02-21|
    CN102549005A|2012-07-04|
    AU2010303123A1|2012-03-15|
    CA2775961A1|2011-04-07|
    JP5736377B2|2015-06-17|
    MX2012002942A|2012-04-11|
    CN102549005B|2015-08-26|
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    CA2775961C|2017-11-07|
    ES2596202T3|2017-01-05|
    HUE029381T2|2017-02-28|
    EP2483286B1|2016-07-13|
    CL2012000810A1|2012-08-31|
    TWI482778B|2015-05-01|
    EP2483286A1|2012-08-08|
    EA020798B1|2015-01-30|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-01-29| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-04-24| B06T| Formal requirements before examination|
    2019-08-27| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2020-01-28| B09A| Decision: intention to grant|
    2020-03-31| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/09/2010, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP09171847|2009-09-30|
    EP09171847.8|2009-09-30|
    PCT/EP2010/064117|WO2011039107A1|2009-09-30|2010-09-24|Method for the preparation of a crystalline form of 1-chloro-4- -2--tetrahydrofuran-3-yloxy)benzyl)benzene|
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