Method for preparing crystalline type II sogliflozin

Abstract

The present invention relates to a method for preparing crystalline type II sotagliflozin, wherein crystalline type II sotagliflozin is directly obtained from a compound of the following formula (A) by using toluene or xylene or a mixture thereof as a solvent medium for crystallization.

Description

Technical Field

[0001] The present invention relates to a novel method for preparing crystalline type II sotagliflozin. Background Art

[0002] Sogliflozin, also known as (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol or methyl (5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-thio-β-L-xylopyranoside, is a drug developed for the treatment of diabetes.

[0003] Today, 13 different forms of sotagliflozin have been identified, in particular two anhydrous polymorphic forms, named Type 1 and Type 4, corresponding to Form I (crude sotagliflozin) and Form II (pure sotagliflozin), respectively.

[0004] These formats have been described in detail in WO 2010 / 009197.

[0005] Type I and Type II behave like a univariable system, with Type II being the most thermodynamically stable.

[0006] Therefore, Form II is the most interesting form of sogliflozin.

[0007] According to the current industrial process, Sogliflozin Form II is manufactured from a methyl sulfide derivative in a two-stage manner, wherein a mixture of methanol and water is used as a solvent during the first stage, and a mixture of methyl ethyl ketone and heptane is used during the second stage. The first stage corresponds to the synthesis, crystallization and isolation of Sogliflozin Form I, and the second stage corresponds to the crystallization and isolation of Sogliflozin Form II.

[0008] Pure Form II of crystalline sotagliflozin suspended in a methyl ethyl ketone / heptane mixture is in the form of elongated needles. As a result, the medium at the end of crystallization is difficult to stir, and the filter cake after filtration is difficult to purify and remains very wet, since it still contains 50-60% of solvent. After drying, on the drying filter, sotagliflozin is in the form of very short broken needles, some of which form more or less hard lumps.

[0009] Therefore, there is still a need for a new method for preparing crystalline Form II sogliflozin that avoids previous disadvantages.

[0010] There is also a need for a new method for preparing crystalline Form II sogliflozin, the industrial production cost of which is significantly reduced.

[0011] There is also a need for a new process for preparing crystalline Form II sotagliflozin which is easy to carry out, ie does not require the performance of discrete steps.

[0012] There is also a need for a new process for preparing crystalline Form II sotagliflozin, which process can be advantageously carried out in a continuous manner together with the industrial preparation of a precursor of the crystalline Form II sotagliflozin. Summary of the invention

[0013] Thus, exemplary embodiments relate to a specific method for preparing crystalline Form II sogliflozin:

[0014]

[0015] The crystalline type II sogliflozin is directly obtained from the compound of the following formula (A) by using toluene or xylene or a mixture thereof as a solvent medium for crystallization:

[0016]

[0017] Advantageously, crystalline Form II sotagliflozin is prepared without forming crystalline Form I sotagliflozin.

[0018] According to a preferred embodiment, the method comprises the steps of:

[0019] a) reacting a compound of formula (A) with an alcohol in a non-aqueous solvent medium comprising a base and including at least toluene or xylene or a mixture thereof, preferably at least toluene;

[0020] b) washing the solvent medium with water;

[0021] c) dehydrating the solvent medium;

[0022] d) crystallizing the Form II sogliflozin; and

[0023] e) recovering the crystalline Form II sogliflozin.

[0024] The process is particularly advantageous over the processes disclosed in the prior art since it provides crystalline Form II sogliflozin in good yield and good chemical purity.

[0025] “Good yield” means that the Form II sogliflozin is obtained in a yield higher than or equal to 90%.

[0026] As used herein, "good chemical purity" is a purity greater than or equal to 99%.

[0027] In fact, the method advantageously enables a clean synthesis in which no side reactions or degradation occur leading to the formation of impurities.

[0028] Furthermore, this method can advantageously be carried out continuously.

[0029] Thus, crystalline Form II sogliflozin can be synthesized in a batch process or a continuous process.

[0030] In particular, crystalline Form II sogliflozin was synthesized in a batch process.

[0031] Preferably, crystalline Form II sogliflozin is synthesized in a continuous process.

[0032] A "continuous process" refers to a process that can be carried out continuously without interruptions for feeding and / or removing the products involved, as opposed to a "batch process".

[0033] Synthesis of Sogliflozin

[0034] Sogliflozin was synthesized from the compound of the following formula (A):

[0035]

[0036] This compound (A) is dissolved in a non-aqueous solvent medium comprising at least toluene or xylene or a mixture thereof, preferably at least toluene.

[0037] Toluene or xylene are particularly advantageous since they solubilize compound (A) and sogliflozin.

[0038] In a preferred embodiment, compound (A) is reacted with an alcohol to form sogliflozin.

[0039] The alcohol may be selected, for example, from methanol, ethanol, 1-propanol, 2-propanol, butanol, pentanol or hexadecanol, in particular from lower alcohols such as methanol, ethanol, 1-propanol or 2-propanol, preferably from methanol and ethanol, more preferably methanol.

[0040] The content of the alcohol is at least equal to the catalytic amount, preferably higher than 12 equivalents, more preferably 12 to 20 equivalents.

[0041] In a preferred embodiment, the synthesis of crystalline Sogliflozin Form II is carried out at a temperature below the boiling point of methanol. The boiling point of methanol at atmospheric pressure (760 mm Hg) is 64.7°C.

[0042] In particular, the synthesis is carried out at atmospheric pressure at a temperature below 65°C and preferably below 63°C.

[0043] More specifically, it is carried out at atmospheric pressure at a temperature of 60° C. to 65° C. and preferably 60° C. to 63° C. More preferably, the synthesis is carried out at 60° C.

[0044] In case the synthesis is carried out under high pressure, this temperature may be higher. For example, if the pressure is 7-8 bar, the temperature may be about 110°C.

[0045] In a preferred embodiment, a first solution of compound (A) in toluene or xylene or a mixture of toluene and xylene is prepared. This solution may be heated to completely dissolve compound (A), in particular at a temperature of 25°C to 45°C and preferably 30°C to 40°C.

[0046] Preferably, according to this embodiment, a first solution of compound (A) in toluene is prepared.

[0047] The content of toluene can be 5 to 19 times by volume, particularly 10 to 19 times by volume, preferably 10 to 15 times by volume, more preferably 10 times by volume.

[0048] For the synthesis of sogliflozin from compound (A), the non-aqueous solvent medium advantageously also comprises a base, in particular a base selected from sodium hydroxide, sodium methoxide or sodium ethoxide, preferably the base is sodium methoxide.

[0049] The content of base is at least equal to the catalytic amount, in particular higher than 0.5 equivalents, preferably higher than 0.6 equivalents.

[0050] Preferably, the non-aqueous solvent medium comprises sodium methoxide (MeONa) and methanol (MeOH).

[0051] According to this variant, and when the non-aqueous solvent medium comprises toluene, the concentration of compound (A) may comprise from 10 volumes to 19 volumes of toluene, preferably may comprise equal to 10 volumes of toluene.

[0052] When sogliflozin is synthesized from compound (A) using a non-aqueous solvent medium comprising toluene, the solution of compound (A) in toluene is advantageously supplemented with a solution of MeONa and MeOH.

[0053] To this end, a solution of MeONa and MeOH can be prepared in which the content of MeONa is at least equal to the catalytic amount, in particular higher than 0.5 equivalents, preferably higher than 0.6 equivalents, and the content of MeOH is at least equal to the catalytic amount, preferably higher than 12 equivalents.

[0054] In particular, the content of MeONa is a catalytic amount to 1 equivalent, in particular 0.5 equivalent to 1 equivalent, preferably 0.6 equivalent to 1 equivalent, and the content of MeOH is 12 equivalent to 20 equivalents. For example, 0.6 equivalent of MeONa and 15 equivalents of MeOH can be used.

[0055] The "catalytic amount" means that a material such as MeONa or MeOH is used in an amount which is small relative to the starting material, ie, compound (A), but sufficient to carry out the reaction.

[0056] The MeONa / MeOH solution may also be preheated before mixing into the solution of compound (A) in toluene.

[0057] For the synthesis, a continuous stirred tank reactor (CSTR) can be used.

[0058] Preferably, the synthesis is carried out under stirring.

[0059] The stirring speed can be set by the skilled person through experiments of different routes. This depends mainly on the volume of the chamber used.

[0060] For example, for a reactor with a volume below 1 liter, the stirring speed may be 500 tr / min.

[0061] Washing

[0062] After the synthesis of sogliflozin from compound A, water washing may be considered.

[0063] Preferably, the medium is washed with 0.5 to 1 volume of water.

[0064] The temperature during the water wash may be between 55° C. and 65° C., for example 60° C. Such a temperature is advantageous in avoiding cooling of the intermediate product and in preventing crystallization at this stage of the process.

[0065] This step can be carried out using a mixer / settler.

[0066] Preferably, the water washing is carried out under stirring.

[0067] For example, the stirring may be 450 tr / min.

[0068] Dehydration

[0069] When water washing is performed, a subsequent dehydration step is considered.

[0070] This dehydration step is advantageous to prevent the formation of sogliflozin hydrates, avoid the loss of sogliflozin in, for example, methyl acetate and / or methanol in which it is soluble, and remove residual solvents such as methyl acetate and methanol present.

[0071] Dehydration is preferably performed by evaporation.

[0072] The dehydration can be performed under atmospheric pressure or under reduced pressure.

[0073] For example, a falling film evaporator may be used.

[0074] Preferably, at least 10 v / v %, preferably at least 15 v / v % of the solution is evaporated.

[0075] Advantageously, the water content in the medium after dehydration is less than 300 ppm.

[0076] Furthermore, after evaporation, the medium is advantageously substantially free of methyl acetate and MeOH.

[0077] Preferably, before crystallization, the concentration of the toluene solution may be adjusted from 40 g / l to 80 g / l, preferably from 45 g / l to 50 g / l, more preferably to 50 g / l.

[0078] crystallization

[0079] Due to the described process, crystalline Sotagliflozin Form II is directly crystallized without forming Sotagliflozin Form I.

[0080] In addition, the loss of the synthesized crystalline Form II sotagliflozin in the mother liquor is very low.

[0081] In particular, the crystallization of solafloxacin is carried out at the crystallization temperature of solafloxacin Form II. The crystallization temperature depends on the concentration. It can be determined according to e.g. Figure 1 The solubility profiles of Form I and Form II sotagliflozin are shown for selection.

[0082] Preferably, the crystallization is carried out at atmospheric pressure at a temperature of 60 to 70°C, preferably 62 to 67°C and more preferably 65°C.

[0083] In particular, when the non-aqueous solvent medium comprises toluene, the content of toluene used in the crystallization process may be 40 g / l to 80 g / l.

[0084] According to a preferred embodiment, the formation of crystalline Sotagliflozin Form II is initiated by pre-existing crystalline Sotagliflozin Form II. Such pre-existing crystalline Sotagliflozin Form II can be synthesized, for example, according to the method described in WO 2010 / 009197.

[0085] In particular, the formation of crystalline Form II sotagliflozin can be initiated with 2 wt / wt% to 15 wt / wt% pre-existing Form II sotagliflozin and preferably 2 wt / wt% to 10 wt / wt% pre-existing Form II sotagliflozin.

[0086] During the crystallization process, it is advantageous to wet-mill the medium to make it easier to stir.

[0087] For the crystallization, a continuous stirred tank reactor (CSTR) can advantageously be used.

[0088] According to a preferred embodiment, the crystallization is carried out in two steps. In the first step, the sogliflozin solution is heated to a temperature of 60° C. to 70° C., preferably 62° C. to 67° C. and more preferably 65° C. at atmospheric pressure. In the second step, the obtained suspension is cooled to a temperature of 20° C. to 30° C., preferably 20° C. to 25° C., and more preferably 20° C.

[0089] In this variant, wet grinding may be performed during the first step.

[0090] According to this variant, the crystallization of sogliflozin can be carried out in two or more continuously stirred tank reactors connected in series.

[0091] Preferably, the crystallization of sogliflozin is carried out in two continuously stirred tank reactors connected in series.

[0092] Filtration and washing

[0093] Crystalline Form II sogliflozin may be recovered by filtering and washing, preferably with toluene or xylene or a mixture thereof, and more preferably with toluene.

[0094] In this step, the mother liquor and the washing liquid are removed.

[0095] In particular, the filtration of the mother liquor may be carried out at a temperature below 40°C, in particular below 30°C and preferably at 20°C.

[0096] Preferably, the obtained wet cake is washed with 2 volumes of toluene at 25°C.

[0097] The filtration can be carried out under vacuum or high pressure. Preferably, the filtration is carried out under high pressure, for example at 3 bar.

[0098] For example, the filtration can be performed on a sinter or a filter tank.

[0099] In a continuous process, the filtration can be carried out on a continuous filter, for example on a rotary pressure filter or on a vacuum belt filter.

[0100] The washing can be carried out with a solvent, for example with toluene or xylene or a mixture thereof, preferably with toluene.

[0101] Filtration and washing may be followed by a drying step.

[0102] dry

[0103] In particular, the drying step is carried out at a temperature of 45 to 65°C and in particular at 50 to 55°C.

[0104] The drying step may be carried out at a pressure below 100 mbar and in particular below 50 mbar.

[0105] The drying step may be performed in a vacuum oven.

[0106] Conical spiral dryers or tray dryers may also be used.

[0107] calibration

[0108] In particular, the calibration is performed at a temperature of 20°C to 30°C and preferably 25°C.

[0109] In particular, conical screen mills can be used.

[0110] This step eliminates the clusters that formed during the drying step. DETAILED DESCRIPTION

[0111] The following examples describe the preparation of Sogliflozin Form II. These examples are not limiting and are only used to illustrate the method.

[0112] Example

[0113] Example 1: Preparation of crystals using toluene II Batch method for the administration of sogliflozin

[0114] Synthesis of Sogliflozin in Toluene

[0115] Sogliflozin was synthesized in a batch reactor at 60°C and atmospheric pressure using 10 volumes of toluene, 0.6 equivalents of MeONa and 12 equivalents of MeOH. The content of compound (A) was equal to 30 g / 10 volumes of toluene.

[0116] The residence time in the batch reactor was 15 minutes.

[0117] Sogliflozin was synthesized with a yield of 99.5%.

[0118] Washing

[0119] The reaction medium was washed with 1 volume of water at 60° C. The sodium salts were removed well.

[0120] Dehydration

[0121] The medium was dehydrated by evaporation of a 15 v / v % solution.

[0122] crystallization

[0123] Crystallization of sotagliflozin was performed by seeding with 7.5 w / w % of Sotagliflozin Form II at 67°C and cooling to 40°C.

[0124] filter

[0125] The suspension was filtered on a filter bed at 40°C.

[0126] washing

[0127] The medium was washed with 2 volumes of toluene at 25°C.

[0128] dry

[0129] The medium was then dried in a vacuum oven at 50°C.

[0130] Sogliflozin Form II was crystallized with a yield of 92%.

[0131] XRPD (X-ray diffraction) analysis confirmed that Form II sogliflozin was obtained.

[0132] Example 2: Preparation of crystals using toluene II Continuous process for the preparation of sogliflozin

[0133] Synthesis of Sogliflozin in Toluene

[0134] Sogliflozin was synthesized in a continuous stirred tank reactor with a reactor volume of 230 mL and under stirring at 500 tr / min.

[0135] 450 g of compound (A) was used together with 10 volumes of toluene to prepare 92.3 g / l (893 kg / m 3 ) in toluene. The solution was fed to the reactor at a flow rate of 372 g / h.

[0136] 828 kg / m was prepared using 0.6 equivalent of MeONa and 15 equivalent of MeOH. 3 The solution was fed into the reactor at a flow rate of 35.8 g / h.

[0137] The synthesis was carried out at 60-61 °C.

[0138] The residence time in the reactor was 30 minutes.

[0139] Sogliflozin was synthesized with a yield of 98%.

[0140] Washing

[0141] The reaction medium was washed with water using a mixer (264 ml) and a settler (631 ml) under stirring at 450 tr / min.

[0142] Washing was carried out at 61° C. at a flow rate of 460 g / h with 1 volume of water / reaction medium.

[0143] The residence time in the mixer was 15 minutes.

[0144] The residence time in the settler was 45 minutes.

[0145] Sodium salts are removed well.

[0146] Dehydration

[0147] The medium was dehydrated by evaporation of 15 v / v % of the solution at 67° C.-109° C. After evaporation, the content of MeOH was 0 w / w %, the content of AcCOMe was 0.15 w / w % and the content of water was 140 ppm.

[0148] The concentration of the toluene solution of sogliflozin was adjusted to 50 g / l by adding toluene.

[0149] The toluene solution of sogliflozin (50 g / l) was maintained at a temperature of 70-75°C.

[0150] crystallization

[0151] Crystallization of sogliflozin was carried out in two continuously stirred tank reactors (600 ml each) connected in series.

[0152] The solution is delivered to the reactor by pressure.

[0153] Initially, the first reactor was seeded with 10 wt / wt% of Sogliflozin Form II.

[0154] A toluene solution of sogliflozin (50 g / l, 829 kg / m 2 ) was stirred at 400 tr / min at a flow rate of 1160 g / h (1400 ml / h) at 65°C-66°C. 3 ) is fed into the first reactor. The residence time in the reactor is 30 minutes.

[0155] The medium obtained in the first crystallization chamber is collected, wet-milled, and fed back into the first crystallization chamber.

[0156] The sogliflozin suspension obtained at the end of the first reactor was transferred to the second reactor using a peristaltic pump.

[0157] The suspension of sogliflozin obtained at the end of the first reactor was fed into the second reactor at 25° C.-26° C. and under stirring at 600 tr / min. The residence time in the reactor was 30 minutes.

[0158] The suspension obtained at the end of the second reactor is recovered in order to separate it (filter, wash and dry).

[0159] filter

[0160] The suspension was filtered on a rotary pressure filter at 25 °C.

[0161] washing

[0162] The medium was washed with 2 volumes of toluene at 25°C.

[0163] dry

[0164] The medium was then dried at 50° C. under a pressure of less than 50 mbar.

[0165] Sogliflozin Form II was synthesized with a yield of 97%.

[0166] XRPD (X-ray diffraction) analysis confirmed that Form II sogliflozin was obtained.

[0167] Example 3: Preparation of crystals with toluene in an enhanced reactor II Continuous process for the preparation of sogliflozin

[0168] Synthesis of Sogliflozin in Toluene

[0169] Sogliflozin was synthesized in an intensified reactor at 113 °C and 8 bar pressure.

[0170] A solution of compound (A) in 10 volumes of toluene at a flow rate of 1194.6 g / h and a methanol solution of MeONa (0.6 equivalent of MeONa and 15 equivalent of MeOH) at a flow rate of 114.6 g / h were fed into the reactor, and the solutions were preheated at 113°C.

[0171] The residence time in the reactor was 20 seconds.

[0172] The system was maintained at a pressure of 8 bar.

[0173] Sogliflozin was synthesized with a yield of 99.7%.

[0174] The washing, dehydration, crystallization, filtration, washing and drying were carried out in accordance with Example 2.

[0175] XRPD (X-ray diffraction) analysis confirmed that Form II sogliflozin was obtained.

Claims

1. A method for preparing crystalline type II sogliflozin: The method comprises: a) reacting a compound of formula (A) with methanol and sodium methoxide in a non-aqueous solvent medium comprising toluene, xylene or a mixture thereof to provide a reaction mixture; b) washing the reaction mixture with water; c) dehydrating the reaction mixture after washing; d) crystallizing Sogliflozin Form II from the dehydrated reaction mixture; e) recovering crystalline Form II sogliflozin.

2. The process according to claim 1, wherein step a) is carried out at a temperature below the boiling point of methanol.

3. The process according to claim 1, wherein step a) is carried out at a temperature below 65°C at atmospheric pressure.

4. The method according to claim 1, wherein step c) is performed by evaporation.

5. The method according to claim 1, wherein step d) is performed at the crystallization temperature of Form II sogliflozin.

6. The process according to claim 1, wherein step d) is carried out at a temperature of 60°C to 70°C under atmospheric pressure.

7. The method of claim 1, wherein the formation of crystalline Form II sotagliflozin is initiated by pre-existing crystalline Form II sotagliflozin.

8. The process according to claim 1, wherein step d) is followed by filtering and washing.

9. The method according to claim 8, wherein the washing is performed with toluene, xylene or a mixture thereof.

10. The process of claim 8, wherein the filtering and washing are followed by a drying step.

11. The method according to claim 10, wherein the drying step is performed at a temperature of 45°C to 65°C.

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