Continuous process for preparing crystalline Form II sogliflozin

Abstract

The present invention relates to a method for preparing crystalline type II sotagliflozin from a compound of formula (A), which method is carried out continuously and comprises at least the following steps: a) in a reaction chamber, at a temperature below the boiling point of methanol, reacting a solution of the compound of formula (A) in toluene or xylene or a mixture thereof and preferably in toluene with at least sodium methoxide and methanol to form sotagliflozin in the form of a mixture with a sodium salt; b) in a crystallization chamber, at the crystallization temperature of type II sotagliflozin, crystallizing the sotagliflozin formed in step a) in a non-aqueous solvent medium, wherein the non-aqueous solvent medium comprises at least toluene or xylene or a mixture thereof and does not contain a sodium salt; and c) separating the crystalline type II sotagliflozin.

Description

Technical Field

[0001] The present invention relates to a novel continuous process for preparing crystalline Form 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 forms and methods for their preparation 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 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 crystalline sogliflozin Form II.

[0008] The pure Form II of the crystalline sogliflozin thus obtained, suspended in a methyl ethyl ketone / heptane mixture, is in the form of elongated needles. As a result, the medium at the end of the 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.

[0009] After drying, on the filter drying filter, sogliflozin was in the form of very short broken needles, some of which formed more or less hard clumps.

[0010] On an industrial scale it is highly advantageous that this process can be carried out in a continuous manner.

[0011] In fact, continuous flow synthesis has many advantages over traditional batch synthesis because it can achieve better yields, better purity, lower costs, and better reproducibility. Summary of the invention

[0012] The present invention is therefore specifically directed to providing such a method.

[0013] Specifically, the exemplary embodiments relate to a specific method for preparing crystalline Form II sogliflozin from a compound of the following formula (A):

[0014]

[0015] The method is carried out continuously and comprises at least the following steps:

[0016] a) reacting a solution of the compound of formula (A) in toluene or xylene or a mixture thereof, preferably in toluene, with at least sodium methoxide and methanol in a reaction chamber at a temperature below the boiling point of methanol to form sogliflozin in a mixture with the sodium salt;

[0017] b) crystallizing the sotagliflozin formed in step a) in a non-aqueous solvent medium comprising at least toluene or xylene or a mixture thereof and without sodium salt at a crystallization temperature of sotagliflozin Form II in a crystallization chamber; and

[0018] c) isolating the crystalline Form II sogliflozin.

[0019] "Continuous process" or "continuously carried out 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".

[0020] Preferably, the reaction and / or crystallization chamber is a continuous stirred tank reactor (CSTR).

[0021] Advantageously, the crystalline Form II sotagliflozin is prepared without forming crystalline Form I sotagliflozin.

[0022] 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.

[0023] “Good yield” means that the Form II sogliflozin is obtained in a yield higher than or equal to 90%.

[0024] As used herein, "good chemical purity" is a purity greater than or equal to 99%.

[0025] In fact, the method advantageously enables a clean synthesis in which no side reactions or degradation occur leading to the formation of impurities.

[0026] Formation of Sogliflozin: Step a)

[0027] The method comprises the following steps a): in a reaction chamber, at a temperature below the boiling point of methanol, reacting a solution of the compound of formula (A) in toluene or xylene or a mixture thereof, and preferably at least in toluene, with at least sodium methoxide and methanol to form sogliflozin in the form of a mixture with the sodium salt.

[0028] The boiling point of methanol at atmospheric pressure (760 mm Hg) is 64.7°C.

[0029] In particular, the method comprises the following steps a): promoting the reaction of a solution of the compound of formula (A) in toluene or xylene or a mixture thereof, and preferably at least in toluene, with at least sodium methoxide and methanol in a reaction chamber at a temperature below the boiling point of methanol to form sogliflozin in the form of a mixture with the sodium salt.

[0030] "Promote" means to optimize the conditions for conducting a reaction so as to help the reaction proceed.

[0031] In the reaction chamber, sogliflozin is synthesized from a compound of the following formula (A):

[0032]

[0033] Prior to the reaction, 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.

[0034] A solution of compound (A) in 10 volumes of toluene can be particularly used.

[0035] Toluene or xylene are particularly advantageous since they solubilize compound (A) and sogliflozin.

[0036] Thus, 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.

[0037] Preferably, according to this embodiment, a first solution of compound (A) in toluene is prepared.

[0038] 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.

[0039] For example, when the first solution of compound (A) is in toluene, the flow rate of the solution of compound (A) in toluene in the reaction chamber may be 55 kg / h to 65 kg / h, specifically 58 kg / h to 62 kg / h.

[0040] It should be understood that the flow rates of different materials in the chamber can vary according to different parameters, such as, but not limited to, the volume (diameter / length) of the chamber and the residence time in the chamber. The flow rates can be set by the technician through different route calculations and / or experiments.

[0041] The solution of compound (A) in toluene or xylene or a mixture of toluene and xylene may be supplemented with a solution of sodium methoxide and methanol.

[0042] When the first solution of compound (A) is in toluene, the concentration of compound (A) may include 10 volumes to 19 volumes of toluene, and preferably may be equal to 10 volumes of toluene.

[0043] According to this variant, 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.

[0044] 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.

[0045] The MeONa / MeOH solution may also be preheated before mixing into the solution of compound (A) in toluene, xylene or a mixture thereof.

[0046] 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.

[0047] For example, the flow rate of the solution of sodium methoxide and methanol in the reaction chamber may be 3 kg / h to 8 kg / h, specifically 4 kg / h to 6 kg / h.

[0048] According to a preferred embodiment, a solution of compound (A) in toluene or xylene or a mixture of toluene and xylene and a solution of sodium methoxide and methanol can be fed simultaneously into the reaction chamber.

[0049] A pump such as a gear pump, a diaphragm pump, or a peristaltic pump may be used to drive the solution into the reaction chamber.

[0050] In a preferred embodiment, the temperature in step a) is below 65°C, preferably below 63°C at atmospheric pressure.

[0051] 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 reaction is carried out at 60° C.

[0052] In the case where the reaction is carried out at elevated pressure, this temperature may be higher. For example, if the pressure is 7-8 bar, the temperature may be about 110°C.

[0053] Preferably, the reaction is carried out with stirring.

[0054] 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.

[0055] The residence time in the reaction chamber is set in such a way that the compounds can react completely. The residence time can vary according to different parameters, such as, but not limited to, the reaction temperature, the volume (diameter / length) of the chamber, the concentration of the compound to be reacted, and the flow rate of the reactants flowing into the chamber. The residence time can be set by the technician through experiments of different routes.

[0056] In a preferred variant, the residence time in the reaction chamber is at least 10 minutes, in particular at least 15 minutes, preferably at least 20 minutes, more preferably at least 30 minutes.

[0057] The reaction carried out in the first chamber results in the formation of a mixture comprising sogliflozin and the sodium salt.

[0058] In a preferred variation, the reaction chamber is a continuous stirred tank reactor (CSTR).

[0059] The reaction in step a) can also be carried out in an enhanced reactor.

[0060] According to this variant, the residence time in the reactor can advantageously be short, for example it can be at least 20 seconds.

[0061] Washing and dehydration

[0062] According to a preferred embodiment, the process comprises, between steps a) and b), a further step of removing sodium salts from the medium obtained at the end of step a) by washing the medium with water, followed by dehydration of the medium.

[0063] This step allows the removal of the sodium salt formed during the reaction of a solution of the compound of formula (A) in toluene, xylene or a mixture thereof with at least sodium methoxide and methanol.

[0064] Preferably, the water washing of the medium is carried out using 0.5 volume to 1 volume of water.

[0065] For example, the flow rate of water may be 66 kg / h to 79 kg / h, specifically 71 kg / h to 75 kg / h.

[0066] 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.

[0067] This step can be performed using a mixer / settler.

[0068] The residence time in the mixer may be at least 10 minutes, preferably at least 15 minutes.

[0069] The residence time in the settler may be at least 20 minutes, in particular at least 25 minutes, preferably at least 30 minutes, more preferably at least 40 minutes.

[0070] Preferably, the water washing is carried out under stirring.

[0071] The dehydration step is advantageous in preventing the formation of sogliflozin hydrates, avoiding the loss of sogliflozin in soluble methyl acetate and / or methanol, and removing any residual solvents present, such as methyl acetate and methanol.

[0072] The dehydration of the medium is preferably carried out by evaporation.

[0073] The dehydration can be performed under atmospheric pressure or under reduced pressure.

[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 substantially free of methyl acetate and MeOH.

[0077] Preferably, before step b), when toluene is used, the concentration of the toluene solution can 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. This adjustment can be performed by adding toluene.

[0078] Crystallization: step b)

[0079] The method comprises step b): crystallizing the sotagliflozin formed in step a) in a non-aqueous solvent medium at the crystallization temperature of Form II sotagliflozin in a crystallization chamber, wherein the non-aqueous solvent medium comprises at least toluene, xylene or a mixture thereof and preferably at least toluene and does not contain a sodium salt.

[0080] Due to the described process, crystalline Sotagliflozin Form II is directly crystallized without forming Sotagliflozin Form I.

[0081] In addition, the loss of the synthesized crystalline Form II sotagliflozin in the mother liquor is very low.

[0082] 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.

[0083] Preferably, step b) is carried out at atmospheric pressure at a temperature of 60 to 70°C, preferably 62 to 67°C and more preferably 65°C.

[0084] The solution can be delivered to the crystallization chamber by pressure.

[0085] In particular, when the solution contains toluene, the content of toluene used in the crystallization process may be 40 g / l to 80 g / l.

[0086] For example, the flow rate of the sogliflozin solution in the crystallization chamber may be 80 kg / h to 90 kg / h.

[0087] Preferably, the residence time in the crystallization chamber is at least 10 minutes, in particular at least 15 minutes, preferably at least 20 minutes, more preferably at least 30 minutes.

[0088] Preferably, the crystallization is carried out under stirring.

[0089] 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.

[0090] 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.

[0091] According to this embodiment, the crystallization chamber in step b) is seeded with pre-existing crystalline sotagliflozin Form II.

[0092] During the crystallization process, it is advantageous to wet-mill the medium to facilitate stirring.

[0093] According to this variant, the medium obtained in the crystallization chamber is collected, wet-milled and returned to said crystallization chamber.

[0094] Preferably, the crystallization chamber is a continuous stirred tank reactor (CSTR).

[0095] According to a particular embodiment, step b) 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 preferably 65° C. at atmospheric pressure. In the second step, the resulting suspension is cooled to a temperature of 20° C. to 30° C., preferably 20° C. to 25° C., and preferably 20° C.

[0096] According to this embodiment, the process therefore comprises, between steps b) and c), a further step b') of feeding the medium obtained at the end of step b) to the subsequent crystallization chamber at a temperature lower than that of the previous crystallization chamber.

[0097] In particular, the temperature in step b') is from 20°C to 30°C, preferably from 20°C to 28°C, more preferably 20°C at atmospheric pressure.

[0098] In this variant, wet grinding may be performed during the first step.

[0099] According to this variant, the crystallization of sogliflozin can be carried out in two or more continuously stirred tank reactors connected in series.

[0100] Preferably, the crystallization of sogliflozin is carried out in two continuously stirred tank reactors connected in series.

[0101] Thus, the sogliflozin suspension obtained at the end of the first crystallization chamber can be transferred to the subsequent crystallization chambers, for example, using a peristaltic pump.

[0102] In this variant, the residence time in the first crystallization chamber may be at least 25 minutes, preferably at least 30 minutes, and the residence time in the subsequent crystallization chamber may be at least 25 minutes, preferably at least 30 minutes.

[0103] Specifically, the flow rate of the sogliflozin solution in the first crystallization chamber can be, for example, 80 kg / h to 90 kg / h, and the residence time in the first crystallization chamber can be at least 25 minutes, preferably at least 30 minutes. The flow rate of the sogliflozin suspension in the subsequent crystallization chamber can be, for example, 80 kg / h to 90 kg / h, and the residence time in the subsequent crystallization chamber can be at least 25 minutes, preferably at least 30 minutes.

[0104] Isolation of crystalline Form II sogliflozin: step c)

[0105] The method comprises the step c) of isolating crystalline Form II sotagliflozin.

[0106] The isolation of crystalline Sogliflozin Form II may advantageously be carried out at a temperature below 40°C, in particular below 30°C and preferably at 20°C.

[0107] Filtration and washing

[0108] The mixture obtained after step b) or step b') can be filtered and washed preferably with toluene or xylene or a mixture thereof, more preferably with toluene.

[0109] In this step, the mother liquor and the washing liquid are removed.

[0110] For example, the flow rate of the sogliflozin suspension used for filtration may be 80 kg / h to 90 kg / h.

[0111] 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.

[0112] Preferably, the obtained wet cake is washed with 2 volumes of toluene at 25°C.

[0113] 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.

[0114] For example, the filtration can be carried out on a continuous filter, for example on a rotary pressure filter or on a vacuum belt filter.

[0115] The washing can be carried out with a solvent, for example with toluene or xylene or a mixture thereof, preferably with toluene.

[0116] dry

[0117] Filtration and washing may be followed by a drying step.

[0118] In particular, the drying step is carried out at a temperature of 45 to 65°C and in particular at 50 to 55°C.

[0119] The drying step may be carried out at a pressure below 100 mbar and in particular below 50 mbar.

[0120] In particular, conical screw dryers or tray dryers can also be used for the drying step.

[0121] calibration

[0122] In particular, the calibration is performed at a temperature of 20°C to 30°C and preferably 25°C.

[0123] In particular, conical screen mills can be used.

[0124] This step eliminates the clusters that formed during the drying step. DETAILED DESCRIPTION

[0125] The following examples describe the preparation of Sogliflozin Form II. These examples are not limiting but are merely illustrative of the process.

[0126] Example

[0127] Example 1: Continuous process for preparing crystalline Form II sogliflozin using toluene

[0128] Synthesis of Sogliflozin in Toluene

[0129] A toluene solution of compound (A) was prepared with 10 volumes of toluene at room temperature (25° C.) The medium was heated at 30° C. to 40° C. to completely dissolve compound (A).

[0130] 0.6 equivalents of MeONa and 15 equivalents of MeOH were used to prepare a methanolic solution of MeONa.

[0131] Both solutions were fed under stirring at 180 tr / min and at atmospheric pressure into a first continuously stirred tank reactor with a reactor volume of 37 L. The flow rate of the toluene solution of compound (A) was 60.5 kg / h and the flow rate of the methanol solution of MeONa was 5.8 kg / h.

[0132] The synthesis was carried out at 62°C.

[0133] The residence time in the reactor was 30 minutes.

[0134] Washing

[0135] The resulting solution was transferred to another reactor at a flow rate of 66.3 kg / h.

[0136] The reaction medium was washed with water at 60°C.

[0137] Wash with 1 volume of water / reaction medium.

[0138] Sodium salts are fully removed.

[0139] Dehydration

[0140] The solution was dehydrated in a reactor by evaporation at 70-110°C under atmospheric pressure.

[0141] crystallization

[0142] Crystallization of sogliflozin was carried out in two continuously stirred tank reactors connected in series.

[0143] The solution is delivered to the reactor by pressure.

[0144] Initially, the reactor was seeded with 7 wt / wt% of Sogliflozin Form II.

[0145] Under stirring at 134 tr / min, a toluene solution of sogliflozin (50 g / l) was fed into the reactor at a flow rate of 84.9 kg / h at 65° C. The residence time in the reactor was 30 minutes.

[0146] The media obtained in the crystallization chamber is collected, wet-milled, and returned to the crystallization chamber.

[0147] The sogliflozin suspension obtained at the end of the crystallization chamber is conveyed to another subsequent crystallization chamber.

[0148] The reactor was fed with 84.9 kg / h of the sogliflozin suspension obtained at the end of the previous reactor at 20° C. under stirring at 134 tr / min. The residence time in the reactor was 30 minutes.

[0149] The suspension obtained at the end of the reactor is recovered in order to separate it (filter, wash and dry).

[0150] filter

[0151] The suspension was filtered on a rotary pressure filter at a pressure of 2.5 bar at 20° C. The suspension was conveyed at a flow rate of 84.9 kg / h.

[0152] washing

[0153] The medium was washed with 2 volumes of toluene at a pressure of 2.5 bar at 20° C. The medium was fed at a flow rate of 12.5 l / h.

[0154] dry

[0155] The medium was then dried at 55° C. under a pressure of less than 100 mbar.

[0156] Sogliflozin Form II was crystallized with a yield of 97%.

[0157] XRPD (X-ray diffraction) analysis confirmed that Form II sogliflozin was obtained.

[0158] Example 2: Continuous process for preparing sogliflozin using toluene in an enhanced reactor

[0159] Synthesis of Sogliflozin in Toluene

[0160] Sogliflozin was synthesized in an intensified reactor at 113 °C and 8 bar pressure.

[0161] 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.

[0162] The residence time in the reactor was 20 seconds.

[0163] The system was maintained at a pressure of 8 bar.

[0164] Sogliflozin was synthesized with a yield of 99.7%.

[0165] The washing, dehydration, crystallization, filtration, washing and drying were carried out in accordance with Example 1.

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

Claims

1. A continuous method for preparing crystalline Form II sogliflozin from a compound of formula (A): The method comprises the following steps performed continuously: a) reacting a compound of formula (A) in a solution of toluene, xylene or a mixture thereof with sodium methoxide and methanol at a temperature below the boiling point of methanol in a reaction chamber to form a mixture of sogliflozin and the sodium salt; a′) washing the mixture formed in step (a) with water to provide a second mixture comprising sogliflozin; a″) dehydrating the second mixture to provide a third mixture comprising sogliflozin; b) crystallizing the sotagliflozin in the third mixture in a non-aqueous solvent medium at a crystallization temperature of sotagliflozin Form II in a crystallization chamber, wherein the non-aqueous solvent medium comprises toluene, xylene or a mixture thereof and does not contain a sodium salt; and c) isolating the crystalline Form II sogliflozin.

2. The process according to claim 1, wherein the compound of formula (A) in step a) is in solution in toluene.

3. The process according to claim 1 or 2, wherein the non-aqueous solvent medium in step b) comprises toluene.

4. The process according to claim 1 or 2, wherein the temperature in step a) is below 65°C at atmospheric pressure.

5. The method of claim 1 or 2, wherein the residence time in the reaction chamber is at least 10 minutes. The method of claim 1 , wherein the medium is dehydrated by evaporation.

7. The method according to claim 1 or 2, wherein the temperature in step b) is 60°C to 70°C at atmospheric pressure.

8. The process according to claim 1 or 2, wherein the crystallization chamber in step b) is seeded with pre-existing crystalline Form II sogliflozin.

9. The process according to claim 1 or 2, wherein the residence time in the crystallization chamber is at least 10 minutes.

10. The process according to claim 1 or 2, wherein the medium obtained in the crystallization chamber is collected, wet-milled, and returned to the crystallization chamber.

11. The process according to claim 1 or 2, comprising between steps b) and c) an additional step b') of feeding the medium obtained at the end of step b) to the subsequent crystallization chamber at a temperature lower than the temperature of the previous crystallization chamber.

12. The process according to claim 11, wherein the temperature in step b') is 20 to 30°C at atmospheric pressure.

13. The process according to claim 11, wherein the mixture obtained after step b) or step b') is filtered and washed.

14. The method of claim 13, wherein the washing is performed with toluene, xylene, or a mixture thereof.

15. The method of claim 13, wherein the filtering and washing are followed by a drying step.

16. The method of claim 15, wherein the drying step is performed at a temperature of 45°C to 65°C.

17. The process of claim 1 or 2, wherein the reaction chamber and / or one or more crystallization chambers are continuous stirred tank reactors.

Images