Process for preparing the crystalline form ii of sotagliflozin

Abstract

To provide a process for the preparation of the crystalline form II of sotagliflozin.SOLUTION: Provided is a process for the preparation of the crystalline form II of sotagliflozin represented by the following formula, the crystalline form II of sotagliflozin being 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.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present specification relates to a new method for preparing crystalline form II of sotagliflozin. [Background technology]

[0002] Sotagliflozin, 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 designated Class 1 and Class 4, corresponding to Form I (crude sotagliflozin) and Form II (pure sotagliflozin), respectively.

[0004] These forms are described in particular in US Pat. No. 5,399,633.

[0005] Forms I and II behave like monotropic systems, and Form II It is the most thermodynamically stable.

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

[0007] In the current industrial process, sotagliflozin form II is produced from the methyl thioether derivative in two steps, using a mixture of methanol and water as the solvent during the first step and a mixture of methyl ethyl ketone and heptane during the second step. The first step corresponds to the synthesis, crystallization and isolation of sotagliflozin form I, and the second step corresponds to the crystallization and isolation of sotagliflozin crystalline form II.

[0008] Crystalline sotagliflozin pure form II suspended in a methyl ethyl ketone / heptane mixture is in the form of long thin needles. As a result, the medium at the end of crystallization is difficult to stir, and the cake after filtration is insufficiently purged and still contains 50%-60% solvent, leaving a lot of moisture. After drying, on the drying filter, sotagliflozin is in the form of very short broken needles, some forming somewhat hard agglomerates. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2010 / 009197 Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, there remains a need for new methods for preparing crystalline form II of sotagliflozin that do not suffer from the above drawbacks.

[0011] There also remains a need for new methods for preparing crystalline form II of sotagliflozin with significantly reduced industrial production costs.

[0012] There also remains a need for new processes for preparing crystalline form II of sotagliflozin that are easy to carry out, i.e., do not require discontinuous steps.

[0013] There also remains a need for new processes for preparing crystalline form II of sotagliflozin, which can be advantageously carried out continuously by industrial preparation of said precursor of form II of sotagliflozin. [Means for solving the problem]

[0014] Thus, an exemplary embodiment provides crystalline form II of sotagliflozin: [ka] A particular method for preparing The above crystalline form II of sotagliflozin has the following formula (A): [ka] by using toluene or xylene, or a mixture thereof, as the solvent medium for crystallization.

[0015] Advantageously, the preparation of crystalline form II of sotagliflozin is carried out without forming crystalline form I of sotagliflozin.

[0016] According to a preferred embodiment, the method comprises the steps of: a) reacting a compound of formula (A) with an alcohol in a non-aqueous solvent medium containing a base and at least toluene or xylene, or a mixture thereof, preferably at least toluene; b) performing an aqueous wash of said solvent medium; c) dehydrating the solvent medium; d) crystallizing sotagliflozin Form II; and e) recovering sotagliflozin in crystalline form II; Includes.

[0017] The above process is particularly advantageous over the processes disclosed in the prior art as it provides Form II sotagliflozin in good yield and good chemical purity. [Brief description of the drawings]

[0018] [Figure 1] The crystallization temperature may be selected based on the solubility curves of sotagliflozin Form I and Form II, as shown in FIG.

[0019] "Good yield" means that the said Form II sotagliflozin is obtained in a yield of 90% or more.

[0020] As used herein, "good chemical purity" is 99% or greater purity.

[0021] Indeed, said method advantageously makes it possible to achieve a clean synthesis, which is free of side reactions or decompositions leading to the production of impurities.

[0022] Moreover, such processes can advantageously be carried out continuously.

[0023] Thus, crystalline form II of sotagliflozin may be synthesized in a batch or continuous manner.

[0024] In particular, crystalline form II of sotagliflozin is synthesized by a batch process.

[0025] Preferably, crystalline form II of sotagliflozin is synthesized in a continuous process.

[0026] "Continuous process" means a process that is distinct from a "batch process" and that can be continued without interruption for the supply and / or removal of products of interest.

[0027] Synthesis of sotagliflozin The following formula (A): [ka] Sotagliflozin is synthesized from the compound.

[0028] This compound (A) is dissolved in a non-aqueous solvent medium containing at least toluene or xylene, or a mixture thereof, preferably at least toluene.

[0029] Toluene or xylene are particularly advantageous since they allow solubilization of compound (A) and sotagliflozin.

[0030] In a preferred embodiment, compound (A) reacts with an alcohol to form sotagliflozin.

[0031] The alcohol may for example be selected 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.

[0032] The content of the alcohol is at least equal to the catalytic amount, preferably more than 12 equivalents, more preferably 12 to 20 equivalents.

[0033] In a preferred embodiment, the synthesis of crystalline form II of sotagliflozin is carried out at a temperature below the boiling point of methanol. The boiling point of methanol at atmospheric pressure (760 mmHg) is 6 The temperature is 4.7℃.

[0034] In particular, the synthesis is carried out at atmospheric pressure and at a temperature below 65°C, preferably below 63°C.

[0035] More particularly, the synthesis is carried out at atmospheric pressure and at a temperature between 60° C. and 65° C., preferably between 60° C. and 63° C. More preferably, the synthesis is carried out at 60° C.

[0036] Such temperatures can be high when the synthesis is carried out under high pressure, for example at a pressure of 7-8 bar the temperature can be around 110°C.

[0037] 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 between 25° C. and 45° C., preferably between 30° C. and 40° C.

[0038] According to this embodiment, it is preferred to prepare a first solution of compound (A) in toluene.

[0039] The toluene content may be 5 volumes to 19 volumes, particularly 10 volumes to 19 volumes, preferably 10 volumes to 15 volumes, and more preferably 10 volumes.

[0040] To carry out the synthesis of sotagliflozin from compound (A), the non-aqueous solvent medium also advantageously comprises a base, in particular selected from sodium hydroxide, sodium methoxide or sodium ethoxide, preferably the base is sodium methoxide.

[0041] The content of base(s) is at least equal to the catalytic amount, in particular more than 0.5 equivalents, preferably more than 0.6 equivalents.

[0042] Preferably, the non-aqueous solvent medium comprises sodium methoxide (MeONa) and methanol (MeOH).

[0043] According to this variant, when the non-aqueous solvent medium comprises toluene, the concentration of compound (A) may be comprised between 10 and 19 volumes of toluene, preferably equal to 10 volumes of toluene.

[0044] When the synthesis of sotagliflozin from compound (A) is carried out 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.

[0045] For this purpose, 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 more than 0.5 equivalents, preferably more than 0.6 equivalents, and the content of MeOH is at least equal to the catalytic amount, preferably more than 12 equivalents.

[0046] In particular, the content of MeONa is a catalytic amount to 1 equivalent, particularly 0.5 equivalent to 1 equivalent, preferably 0.6 equivalent to 1 equivalent, and the content of MeOH is 12 equivalent to 20 equivalent. For example, 0.6 equivalents of MeONa and 15 equivalents of MeOH can be used.

[0047] By "catalytic amount" it is meant that a substance such as MeONa or MeOH is used in a small amount relative to the starting material, i.e., compound (A), but sufficient to effect the reaction.

[0048] The MeONa / MeOH solution may also be preheated before being mixed with the solution of compound (A) in toluene.

[0049] A continuous stirred-tank reactor (CSTR) can be used to carry out the synthesis.

[0050] The synthesis is preferably carried out under stirring.

[0051] The stirring speed can be set by one skilled in the art through various routine experiments and depends in particular on the volume of the chamber used.

[0052] For example, for a reactor with a volume of less than 1 liter, the stirring speed may be 500 tr / min.

[0053] Aqueous Cleaning After synthesis of sotagliflozin from compound A, aqueous washes may be contemplated.

[0054] Aqueous washing of the medium is preferably carried out with 0.5 to 1 volume of water.

[0055] The temperature during the aqueous wash may be between 55° C. and 65° C., for example 60° C. Such a temperature is advantageous to avoid intermediate cooling and to prevent crystallization at this stage of the process.

[0056] This step can be carried out using a mixer / settler.

[0057] It is preferred that the aqueous wash be carried out under stirring.

[0058] For example, the stirring may be 450 tr / min.

[0059] dehydration If an aqueous wash is performed, a subsequent dehydration step is considered.

[0060] Such a dehydration step is advantageous to prevent the formation of hydrates of sotagliflozin, to avoid loss of sotagliflozin in solutions in which sotagliflozin is soluble, e.g., methyl acetate and / or methanol, and to remove residual solvents, if present, such as methyl acetate and methanol.

[0061] Dehydration is preferably accomplished by evaporation.

[0062] The dehydration can be carried out at atmospheric pressure or under reduced pressure.

[0063] For example, a falling film evaporator can be used.

[0064] It is preferred to evaporate at least 10% v / v, preferably 15% v / v of the solution.

[0065] Advantageously, the water content in the medium after dehydration is less than 300 ppm.

[0066] Furthermore, after evaporation, the medium is advantageously substantially free of methyl acetate and MeOH.

[0067] Preferably, before crystallization, the concentration of the toluene solution is 40 g / l to 80 g / l, preferably It can be adjusted to 45 g / l to 50 g / l, more preferably 50 g / l.

[0068] Crystallization By the described method, crystalline form II of sotagliflozin is directly crystallized without forming form I of sotagliflozin.

[0069] Furthermore, the loss of the synthesized crystalline form II sotagliflozin in the mother liquor is very low.

[0070] The crystallization of sotagliflozin is carried out at the crystallization temperature of sotagliflozin Form II in particular. The crystallization temperature is concentration dependent. The crystallization temperature can be selected based on the solubility curves of sotagliflozin Form I and Form II, as shown in FIG.

[0071] Preferably, the crystallization is carried out at atmospheric pressure and at a temperature between 60°C and 70°C, preferably between 62°C and 67°C, more preferably 65°C.

[0072] In particular, when the non-aqueous solvent medium contains toluene, the content of toluene used during crystallization may be from 40 g / l to 80 g / l.

[0073] According to a preferred embodiment, the formation of sotagliflozin in crystalline form II is initiated by existing sotagliflozin in crystalline form II. Such existing sotagliflozin in crystalline form II can be synthesized, for example, according to the method described in Patent Document 1.

[0074] In particular, the formation of crystalline form II sotagliflozin can be initiated with 2% wt / w to 15% wt / w of existing form II sotagliflozin, preferably 2% wt / w to 10% wt / w of existing form II sotagliflozin.

[0075] During crystallization, it may be advantageous to use wet milling media to facilitate agitation.

[0076] To carry out the crystallization, a continuous stirred tank reactor (CSTR) can be advantageously used.

[0077] According to a preferred embodiment, the crystallization is carried out in two steps: in a first step, a solution of sotagliflozin is heated at atmospheric pressure to a temperature between 60° C. and 70° C., preferably between 62° C. and 67° C., more preferably at 65° C. In a second step, the resulting suspension is cooled to a temperature between 20° C. and 30° C., preferably between 20° C. and 25° C., more preferably at a temperature of 20° C.

[0078] In this variant, wet grinding can be carried out during the first step.

[0079] According to this variant, the crystallization of sotagliflozin can be carried out in a cascade of two or more continuous stirred tank reactors.

[0080] The crystallization of sotagliflozin is preferably carried out in a cascade of two continuous stirred tank reactors.

[0081] Filtration and washing Crystalline form II sotagliflozin may be recovered by filtration and washing, preferably with toluene or xylene, or a mixture thereof, more preferably with toluene.

[0082] During this step the mother liquor and washes are removed.

[0083] In particular, the filtration of the mother liquor can be carried out at a temperature below 40°C, in particular below 30°C, preferably below 20°C.

[0084] The resulting wet cake is preferably washed with 2 volumes of toluene at 25°C.

[0085] The filtration can be carried out under vacuum or under high pressure, preferably the filtration is carried out under high pressure, for example 3 bar.

[0086] For example, the filtration can be carried out in a sintered cell or a filtration cell.

[0087] In a continuous process, the filtration can be carried out on a continuous filter, for example a rotary pressure filter or a vacuum band filter.

[0088] Washing is carried out with a solvent such as toluene or xylene or a mixture thereof, preferably toluene.

[0089] After filtration and washing, a drying step may be performed.

[0090] Drying In particular, the drying step is carried out at a temperature of 45°C to 65°C, in particular 50°C to 55°C.

[0091] The drying step can be carried out under a pressure of less than 100 mbar, in particular less than 50 mbar.

[0092] The drying step can be carried out in a vacuum oven.

[0093] A conical screw dryer or a pallet dryer can also be used.

[0094] calibration In particular, the calibration is carried out at a temperature between 20°C and 30°C, preferably at 25°C.

[0095] In particular, a conical sieve mill can be used.

[0096] This step makes it possible to remove clusters that may have formed during the drying step.

[0097] The following examples describe the preparation of sotagliflozin Form II. These examples are not limiting and are intended only to illustrate the above method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0098] Example 1: Batch preparation method of crystalline form II of sotagliflozin with toluene Synthesis of sotagliflozin in toluene Sotagliflozin was synthesized in a batch reactor using 10 volumes of toluene, 0.6 equivalents of MeONa and 12 equivalents of MeOH at atmospheric pressure and at a temperature of 60° C. The content of compound (A) was equal to 30 g in 10 volumes of toluene.

[0099] The residence time in the batch reactor was 15 minutes.

[0100] Sotagliflozin was synthesized with a yield of 99.5%.

[0101] Aqueous Cleaning An aqueous wash of the reaction medium was carried out with one volume of water at 60° C. The sodium salts were thoroughly removed.

[0102] dehydration The medium was dehydrated by evaporating 15% volume / volume of the solution.

[0103] Crystallization Crystallization of sotagliflozin was carried out at 67°C by seeding with 7.5% w / w Form II sotagliflozin and cooling to 40°C.

[0104] filtration Filtration of the suspension was carried out at 40° C. on a filtration cell.

[0105] Washing Washing of the medium was carried out with 2 volumes of toluene at 25°C.

[0106] Drying The medium was then dried in a vacuum oven at 50°C.

[0107] Sotagliflozin Form II was crystallized in 92% yield.

[0108] XRPD (X-ray diffraction) analysis confirmed that sotagliflozin form II was obtained.

[0109] Example 2: Continuous preparation method of crystalline form II of sotagliflozin with toluene Synthesis of sotagliflozin in toluene Sotagliflozin was synthesized in a continuous stirred tank reactor equipped with a reactor volume of 230 mL and stirred at 500 tr / min.

[0110] 450 g of compound (A) was used with 10 volumes of toluene to produce a 92.3 g / l (893 kg / m 3A solution of compound (A) in toluene was prepared. The solution was fed to the reactor at a flow rate of 372 g / h.

[0111] 828 kg / m using 0.6 equivalents of MeONa and 15 equivalents of MeOH 3 A solution of MeONa in methanol was prepared. The solution was fed to the reactor at a flow rate of 35.8 g / h.

[0112] The synthesis was carried out at 60℃-61℃.

[0113] The residence time in the reactor was 30 minutes.

[0114] Sotagliflozin was synthesized with a yield of 98%.

[0115] Aqueous Cleaning Aqueous washing of the reaction medium was carried out using a mixer (264 ml) and a settler (631 ml) with stirring at 450 tr / min.

[0116] Washing was done with 1 volume of water / reaction medium at 61° C. and a flow rate of 460 g / h.

[0117] The residence time in the mixer was 15 minutes.

[0118] The residence time in the settler was 45 minutes.

[0119] The sodium salts were thoroughly removed.

[0120] dehydration The medium was dehydrated by evaporation of 15% vol / vol of the solution at 67 °C to 109 °C. After evaporation, the MeOH content was 0% wt / wt, the AcOMe content was 0.15% wt / wt, and the water content was 140 ppm.

[0121] The concentration of the toluene solution of sotagliflozin was adjusted to 50 g / l by adding toluene.

[0122] A toluene solution of sotagliflozin (50 g / l) was maintained at a temperature of 70°C to 75°C.

[0123] Crystallization Crystallization of sotagliflozin was carried out in a cascade of two continuous stirred tank reactors (600 ml each).

[0124] The solution was forced into the reactor by pressure.

[0125] Initially, the first reactor was seeded with 10% w / w Form II sotagliflozin.

[0126] The first reactor was charged with sotagliflozin (50 g / l, 829 kg / m) at a flow rate of 1160 g / h (1400 ml / h) at 65° C. to 66° C. with stirring at 400 tr / min. 3 The residence time in the reactor was 30 minutes.

[0127] The media obtained in the first crystallization chamber was collected, subjected to wet milling, and returned to the first crystallization chamber.

[0128] The suspension of sotagliflozin obtained at the end of the first reactor was pumped into the second reactor using a peristaltic pump.

[0129] The suspension of sotagliflozin obtained at the end of the first reactor was fed to the second reactor with stirring at 600 tr / min at 25° C. to 26° C. The residence time in the reactor was 30 minutes.

[0130] The suspension obtained at the end of the second reactor was collected for isolation (filtration, washing, drying).

[0131] filtration Filtration of the suspension was carried out in a rotary pressure filter at 25°C.

[0132] Washing Washing of the medium was carried out with 2 volumes of toluene at 25°C.

[0133] Drying Drying of the medium was then carried out at 50° C. under a pressure of less than 50 mbar.

[0134] Sotagliflozin Form II was crystallized in 97% yield.

[0135] XRPD (X-ray diffraction) analysis confirmed that sotagliflozin form II was obtained.

[0136] Example 3: Continuous preparation method of sotagliflozin in crystallized form II with toluene in a boosted reactor Synthesis of sotagliflozin in toluene Sotagliflozin was synthesized in an intensive reactor at 113° C. under a pressure of 8 bar.

[0137] The reactor was fed with a solution of compound (A) in 10 volumes of toluene at a flow rate of 1194.6 g / h and a methanolic solution of MeONa (0.6 equivalents of MeONa and 15 equivalents of MeOH) at a flow rate of 114.6 g / h, both preheated to 113° C.

[0138] The residence time in the reactor was 20 seconds.

[0139] The system was maintained at a pressure of 8 bar.

[0140] Sotagliflozin was synthesized with a yield of 99.7%.

[0141] Aqueous washing, dehydration, crystallization, filtration, washing and drying were carried out according to Example 2.

[0142] XRPD (X-ray diffraction) analysis confirmed that sotagliflozin form II was obtained.

Claims

1. Sotagliflozin in crystalline form II: 【Chemistry 1】 A method for preparing The crystalline form II of sotagliflozin has the following formula (A): 【Chemistry 2】 by using toluene or xylene, or a mixture thereof, as the solvent medium for crystallization.

2. 2. The method according to claim 1, wherein the crystalline form II of sotagliflozin is obtained directly from the compound of formula (A) by using toluene as a solvent medium for crystallization.

3. a) reacting a compound of formula (A) with an alcohol in a non-aqueous solvent medium containing a base and at least toluene or xylene, or a mixture thereof, preferably at least toluene; b) performing an aqueous wash of said solvent medium; c) dehydrating the solvent medium; d) crystallizing the sotagliflozin Form II; and e) recovering the crystalline form II of sotagliflozin; The method of claim 1 or 2, comprising:

4. 4. The method of claim 3, wherein the solvent medium further comprises sodium methoxide and methanol.

5. 5. The process according to claim 3 or 4, wherein step a) is carried out at a temperature below the boiling point of methanol.

6. The process according to any one of claims 3 to 5, wherein step a) is carried out at atmospheric pressure and at a temperature below 65°C, preferably below 63°C.

7. The method according to any one of claims 3 to 6, wherein step c) is carried out by evaporation.

8. The method according to any one of claims 3 to 7, wherein step d) is carried out at a temperature of crystallization of the Form II sotagliflozin.

9. Step d) is carried out at atmospheric pressure at 60° C. to 70° C., preferably at 62° C. to 67° C., more preferably The process according to any one of claims 3 to 8, which is carried out at a temperature of 65°C.

10. The method according to any one of claims 1 to 9, wherein the formation of crystalline form II of sotagliflozin is initiated with existing crystalline form II of sotagliflozin.

11. The process according to any one of claims 3 to 10, wherein step d) is followed by filtration and washing, preferably with toluene or xylene or a mixture thereof.

12. 12. The method of claim 11, wherein the filtering and washing is followed by a drying step.

13. The method according to claim 12, wherein the drying step is carried out at a temperature of from 45°C to 65°C, in particular from 50°C to 55°C.

14. The method according to any one of claims 1 to 13, wherein the crystalline form II of sotagliflozin is synthesized by a batch process.

15. The method according to any one of claims 1 to 13, wherein the crystalline form II of sotagliflozin is synthesized in a continuous process.

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