Method for preparing epalrestat

Abstract

To provide a method of preparing epalrestat crystal B.SOLUTION: The method of preparing epalrestat crystal B comprises: a. suspending an epalrestat DMF solvate in a solvent and keeping the suspension at 30-60°C; and b. isolating and drying epalrestat crystal B; where the solvent is ester, water or alcohol, or a mixture thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] This application provides a method for preparing Epalrestat. This application also provides an industrially applicable method for preparing Epalrestat.

Background Art

[0002] The pharmaceutical compound with the common name "Epalrestat" has the chemical name 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid. Epalrestat has the structure of formula (I).

Chemical Formula 1

[0003] Epalrestat is an aldose reductase inhibitor approved in Japan for the purpose of improving the subjective symptoms of neuropathy, abnormal vibration sense, and abnormal heart rate variability associated with diabetic peripheral neuropathy.

[0004] Epalrestat is poorly soluble in water. Epalrestat has a total of four structural isomers. Those isomers are Z / E, Z / Z, E / E, and E / Z. Among the four configurations, only the Z / E isomer is an active substance effective as a pharmaceutical composition. Therefore, the study of Epalrestat having the Z / E configuration is very important.

[0005] U.S. Patent No. 4,464,382 discloses a method for preparing Epalrestat by reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrolein in the presence of sodium acetate and acetic acid. There is no information about the purity of Epalrestat in the description of this patent. However, according to the results of experiments conducted by the inventors, the method for preparing Epalrestat described in U.S. Patent No. 4,464,382 is limited in industrial application for the following reasons. 1. Epallestat has a high Z / Z isomer (II) content (3.75%), and its purity is approximately 88%, requiring further purification through repeated crystallization. 2. Longer reaction time. 3. Low yield (64%). 4. The product is of generally poor quality. [chemical 2]

[0006] Japanese Patent Publication No. 4892821 discloses a method for preparing epalrestat by reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrylaldehyde in the presence of an organic base and a solvent. However, this method produces epalrestat in which the Z / Z isomer content is 0.1% or more.

[0007] CN102516197, CN102977047, and CN104072441 disclose different methods for preparing epalrestat. However, not all of the described methods yield the desired purity profile of epalrestat. Each of the described methods has one or more drawbacks, such as low purity and low yield.

[0008] Therefore, there is a need to provide a simple, economical, and industrially applicable method for producing epallestat.

[0009] Further other objects of the present invention will be understood by those skilled in the art from the following summary and detailed description of the invention. [Overview of the Initiative]

[0010] This application relates to a method for preparing epalrestat. In a particular embodiment, this application relates to the preparation of epalrestat via epalrestat DMF solvate.

[0011] An aspect of the present invention provides crystals of epallestat DMF solvate having an X-ray powder diffraction pattern including a peak at a 2θ angle of 5.98 ± 0.2 degrees.

[0012] Another aspect of the present invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern with peaks at approximately 5.98, 14.59, and 26.69 ± 0.2 degrees.

[0013] A further aspect of the present invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern with peaks at 2θ angles of 5.98, 14.59, 19.76, 26.06, 27.00 and 32.63 ± 0.2 degrees. The crystals of epalrestat DMF solvate may further feature an X-ray powder diffraction pattern with peaks at 2θ angles of 12.48, 14.05, 15.37, 22.39, 22.73 and 26.69 ± 0.2 degrees.

[0014] Yet another aspect of the present invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern substantially consistent with that of Figure 1.

[0015] In yet another aspect of the present invention, the crystals of epalrestat DMF solvate are characterized by a differential scanning calorimetry thermogram that endotherms at approximately 118.91°C and at approximately 226.03°C.

[0016] Yet another aspect of the present invention provides crystals of epalrestat DMF solvate characterized by a differential scanning calorimetry (DSC) curve substantially consistent with that of Figure 2.

[0017] Another aspect of the present invention is a) A step of reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrylaldehyde in the presence of an ammonium salt(s) of an organic acid and a DMF-containing solvent(s), b) The step of isolating and drying the epallestat DMF solvate. This invention relates to a method for preparing epalrestat DMF solvate, which contains [the specified substance].

[0018] Another aspect of the present invention relates to a) suspending epalrestat DMF solvate in a solvent while maintaining the solution at 30 to 60 °C; b) isolating and drying epalrestat crystal B and relates to a method for preparing epalrestat crystal B from epalrestat DMF solvate.

[0019] Another aspect of the present invention relates to a) suspending epalrestat DMF solvate in a solvent while maintaining the suspension at 10 to 30 °C; b) isolating and drying epalrestat crystal A and relates to a method for preparing epalrestat crystal A from epalrestat DMF solvate.

[0020] Another aspect of the present invention is to provide high purity epalrestat.

Brief Description of the Drawings

[0021] [Figure 1] It is a diagram showing an X-ray powder diffraction (XRPD) pattern of a crystalline epalrestat DMF solvate. [Figure 2] It is a diagram showing a differential scanning calorimetry (DSC) curve of a crystalline epalrestat DMF solvate.

Modes for Carrying Out the Invention

[0022] As used herein, "DMF" is N,N-dimethylformamide.

[0023] As used herein, a "solvate" is a crystalline molecular compound in which solvent molecules are incorporated into a host lattice composed of non-solvated molecules. A "hydrate" is a special type of solvate in which the incorporated solvent is water. Thus, the "anhydrous" form is a form in which water molecules are not incorporated into the crystal lattice of the host molecule.

[0024] As used herein, the term “peaks” means characteristic peaks as generally understood by those skilled in the art for characterization in XRPD. For example, “peaks” can generally be defined as having a relative intensity of at least 10%, preferably at least 20%, and more preferably at least 30%, of the strongest peak.

[0025] Aspects of the present invention relate to a method for preparing epalrestat. In certain embodiments, aspects of the present invention relate to the preparation of pure epalrestat via epalrestat DMF solvate.

[0026] The epalrestat DMF solvate can be characterized by any one or more analytical techniques, which may include XRPD patterns, infrared absorption spectra, differential scanning calorimetry (DSC) curves, and thermogravimetric analysis (TGA) curves.

[0027] Another aspect of this application provides crystals of epallestat DMF solvate characterized by using one or more analytical methods.

[0028] Yet another aspect of the present invention provides crystals of epallestat DMF solvate having an X-ray powder diffraction pattern including a peak at a 2θ angle of 5.98 ± 0.2 degrees.

[0029] A further aspect of the present invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern including peaks at 2θ angles of 5.98, 14.59, and 26.69 ± 0.2 degrees.

[0030] A further aspect of the present invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern with peaks at 2θ angles of 5.98, 14.59, 19.76, 26.06, 27.00 and 32.63 ± 0.2 degrees. The crystals of epalrestat DMF solvate may further feature an X-ray powder diffraction pattern with peaks at 2θ angles of 12.48, 14.05, 15.37, 22.39, 22.73 and 26.69 ± 0.2 degrees.

[0031] Table 1 shows their peaks and intensities.

[0032] [Table 1]

[0033] Another aspect of the present invention is a) A step of reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrylaldehyde in the presence of an ammonium salt(s) of an organic acid and a DMF-containing solvent(s), b) The step of isolating and drying the epallestat DMF solvate. This invention relates to a method for preparing an epalrestat DMF solvate containing [unclear].

[0034] Step a) is carried out in a DMF-containing solvent. The solvent may further contain, but is not limited to, water; polar aprotic solvents such as N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethyl sulfoxide, sulfolane, formamide, acetamide, propanamide, etc.; alcoholic solvents such as methanol, ethanol, propanol, butanol, isopropanol; esteric solvents such as ethyl acetate, methyl acetate, isobutyl acetate, isopropyl acetate, or any mixture thereof. The solvent preferably further contains ethyl acetate, methanol, or a mixture thereof. It is more preferable that the solvent does not contain any solvent other than DMF.

[0035] Step a) is carried out in the presence of one or more ammonium salts of an organic acid. The ammonium ion portion of the ammonium salt(or ammonium salt) is given by the formula N(R1R2R3R4) + Represented by the formula, where R1, R2, R3, and R4 are each independently a hydrogen atom or a C1-C6 alkyl group. The C1-C6 alkyl group may be linear or branched.

[0036] Of all the listed organic acids, preferred acids are selected from the group of carboxylic acids consisting of salicylic acid, benzoic acid, succinic acid, glutaric acid, adipic acid, malonic acid, fumaric acid, maleic acid, pimelic acid, citric acid, tartaric acid, suberic acid, pyroglutamic acid, dipicolinic acid, tartaric acid, malic acid, maleic acid, citric acid, acetic acid, and combinations thereof. The organic acid is more preferably selected from acetic acid and citric acid.

[0037] The ammonium salt(s) of the organic acid is preferably selected from the group consisting of ammonium citrate, ammonium acetate, methaneamium acetate, diethylammonium acetate, triethylammonium acetate, and butylammonium acetate, as well as combinations thereof.

[0038] The appropriate temperature for the reaction in step a) may be less than approximately 150°C, less than approximately 100°C, less than approximately 80°C, less than approximately 60°C, less than approximately 40°C, less than approximately 30°C, less than approximately 20°C, less than approximately 10°C, or any other appropriate temperature.

[0039] The reaction mixture obtained in step a) may optionally be filtered to remove insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for removing solids.

[0040] Step b) includes isolating the solid obtained in step a). The solid can be isolated from the suspension using general techniques known to those skilled in the art for separating solids from liquids. For example, the solid may be isolated using techniques such as gravity or suction filtration, centrifugation, decantation, or any other technique for removing the solid. After the solid has been isolated, it may be optionally washed with the solvent used in step a).

[0041] The recovered solid is further dried. Drying can be carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, etc. Drying can be carried out at atmospheric pressure or reduced pressure at any suitable temperature, such as below approximately 150°C, below approximately 120°C, below approximately 100°C, below approximately 80°C, below approximately 60°C, or any other suitable temperature, as long as the compound does not deteriorate in terms of quality. Drying may be carried out for a desired time until the required purity is reached. For example, the drying time may vary from about 1 hour to about 15 hours, or longer.

[0042] Another aspect of this application is, a) The step of suspending epalrestat DMF solvate in a solvent while maintaining the solution at 30-60°C, b) The step of isolating and drying epallestat crystal B This invention provides a method for preparing epallestat crystals B when prepared by a method including [a specific component]. Each step is described separately below in this specification.

[0043] Suitable solvents that can be used in step a) include, but are not limited to, esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, and ethyl butanoate; water; alcohols such as methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or mixtures thereof. Ethanol is the most preferred solvent.

[0044] Step b) includes isolating the solid obtained in step a). The solid can be isolated from the suspension using general techniques known to those skilled in the art for separating solids from liquids. For example, the solid may be isolated using techniques such as gravity or suction filtration, centrifugation, decantation, or any other technique for removing the solid. After the solid has been isolated, it may optionally be washed with the solvent used in step a).

[0045] The recovered solid may be further dried as needed. Drying can be carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, etc. The drying may be carried out at atmospheric pressure or reduced pressure at any suitable temperature, such as below approximately 150°C, below approximately 120°C, below approximately 100°C, below approximately 80°C, below approximately 60°C, or any other suitable temperature, as long as the compound does not deteriorate in terms of quality. Drying may be carried out for a desired time until the required purity is reached. For example, the drying time may vary from about 1 hour to about 15 hours, or longer.

[0046] Another aspect of the present invention is a) The step of suspending epalrestat DMF solvate in a solvent while maintaining the suspension at 10-30°C, b) The step of isolating and drying epallestat crystal A The objective is to provide epallestat crystal A when prepared by a method including [a specific component]. Each step is described separately below in this specification.

[0047] Suitable solvents that can be used in step a) include, but are not limited to, water; alcohols such as methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or mixtures thereof. Water, methanol, or mixtures thereof are the most preferred solvents.

[0048] Step b) includes isolating the solid obtained in step a). The solid can be isolated from the suspension using general techniques known to those skilled in the art for separating solids from liquids. For example, the solid may be isolated using techniques such as gravity or suction filtration, centrifugation, decantation, or any other technique for removing the solid. After the solid has been isolated, it may optionally be washed with the solvent used in step a).

[0049] The recovered solid may be further dried as needed. Drying can be carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, etc. Drying can be carried out at atmospheric pressure or reduced pressure at any suitable temperature, such as below approximately 150°C, below approximately 120°C, below approximately 100°C, below approximately 80°C, below approximately 60°C, or any other suitable temperature, as long as the compound does not deteriorate in terms of quality. Drying may be carried out for a desired time until the required purity is reached. For example, the drying time may vary from about 1 hour to about 15 hours, or longer.

[0050] Unless otherwise specified, all percentages and ratios used herein are by weight of the whole composition, and all measurements are taken at approximately 25°C and approximately atmospheric pressure. Unless otherwise noted, all temperatures are expressed in Celsius. As used herein, “contains” means the element described, or an equivalent of the element described above in terms of structure or function, or any other element not described. The terms “has,” “contains,” and “includes” should also be interpreted as open-ended. All ranges described herein include the endpoint of that range and include values ​​that indicate a range “between” two values. Whether indicated or not, all values ​​described herein approximate values ​​determined by circumstances and include the degree of expected experimental error, method error, and instrument error of a given method used to measure the value.

[0051] Other features, advantages, and aspects of the present invention will be apparent to those skilled in the art from the following description. The description and the specific examples below illustrate preferred embodiments of the present invention, but should be understood to be provided for illustrative purposes only. Any changes and modifications to the spirit and scope of the disclosed invention will be readily apparent to those skilled in the art by reading the description and other portions of this disclosure.

[0052] definition Unless the context indicates otherwise, the following definitions shall be used in relation to this application.

[0053] Certain aspects and embodiments of the present invention are described in further detail by the following examples, which are provided for illustrative purposes only and shall not in any way limit the scope of the present invention.

[0054] XRPDs were recorded using Cu-Kα lines at 45kV and 40mA with a PANalytical EMPYREAN (PANalytical, Netherlands) diffractometer. Diffraction patterns were collected over a 2θ range of 5–40 degrees with a step size of 0.01 degrees.

[0055] Differential scanning calorimetry (DSC) was performed using a DSC-60 (Shimadzu) with an aluminum crucible under a nitrogen stream at a heating rate of 5°C / min. [Examples]

[0056] Example 1 Preparation of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate Rhodanine-3-acetic acid (65.40 g) and (E)-2-methyl-3-phenylacrylaldehyde (50.0 g) were dissolved in DMF (500 ml) at 25–30°C. Ammonium acetate solution (31.63 g, dissolved in 30.0 ml of water) was added to the reaction mixture and stirred at 25–35°C for 12 hours. After the reaction was complete, the reaction mixture was cooled to 5–15°C. 50.0 g of concentrated HCl was slowly added over 15 minutes at 5–15°C. The reaction was maintained at 5–15°C for 2 hours. The reaction mixture was filtered and washed with cooled DMF (150 ml). The substance was dried by suction for 2 hours to obtain the title compound. Yield: 153.0g

[0057] Preparation of crystal B of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid 153.0 g of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate was suspended in 500 ml of ethanol at 25-30°C. The temperature was increased to 55-60°C and the reaction was maintained for 2 hours. The reaction mixture was cooled to 35-40°C and maintained for 2 hours. The reaction mixture was filtered and washed with ethanol (200 ml). This substance was vacuum-dried for 30 minutes. The resulting wet cake was suspended in water (500 ml) at 25-30°C. The reaction was maintained at 25-30°C for 30 minutes. The reaction mixture was filtered and washed twice with 100 ml of water and ethanol (100 ml once). The above substance was dried under vacuum at 50-60°C for 15 hours. Yield: 78.50g (72.02%) Purity by HPLC: 99.94% Z / Z isomer: 0.01% HPLC conditions: Measurement equipment: Waters e2695 separation module with 2489uv / vis detector, Column: C18 (150x4.6) mm, 5 μm, Detector: 280 nm UV, Flow rate: 1.0 mL / min, Elution: Uniform concentration, Runtime: 40 minutes

[0058] Example 2 Preparation of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate Rhodanine-3-acetic acid (131.0 g) was dissolved in 700 mL of DMF, and then (E)-2-methyl-3-phenylacrylaldehyde (100.0 g) and 200 mL of DMF were added to the reaction mixture at 25–35°C. Ammonium acetate solution (63.27 g, dissolved in 60 mL of water) was added to the reaction mixture and stirred at 30–35°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to 10–15°C. 100.0 g of concentrated HCl was slowly added at 10–15°C. The reaction was maintained at 10–15°C for 2 hours. The reaction mixture was filtered and washed with DMF. The above substance was spin-dried for 2–4 hours to obtain the title compound. Yield: 260.50g

[0059] Preparation of crystal B of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid 260.5 g of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate was suspended in 1200 ml of ethanol at 25–35°C. The temperature was increased to 55–60°C and the reaction was maintained for 2 hours. The reaction mixture was cooled to 35–40°C and maintained for 2 hours. The reaction mixture was filtered and washed with ethanol (400 ml). This substance was spin-dried for 2 hours. The resulting wet cake was suspended in water (1000 ml) at 30–35°C. The reaction was maintained for 30–60 minutes. The reaction mixture was filtered and washed with water (400 ml) and ethanol (200 ml). The above substance was dried under vacuum at 50–60°C for 8–10 hours. Yield: 162.5g (74.54%) Purity by HPLC: 99.92% Z / Z isomer: 0.02% HPLC conditions: Waters e2695 separation module 2489uv / vis, detector: C18 (150x4.6) mm, 5 μm column, detector: 280 nm UV, flow rate: 1.0 mL / min, elution: homogeneous concentration, runtime: 40 minutes.

[0060] Example 3 Preparation of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate 78.6 kg of rhodanine-3-acetic acid was dissolved in 377.6 kg of DMF, and then (E)-2-methyl-3-phenylacrylaldehyde (60.0 kg) and 169.9 kg of DMF were added to the reaction mixture at 25–35°C. Ammonium acetate solution (38.0 kg dissolved in 34 kg of water) was added to the reaction mixture and stirred at 30–35°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to 10–15°C. 60.0 kg of concentrated HCl was slowly added at 10–15°C. The reaction was maintained at 10–15°C for 2 hours. The reaction mixture was filtered and washed with 169.9 kg of cooled DMF. The above substance was spin-dried for 2 hours to obtain the title compound. Yield: 164.06 kg

[0061] Preparation of crystal B of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid 164.06 kg of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate was suspended in 568.0 kg of ethanol at 30–35°C. The temperature was increased to 55–60°C and the reaction was maintained for 2 hours. The reaction mixture was cooled to 35–40°C and maintained for 2 hours. The reaction mixture was filtered and washed with ethanol (189.4 kg). The substance was spin-dried for 2 hours. The resulting wet cake was suspended in water (600 liters) at 30–35°C. The reaction was maintained at 25–30°C for 30–60 minutes. The reaction mixture was filtered and washed with water (240 liters) and ethanol (94.7 kg). The substance was dried under vacuum at 50–60°C for 8–10 hours. Yield: 102.0 kg (77.98%) Purity by HPLC: 99.94% Z / Z isomer: 0.01% HPLC conditions: Waters e2695 separation module 2489uv / vis, detector: C18 (150x4.6) mm, 5 μm column, detector: 280 nm UV, flow rate: 1.0 mL / min, elution: homogeneous concentration, runtime: 40 minutes.

[0062] Example 4 Preparation of crystal A of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid 15.0 g of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate was suspended in 150 ml of water and stirred at 25-30°C for 6 hours. The substance was filtered and washed with a mixture of water and methanol. The substance was dried under vacuum at 55-60°C for 6 hours. Yield: 9.15g (72.75%)

[0063] Example 5 Preparation of crystal A of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid 15.0 g of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidine-3-yl)acetic acid DMF solvate was suspended in 150 ml of methanol and stirred at 20-30°C for 6 hours. The substance was filtered and washed with methanol. The substance was dried under vacuum at 55-60°C for 12 hours. Yield: 9.0g (71.55%)

Claims

1. a. suspending epalrestat DMF solvate in a solvent and maintaining the suspension at 30-60°C; b. isolating and drying epalrestat crystal B; Including, The method for preparing epalrestat crystalline B, wherein the solvent is an ester, water, or alcohol, or a mixture thereof.

2. 10. The method of claim 1, wherein the solvent is ethanol.

3. a. suspending epalrestat DMF solvate in a solvent and maintaining the suspension at 10-30°C; b. isolating and drying epalrestat crystals A; Including, The method for preparing epalrestat crystal A, wherein the solvent is water or alcohol or a mixture thereof.

4. 4. The method of claim 3, wherein the solvent is water or methanol or a mixture thereof.

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