JP2023154056A - Method of preparing epalrestat - Google Patents

Abstract

To provide a method of preparing epalrestat that is simple, cost-effective and suitable for industrial applications.SOLUTION: A method of preparing epalrestat comprises the steps: a. suspending an epalrestat DMF solvate in a solvent and keeping the suspension at 30-60°C; and b. isolating and drying epalrestat; where the solvent is ester, water or alcohol, or a mixture thereof.SELECTED DRAWING: None

Description

The present application provides a method of preparing Epalrestat. The present application also provides an industrially applicable method for preparing epalrestat.

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

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

Epalrestat is sparingly soluble in water. Epalrestat has a total of four structural isomers. The isomers are Z/E, Z/Z, E/E and E/Z. Of the four configurations, only the Z/E isomer is an effective active agent as a pharmaceutical composition. Therefore, research on epalrestat with Z/E configuration is very important.

US Pat. No. 4,464,382 discloses a method for preparing epalrestat by reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrylaldehyde in the presence of sodium acetate and acetic acid. There is no information about the purity of epalrestat in the patent description. However, according to the results of experiments conducted by the present inventors, the method for preparing epalrestat described in US Pat. No. 4,464,382 has limited industrial application for the following reasons.
1. The Z/Z isomer (II) content of epalrestat is high (3.75%) and the purity of epalrestat is approximately 88%, requiring further purification by repeated crystallizations.
2. Longer reaction time.
3. Low yield (64%).
4. The quality of the product is generally poor.

Japanese Patent No. 4,892,821 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, the above method produces epalrestat in which the Z/Z isomer content of epalrestat is greater than or equal to 0.1%.

CN102516197, CN102977047 and CN104072441 disclose different methods of preparing epalrestat. However, not all described methods yield the desired purity profile of epalrestat. All of the described methods have one or more drawbacks such as low purity and low yield.

Therefore, there is a need to provide a simple, economical, and industrially viable method for producing epalrestat.

Still other objects of the invention will be understood by those skilled in the art from the following Summary of the Invention and Detailed Description of the Invention.

The present application relates to a method of preparing epalrestat. In certain embodiments, the present application relates to the preparation of epalrestat via epalrestat DMF solvate.

Embodiments of the present invention provide crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern containing a peak at a two-theta angle of 5.98±0.2 degrees.

Another aspect of the invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern containing peaks at about 5.98, 14.59 and 26.69±0.2 degrees.

Yet another aspect of the invention provides an X-ray powder diffraction pattern containing peaks at 2-theta angles of 5.98, 14.59, 19.76, 26.06, 27.00 and 32.63 ± 0.2 degrees. Crystals of epalrestat DMF solvate are provided. Crystals of epalrestat DMF solvate have an X-ray powder diffraction pattern containing peaks at 2θ angles of 12.48, 14.05, 15.37, 22.39, 22.73, and 26.69 ± 0.2 degrees. Further features can be provided.

Yet another aspect of the invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern substantially matching that of FIG.

In yet another aspect of the invention, crystals of epalrestat DMF solvate are characterized by a differential scanning calorimetry thermogram with an endotherm at about 118.91°C and another endotherm at about 226.03°C.

Yet another aspect of the invention provides crystals of epalrestat DMF solvate characterized by a differential scanning calorimetry (DSC) curve substantially consistent with FIG.

Yet another aspect of the invention is
a) reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrylaldehyde in the presence of ammonium salt(s) of an organic acid and DMF-containing solvent(s);
b) isolating and drying the epalrestat DMF solvate.

Yet another aspect of the invention is
a) suspending epalrestat DMF solvate in a solvent while maintaining the solution at 30-60°C;
b) isolating and drying epalrestat crystals B.

Yet another aspect of the invention is
a) suspending epalrestat DMF solvate in a solvent while maintaining the suspension at 10-30°C;
b) isolating and drying epalrestat crystals A.

Yet another aspect of the invention is to provide highly purified epalrestat.

FIG. 2 shows an X-ray powder diffraction (XRPD) pattern of crystalline epalrestat DMF solvate. FIG. 2 shows a differential scanning calorimetry (DSC) curve of crystalline epalrestat DMF solvate.

As used herein, "DMF" is N,N-dimethylformamide.

As used herein, a "solvate" is a crystalline molecular compound in which molecules of a solvent are incorporated into a host lattice of unsolvated molecules. "Hydrates" are a special type of solvate in which the incorporated solvent is water. Thus, an "anhydrous" form is one in which water molecules are not incorporated into the crystal lattice of the host molecule.

As used herein, the term "peak(s)" refers to characteristic peaks that are commonly understood by those skilled in the art for characterization in XRPD. For example, "peak(s)" can be generally defined by having a relative intensity of at least 10%, preferably at least 20%, more preferably at least 30% relative to the strongest peak.

Aspects of the invention relate to methods of preparing epalrestat. In certain embodiments, aspects of the invention relate to the preparation of pure epalrestat via epalrestat DMF solvate.

Epalrestat DMF solvate can be characterized by any one or more analytical techniques, including XRPD patterns, infrared absorption spectra, differential scanning calorimetry (DSC) curves, and thermogravimetric analysis (TGA). ) can contain curves.

Another aspect of the present application provides crystals of epalrestat DMF solvate characterized by using one or more analytical methods.

Yet another aspect of the present invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern containing a peak at a two-theta angle of 5.98±0.2 degrees.

Yet another aspect of the invention provides crystals of epalrestat DMF solvate having an X-ray powder diffraction pattern containing peaks at 2-theta angles of 5.98, 14.59, and 26.69±0.2 degrees.

Yet another aspect of the invention provides an X-ray powder diffraction pattern containing peaks at 2-theta angles of 5.98, 14.59, 19.76, 26.06, 27.00 and 32.63 ± 0.2 degrees. Crystals of epalrestat DMF solvate are provided. Crystals of epalrestat DMF solvate have an X-ray powder diffraction pattern containing peaks at 2θ angles of 12.48, 14.05, 15.37, 22.39, 22.73, and 26.69 ± 0.2 degrees. Further features can be provided.

Table 1 shows their peaks and intensities.

Yet another aspect of the invention is
a) reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrylaldehyde in the presence of ammonium salt(s) of an organic acid and DMF-containing solvent(s);
b) isolating and drying the epalrestat DMF solvate.

Step a) is carried out in a DMF-containing solvent. The above solvents include, but are not limited to, water; polar aprotic solvents such as N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide; methanol, ethanol; , propanol, butanol, isopropanol, etc.; ester solvents such as ethyl acetate, methyl acetate, isobutyl acetate, isopropyl acetate, etc., or any mixture thereof. Preferably, the solvent further contains ethyl acetate, methanol or a mixture thereof. More preferably, the solvent does not contain any solvent other than DMF.

Step a) is carried out in the presence of ammonium salt(s) of an organic acid. The ammonium ion moiety of the ammonium salt(s) has the formula N(R ₁ R ₂ R ₃ R ₄ ) ⁺ , where R ₁ , R ₂ , R ₃ and R ₄ are each independently: It is a hydrogen atom or a C ₁ to C ₆ alkyl group. The C ₁ -C ₆ alkyl group may be straight chain or branched.

Of all the organic acids listed, preferred acids are 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, selected from the group of carboxylic acids consisting of dipicolinic acid, tartaric acid, malic acid, maleic acid, citric acid, acetic acid, and combinations thereof. More preferably, the organic acid is selected from acetic acid and citric acid.

Preferably, the ammonium salt(s) of the organic acid is selected from the group consisting of ammonium citrate, ammonium acetate, methanaminium acetate, diethylammonium acetate, triethylammonium acetate and butylammonium acetate, and combinations thereof.

Suitable temperatures for the reaction of step a) include less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C. , or any other suitable temperature.

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

Step b) comprises isolating the solid obtained in step a). Solids can be isolated from suspensions using common techniques known to those skilled in the art for separating solids from liquids. For example, solids may be isolated using techniques such as, for example, filtration by gravity or suction, centrifugation, decantation, or any other technique for removing solids. After isolating the solid, it can optionally be washed with the solvent used in step a).

The recovered solids are further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, etc. Drying can be carried out at atmospheric pressure at a temperature below about 150°C, below about 120°C, below about 100°C, below about 80°C, below about 60°C, or any other suitable temperature so long as the compound does not deteriorate in quality. Alternatively, it can be carried out under reduced pressure. Drying may be carried out for a desired period of time until the required purity is achieved. For example, drying times may vary from about 1 hour to about 15 hours, or longer.

Yet another aspect of the present application is:
a) suspending epalrestat DMF solvate in a solvent while maintaining the solution at 30-60°C;
b) isolating and drying the epalrestat crystals B.
The individual steps are described separately herein below.

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

Step b) comprises isolating the solid obtained in step a). Solids can be isolated from suspensions using common techniques known to those skilled in the art for separating solids from liquids. For example, solids may be isolated using techniques such as filtration by gravity or suction, centrifugation, decantation, or any other technique for removing solids. After isolating the solid, it can optionally be washed with the solvent used in step a).

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

Yet another aspect of the invention is
a) suspending epalrestat DMF solvate in a solvent while maintaining the suspension at 10-30°C;
b) isolating and drying the epalrestat crystals A.
The individual steps are described separately herein below.

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.

Step b) comprises isolating the solid obtained in step a). Solids can be isolated from suspensions using common techniques known to those skilled in the art for separating solids from liquids. For example, solids may be isolated using techniques such as filtration by gravity or suction, centrifugation, decantation, or any other technique for removing solids. After isolating the solid, it can optionally be washed with the solvent used in step a).

The recovered solids may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, etc. Drying can be carried out at atmospheric pressure at a temperature below about 150°C, below about 120°C, below about 100°C, below about 80°C, below about 60°C, or any other suitable temperature so long as the compound does not deteriorate in quality. Alternatively, it can be carried out under reduced pressure. Drying may be carried out for a desired period of time until the required purity is achieved. For example, drying times may vary from about 1 hour to about 15 hours, or longer.

Unless otherwise specified, all percentages and ratios used herein are by weight of the entire composition and all measurements are taken at about 25° C. and approximately atmospheric pressure. All temperatures are expressed in degrees Celsius unless otherwise noted. As used herein, "comprising" means the described element, or an equivalent in structure or function of the above element, as well as any other element(s) not described. The terms "having," "comprising," and "containing" are also to be construed as open-ended. All ranges recited herein are inclusive of the endpoints of the range and include values indicating ranges "between" the two values. All values set forth herein, whether indicated or otherwise, approximate values dictated by the circumstances and are subject to expected experimental error, methodological error, and use in determining the values. Contains the degree of instrument error for a given technique.

Other features, advantages, and aspects of the invention will be apparent to those skilled in the art from the following description. It is to be understood that the description and the following specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the description and other portions of this disclosure.

DEFINITIONS Unless the context indicates otherwise, the following definitions are used in connection with this application.

Certain aspects and embodiments of the invention are described in further detail by the following examples, which are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way. do not have.

XRPD was recorded on a PANalytical EMPYREAN (PANalytical, Netherlands) diffractometer using Cu-Kα radiation at 45 kV and 40 mA. Diffraction patterns were collected over a 2θ range of 5 to 40 degrees with a step size of 0.01 degrees.

DSC (differential scanning calorimetry) was performed on a DSC-60 (Shimadzu) at a heating rate of 5° C./min by using an aluminum crucible under a nitrogen stream.

Example 1
Preparation of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-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 water) was added to the reaction mixture and stirred at 25-35° C. for 12 hours. After the reaction was completed, the reaction mixture was cooled to 5-15°C. 50.0 g of concentrated HCl was added slowly over 15 minutes at 5-15°C. The reaction was maintained at 5-15°C for 2 hours. The reaction mass was filtered and washed with cold DMF (150ml). This material was sucked dry for 2 hours to give the title compound.
Yield: 153.0g

Preparation of crystals B of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid 2-((Z) )-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid DMF solvate (153.0 g) was heated at 25 to 30°C. Then, it was suspended in 500 ml of ethanol. 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 mass was filtered and washed with ethanol (200ml). This material was sucked dry for 30 minutes. The wet cake thus obtained was suspended in water (500 ml) at 25-30°C. The reaction was maintained at 25-30°C for 30 minutes. The reaction mass was filtered and washed twice with 100 ml of water and ethanol (1 x 100 ml). The material 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:
Instrumentation: Waters e2695 separation module 2489 uv/vis detector, column: C18 (150x4.6) mm, 5 μm, detector: UV at 280 nm, flow rate: 1.0 mL/min, elution: isocratic, run time 40 min

Example 2
Preparation of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid DMF solvate Rhodanine-3- Acetic acid (131.0 g) was dissolved in 700 mL of DMF, 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 water) was added to the reaction mixture and stirred at 30-35° C. for 4 hours. After the reaction was completed, the reaction mixture was cooled to 10-15°C. 100.0 g of concentrated HCl was added slowly at 10-15°C. The reaction was maintained at 10-15°C for 2 hours. The reaction mass was filtered and washed with DMF. The above material was spin dried for 2-4 hours to yield the title compound.
Yield: 260.50g

Preparation of crystals B of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid 2-((Z) )-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid DMF solvate (260.5 g) was heated at 25 to 35°C. Then, it was suspended in 1200 ml of ethanol. 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 mass was filtered and washed with ethanol (400ml). This material was spin dried for 2 hours. The wet cake thus obtained was suspended in water (1000 ml) at 30-35°C. The reaction was maintained for 30-60 minutes. The reaction mass was filtered and washed with water (400ml) and ethanol (200ml). The material 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, column: C18 (150x4.6) mm, 5 μm, detector: UV at 280 nm, flow rate: 1.0 mL/min, elution: isocratic, run time 40 minutes

Example 3
Preparation of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid DMF solvate Rhodanine-3- Acetic acid (78.6 kg) was dissolved in 377.6 kg of DMF, 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. Added with. 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 completed, the reaction mixture was cooled to 10-15°C. 60.0 kg of concentrated HCl was added slowly at 10-15°C. The reaction was maintained at 10-15°C for 2 hours. The reaction mass was filtered and washed with 169.9 kg of chilled DMF. The above material was spin dried for 2 hours to give the title compound.
Yield: 164.06kg

Preparation of crystals B of 2-((Z)-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid 2-((Z) )-5-((E)-2-methyl-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid DMF solvate (164.06 kg) was heated at 30 to 35°C. Then, it was suspended in 568.0 kg of ethanol. 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 mass was filtered and washed with ethanol (189.4 kg). The material was spin dried for 2 hours. The wet cake thus obtained was suspended in water (600 liters) at 30-35°C. The reaction was maintained at 25-30°C for 30-60 minutes. The reaction mass was filtered and washed with water (240 liters) and ethanol (94.7 kg). The material was dried under vacuum at 50-60° C. for 8-10 hours.
Yield: 102.0kg (77.98%)
Purity by HPLC: 99.94% Z/Z isomer: 0.01%
HPLC conditions:
Waters e2695 separation module 2489uv/vis detector, column: C18 (150x4.6) mm, 5 μm, detector: UV at 280 nm, flow rate: 1.0 mL/min, elution: isocratic, run time 40 minutes

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

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

Claims (4)

a. suspending epalrestat DMF solvate in a solvent and maintaining the suspension at 30-60°C;
b. isolating and drying the epalrestat;
A method of preparing epalrestat, wherein the solvent is an ester, water or alcohol or a mixture thereof. a. reacting rhodanine-3-acetic acid with (E)-2-methyl-3-phenylacrylaldehyde in the presence of an ammonium salt of an organic acid and a DMF-containing solvent;
b. isolating and drying the product obtained in step a;
c. suspending the product obtained in step b in a solvent and maintaining the suspension at 30-60°C;
d. isolating and drying the epalrestat obtained in step c;
the ammonium salt of an organic acid is selected from ammonium citrate and ammonium acetate and combinations thereof;
A method of preparing epalrestat, wherein the solvent is an ester, water or alcohol or a mixture thereof. 3. The method according to claim 1 or 2, wherein the solvent is ethanol. The method according to claim 1 or 2, wherein the purity of the epalrestat prepared is 99.9% or more.

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