EP3207040A1 - A process for preparing highly pure azilsartan - Google Patents

A process for preparing highly pure azilsartan

Info

Publication number
EP3207040A1
EP3207040A1 EP15784925.8A EP15784925A EP3207040A1 EP 3207040 A1 EP3207040 A1 EP 3207040A1 EP 15784925 A EP15784925 A EP 15784925A EP 3207040 A1 EP3207040 A1 EP 3207040A1
Authority
EP
European Patent Office
Prior art keywords
azilsartan
ethyl ester
solvate
methyl isobutyl
isobutyl ketone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15784925.8A
Other languages
German (de)
French (fr)
Inventor
Jan Stach
Josef Cerny
Ondrej Dammer
Lukas KREJCIK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP3207040A1 publication Critical patent/EP3207040A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to a process for preparing l-[[2'-(2,5-dihydro-5-oxo-l,2 J 4-oxadiazol-3- yl)[l f -biphenyl]-4-yl]methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid (azilsartan) of formula (I)
  • the invention also relates to preparation of new solid forms of intermediates that make it possible to obtain azilsartan with a high purity over 99.7 % (HPLC) and to their characterization.
  • Azilsartan (I) which is a highly selective blocker of angiotensin II ATI receptors, was developed by Takeda and is used for the treatment of high blood pressure. Its synthesis is described in EP 0 520423 (Scheme 1)
  • the application WO2012107814 discusses a process for preparing azilsartan using various cyclizing agents in the presence of a base.
  • the application WO2012157980 describes cyclization with the use of carbonyl imidazole.
  • a process for preparing azilsartan, comprising a cyclizing reaction without the presence of a solvent, is described in WO2014049512.
  • the invention relates to preparation of very pure azilsartan.
  • the process is based on the use and preparation of new solid forms of the key intermediates that have a principal influence on the purity of the final product - azilsartan.
  • they are hemisolvates (2:1) of the ethyl ester (III) with 2-methyltetrahydrofuran (Ilia) or with methyl isobutyl ketone.
  • MIBK Methyl isobutyl ketone
  • Solvates can also be produced in mixtures of solvents containing 2-methyltetrahydrofuran or methyl isobutyl ketone.
  • Solvents in which the above mentioned crystalline solvates can develop include primary or secondary alcohols and ketones. The use of ethanol, methanol, isopropanol or acetone and methyl ethyl ketone is especially convenient.
  • azilsartan ethyl ester (III) is transformed to azilsartan (I) by means of alkaline hydrolysis, which may be carried out with the use of sodium or potassium hydroxide in water or suitable solvents of the alcohol type at a temperature from 25 °C to 80°C.
  • alkaline hydrolysis does not virtually change the chemical purity of the intermediate, azilsartan can be, after acidification, obtained in an excellent purity of about 99.8%.
  • Hydrochloric or acetic acid can be used for the acidification.
  • Table 2 XRPD - diffraction peaks corresponding to the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia)
  • the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran exhibits the following main characteristic peaks in X-ray powder diffraction, measured with the use of CuKa radiation: 8.9; 10.5; 12.0; 16.8; 19.6 and 23.5 ⁇ 0.2° 2-theta.
  • the prepared solvate is further characterized with the use of DSC (Fig. 2).
  • Table 3 XRPD - characteristic diffraction peaks corresponding to the hemisolvate of azilsartan ethyl ester with methyl isobutyl ketone (Illb)
  • the solvate of azilsartan ethyl ester with methyl isobutyl ketyone exhibits the following main characteristic peaks in X-ray powder diffraction, measured with the use of CuK ⁇ radiation: 8.6; 11.7; 16.6; 19.2; 21.4 and 25.5 ⁇ 0.2° 2-theta.
  • Fig. 1 XRPD pattern for the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia)
  • Fig. 2 DSC curve for the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia)
  • Fig. 3 TGA curve for the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia)
  • Fig. 4 XRPD pattern for the solvate of azilsartan ethyl ester with methyl isobutyl ketone (Illb)
  • Fig. 5 DSC curve for the solvate of azilsartan ethyl ester with methyl isobutyl ketone (Mb)
  • Fig. 6 TGA curve for the solvate of azilsartan ethyl ester with methyl isobutyl ketone (Illb)
  • the samples in the examples below were characterized by the X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) methods.
  • XRPD X-ray Powder Diffraction
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • a flat powder sample was used that was placed on a Si plate.
  • 0.02 rad Soller slits and a 1 ⁇ 4 anti-diffusion slit were used.
  • For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti- diffusion slit were used.
  • DSC Differential scanning calorimetry
  • the temperature program that was used consists of 1 minute's stabilization at the temperature of 22°C and then of heating up to 250(300)°C at the heating rate of 10°C/min. 4.0 N 2 at the flow of 20 ml/min was used as the carrier gas.
  • the ethoxy oxime (II) (150 g; 327 mmol) is suspended in 1370 ml of diethyl carbonate. The suspension is heated up to 65 °C. A solution of sodium ethoxide in ethanol (21 %, 154 ml, 412 mmol) is added dropwise to the reaction mixture at 65°C during 30 minutes. After completion of the addition the reaction mixture is agitated at 65 °C for 30 minutes. The reaction mixture is cooled down to 60 °C and water (520 ml) is added. The resulting emulsion is agitated for at least 15 minutes. After separation of the layers the organic phase is extracted with water (520 ml).
  • the combined aqueous extracts are diluted with ethanol (600 ml) and methyl isobutyl ketone (100 ml). The temperature of the solution is adjusted to 40°C. Acetic acid (43 ml, 750 mmol) is added to the solution dropwise at 40°C during 30 minutes. The resulting suspension is agitated at 40°C for 30 minutes and then cooled down to 20°C. The separated substance is aspirated and washed with water (2 x 150 ml). The final product is dried in a vacuum drier at 45°C. 154 g (88% of the theoretical quantity, HPLC 99.5%) of azilsartan ethyl ester hemisolvate with methyl isobutyl ketone (Illb) was obtained.
  • Example 3 Example 3:
  • a solution of sodium ethoxide in ethanol (21 %, 77 ml, 206 mmol) is added dropwise to the reaction mixture at 65°C during 30 minutes. After completion of the addition the reaction mixture is agitated at 65°C for 30 minutes. The reaction mixture is cooled down to 60 °C and water (260 ml) is added. The resulting emulsion is agitated for at least 15 minutes. After separation of the layers the organic phase is extracted with water (260 ml). The combined aqueous extracts are diluted with ethanol (260 ml) and 2-methyltetrahydrofuran (150 ml). The temperature of the solution is adjusted to 40°C.
  • Acetic acid (21 ml, 370 mmol) is added to the solution dropwise at 40°C during 30 minutes.
  • the resulting suspension is agitated at 40°C for 30 minutes and then cooled down to 20°C.
  • the separated substance is aspirated and washed with water (2 x 75 ml).
  • the final product is dried in a vacuum drier at 45°C. 72.5 g (84% of the theoretical quantity, HPLC 99.4%) of azilsartan ethyl ester hemisolvate 2-methyltetrahydrofuran (Ilia) was obtained.
  • Azilsartan ethyl ester (III) (380 g; 784 mmol) is suspended in 2600 ml of 2-methyltetrafuran. The suspension is heated up to reflux. 1200 ml of distillate is removed from the reaction mixture by distillation. The resulting suspension is cooled down to 45 °C. The reaction mixture is agitated at 45°C for 30 minutes and then cooled down to 20°C. The separated substance is aspirated and washed with cooled 2-memyltelrafuran (75 ml). The final product is dried in a vacuum drier at 45°C. 372 g (90% of the theoretical quantity, HPLC 99.7%) of azilsartan ethyl ester hemisolvate 2-methyltetrahydrofuran (Ilia) was obtained.
  • Example 5 Example 5:
  • ethoxy- lH-benzimidazole-7-carboxy lie acid (I).
  • Ethoxy azilsartan hemisolvate with 2-methyltetrafuran (Ilia) (160 g) was weighed into a 5 liter pot and suspended in a NaOH/water solution (38g/500 ml). The reaction mixture is heated up to 50°C and agitated for 4 hours. The reaction mixture is diluted with acetone (250 ml), acetic acid (101 g) is added and the mixture is left to crystallize at 50°C for lh. After cooling to 20°C and agitation for half an hour the product is aspirated and washed with water (2 x 110 ml). The final product is then dried in a vacuum drier at 45°C. 129 g (93% of the theoretical quantity, HPLC 99.8%) of azilsartan (I) was obtained.
  • Ethoxy azilsartan hemisolvate with methyl isobutyl ketone (Illb) 100 g was weighed into a 5 liter pot and suspended in a NaOH/water solution (23g 315 ml). It was heated up to 50°C and agitated for 4 hours. The reaction mixture is diluted with acetone (160 ml), acetic acid (63 g) is added and the mixture is left to crystallize at 50°C for 1 hour. Then, the suspension is cooled down to 20°C and, after half an hour, aspirated and washed with water (2 x 70 ml). The resulting product is dried in a vacuum drier at 45°C. 82 g (95% of the theoretical quantity, HPLC 99.7%) of azilsartan (I) was obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a process for preparing 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[ 1,1'-biphenyl]-4-yl]methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid of formula (I) (azilsartan). The invention also relates to preparation of new solid forms of intermediates that make it possible to obtain azilsartan with a high purity over 99.7% (HPLC) and to their characterization.

Description

A PROCESS FOR PREPARING HIGHLY PURE AZILSARTAN
Technical Field
This invention relates to a process for preparing l-[[2'-(2,5-dihydro-5-oxo-l,2J4-oxadiazol-3- yl)[lf -biphenyl]-4-yl]methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid (azilsartan) of formula (I)
The invention also relates to preparation of new solid forms of intermediates that make it possible to obtain azilsartan with a high purity over 99.7 % (HPLC) and to their characterization.
Background Art
Azilsartan (I), which is a highly selective blocker of angiotensin II ATI receptors, was developed by Takeda and is used for the treatment of high blood pressure. Its synthesis is described in EP 0 520423 (Scheme 1)
Scheme 1 wherein examples of azilsartan formulations are also given. The applications WO2011063764, WO2012097697 and WO2013088384 describe salts of azilsartan with organic amines, crystalline forms of azilsartan, Jl and J2, as well as an amorphous form of azilsartan. An isopropanol solvate of azilsartan is described in the new application US2014113942.
The application WO2012107814 discusses a process for preparing azilsartan using various cyclizing agents in the presence of a base. The application WO2012157980 describes cyclization with the use of carbonyl imidazole. A process for preparing azilsartan, comprising a cyclizing reaction without the presence of a solvent, is described in WO2014049512.
Disclosure of Invention: The invention relates to preparation of very pure azilsartan. The process is based on the use and preparation of new solid forms of the key intermediates that have a principal influence on the purity of the final product - azilsartan. In particular, they are hemisolvates (2:1) of the ethyl ester (III) with 2-methyltetrahydrofuran (Ilia) or with methyl isobutyl ketone.
Azilsartan (I), obtained according to the patent EP 2 119 715, exhibits a 95.0% HPLC purity at the most. Purity of the last intermediate, which is azilsartan ethyl ester (III), is of key importance for its preparation as the final compound is difficult to crystallize. In our process, where we obtain the ethyl ester (III), it is the impurity A, produced during the reaction of the intermediate (II) with diethyl carbonate under basic catalysis, that is the most problematic.
It has surprisingly been found, during the investigation of purification of the ethyl ester (III), that the ethyl ester (III) is best purifies in the form of the newly discovered, highly crystalline solvates with 2-methyltetrahydrofuran (Ilia), or methyl isobutyl ketone (Illb). The table below illustrates advantages of purification of the ethyl ester during recrystallization in the form of the new crystalline solvates; the input raw material contained 3.6% of impurity A. Both the solvates are in the form of hemisolvates (2:1); they contain one molecule of the solvent per a molecule of the ethyl ester.
Table 1
Exp. 1 g /lO ml Dimer A % Yield %
1 Acetone 0.6 55
2 Tetrahydrofuran not.cryst
3 Ethyl acetate 0.7 48
4 Methyl ethyl ketone (MEK) 0.72 37
5 2-Methyl-THF 0.25 88
6 Acetonitrile 0.88 71
7 Isopropanol 0.4 56
8 2-Butanol 0.37 57
9 Methylcyclohexane not.cryst
10 Toluene not.cryst
11 n-Butanol 1.35 51
12 Methyl isobutyl ketone (MIBK) 0.32 86
13 Butyl acetate notcryst
14 Dimethyl acetamide not.cryst
Solvates can also be produced in mixtures of solvents containing 2-methyltetrahydrofuran or methyl isobutyl ketone. Solvents in which the above mentioned crystalline solvates can develop include primary or secondary alcohols and ketones. The use of ethanol, methanol, isopropanol or acetone and methyl ethyl ketone is especially convenient.
Then, a solvate produced this way can be transformed to a free acid of azilsartan with a high yield without problems.
The resulting solvate of azilsartan ethyl ester (III) is transformed to azilsartan (I) by means of alkaline hydrolysis, which may be carried out with the use of sodium or potassium hydroxide in water or suitable solvents of the alcohol type at a temperature from 25 °C to 80°C. As the hydrolysis does not virtually change the chemical purity of the intermediate, azilsartan can be, after acidification, obtained in an excellent purity of about 99.8%. Hydrochloric or acetic acid can be used for the acidification. Table 2: XRPD - diffraction peaks corresponding to the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia)
The solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran exhibits the following main characteristic peaks in X-ray powder diffraction, measured with the use of CuKa radiation: 8.9; 10.5; 12.0; 16.8; 19.6 and 23.5 ± 0.2° 2-theta. The prepared solvate is further characterized with the use of DSC (Fig. 2). Table 3: XRPD - characteristic diffraction peaks corresponding to the hemisolvate of azilsartan ethyl ester with methyl isobutyl ketone (Illb)
The solvate of azilsartan ethyl ester with methyl isobutyl ketyone exhibits the following main characteristic peaks in X-ray powder diffraction, measured with the use of CuK^ radiation: 8.6; 11.7; 16.6; 19.2; 21.4 and 25.5 ± 0.2° 2-theta.
The prepared solvate is further characterized with the use of DSC (Fig. 5). Brief Description of Drawings
Fig. 1: XRPD pattern for the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia)
Fig. 2: DSC curve for the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia) Fig. 3: TGA curve for the solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran (Ilia) Fig. 4: XRPD pattern for the solvate of azilsartan ethyl ester with methyl isobutyl ketone (Illb)
Fig. 5: DSC curve for the solvate of azilsartan ethyl ester with methyl isobutyl ketone (Mb) Fig. 6: TGA curve for the solvate of azilsartan ethyl ester with methyl isobutyl ketone (Illb)
Examples
The samples in the examples below were characterized by the X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) methods. The amounts of solvents were determined with the use of GC.
Measurement parameters of XRPD: The diffraction patterns were measured using an X'PERT PRO MPD PANalyticai diffractometer with a graphite monochromator, used radiation CuKa (λ= 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ. For the measurement a flat powder sample was used that was placed on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a ¼ anti-diffusion slit were used. For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti- diffusion slit were used.
Differential scanning calorimetry (DSC) records were measured using a DSC Pyris 1 device from Perkin Elmer. The sample charge in a standard Al pot was between 3 and 4 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 50°C and then of heating up to 250°C at the heating rate of 10°C/min. 4.0 N2 at the flow rate of 20 ml/min was used as the carrier gas. Thermogravimetric analysis (TGA) records were measured using a TGA 6 device from Perkin Elmer. The sample charge in a corundum pot was between 19 and 20 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 minute's stabilization at the temperature of 22°C and then of heating up to 250(300)°C at the heating rate of 10°C/min. 4.0 N2 at the flow of 20 ml/min was used as the carrier gas.
The invention is clarified in a more detailed way using the working examples below. The examples, which illustrate the improvement of the procedure in accordance with the invention, only have an illustrative character and do not restrict the scope of the invention in any respect.
Example 1:
Preparation of 2-ethoxy- 1 -((2'-(5 -oxo-4,5-dihydro- 1 ,2 ,4-oxadiazol-3 -yl)biphenyl-4- yl)methyl)-lH-benzo[i ]-imidazole-7-carboxylic acid ethyl ester (III). The ethoxy oxime (II) (390 g; 851 mmol) is suspended in 3600 ml of diethyl carbonate. The suspension is heated up to 65°C. A solution of sodium ethoxide in ethanol (21 %, 400 ml, 1072 mmol) is added dropwise to the reaction mixture at 65°C during 30 minutes. After completion of the addition the reaction mixture is agitated at 65 °C for 30 minutes. The reaction mixture is cooled down to 60°C and water (1350 ml) is added. The resulting emulsion is agitated for at least 15 minutes. After separation of the layers the organic phase is extracted with water (1350 ml). The combined aqueous extracts are diluted with ethanol (1350 ml) and the temperature is adjusted to 40°C. Acetic acid (111 ml, 1940 mmol) is added to the solution dropwise at 40°C during 30 minutes. The resulting suspension is agitated at 40°C for 30 minutes and then cooled down to 20°C. The separated substance is aspirated and washed with water (2 x 450 ml). The resulting product is then dried in a vacuum drier at 45°C. 397 g (86% of the theoretical quantity, HPLC 95.8%) of azilsartan ethyl ester (III) was obtained. Example 2:
Preparation of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l ,254-oxadiazol-3-yl)biphenyl-4- yl)methyl)-lH-benzo[£f|-imidazole-7-carboxylic acid ethyl ester hemisolvate with methyl isobutyl ketone (UJb).
The ethoxy oxime (II) (150 g; 327 mmol) is suspended in 1370 ml of diethyl carbonate. The suspension is heated up to 65 °C. A solution of sodium ethoxide in ethanol (21 %, 154 ml, 412 mmol) is added dropwise to the reaction mixture at 65°C during 30 minutes. After completion of the addition the reaction mixture is agitated at 65 °C for 30 minutes. The reaction mixture is cooled down to 60 °C and water (520 ml) is added. The resulting emulsion is agitated for at least 15 minutes. After separation of the layers the organic phase is extracted with water (520 ml). The combined aqueous extracts are diluted with ethanol (600 ml) and methyl isobutyl ketone (100 ml). The temperature of the solution is adjusted to 40°C. Acetic acid (43 ml, 750 mmol) is added to the solution dropwise at 40°C during 30 minutes. The resulting suspension is agitated at 40°C for 30 minutes and then cooled down to 20°C. The separated substance is aspirated and washed with water (2 x 150 ml). The final product is dried in a vacuum drier at 45°C. 154 g (88% of the theoretical quantity, HPLC 99.5%) of azilsartan ethyl ester hemisolvate with methyl isobutyl ketone (Illb) was obtained. Example 3:
Preparation of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)-lH-benzo[£¾-imidazole-7-carboxylic acid ethyl ester hemisolvate with 2- methyltetrafuran (Ilia). The ethoxy oxime (II) (75 g; 164 mmol) is suspended in 690 ml of diethyl carbonate. The suspension is heated up to 65°C. A solution of sodium ethoxide in ethanol (21 %, 77 ml, 206 mmol) is added dropwise to the reaction mixture at 65°C during 30 minutes. After completion of the addition the reaction mixture is agitated at 65°C for 30 minutes. The reaction mixture is cooled down to 60 °C and water (260 ml) is added. The resulting emulsion is agitated for at least 15 minutes. After separation of the layers the organic phase is extracted with water (260 ml). The combined aqueous extracts are diluted with ethanol (260 ml) and 2-methyltetrahydrofuran (150 ml). The temperature of the solution is adjusted to 40°C. Acetic acid (21 ml, 370 mmol) is added to the solution dropwise at 40°C during 30 minutes. The resulting suspension is agitated at 40°C for 30 minutes and then cooled down to 20°C. The separated substance is aspirated and washed with water (2 x 75 ml). The final product is dried in a vacuum drier at 45°C. 72.5 g (84% of the theoretical quantity, HPLC 99.4%) of azilsartan ethyl ester hemisolvate 2-methyltetrahydrofuran (Ilia) was obtained.
Example 4:
Preparation of 2-ethoxy- 1 -((2'-(5 -oxo-4,5 -dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)-lH-benzo[i/]-iraida2ole-7-carboxylic acid ethyl ester hemisolvate with 2- methyltetrafuran (Ilia).
Azilsartan ethyl ester (III) (380 g; 784 mmol) is suspended in 2600 ml of 2-methyltetrafuran. The suspension is heated up to reflux. 1200 ml of distillate is removed from the reaction mixture by distillation. The resulting suspension is cooled down to 45 °C. The reaction mixture is agitated at 45°C for 30 minutes and then cooled down to 20°C. The separated substance is aspirated and washed with cooled 2-memyltelrafuran (75 ml). The final product is dried in a vacuum drier at 45°C. 372 g (90% of the theoretical quantity, HPLC 99.7%) of azilsartan ethyl ester hemisolvate 2-methyltetrahydrofuran (Ilia) was obtained. Example 5:
Preparation of 2-ethoxy- l-((2'-(5-oxo-4,5 -dihydro- 1, 2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)-lH-benzo[£¾-imidazole-7-carboxylic acid ethyl ester hemisolvate with methyl isobutyl ketone (Mb). Azilsartan ethyl ester (III) (150 g; 310 mmol) is suspended in 600 ml of 2-methyl isobutyl ketone. The suspension is heated up to reflux. The solution is cooled down to 95°C and an inoculum of the product is added. The resulting suspension is gradually cooled down to 20°C. The separated substance is aspirated and washed with cooled methyl isobutyl ketone (250 ml). The final product is then dried in a vacuum drier at 45 °C. 140 g (85% of the theoretical quantity, HPLC 99.6%) of azilsartan ethyl ester hemisolvate with methyl isobutyl ketone (Illb) was obtained. Example 6:
Preparation of l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)[^^
ethoxy- lH-benzimidazole-7-carboxy lie acid (I). Ethoxy azilsartan hemisolvate with 2-methyltetrafuran (Ilia) (160 g) was weighed into a 5 liter pot and suspended in a NaOH/water solution (38g/500 ml). The reaction mixture is heated up to 50°C and agitated for 4 hours. The reaction mixture is diluted with acetone (250 ml), acetic acid (101 g) is added and the mixture is left to crystallize at 50°C for lh. After cooling to 20°C and agitation for half an hour the product is aspirated and washed with water (2 x 110 ml). The final product is then dried in a vacuum drier at 45°C. 129 g (93% of the theoretical quantity, HPLC 99.8%) of azilsartan (I) was obtained.
Example 7:
Preparation of l-[[2,-(255-dihydro-5-oxo-l,254-oxadiazol-3-yl)[l,r-biphenyl]-4-yl]methyl]-2- ethoxy- 1 H-benzimidazole-7-carboxy lie acid (I) .
Ethoxy azilsartan hemisolvate with methyl isobutyl ketone (Illb) (100 g) was weighed into a 5 liter pot and suspended in a NaOH/water solution (23g 315 ml). It was heated up to 50°C and agitated for 4 hours. The reaction mixture is diluted with acetone (160 ml), acetic acid (63 g) is added and the mixture is left to crystallize at 50°C for 1 hour. Then, the suspension is cooled down to 20°C and, after half an hour, aspirated and washed with water (2 x 70 ml). The resulting product is dried in a vacuum drier at 45°C. 82 g (95% of the theoretical quantity, HPLC 99.7%) of azilsartan (I) was obtained.

Claims

Claims:
1. A process for preparing azilsartan of formula (I),
characterized in that azilsartan ethyl ester of formula (III)
is transformed to a solvate with a solvent selected from 2-methyltetrahydrofuran and methyl isobutyl ketone, which solvate is transformed to azilsartan by subsequent basic hydrolysis, the preparation of the solvate being optionally conducted in the presence of another solvent.
2. The process for preparing azilsartan according to claim 1, characterized in that the preparation of the solvate is conducted in the presence of ethanol at 40°C.
3. The process for preparing azilsartan according to claim 1, characterized in that the hydrolysis is conducted in the presence of a base selected from NaOH and KOH at 50°C.
4. The solvate of azilsartan ethyl ester with 2-methyltetrahydrofuran, which exhibits the following main characteristic peaks in X-ray powder diffraction, measured with the use of CuKa radiation: 8.9; 10.5; 12.0; 16.8; 19.6 and 23.5 ± 0.2° 2-theta.
5. The solvate of azilsartan ethyl ester with methyl isobutyl ketone, which exhibits the following main characteristic peaks in X-ray powder diffraction, measured with the use of CuKa radiation: 8.6; 11.7; 16.6; 19.2; 21.4 and 25.5 ± 0.2° 2-theta.
EP15784925.8A 2014-10-15 2015-10-02 A process for preparing highly pure azilsartan Withdrawn EP3207040A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2014-702A CZ2014702A3 (en) 2014-10-15 2014-10-15 Process for preparing extremely pure azilsartan
PCT/CZ2015/000115 WO2016058563A1 (en) 2014-10-15 2015-10-02 A process for preparing highly pure azilsartan

Publications (1)

Publication Number Publication Date
EP3207040A1 true EP3207040A1 (en) 2017-08-23

Family

ID=54352451

Family Applications (1)

Application Number Title Priority Date Filing Date
EP15784925.8A Withdrawn EP3207040A1 (en) 2014-10-15 2015-10-02 A process for preparing highly pure azilsartan

Country Status (4)

Country Link
EP (1) EP3207040A1 (en)
JP (1) JP2017535533A (en)
CZ (1) CZ2014702A3 (en)
WO (1) WO2016058563A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109071519A (en) * 2016-01-28 2018-12-21 株式会社德山 Azilsartan and its manufacturing method

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL102183A (en) 1991-06-27 1999-11-30 Takeda Chemical Industries Ltd Biphenyl substituted heterocyclic compounds their production and pharmaceutical compositions comprising them
US7157584B2 (en) 2004-02-25 2007-01-02 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use thereof
BR112012012484A2 (en) 2009-11-30 2016-04-12 Jiangsu Hansoh Pharmaceutical "Organic amine salts of azilsartan, method of preparation and use thereof".
US9233954B2 (en) 2011-01-20 2016-01-12 Jiangsu Hansoh Pharmaceutical Co., Ltd. Organic amine salts of Azilsartan, preparation method and use thereof
JP2014505097A (en) 2011-02-08 2014-02-27 ジュビラント ライフ サイエンセズ リミテッド Improved production method of azilsartan medoxomil
CZ2011208A3 (en) * 2011-04-11 2012-10-24 Zentiva, K. S Process for preparing 2-ethoxy-1-((2?-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylates and their conversion to azilsartan
CZ304252B6 (en) * 2011-04-11 2014-01-29 Zentiva, K. S. Process for preparing 2-ethoxy-1-((2´-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylates and their conversion to azilsartan
KR101275092B1 (en) 2011-05-19 2013-06-17 한미정밀화학주식회사 Manufacturing Method Of Azilsartan
WO2013088384A2 (en) 2011-12-15 2013-06-20 Jubilant Life Sciences Limited Solid state forms of azilsartan and azilsartan medoxomil monopotassium and preparation thereof
CN103664920B (en) * 2012-09-24 2016-03-09 上海医药工业研究院 Azilsartan intermediate and the preparation method with Azilsartan thereof
WO2014049512A2 (en) 2012-09-26 2014-04-03 Lupin Limited Novel process for preparation of azilsartan medoxomil
CZ305318B6 (en) * 2012-09-26 2015-07-29 Zentiva, K.S. Process for preparing extremely pure azilsartan medoxomil potassium salt
US20140113942A1 (en) 2012-10-12 2014-04-24 Cadila Healthcare Limited Process for the preparation and purification of azilsartan medoxomil
CN103664921B (en) * 2013-11-27 2016-08-24 湖南千金湘江药业股份有限公司 A kind of Azilsartan crystal formation A and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2016058563A1 *

Also Published As

Publication number Publication date
WO2016058563A1 (en) 2016-04-21
JP2017535533A (en) 2017-11-30
CZ2014702A3 (en) 2016-04-27

Similar Documents

Publication Publication Date Title
JP6389174B2 (en) Chemical method
EP3230280A1 (en) Process for preparation of luliconazole
WO2016055918A1 (en) Novel stable polymorphs of isavuconazole or its salt thereof
US10040793B2 (en) Key intermediates and impurities of the synthesis of Apixaban: Apixaban glycol esters
CZ2007455A3 (en) Method of isolation and purification of montelukast
WO2013042067A1 (en) Process for the preparation of potassium salt of azilsartan medoxomil
KR20200053481A (en) Inhibitors of RORγ
WO2014048404A1 (en) A method of preparing a highly pure potassium salt of azilsartan medoxomil
EP3286168A1 (en) A solid form of apremilast and a process for preparing the same
WO2016058563A1 (en) A process for preparing highly pure azilsartan
WO2018185711A1 (en) Solvates of eluxadoline
CA2594114A1 (en) Synthesis of ccr5 receptor antagonists
WO2016120635A1 (en) Processes for the preparation of compounds, such as 3-arylbutanals, useful in the synthesis of medetomidine
WO2018185664A1 (en) Solvates of eluxadoline
EA012852B1 (en) Preparation of irbesartan
EP3109236B1 (en) Scalable process for the preparation of sorafenib tosylate ethanol solvate and sorafenib tosylate form iii
WO2021001044A1 (en) Process for the preparation of key intermediates for the synthesis of eltrombopag or salt thereof
CZ2012274A3 (en) Process for preparing extremely pure potassium salt of azilsartan medoxomil
WO2013164794A1 (en) Crystalline forms of vilazodone hydrochloride
JP2014530248A (en) Bosentan acid addition salt
EP2647635B1 (en) Pyrrole derivative and process for production thereof
JP2012516327A (en) Novel process for the production of carboxy-containing pyrazole amide compounds
WO2018011721A1 (en) Novel polymorphic forms of ((1s,2s,3s,4r,5s))-2,3,4-(tris-benzyloxy)-5-(4-chloro-3-(4-ethoxy-benzyl)phenyl)-6,8-dioxa-bicyclo[3.2.1]oct-1-yl-methanol
WO2020065475A1 (en) Title: process for the preparation of bilastine
JP5432910B2 (en) High purity synthetic process for the preparation of dodecahydro-naphtho-furanyl-carbamic acid ester intermediate

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20170510

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
17Q First examination report despatched

Effective date: 20180717

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20181128