WO2012139536A1 - A method of 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 conversion thereof to azilsartan - Google Patents

A method of 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 conversion thereof to azilsartan Download PDF

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WO2012139536A1
WO2012139536A1 PCT/CZ2012/000031 CZ2012000031W WO2012139536A1 WO 2012139536 A1 WO2012139536 A1 WO 2012139536A1 CZ 2012000031 W CZ2012000031 W CZ 2012000031W WO 2012139536 A1 WO2012139536 A1 WO 2012139536A1
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formula
methyl
ethoxy
benzo
biphenyl
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PCT/CZ2012/000031
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French (fr)
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Stanislav Radl
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Zentiva, K.S.
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Priority to HU1300730A priority Critical patent/HU230540B1/en
Publication of WO2012139536A1 publication Critical patent/WO2012139536A1/en

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    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to an improved method of preparing alkyl 2-ethoxy- l -((2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-l H-benzo[if)imidazole-7-carboxylates of formula I,
  • R is either a branched or unbranched C 1 -C4 alkyl ArCH 2 , Ar 2 CH, or Ar 3 C, wherein Ar is a substituted or unsubstituted phenyl, and conversion thereof to azilsartan of formula II.
  • This compound is an efficient angiotensin II ATI receptor antagonist, which is used in the form of the prodrug azilsartan medoxomil of formula III in the treatment of hypertension.
  • Azilsartan of formula II is prepared, according to the published patents (US 5,583, 141 and EP 0 520 423) from the starting methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy- lH- benzo[t/]imidazole-7-carboxylate of formula IVa.
  • This compound which is a well-known intermediate of synthesis of candesartan, is first converted, by reaction with hydroxylamine generated in situ from hydroxylamine hydrochloride, to methyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- lH-benzo[ ⁇ i]imidazole-7-carboxylate (Va), which is then converted to methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3- yl)bipheiiyl-4-yl)methyl)- lH-benzo[ ⁇ fjimidazole-7-carboxylate of formula la, saponification of which produces azilsartan of formula II.
  • the invention relates to a new method of preparing azilsartan, which makes use of cyclization of compounds of the general formula V,
  • Esters of the general formula I are then saponified to the final azilsartan of formula II.
  • the essence of this invention is based on a quite surprising finding that with a suitable combination of the solvent, the base and cychzation agent used this ethoxy group in position 2 of the benzimidazole skeleton is relatively stable and that the above mentioned direct cychzation of amidoximes of formula V to alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[cf]imidazole-7-carboxylates of formula I is feasible.
  • Suitable cychzation agents include phosgene, diphosgene, triphosgene, dialkyl carbonates, carbonyl diimidazole or carbonyl-di-l ,2,4-triazole, or other known phosgene surrogates, in the presence of suitable bases.
  • the invention relates to a new method of preparing azilsartan, which makes use of cychzation of compounds of the general formula V
  • R is a branched or unbranched C 1-C4 alkyl, ArC3 ⁇ 4, A ⁇ CH, or Ar 3 C, wherein Ar is a substituted or unsubstituted phenyl, which are cyclized by reaction with a cychzation agent in a solvent, in the presence of suitable bases.
  • the cychzation agent is to be understood as meaning phosgene, diphosgene, triphosgene, carbonyl diimidazole or carbonyl-di-l ,2,4-triazole, or a dialkyl carbonate of formula R"-0- CO-O-R", wherein R" is either a branched or unbranched C 1 -C4 alkyl or unsubstituted or substituted phenyl. Unlike the prior thermal cyclizations, this cyclization proceeds under considerably milder conditions and secondary reactions are significantly minimized during this procedure.
  • polar aprotic solvents such as sulfoxides (e.g. DMSO); amides (e.g. NN-dimethyl formamide (D F), N,N- dimethyl acetamide (DMAc), 1 -methyl pyrrolidone (NMP)); urea derivatives (e.g.
  • TMU 1 , 1 ,3,3- tetramethyl urea
  • DI 1 ,3-dimethyl imidazolidin-2-one
  • DMPU 1 ,3-dimefhyl-3 ,4,5,6- tetrahydro-2( l //)-pyrimidinone
  • HMPA hexamethyl phosphoramide
  • the reaction is carried out at an elevated temperature, it can in some cases be preferably performed in polar protic solvents as well, e.g. in alcohols.
  • reaction can also be carried out in mixtures of the above mentioned solvents with other cosolvents such as ethers (THF, dioxan, 1 ,2-dimethoxyethane, diglyme), esters (e.g. alkyl acetates) or aromatic hydrocarbons (e.g. toluene).
  • cosolvents such as ethers (THF, dioxan, 1 ,2-dimethoxyethane, diglyme), esters (e.g. alkyl acetates) or aromatic hydrocarbons (e.g. toluene).
  • Cyclization of amidoximes of formula V by reaction with phosgene, diphosgene, triphosgene, dialkyl carbonates, carbonyl diimidazole or carbonyl-di- l ,2,4-triazole is performed in the presence of inorganic or organic bases.
  • Useful organic bases include various amines (e.g.
  • Useful inorganic bases include alkali metal carbonates (Na 2 C0 3 , 2 C0 3 , Cs 2 C0 3 ), alkali metal hydrogen carbonates or acetates ( aHC0 3 , KHC0 3 NaOAc, KOAc).
  • reaction times need to be used to achieve complete conversion, or it is necessary to perform the reaction in a suitable pressure vessel at higher temperatures than the boiling point of the alcohols used. If the reaction is conducted in such a way that the conversion of the starting substances of formula V is not complete, these can be easily eliminated from the reaction mixture with regard to their considerable basicity either during the processing, which consists in pouring into water (after possible partial or complete removal of the original solvent) and subsequent acidification, or they can be removed by washing the product on a filter with diluted acids, or by dissolution in a suitable solvent and shaking with diluted acids.
  • Polar aprotic solvents selected from the group of dimethyl sulfoxide (DMSO), NN-dimethyl formamide (DMF), NN-dimethyl acetamide (DMAc), 1 -methyl pyrrolidone (NMP), 1 , 1 ,3,3- tetramethyl urea (TMU), 1 ,3 -dimethyl imidazolidin-2-one (DMI), l ,3-dimefhyl-3,4,5,6- tetrahydro-2(l H)-pyrimidinone (DMPU), or hexamethyl phosphoramide ( ⁇ ), preferably DMSO, are chosen as suitable solvents.
  • DMSO dimethyl sulfoxide
  • DMF NN-dimethyl formamide
  • DMAc NN-dimethyl acetamide
  • NMP 1 -methyl pyrrolidone
  • TMU 1 , 1 ,3,3- tetramethyl urea
  • DI 1,3 -di
  • reaction mixture After the cyclization, the reaction mixture is processed by dilution with water or pouring of the reaction mixture into water, acidification and subsequent isolation of the insoluble product by filtration or centrifugation.
  • amides N,N-dimethyl formamide, NN-dimefhyl acetamide, 1 -methyl pyrrolidone
  • ethers e.g. dioxan, 1 ,2- dimethoxyethane, 1 -methoxy-2-(2-methoxyethoxy)ethane
  • esters of aliphatic acids selected from methyl acetate, ethyl acetate, isopropyl acetate; amides selected from N V-dimethyl formamide, N,N- dimethyl acetamide, 1 -methyl pyrrolidone; ethers such as dioxan, 1 ,2-dimethoxyethane, 1 - methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents
  • esters of the general formula I are then saponified to the final azilsartan of formula (II).
  • An aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide, is added to a suspension or solution of the compound of formula I in a suitable solvent, which is, e.g., alcohols or dipolar aprotic solvents such as DMSO or NMP, and the resulting solution or mixture is stirred at a temperature in the range from 0°C to the boiling point of the mixture, preferably at the room temperature.
  • a suitable solvent which is, e.g., alcohols or dipolar aprotic solvents such as DMSO or NMP
  • the compounds of formula I are prepared by cyclization with a cyclization agent in a suitable solvent in the presence of a base.
  • this base is used in a higher quantity than 2 equivalents, which directly results in the corresponding salt of azilsartan, which is directly converted to azilsartan after suitable processing.
  • a dipolar aprotic solvent most preferably DMSO
  • the base used includes at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched C
  • R"OM alkali metal alcoholate
  • R" is a branched or unbranched C
  • M is an alkali metal.
  • the reaction is carried out at a temperature in the range of 0 °C to the boiling point of the solvent used, preferably at a temperature of 0° C to 50°C, most preferably at the room temperature.
  • Azilsartan prepared by both the above mentioned methods can be r-purified by crystallization from suitable solvents, including alcohols (e.g. methanol, ethanol, isopropanol), esters of aliphatic acids (e.g. methyl acetate, ethyl acetate, isopropyl acetate), amides (N,N-dimethyl formamide, N,N-dimethyl acetamide, 1 -methyl pyrrolidone), ethers (e.g. dioxan, 1 ,2- dimethoxyethane, l -methoxy-2-(2-methoxyethoxy)ethane), or mixtures of these solvents.
  • suitable solvents including alcohols (e.g. methanol, ethanol, isopropanol), esters of aliphatic acids (e.g. methyl acetate, ethyl acetate, isopropyl acetate), amides (N,N-dimethyl form
  • the method of purifying azilsartan of formula II obtained by the method described herein is carried out by crystallization from suitable solvents, including alcohols selected from methanol, ethanol and isopropanol; esters of aliphatic acids selected from methyl acetate, ethyl acetate, isopropyl acetate; amides selected from the group of N,N-dimethyl formamide, N,N- dimethyl acetamide, 1 -methyl pyrrolidone; ethers selected from the group of dioxan, 1 ,2- dimethoxyethane, l-methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents.
  • suitable solvents including alcohols selected from methanol, ethanol and isopropanol; esters of aliphatic acids selected from methyl acetate, ethyl acetate, isopropyl acetate; amides selected from the group of N,N-dimethyl formamide
  • the total content of the product of formula la corresponds to a yield of 64 %.
  • the reaction mixture contained 5.2 % of the starting compound Vc and 86.1 % of the product of formula Ic according to HPLC. After stirring at the room temperature for another 2 hours the mixture was poured into water (25 ml), acidified with acetic acid and the separated insolubles were aspirated and washed with water. 0.53 g of a product was obtained, which contained 1.6 % of the starting compound of formula Vc and 84.2 % of the compound of formula Ic according to HPLC. Crystallization from ethyl acetate yielded 0.41 g of a product with the melting point 163- 165 °C, which contained 98.3 % of the compound of formula Ic according to HPLC.
  • Diphenyl carbonate (DPC; 0.32 g, 1 .5 mmol) was added to a mixture of methyl 2-ethoxy-l- ((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- lH-benzo[i/]imidazole-7- carboxylate (of formula Va; 0.44 g, 1 mmol), DMSO (10 ml) and K 2 C0 3 (0.2 g, 1 .4 mmol) and the mixture was stirred at the room temperature for 2 h.
  • the mixture contained 12.4 % of the starting compound of formula Va, 8.3 % of phenol and 71.8 % of the substance of formula la according to HPLC.
  • the mixture contained 26.9 % of the starting compound of formula Va and 62.4 % of the compound of formula la according to HPLC.
  • a second portion of DMC (0.4 g, 4.4 mmol) was added and the mixture was stirred under moderate reflux for another 24 hours.
  • the mixture contained 12.9 % of the starting compound of formula Va and 73.4 % of the compound of formula la according to HPLC. After evaporation the residue was dissolved in water (20 ml) and the solids separated after acidification with 5% HC1 were aspirated and washed with water. 0.35 g (78.7 %) of a product was obtained, containing 95.2 % of the compound of formula la according to HPLC.
  • MeONa (0.1 g, 1.8 mmol) was added to a solution of methyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[ci jimidazole-7-carboxylate (of formula Va; 0.44 g, 1 mmol) and dimethyl carbonate (DMC; 0.25 ml, 3 mmol) in DMSO (5 ml) and the mixture was stirred at the room temperature for 1 hour. The mixture did not contain the starting compound of formula la and contained 88.9 % of the compound of formula II according to HPLC.
  • EtONa (0.12 g, 1.8 mmol) was added to a suspension of ethyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[cflimidazoIe-7-carboxyIate (of formula Vb; 0.46 g, 1 mmol) in dry ethanol (20 ml) and the mixture was stirred at the room temperature for 10 minutes. After adding diethyl carbonate (DEC; 0.6 g, 5.0 mmol) the mixture was stirred in a pressure flask at the temperature of 100 °C for 24 hours.
  • DEC diethyl carbonate
  • the mixture contained 48.3% of the starting compound of formula Vb and 33.1 % of the compound of formula lb according to HPLC. After stirring in a pressure flash at 100 °C for another 24 hours the mixture contained 1 1.3 % of the starting compound of formula Vb and 77.1 % of the compound of formula lb according to HPLC. After evaporation the residue was dissolved in water (20 ml) and the solids separated after acidification with 5% HCl were aspirated and washed with water. 0.32 g (66.0 %) of the product containing 92.7 % of the compound of formula lb according to HPLC was obtained.

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Abstract

A method of preparing alkyl 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 of the general formula I, wherein R is either a branched or unbranched C1-C4 alkyl, ArCH2, Ar2CH, or Ar3C, wherein Ar is a substituted or unsubstituted phenyl, in which an alkyl 2-ethoxy-1 -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- 1H-benzo[d]imidazole-7-carboxylate of the general formula V is reacted with a cyclization agent in a solvent in the presence of suitable bases. (I) (V)

Description

A method of preparing 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-lH-benzo[rf]imidazole-7-carboxyIates and conversion thereof to azilsartan
Technical Field
The invention relates to an improved method of preparing alkyl 2-ethoxy- l -((2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-l H-benzo[if)imidazole-7-carboxylates of formula I,
Figure imgf000003_0001
wherein R is either a branched or unbranched C 1 -C4 alkyl ArCH2, Ar2CH, or Ar3C, wherein Ar is a substituted or unsubstituted phenyl, and conversion thereof to azilsartan of formula II. This compound is an efficient angiotensin II ATI receptor antagonist, which is used in the form of the prodrug azilsartan medoxomil of formula III in the treatment of hypertension.
Figure imgf000003_0002
Background Art
Azilsartan of formula II is prepared, according to the published patents (US 5,583, 141 and EP 0 520 423) from the starting methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy- lH- benzo[t/]imidazole-7-carboxylate of formula IVa. This compound, which is a well-known intermediate of synthesis of candesartan, is first converted, by reaction with hydroxylamine generated in situ from hydroxylamine hydrochloride, to methyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- lH-benzo[<i]imidazole-7-carboxylate (Va), which is then converted to methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3- yl)bipheiiyl-4-yl)methyl)- lH-benzo[<fjimidazole-7-carboxylate of formula la, saponification of which produces azilsartan of formula II.
Figure imgf000004_0001
CICOOR'
Et3N or Py
Figure imgf000004_0002
LiOH or NaOH
aq. MeOH
(II)
azlsartan In the above cited patents the conversion of the amidoxime of formula Va to the compound of formula la is performed by reaction with ethyl chloroformate in the presence of triethylamine in dichloromethane, followed by cyclization of the thus formed ethyloxycabonyl derivative of formula VI by boiling in xylene for 1.5 hrs. The product of formula la was then obtained from the mixture, after processing and chromatography, in 23% yield. In more recent publications the same authors (Kohara Y., Imamiya E., Kubo K., Wada T., Inada Y., Naka T.: Bioorg. Med. Chem, Lett. 1995, 5(7), 1903-1908; Kohara Y., Kubo K., Imamiya E., Wada T., Inada Y., Naka T. : J. Med. Chem. 1996, 39(26), 5228-5235) have used either methyl chloroformate or 3-exthylhexyl chloroformate instead of ethyl chloroformate. Cyclization of the intermediates of formula VI is again performed thermally, by boiling in xylene for 2 hrs. In the only working example presented in the cited reference of Kohara Y., Kubo K., Imamiya E., Wada T., Inada Y., Naka T. : J. Med. Chem. 1996, 39(26), 5228-5235, the product of formula la is obtained, using 3-octyl chloroformate, in 52% yield as colourless crystals with the melting point of 196- 197 °C. The reference Kohara Y., Imamiya E., Kubo K., Wada T., Inada Y., Naka T.: Bioorg. Med. Chem. Lett. 1995, 5(7), 1903-1908, mentions the possibility of cyclization of the intermediates of formula VI by the effect of DBU without quoting any details; being silent about the yield or the method of isolation of the intermediate of formula la, or information about the making up of the subsequent reaction without isolation of the compound of formula la.
Disclosure of Invention
The invention relates to a new method of preparing azilsartan, which makes use of cyclization of compounds of the general formula V,
(V)
Figure imgf000005_0001
which are cyclized by reaction with phosgene, diphosgene, triphosgene, dialkyl carbonates, carbonyl diimidazole or carbonyl-di-l ,2,4-triazole in the presence of suitable bases. Unlike the currently known thermal cyclizations, this cyclization is carried out under substantially milder conditions and secondary reactions are significantly minimized during this procedure.
Esters of the general formula I are then saponified to the final azilsartan of formula II.
Figure imgf000006_0001
Detailed description of the invention:
Reproduction of the previously described thermal methods of the synthesis of formula la (see Examples 1 -3) showed that besides the desired product the reaction mixture also contained the starting substance as well as several other impurities, including the desethyl derivative of formula Vila in spite of using anhydrous xylene.
Figure imgf000006_0002
Although the compound of formula Vila is formally a product of hydrolysis of the ethoxy group in position 2 of the benzimidazole skeleton of the corresponding derivative of formula la, it must be produced through a different mechanism. We have previously described a similar reaction in case of candesartan cilexetil, wherein deethylation and intermolecular ethylation of another molecule of candesartan cilexetil occurred (Havlicek J., Mandelova Z., Weisemann R., Stfelec I., Placek L., Radl S. : Collect. Czech. Chem. Commun. 2009, 74(2), 347-362). In an effort to make the synthesis of alkyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol- 3-yl)biphenyl-4-yl)methyl)- lH-benzo[if|imidazole-7-carboxylates of formula I shorter and more efficient we focused on direct conversion of the amidoximes of formula V to esters of azilsartan. The above mentioned findings indicate that the ethoxy group in position 2 of the benzimidazole skeleton is very sensitive to the reaction conditions used and is not compatible with the use of higher temperatures. Therefore, we have focused on the use of procedures leading to the production of l ,2,4-oxadiazol-5(4H)-ones that would run under mild reaction conditions.
The essence of this invention is based on a quite surprising finding that with a suitable combination of the solvent, the base and cychzation agent used this ethoxy group in position 2 of the benzimidazole skeleton is relatively stable and that the above mentioned direct cychzation of amidoximes of formula V to alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[cf]imidazole-7-carboxylates of formula I is feasible. Suitable cychzation agents include phosgene, diphosgene, triphosgene, dialkyl carbonates, carbonyl diimidazole or carbonyl-di-l ,2,4-triazole, or other known phosgene surrogates, in the presence of suitable bases. The invention relates to a new method of preparing azilsartan, which makes use of cychzation of compounds of the general formula V
Figure imgf000007_0001
wherein R is a branched or unbranched C 1-C4 alkyl, ArC¾, A^CH, or Ar3C, wherein Ar is a substituted or unsubstituted phenyl, which are cyclized by reaction with a cychzation agent in a solvent, in the presence of suitable bases.
The cychzation agent is to be understood as meaning phosgene, diphosgene, triphosgene, carbonyl diimidazole or carbonyl-di-l ,2,4-triazole, or a dialkyl carbonate of formula R"-0- CO-O-R", wherein R" is either a branched or unbranched C 1 -C4 alkyl or unsubstituted or substituted phenyl. Unlike the prior thermal cyclizations, this cyclization proceeds under considerably milder conditions and secondary reactions are significantly minimized during this procedure.
With regard to limited solubility of certain starting amidoximes of formula V, polar aprotic solvents such as sulfoxides (e.g. DMSO); amides (e.g. NN-dimethyl formamide (D F), N,N- dimethyl acetamide (DMAc), 1 -methyl pyrrolidone (NMP)); urea derivatives (e.g. 1 , 1 ,3,3- tetramethyl urea (TMU), 1 ,3-dimethyl imidazolidin-2-one (DMI), l ,3-dimefhyl-3 ,4,5,6- tetrahydro-2( l //)-pyrimidinone (DMPU)), hexamethyl phosphoramide (HMPA), or their mixtures, have proved best. If the reaction is carried out at an elevated temperature, it can in some cases be preferably performed in polar protic solvents as well, e.g. in alcohols. The reaction can also be carried out in mixtures of the above mentioned solvents with other cosolvents such as ethers (THF, dioxan, 1 ,2-dimethoxyethane, diglyme), esters (e.g. alkyl acetates) or aromatic hydrocarbons (e.g. toluene).
Cyclization of amidoximes of formula V by reaction with phosgene, diphosgene, triphosgene, dialkyl carbonates, carbonyl diimidazole or carbonyl-di- l ,2,4-triazole is performed in the presence of inorganic or organic bases. Useful organic bases include various amines (e.g. triethylamine, diisopropylethylamine (DIPEA) l ,4-diazabicyclo[2.2.2]octane (DABCO), or 8- diazabicyclo[5.4.0.]undec-7-ene (DBU), l ,8-bis-(dimethylamino)naphthalene, 1 - methylmorpholine, 1 -ethylpiperidine), alcoholates (e.g. CH3ONa, CH3OK, C2H5ONa, t- C4Ht)ONa, /-C4H9OK, f-AmONa, f-AmOK). Useful inorganic bases include alkali metal carbonates (Na2C03, 2C03, Cs2C03), alkali metal hydrogen carbonates or acetates ( aHC03, KHC03 NaOAc, KOAc).
In some cases, e.g. when dialkyl carbonates are used in lower-boiling alcohols under reflux, longer reaction times need to be used to achieve complete conversion, or it is necessary to perform the reaction in a suitable pressure vessel at higher temperatures than the boiling point of the alcohols used. If the reaction is conducted in such a way that the conversion of the starting substances of formula V is not complete, these can be easily eliminated from the reaction mixture with regard to their considerable basicity either during the processing, which consists in pouring into water (after possible partial or complete removal of the original solvent) and subsequent acidification, or they can be removed by washing the product on a filter with diluted acids, or by dissolution in a suitable solvent and shaking with diluted acids. Polar aprotic solvents selected from the group of dimethyl sulfoxide (DMSO), NN-dimethyl formamide (DMF), NN-dimethyl acetamide (DMAc), 1 -methyl pyrrolidone (NMP), 1 , 1 ,3,3- tetramethyl urea (TMU), 1 ,3 -dimethyl imidazolidin-2-one (DMI), l ,3-dimefhyl-3,4,5,6- tetrahydro-2(l H)-pyrimidinone (DMPU), or hexamethyl phosphoramide (ΗΜΡΑ), preferably DMSO, are chosen as suitable solvents.
After the cyclization, the reaction mixture is processed by dilution with water or pouring of the reaction mixture into water, acidification and subsequent isolation of the insoluble product by filtration or centrifugation.
The obtained crude alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)- l H-benzo[if)imidazole-7-carboxylates of formula I are purified by crystallization from suitable solvents, including alcohols (e.g. methanol, ethanol, isopropanol), esters of aliphatic acids (e.g. methyl acetate, ethyl acetate, isopropyl acetate), amides (N,N-dimethyl formamide, NN-dimefhyl acetamide, 1 -methyl pyrrolidone), ethers (e.g. dioxan, 1 ,2- dimethoxyethane, 1 -methoxy-2-(2-methoxyethoxy)ethane), or mixtures of these solvents. The method of purifying the alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)- l H-benzo[c/]imidazole-7-carboxylates of formula I, obtained by the above mentioned method, is carried out by crystallization from suitable solvents, including alcohols, e.g. methanol, ethanol, isopropanol; esters of aliphatic acids selected from methyl acetate, ethyl acetate, isopropyl acetate; amides selected from N V-dimethyl formamide, N,N- dimethyl acetamide, 1 -methyl pyrrolidone; ethers such as dioxan, 1 ,2-dimethoxyethane, 1 - methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents
The esters of the general formula I are then saponified to the final azilsartan of formula (II).
(I)
Figure imgf000009_0001
An aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide, is added to a suspension or solution of the compound of formula I in a suitable solvent, which is, e.g., alcohols or dipolar aprotic solvents such as DMSO or NMP, and the resulting solution or mixture is stirred at a temperature in the range from 0°C to the boiling point of the mixture, preferably at the room temperature.
For preparation of azilsartan another method can be used wherein the compounds of formula I are prepared by cyclization with a cyclization agent in a suitable solvent in the presence of a base. For the cyclization, this base is used in a higher quantity than 2 equivalents, which directly results in the corresponding salt of azilsartan, which is directly converted to azilsartan after suitable processing. In this embodiment, a dipolar aprotic solvent, most preferably DMSO, is used as the solvent and the base used includes at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched C | -C8 alkyl and M is an alkali metal. The reaction is carried out at a temperature in the range of 0 °C to the boiling point of the solvent used, preferably at a temperature of 0° C to 50°C, most preferably at the room temperature.
Azilsartan prepared by both the above mentioned methods can be r-purified by crystallization from suitable solvents, including alcohols (e.g. methanol, ethanol, isopropanol), esters of aliphatic acids (e.g. methyl acetate, ethyl acetate, isopropyl acetate), amides (N,N-dimethyl formamide, N,N-dimethyl acetamide, 1 -methyl pyrrolidone), ethers (e.g. dioxan, 1 ,2- dimethoxyethane, l -methoxy-2-(2-methoxyethoxy)ethane), or mixtures of these solvents.
The reactions were routinely monitored by means of HPLC in an HP 1050 instrument equipped with a Phenomenex Luna 5μ CI 8(2), 250 x 4.6 mm column with a 227nm UV detector. Phase A: 1.2 g of NaH2P0 /l 1 of water (pH = 3.0; Phase B: methanol.
The method of purifying azilsartan of formula II obtained by the method described herein is carried out by crystallization from suitable solvents, including alcohols selected from methanol, ethanol and isopropanol; esters of aliphatic acids selected from methyl acetate, ethyl acetate, isopropyl acetate; amides selected from the group of N,N-dimethyl formamide, N,N- dimethyl acetamide, 1 -methyl pyrrolidone; ethers selected from the group of dioxan, 1 ,2- dimethoxyethane, l-methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents. The invention is elucidated in a more detailed way in the working examples below. These examples, which illustrate the improvement of the method according to the invention, have exclusively an illustrative character and do not limit the scope of the invention in any respect.
Working Examples
Comparative Examples:
Example 1
Methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[d]imidazole-7-carboxylate of formula la - reproduction of the procedure (US
5,583, 141 ; EP 0 520 423).
A solution of ethyl choroformate (0.22 g, 2 mmol) in dichloromethane (2 ml) was added dropwise to a stirred mixture of methyl 2-ethoxy-l -((2'-((hydroxyamino)iminomethyl)- biphenyl-4-yl)methyl)- l H-benzo[ii]imidazole-7-carboxylate of formula Va; 0.89 g, 2 mmol), dry THF (30 ml) and triethylamine (0.2 g) under cooling in a water-ice mixture and the mixture was stirred at the room temperature for 2 hours. The insolubles were aspirated and the filtrate was evaporated to dryness; the evaporation residue was diluted with ethyl acetate (5 ml), the insolubles were aspirated and the filtrate was evaporated again. The evaporation residue (1.0 g) contained 98.2% of the intermediate (of formula Vlab; R' = Et) according to HPLC.
A mixture of the evaporation residue and xylene (10 ml) was heated up to reflux for 1.5 hours. Ethyl acetate (25 ml) was added to the partially cooled reaction mixture; the solution was washed with water (2 10 ml) and then dried with MgSC>4. 0.9 g of an evaporation residue was obtained, containing 2.2 % of the intermediate (VI; R' = Et), 47.5 % of the product of formula la and 15.8 % of the compound of formula Vila according to HPLC. The total content of the product of formula la corresponds to a yield of 46 %. Example 2
Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l )2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[if]imidazole-7-carboxylate of formula lb - modification of the procedure (US 5,583, 141 ; EP O 520 423)
Using the procedure described in Example 1 , reacting the starting ethyl 2-ethoxy-l -((2'- ((hydiOxyamino)iminomethyl)biphenyl-4-yl)methyl)-lH-benzo[if|imidazole-7-carboxylate of formula Vb with ethyl chloroformate a mixture was obtained containing 96.4% of the corresponding intermediate of formula VI according to HPLC. This mixture was then cyclized by the procedure described in Example 1 providing a product containing 0.7% of the intermediate (of formula VI; R' = Et), 53.7 % of the product of formula lb and 33.2 % of the product of formula Vllb according to HPLC. The total content of the product of formula lb corresponds to a yield of 51 %.
Example 3 Methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH- benzo[<f]imidazole-7-carboxylate of formula la - reproduction of the procedure (J. Med. Chem. 1996, 59(26), 5228-5235)
2-ethylhexyl chloroformate (0.25 g, 2.6 mmol) was added to a stirred mixture of methyl 2- ethoxy- 1 -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- 1 H-benzo [d] imidazole-7- carboxylate (of formula Va; 1 .16 g, 2.6 mmol), dry DMF (5 ml) and pyridine (0.22 g) under cooling in a water-ice mixture and the mixture was stirred at the temperature of 0°C for 30 minutes. After dilution with water (20 ml) the mixture was extracted with ethyl acetate (4 x 10 ml), the extract was washed with water (4 x 5 ml) and dried with MgSC The obtained evaporation residue ( 1 .7 g) contained 92.2 % of the intermediate (of formula VI; R' = 2- ethylhexyl) according to HPLC. A mixture of the evaporation residue and xylene (15 ml) was heated to reflux for 2 hours. The evaporation provided 0.9 g of an evaporation residue containing 0.9% of the intermediate (VI; R' = 2-ethylhexyl), 64.0 % of the product of formula la and 5.2 % of the product of formula Vila according to HPLC. The total content of the product of formula la corresponds to a yield of 64 %.
The evaporation residue was dissolved in a mixture of CHCI3 (3 ml) and ethyl acetate (1 ml); an insoluble product started to separate after a short time. The mixture was left to stand at the room temperature; then the insolubles were aspirated. 0.55 g of ochre crystals was obtained containing 90.4% of the product of formula la and 8.6 % of formula Vila according to HPLC. The total content of the product of formula la corresponds to a yield of 40 %.
Working examples of cyclization of the compounds of formula V by means of phosgene or its derivatives:
Example 4
Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 (2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1H- benzo[< ]imidazole-7-carboxylate of formula la l ,8-Diazabicyclo[5.4.0.]undec-7-ene (DBU; 0.1 g, 0.65 mmol) was added dropwise to a mixture of methyl 2-methoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- lH- benzo[i ]imidazole-7-carboxylate (of formula Va; 0.22 g, 0.5 mmol), the corresponding solvent (3 ml) and carbonyldiimidazole (0.1 g, 0.6 mmol) in a reaction vial under stirring and the mixture was stirred at the room temperature for 3 hours. Then, the content of the vial was poured into water ( 10 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. The yields and purity of the products are summarized in Table I. Table I - Yield and purity of the product of Example 4
Figure imgf000014_0001
* - Also contains 40.4 % of the starting compound of formula Va; ** - Carbonyl-di- 1 ,2,4- triazole was used instead of carbonyldiimidazole.
Example 5
Ethyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate of formula lb l ,8-Diazabicyklo[5.4.0.]undec-7-ene (DBU; 0.1 g, 0.65 mmol) was added dropwise to a mixture of ethyl 2-ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)-l H- benzo[c/]imidazole-7-carboxylate (of formula Vb; 0.23 g, 0.5 mmol), the corresponding solvent (3 ml) and carbonyldiimidazole (0.1 g, 0.6 mmol) in a reaction vial under stirring and the mixture was stirred at the room temperature for 3 hours. Then, the content of the vial was poured into water (10 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. The yields and purity of the products are summarized in Table II. Table II - Yield and purity of the product of Example 5
Figure imgf000015_0001
Example 6
Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[c/]imidazole-7-carboxylate of formula lb
The corresponding base (0. 1 g) was added to a mixture of ethyl 2-ethoxy- l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l / -benzo[i ]imidazole-7-carboxylate (of formula Vb; 0.23 g, 0.5 mmol), DMSO (3 ml) and carbonyldiimidazole (0.1 g, 0,6 mmol) in a reaction vial under stirring and the mixture was stirred at the room temperature for 3 hours. Then, the content of the vial was poured into water (10 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. The yields and purity of the products are summarized in Table III.
Table III - Yield and purity of the product of Example 6
Figure imgf000016_0001
Example 7
Methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[i ]imidazole-7-carboxylate of formula la
A solution of l ,8-diazabicyclo[5.4.0.]undec-7-ene (DBU; 1.4 g, 9.2 mmol) in dry DMSO (3.5 ml) was added dropwise to a stirred mixture of methyl 2-ethoxy- l -((2'-((hydroxyamino)- iminomethyl)biphenyl-4-yl)methyl)-lH-benzo[(i]imidazole-7-carboxylate (of formula Va; 3.1 g, 7 mmol), dry DMSO (35 ml) and carbonyldiimidazole (1.4 g, 8.6 mmol) under cooling in a water-ice mixture and the mixture was stirred at the room temperature for 8 hours. Then, the mixture was poured into water (200 ml), the mixture was acidified with acetic acid and, after stirring for 30 minutes, the insolubles were aspirated and washed with water. 3.3 g of a product was obtained, containing 87.4 % of the compound of formula lb according to HPLC. Crystallization from ethyl acetate provided 2.7 g (82.0 %) of a product with the melting point of 193- 197 °C, which contained 99.6 % of the compound of formula la according to HPLC. Ή NMR (500 MHz, DMSO) δ (ppm): 12.39 (s, 1H, NH), 7.70 (dd, J = 7.9, 1.1 Hz, 1 H, Ar), 7.68-7.63 (m, 2H, Ar), 7.55 (td, J = 7.4, 1.1 Hz, 1H, Ar), 7.46 (m, 2H, Ar), 7.24 (d, J = 8.1 , 2H, Ar ), 7.19 (t, J = 7.9 Hz, 1H, Ar), 7.00 (d, J = 8.1 Hz, 2H, Ar), 5.54 (s, 2H, N-CH2-Ar), 4.62 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.69 (s, 3H, OCH3), 1.39 (t, J = 7.1 Hz, 3H, OCH2CH3_). Example 8
Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[cf]imidazole-7-carboxalate of formula lb
A solution of l ,8-diazabicyclo[5.4.0.]undec-7-ene (DBU; 2.0 g, 13.1 mmol) in dry DMSO (5 ml) was added dropwise to a stirred mixture of ethyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[<i]imidazole-7-carboxylate (of formula Vb; 4.6 g, 10 mmol), dry DMSO (50 ml) and carbonyldiimidazole (2 g, 12.3 mmol) under cooling in a water-ice mixture and the mixture was stirred at the room temperature for 3 hours. Then, the mixture was poured into water (200 ml), the mixture was acidified with acetic acid and, after stirring for 30 minutes, the insolubles were aspirated and washed with water. 4.9 g of a product was obtained, containing 97.7% of the compound of formula lb according to HPLC. Crystallization from ethyl acetate provided 4.4 g (93.6 %) of the product with the melting point of 179- 182 °C, which contained 99.8 % of the compound of formula lb according to HPLC Ή NMR (500 MHz, DMSO) δ (ppm): 12.40 (s, lH, NH), 7.69 (dd, J = 7.9, 1.2 Hz, 1 H, Ar), 7.50 (m, 1H, Ar), 7.44 (dd, J = 7.9, 1.2 Hz, 1 H, Ar), 7.43-7.40 (m, 4H, Ar), 7.35 (d, J = 7.7 Hz, 1 H, Ar), 7.19 (t, J = 7.9 Hz, 1H, Ar), 6.95 (d, J = 8.3 Hz, 2H, Ar), 6.61 (bs, 2H, NH2), 5.57 (s, 2H, N-CH2-Ar), 4.60 (q, J = 7.1 Hz, 2H, COOCH2CH3), 4.18 (q, J = 7.1 Hz, 2H, OCH2CH3), 1 .39 (t, J = 7.1 Hz, 3H, COOCH7.CH , 1.16 (t, J = 7.1 Hz, 3H,
Example 9
Benzyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[c/]imidazole-7-carboxylate of formula Ic l ,8-Diazabicyclo[5.4.0.]undec-7-ene (DBU; 0.2 g, 1.3 mmol) was added to a stirred mixture of benzyl 2-ethoxy- 1 -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- 1 H- benzo[i/]imidazole-7-carboxylate (of formula Vc; 0.5 g, 1 mmol), dry DMSO (5 ml) and carbonyldiimidazole (0.2 g, 1 .2 mmol) and the mixture was stirred at the room temperature for 4 hours. The reaction mixture contained 5.2 % of the starting compound Vc and 86.1 % of the product of formula Ic according to HPLC. After stirring at the room temperature for another 2 hours the mixture was poured into water (25 ml), acidified with acetic acid and the separated insolubles were aspirated and washed with water. 0.53 g of a product was obtained, which contained 1.6 % of the starting compound of formula Vc and 84.2 % of the compound of formula Ic according to HPLC. Crystallization from ethyl acetate yielded 0.41 g of a product with the melting point 163- 165 °C, which contained 98.3 % of the compound of formula Ic according to HPLC. Ή NMR (500 MHz, DMSO) δ (ppm): 12.40 (bs, 1H, NH), .70 (dd, J = 7.9, 1 .2 Hz, 1 H, Ar),7.68-7.62 (m, 2H, Ar), 7.57-7.52 (m, 1H, Ar), 7.51 (dd, J = 7.8, 1.2 Hz, 1 H, Ar), 7.45-7.30 (m, 6H, Ar), 7.19 (d, J = 8.2 Hz, 2H, Ar), 7.19 (t, J = 7.8 Hz, 1 H, Ar), 6.96 (d, J = 8.3 Hz, 2H, Ar), 5.55 (s, 2H, N-CH2-Ar), 5.24 (s, 2H, COOCH Ph), 4.61 (q, J = 7.1 Hz, 2H, OCH2CH3), 1 .40 (t, J = 7.1 Hz, 3H, OCH2CH3_).
Example 10
Methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[ai]irnidazole-7-carboxylate of formula la
A mixture of methyl 2-ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H- benzo[ii|imidazole-7-carboxylate (of formula Va; 0.1 g, 0.22 mmol), DMSO (2 ml), the corresponding carbonate (0. 1 g; DMC = dimethyl carbonate, DEC = diethyl carbonate, DPC = diphenyl carbonate) and the corresponding base (0.05 g) was stirred in a reaction vial at the room temperature for 2 hours. The results are summarized in Table IV.
Table IV - Yield and purity of the product of Example 10
Figure imgf000019_0001
Example 11
Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[i/]imidazole-7-carboxylate of formula la
A mixture of methyl 2-ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H- benzo[i ]imidazole-7-carboxylate (of formula Va; 0.1 g, 0.22 mmol), DMSO (2 ml), the corresponding carbonate (0.1 g; DMC = dimethyl carbonate, DEC = diethyl carbonate, DPC = diphenyl carbonate) and the corresponding base (0.05 g) was stirred in a reaction vial at the room temperature for 2 hours (HPLC A) or at the temperature of 50 °C for 16 hours (HPLC B). The results are summarized in Table V. Table V - Yield and purity of the product of Example 1 1
Figure imgf000020_0001
Example 12
Methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[£ ]imidazole-7-carboxylate of formula la
Diphenyl carbonate (DPC; 0.32 g, 1 .5 mmol) was added to a mixture of methyl 2-ethoxy-l- ((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- lH-benzo[i/]imidazole-7- carboxylate (of formula Va; 0.44 g, 1 mmol), DMSO (10 ml) and K2C03 (0.2 g, 1 .4 mmol) and the mixture was stirred at the room temperature for 2 h. The mixture contained 12.4 % of the starting compound of formula Va, 8.3 % of phenol and 71.8 % of the substance of formula la according to HPLC. After stirring at the room temperature for another 2 hours the reaction mixture was poured into water (25 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. 0.43 g (91.4 %) of a product containing 93.2 % of the compound (la) according to HPLC was obtained. Crystallization from ethyl acetate yielded 0.35 g (74.4 %) of a compound with the melting point 194-197 °C with the HPLC purity of 98.8 %.
Example 13 Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[t/]imidazole-7-carboxylate of formula la
A 30% solution of MeONa in methanol (0.33 g, 1.8 mmol) was added to a suspension of methyl 2-ethoxy- 1 -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- 1 H-benzo [d] - imidazole-7-carboxylate (of formula Va; 0.44 g, 1 mmol) in methanol (10 ml) and the mixture was stirred at the room temperature for 10 minutes. As the mixture was still very thick, more methanol (10 ml) was added and subsequently dimethyl carbonate (DMC; 0.2 g, 2.2 mmol) was added and the mixture was stirred under moderate reflux for 24 hours. The mixture contained 26.9 % of the starting compound of formula Va and 62.4 % of the compound of formula la according to HPLC. A second portion of DMC (0.4 g, 4.4 mmol) was added and the mixture was stirred under moderate reflux for another 24 hours. The mixture contained 12.9 % of the starting compound of formula Va and 73.4 % of the compound of formula la according to HPLC. After evaporation the residue was dissolved in water (20 ml) and the solids separated after acidification with 5% HC1 were aspirated and washed with water. 0.35 g (78.7 %) of a product was obtained, containing 95.2 % of the compound of formula la according to HPLC. Example 14
Methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[d]imidazol-7-carboxylate of formula la
A 30% solution of MeONa in methanol (0.33 g, 1 .8 mmol) and dimethyl carbonate (DMC; 0.5 g, 5.4 mmol) were added to a suspension of methyl 2-ethoxy- l-((2'-((hydroxyamino)- iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[i/]imidazole-7-carboxylare (of formula Va; 0.44 g, 1 mmol) in methanol (20 ml) and the mixture was stirred in a pressure flask at the temperature of 100°C for 24 hours. The mixture did not contain the starting compound of formula Va and contained 82.5 % of the compound of formula la according to HPLC. After evaporation the residue was dissolved in water and the solids separated after acidification with 5% HC1 were aspirated and washed with water. 0.42 g (89.3 %) of a product containing 92.5 % of the compound of formula la according to HPLC was obtained.
Example 15
Methyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[c ]imidazole-7-carboxylate of formula la
MeONa (0.1 g, 1.8 mmol) was added to a solution of methyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[ci jimidazole-7-carboxylate (of formula Va; 0.44 g, 1 mmol) and dimethyl carbonate (DMC; 0.25 ml, 3 mmol) in DMSO (5 ml) and the mixture was stirred at the room temperature for 1 hour. The mixture did not contain the starting compound of formula la and contained 88.9 % of the compound of formula II according to HPLC. Then, the reaction mixture was poured into water (20 ml) and the resulting solution was acidified with 5 % HC1. The separated product was aspirated, washed with water and air-dried. 0.5 g of a product containing 81.3 % of azilsartan of formula II according to HPLC was obtained. Crystallization from isopropanol yielded 0.35 g (74.4 %) of azilsartan of formula II with the HPLC content of 93.9 % and melting point of 204-207 °C. Example 16
Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[if|imidazole-7-carboxylate of formula lb
EtONa (0.12 g, 1.8 mmol) was added to a suspension of ethyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[cflimidazoIe-7-carboxyIate (of formula Vb; 0.46 g, 1 mmol) in dry ethanol (20 ml) and the mixture was stirred at the room temperature for 10 minutes. After adding diethyl carbonate (DEC; 0.6 g, 5.0 mmol) the mixture was stirred in a pressure flask at the temperature of 100 °C for 24 hours. The mixture contained 48.3% of the starting compound of formula Vb and 33.1 % of the compound of formula lb according to HPLC. After stirring in a pressure flash at 100 °C for another 24 hours the mixture contained 1 1.3 % of the starting compound of formula Vb and 77.1 % of the compound of formula lb according to HPLC. After evaporation the residue was dissolved in water (20 ml) and the solids separated after acidification with 5% HCl were aspirated and washed with water. 0.32 g (66.0 %) of the product containing 92.7 % of the compound of formula lb according to HPLC was obtained.
Example 17
Methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[£/]imidazole-7-carboxylate of formula la Solid triphosgene (0.12 g, 0.4 mmol) was added to a mixture of methyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)-lH-benzo[i/]imidazole-7-carboxylate (of formula Va; 0.44 g, 1 mmol), THF (10 ml) and triethylamine (0.5 g, 5 mmol) and the mixture was stirred in a closed pressure flask at the temperature of 80 °C for 8 hours. After cooling water (20 ml) was added under stirring and, after stirring for 30 minutes, the mixture was acidified with acetic acid. The separated honey-like product was extracted with ethyl acetate, the extract was dried and evaporated to dryness. 0.45 g of a product was obtained, which contained 65.5 % of the compound of formula la according to HPLC. Double crystallization from ethyl acetate yielded 0.28 g (59.5 %) of a product, which contained 95.2 % of the compound of formula la.
Example 18
Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[ci]imidazole-7-carboxylate of formula lb Using the procedure described in Example 22, ethyl 2-ethoxy- l -((2'-((hydroxyamino)- iminomethyl)-biphenyl-4-yl)methyl)-lH-benzo[< )imidazole-7-carboxylate of formula Vb was converted to ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)- l H-benzo[i ]imidazole-7-carboxylate of formula lb. Centrifugal chromatography (Cyclograph from Analtech, plate thickness 2 mm, dichloromethane-methanol 20 : 1 to 10 : 1 system) and subsequent crystallization from ethyl acetate yielded 61 .7 % of a product containing 99.9 % of the compound of formula lb according to HPLC.
Example 19
Methyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[c ]imidazole-7-carboxylate of formula la
First, active carbon (0.1 g) and then a solution of diphosgene (0.15 g, 0.75 mmol) in THE (1 ml) were added to a mixture of methyl 2-ethoxy- 1 -((2'-((hydroxyamino)iminomethyl)- biphenyl-4-yl)methyl)-l H-benzo[(i]imidazole-7-carboxylate (of formula Va; 0.44 g, 1 mmol), THF (10 ml) and triethylamine (0.5 g, 5 mmol) and the mixture was stirred in a closed pressure flask at the room temperature for 1 hour. Then, the temperature was increased to 100 °C and the mixture was stirred at this temperature for 4 hours. After cooling down, water (20 ml) was added under stirring and, after stirring for 30 minutes, the active carbon was aspirated through kieselguhr. The filtration cake was washed with 5 % ammonia (5 ml). The filtrate was then acidified with acetic acid and the resulting mixture was extracted with ethyl acetate (2 x 25 ml). After washing with water (5 5 ml) the extract was dried and after evaporation 0.4 g of a product was obtained, which contained 66.3 % of the compound of formula la according to HPLC. Centrifugal chromatography (Cyclograph from Analtech, plate thickness 2 mm, dichloromethane-methanol 20 : 1 to 10 : 1 system) and subsequent crystallization from ethyl acetate yielded 0.25 g (53.1 %) of a product, which contained 99.8 % of the compound of formula la according to HPLC.
Example 20 Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[cf]imidazole-7-carboxylate of formula lb
A 20 % solution of phosgene in toluene (0.5 ml, 1 mmol) was added to a mixture of ethyl 2- ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[i/|imidazole-7- carboxylate (of formula Vb; 0.23 g, 0.5 mmol), dioxan (5 ml) and triethylamine (0.2 g, 2 mmol) and the mixture was stirred in a closed pressure tube at 50 °C for 8 hours. After cooling down, the solution was bubbled with nitrogen for 8 hours. After evaporation of the solvent the residue was triturated with water ( 10 ml), the resulting turbid solution was acidified with acetic acid and extracted with ethyl acetate (4 x 25 ml). After washing with brine the extract was dried with MgS04 and the obtained evaporation residue was crystallized from ethyl acetate. 0.20 g (82.5 %) of a product was obtained containing 98.4 % of the compound of formula lb according to HPLC.
Examples of obtaining azilsartan (II): Example 21
2-Ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH- benzo[c/]imidazole-7-carboxylic acid - azilsartan of formula II
A mixture of methyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)- l H-benzo[i ]imidazole-7-carboxylate (of formula la; 4.7 g, 10 mmol), methanol (50 ml) and aqueous sodium hydroxide (2 g of NaOH in 10 ml of water) was stirred at the room temperature for 24 hours. Then, methanol was evaporated and the residue was diluted with 50 ml of water and acidified with 5% HCl. The insolubles were aspirated and washed with water. 4.4 g (96.4 %) of a product containing 97.8 % of azilsartan of formula II with the melting point of 208 to 21 1 °C according to HPLC was obtained.
Example 22 2-Ethoxy- 1 -((2'-(5-oxo-4,5 -dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylic acid - azilsartan of formula II
A mixture of ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)- l H-benzo[c/]imidazole-7-carboxylate (of formula la; 3.2 g, 6.6 mmol) and aqueous sodium hydroxide (0.8 g of NaOH in 50 ml of water) was stirred at the temperature of 70°C for 1.5 hours. After cooling to the room temperature the mixture was acidified with 10% HCl to pH 3 while being stirred and cooled. The insolubles were aspirated and washed with water. 2.6 g (86.2 %) of a product was obtained, containing 97.2 % of azilsartan of formula II with the melting point of 208 to 21 1 °C. Ή NMR (500 MHz, DMSO) δ (ppm): 13. 17 (bs, 1 H, OH or NH), 12.42 (bs, 1 H, OH or NH), 7.70-7.60 (m, 3H, Ar), 7.57-7.50 (m, 2H, Ar), 7.50-7.44 (m, 1H, Ar), 7.23 (d, J = 8.3 Hz, 2H, Ar), 7.18 (t, J = 7.9 Hz, 1H, Ar), 7.05 (d, J = 8.3 Hz, 2H, Ar), 5.68 (s, 2H, N-CHrAr), 4.58 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.38 (t, J = 7.1 Hz, 3H, OCH2CH3).
Example 23
2-Ethoxy- l -((2'-(5-oxo-4, 5-dihydro- l, 2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1H- benzo[<f]imidazole-7-carboxylic acid - azilsartan of formula II
/-BuOK (0.56 g, 5.0 mmol) and diethyl carbonate (DMC; 0.6 g, 5.0 mmol) were added to a suspension of methyl 2-ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[c/]imidazole-7-carboxylate (of formula Va; 0.44 g, 1 mmol) in DMSO (5 ml) and the mixture was stirred at the temperature of 100°C for 4 hours. The mixture did not contain the starting compound of formula Va, or the compound of formula la and the content of the compound of formula II was 82.5 % according to HPLC. Then, the reaction mixture was poured into water (20 ml) and the resulting solution was acidified with 5 % HC1. The separated product was aspirated, washed with water and air-dried. 0.45 g of a product was obtained, containing 87.3 % of azilsartan of formula II according to HPLC. Crystallization from isopropanol yielded 0.36 g (78.9 %) of azilsartan of formula II with the HPLC content of 95.2 % and melting point of 203 to 207 °C.

Claims

C L A I M S
1. A method of preparing alkyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-lH-benzo[i ]imidazole-7-carboxylates of the general formula I,
Figure imgf000028_0001
wherein R is either a branched or unbranched C 1 -C4 alkyl, ArCH2, Ar2CH, or Ar3C, wherein Ar is a substituted or unsubstituted phenyl,
characterized in that an alkyl 2-ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl- 4-yl)methyl)-lH-benzo[<f]imidazole-7-carboxylate of general formula V
Figure imgf000028_0002
wherein R has the same meaning as above,
is reacted with a cyclization agent in a solvent in the presence of suitable bases.
The method according to claim 1 , characterized in that R is methyl, ethyl, or benzyl.
The method according to claim 1 , characterized in that the cyclization agent is selected from the group consisting of phosgene, diphosgene, triphosgene, carbonyl diimidazole, carbonyl-di-l ,2,4-triazole, a dialkyl carbonate of formula R"-0-CO-0-R", wherein R" is either a branched or unbranched C 1 -C4 alkyl or unsubstituted or substituted phenyl, preferably carbonyldiimidazole.
4. The method according to claim 1 , characterized in that said base is an organic or inorganic base.
5. The method according to claims 1 and 4, characterized in that the organic base is selected from the group consisting of amines: triethylamine, diisopropylethylamine (DIPEA), 8-diazabicyclo[5.4.0.]undec-7-ene (DBU), l ,4-diazabicyclo[2.2.2]octane (DABCO), l ,8-bis-(dimethylamino)naphthalene, 1 -methylmorpholine, 1 - ethylpiperidine; and alcoholates: CH3ONa, CH3OK, C2H5ONa, t-C4H9ONa, t-C4H9OK, t-AmONa, t-AmOK; preferably DBU.
6. The method according to claims 1 and 4, characterized in that the inorganic base is selected from the group consisting of: alkali metal carbonates (Na2C03, K2COi, Cs2C03), hydrogen carbonates (NaHC03, KHC03) or acetates (NaOAc, KOAc).
7. The method according to claims 1 to 6, characterized in that said solvents are polar aprotic solvents or their mixtures.
8. The method according to claim 7, characterized in that the polar aprotic solvent is dimethyl sulfoxide (DMSO), N N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMAc), 1 -methyl pyrrolidone (ΝΜΡ), 1 ,1 ,3,3-tetramethyl urea (TMU),
' 1 ,3-dimethyl imidazolidin-2-one (DMI), l ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone (DMPU), or hexamethyl phosphoramide (ΗΜΡΑ), preferably DMSO.
9. The method according to claims 1 to 3, characterized in that the solvent is a branched or unbranched C1 -C4 alcohol and the base is an alkali metal alcoholate.
10. The method according to claim 9, characterized in that the reaction is conducted at a temperature in the range from 0 to 150 °C, preferably in the range from 20 °C to the boiling point of the solvent used.
1 1 . The method according to any of the preceding claims, characterized in that the reaction mixture is processed by dilution with water or by pouring of the reaction mixture into water, acidification and subsequent isolation of the insoluble product by filtration or centrifugation.
12. A method of purifying alkyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-l H-benzo[ii]imidazole-7-carboxylates of formula I, obtained by the method according to claims 1 to 1 1 , characterized in that said compounds are crystallized from solvents selected from the group consisting of alcohols such as methanol, ethanol, isopropanol; aliphatic acid esters selected from methyl acetate, ethyl acetate, isopropyl acetate; amides such as N,N-dimethyl formamide, N, TV-dimethyl acetamide, 1 -methyl pyrrolidone; ethers such as dioxan, 1 ,2-dimethoxyethane, 1 - methoxy-2-(2-methoxyethoxy)ethane; and mixtures of these solvents.
13. A method of preparing azilsartan of formula II,
Figure imgf000030_0001
characterized in that an aqueous solution of an alkali metal hydroxide, preferably sodium hydroxide, is added to a suspension or solution of the compound of formula I prepared by the method according to claim 1 in a suitable solvent and the resulting solution or mixture is stirred at a temperature in the range from 0 °C to the boiling point of the mixture, preferably at the room temperature.
14. The method according to claim 13, characterized in that said solvent is selected from alcohols or dipolar aprotic solvents such as DMSO or NMP.
15. A method of preparing azilsartan of formula II, characterized in that an alkyl 2-ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[ii]imidazole-7- carboxylate of formula V
Figure imgf000031_0001
wherein R has the same meaning as above, is cyclized with a cyclization agent in a solvent in the presence of a base, the resulting esters of formula I are directly converted to a salt of azilsartan by means of the base used and, after suitable processing, directly to azilsartan of formula II.
16. The method of preparing azilsartan of formula II according to claim 15, characterized in that the solvent is a dipolar aprotic solvent, preferably DMSO, and the base used is at least two molar equivalents of an alkali metal alcoholate R" OM, wherein R" is a branched or unbranched Ci-C8 alkyl and M is an alkali metal, at a temperature in the range of 0 °C to the boiling point of the solvent used, preferably at a temperature of 0° C to 50°C, most preferably at the room temperature.
17. A method of purifying azilsartan of formula II obtained by the method according to claim 13 or 15, characterized in that said compound is crystallized from a solvent selected from alcohols such as methanol, ethanol, and isopropanol; aliphatic acid esters such as methyl acetate, ethyl acetate, isopropyl acetate; amides such as N,N-dimethyl formamide, N N-dimethyl acetamide, 1 -methyl pyrrolidone; ethers such as dioxan, 1 ,2- dimethoxyethane, l-methoxy-2-(2-methoxyethoxy)ethane; and mixtures of these solvents.
18. Use of alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4- yl)methyl)- l H-benzo[< ]imidazole-7-carboxylates of formula I, wherein R has the same meaning as above, for the preparation of azilsartan of formula II.
PCT/CZ2012/000031 2011-04-11 2012-04-04 A method of 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 conversion thereof to azilsartan WO2012139536A1 (en)

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