WO2009123483A1

WO2009123483A1 - Process for preparation of telmisartan

Info

Publication number: WO2009123483A1
Application number: PCT/PL2009/000027
Authority: WO
Inventors: Mariusz Marek Gruza; Joanna Zagrodzka; Piotr Krzeczynski; Katarzyna Filip
Original assignee: Zaklady Farmaceutyczne Polpharma Sa
Priority date: 2008-03-31
Filing date: 2009-03-30
Publication date: 2009-10-08

Abstract

A process for preparation of telmisartan comprises: (i) oxidation of compound of formula (a), wherein R₂ is a hydrogen atom or a substituent of formula (b), in which R₁ is a protecting group for the carboxyl function, to an aldehyde of formula (c), in which R₂ is defined as in the formula (a), and, optionally, (ii) in case R₂ in the compound (c) thus obtained is a hydrogen atom, iV-alkylation of the compound (c) with a biphenyl derivative, (iii) treatment of the compound (c) thus obtained with N- methyl- o-nitroaniline in a cyclocondensation reaction, and (iv) cleavage of the protecting group R₁.

Description

PROCESS FOR PREPARATION OF TELMISARTAN

Field of the invention

The present invention relates to a process for the preparation of telmisartan.

Telmisartan, 4'-[(l,4'-dimethyl-2'-propyl-[2,6'-bis-lH-benzim- idazol]-r-yl)methyl]-[l, l'-biphenyl]-2-carboxylic acid, is non- peptide ATi -subtype specific angiotensin II antagonist, indicated for the treatment of hypertension, either alone or in combination with other antihypertensive agents.

Background of the invention The prior art general method of the synthesis of telmisartan,

disclosed in EP 0 502 314 Bl, uses as a starting material bisbenzimidazol moiety (DMPBB, l,4'-dimethyl-2'-propyl-lH,3'H- 2,6'-bisbenzimidazol). Alkylation of DMPBB on a nitrogen atom with a derivative of bromomethylbiphenyl (BMBP) in the presence of potassium tert-butanolate in dimethylsulfoxide results in a precursor of telmisartan, wherein a carboxyl group is protected as tert-butyl ester, which is thereafter cleaved to obtain telmisartan in a free form or as a salt. Alternatively, in the reaction of -ΛT-alkylation a cyano-substituted bromomethylbiphenyl is used, which is hydrolyzed to carboxy-derivative at the final step of the synthetic process. The DMPBB system is generated in an acylation reaction of 4-amino-3-methylbenzoic acid methyl ester to methyl 4-butyramido-3-methyl-5-nitrobenzoate, followed by reduction, cyclization to form 2-propyl-4-methylbenzimidazol-6-carboxylic acid methyl ester and its cyclocondensation with JV- methyl- o- phenylendiamine. This is a multistep process that requires the use of high-boiling solvents and their removal upon completion of the synthesis. The drawback of the above-mentioned process is also the burdensome work-up and purification of the intermediates as well as the final compound.

Some technical improvements to the foregoing process are disclosed inter alia in CN 1 344 712, wherein an alkylation reaction is accomplished with the use of 4'-(bromomethyl)biphenyl-2- carboxylic acid methyl or ethyl esters. In WO 2005/ 108 375 Al, alkylation is implemented with the use of 4'-(bromomethyl)- biphenyl-2 -carboxylic acid methyl ester in a one-step process without isolation of intermediate telmisartan ester, and in WO 2006/044 648 - in a biphasic system in low- boiling solvent in the presence of an inorganic base, with the use of 4'- (bromomethyl)biphenyl-2-carboxylic acid Ci-4-alkyl ester.

A different approach to the synthesis of telmisartan is disclosed in EP-A-I 719 766, wherein the starting bisbenzimidazol derivative is alkylated with 4-halomethyl-halobenzene first, followed by coupling the product of the reaction with 2- carboxyphenylboronic acid ester under the Suzuki conditions, or with the Grignard reagent prepared from 2-halophenylcarboxylic acid ester.

Despite of these improvements, a need to find out alternate methods for telmisartan synthesis still exists.

Disclosure of the invention

The object of the present invention is a new process for the preparation of telmisartan, based on generation of the DMPBB moiety at the final step of the synthesis.

The present invention provides a process for the preparation of telmisartan (1)

comprising:

(i) oxidation of a compound of formula (a)

wherein R2 is a hydrogen atom or a substituent of formula (b) :

in which Ri is a protecting group for the carboxyl function, to an aldehyde of formula (c),

in which R2 is as defined in formula (a), and, optionally,

(ii) in case R2 in the compound (c) thus obtained is a hydrogen atom, JV-alkylation of the compound (c) with a biphenyl derivative of formula (b*),

wherein X is a leaving group, and Ri is as defined hereinbefore, to obtain the compound of formula (c), in which R2 is a substituent of formula (b), and R₁ is a protecting group;

(iii) treatment of the compound (c) with iV-methyl-o-nitroaniline

in a reductive cyclocondensation, to obtain a compound of formula

(d)

in which R₁ is a protecting group, and finally,

(iv) cleavage of the protecting group R₁.

Another aspect of the present invention are new intermediates obtained by the process according to the invention which are the derivatives of 4'-((6-formyl)-4-methyl-2-propyl-lH- benzimidazol-l-yl)methyl)biphenyl-2-carboxylic acid of formula (c*)

wherein R₁ is C₁-C4-alkyl.

Preferably, Ci-C-j-alkyl is methyl or text- butyl. The intermediates of formula (c*) have not been disclosed in the prior art. Detailed description of the invention

The best modes of carrying out the process of the invention are presented in the following Scheme 1 :

SCHEME 1

[0] [O]

Telmisartan

One embodiment of the invention comprises the process for preparation of telmisartan wherein the compound of formula (a),

in which R2 is a hydrogen atom, is oxidized, and thereafter the aldehyde thus obtained

is -ΛT-alkylated with a derivative of biphenyl of formula (b*), in which X is a leaving group, and R₁ is a protecting group, to obtain the aldehyde of formula (c*)

in which R₁ is a protecting group.

The alternative embodiment of the invention comprises the process for preparation of telmisartan wherein a compound of formula (a),

in which R₁ is a hydrogen atom, is at first iV-alkylated with the biphenyl derivative of formula (b^*), in which X is a leaving group, and R₁ is a protecting group, and thereafter the compound thus obtained,

in which R₁ is a protecting group is oxidized, to form the aldehyde of formula (c¹)

in which R₁ is a protecting group.

Generally, oxidation of a hydroxy group in a compound of formula (1) or formula (3) into a formyl group may be carried out by means of chromium(VI) compounds, e.g. pyridinium dichromate (PDC); pyridinium chlorochromate (PCC); sodium hypochlorite in the presence of potassium bromide and the TEMPO catalyst (2,2,6,6-tetramethylpiperidinooxy); dimethylsulfoxide (DMSO) in the presence of an activator (e.g. oxalyl chloride), silver carbonate on Celite^® or activated manganese(IV) oxide; in solvents such as methylene chloride, ethyl acetate, 2-butanone (MEK), acetone, tetrahydrofurane, preferably in tetrahydrofurane or 2-butanone, at temperatures 0-100° C, e.g. at temperatures between room temperature and 35° C.

In the preferred embodiment of the invention, the oxidation of a hydroxy group into a formyl of the compound (4) is carried out in the presence of activated manganese(IV) oxide Mnθ2, in tetrahydrofurane, at room temperature, or in the presence of pyridinium dichromate (PDC) in methylene chloride at room temperature.

A crude oxidation product is used in the next step of the synthesis; optionally the product is purified by crystallization from a solvent or a mixture of solvents such as ethyl acetate, alcohols (e.g. methanol, ethanol, isopropanol), tetrahydrofurane, toluene, cyclohexane, methylcyclohexane.

Selective JV-alkylation of compound of formula (c) is carried out in the presence of inorganic bases such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium hydrogen carbonate, potassium teri- butanolate; or organic bases such as trie thy lamine, tributylamine, N- methylmorpholine, pyridine.

In iV-alkylation reaction, a biphenyl derivative of formula (b⁵) is used as an alkylating agent, wherein carboxyl group is protected with the protecting group commonly known to those skilled in the art (see: Protective Groups in Organic Synthesis, 2^nd ed. Greene, T. W.; Wuts, P. G.; Wiley-Interscience, New York, 1991; Protecting Groups, Kocienski, P.J., Georg Thieme Verlag, Stuttgart, New York, 1994). A suitable protecting group may be an ester group of primary, secondary or tertiary alcohols, as well as allyl, benzyl, 2,2,2-trichlorethyl or 2-(trimethylsilyl)ethyl ester group.

Appropriate leaving groups X in the biphenyl derivative of formula (b⁷) may be a halogen atom, such as iodine, bromine, chlorine or fluorine; alkyl-, alkylaryl- or arylsulfonyl group, such as benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl or alkylsulfonyl, a substituted alkylsulfonyl, naphthylsulfonyl, a substituted phenylsulfonyl, chlorosulfonyl, a substituted naphthylsulfonyl or any other good leaving group known in the art.

In the preferred embodiment of the invention, iV-alkylation reaction is carried out in the biphasic system in the presence of sodium hydroxide and a phase transfer catalysts, such as quaternary ammonium salt or crown ether. Preferably, the reaction is carried out in the presence of tetrabutylammonium bromide or tetrabutylammonium hydrogen sulfate (TBAHS), in a solvent or the solvents mixture, such as methylene chloride, diethyl ether, tetrahydrofurane, dioxane, dimethylsulfoxide, iV,iV-dimethylformamide, preferably in tetrahydrofurane, mostly at temperatures 0-100⁰C, e.g. at temperatures between room temperature and 50⁰C.

A crude product of iV-alkylation is used in the next step of the synthesis without further purification or it is purified by crystallization from a solvent or the solvents mixture, such as ethyl acetate, lower alcohols (e.g. methanol, ethanol, and isopropanol), tetrahydrofurane, toluene, cyclohexane, methylcyclohexane.

Finally, a bisbenzimidazole moiety according to the present invention is generated by the reaction of compound of formula (c), wherein R₁ is a protecting group, with iV-methyl-o-nitroaniline. Presumably mechanism of the reaction proceeds by reductive cyclization of a corresponding imine, which is formed in situ, without the need of isolation of that intermediate product [Yang, D.; Fokas, D. et al Synthesis 2005, 47-56]. The reaction may be carried out by means of metals, such as zinc (Zn), tin (Sn), iron (Fe), etc. under acidic conditions (hydrochloric acid), or by means of tin(II) chloride under acidic conditions (hydrochloric acid), optionally by means of zinc (Zn) under basic conditions (sodium hydroxide) or in the presence of ammonium formate; or by catalytic hydrogenation with hydrogen in the presence of catalysts such as Pd(C), Pt(C) or Ni(Raney); or by the use of hydrazine in the presence of catalysts such as Pd(C), Pt, Ru or Ni(Raney); or by the use of formic acid (HCOOH) or ammonium formate in the presence of Pd(C); or by the use of sulfur compounds such as (e.g.) H2S, NaHS, Na2S, (NH4)2S, sodium dithionite (sodium hydrosulfite, Na2S2θ4), sodium hydroxymethylsulfinate (rongalite, HOCH2SO2Na) and others.

The reaction may be carried out in a non-polar or polar solvent or in a mixtures of solvents such as water, methanol, ethanol, JV,i\T-dimethylformamide, diethyl ether, tetrahydrofurane, ethyl acetate, etc.

Preferably, a compound (1) in a cyclocondensation process is treated with 1,0 to 1,5 molar equivalents of iV-methyl-o- nitroaniline, in the presence of 3 to 5 molar equivalents of sodium dithionite (Na2S2θ4) per molar equivalent of compound (1). The reaction in monitored by thin layer chromatography (TLC). After completion of the reaction the obtained compound (7) may be isolated from the reaction mixture under conditions that limit the possibility of hydrolysis of an ester group. Optionally, compound (7) may be purified by chromatography on silica gel or by crystallization.

Alternatively, the compound (7) may be used in the next step of the synthesis without isolation, wherein the removal of a carboxyl protecting group gives telmisartan.

Protecting groups are cleaved by the methods generally known to those skilled in the art (see: Kocienski, P.J.; Protecting

Groups, Georg Thieme Verlag, Stuttgart, New York, 1994). Alkyl protecting groups are cleaved under mild conditions of basic hydrolysis in mixtures of water and an organic solvent such as dioxane, methanol, ethanol or acetone, solubilizing the outgoing product. Benzyl groups may be cleaved (upon)??? under basic hydrolysis; catalytic hydrogenation in the presence of palladium on charcoal; due to the treatment with saturated HBr in acetic acid, with sodium in liquid ammonia or with liquid hydrogen fluoride.

Starting materials in the process according to the invention are commercially available or may be obtained by the known methods.

2-n-Propyl-4-methyl-6-(2-hydroxyethyl)-lH-benzimidazole, may be prepared, e.g., by an esteryfication of 2-propyl-4- methylbenzimidazol-6-carboxylic acid, followed by a reduction of an ester group to a hydroxy group. The esteryfication reaction is carried out with the use of an appropriate alcohol, in the presence of thionyl chloride or inorganic acid, typically at temperatures O- 100⁰C, e.g. at temperatures between +10⁰C and the boiling point of the reaction mixture. Reduction of an ester group is conveniently performed by means of lithium aluminum hydride (LAH) in solvents such as ethers or alcohols, preferably in tetrahydrofurane or methanol, typically at temperatures 0-100⁰C, e.g. at temperatures between 0⁰C and room temperature. The invention is further illustrated by the following non- limiting examples.

Example 1

Methyl 2-n-propyl-4-methyl- lH-benzimidazol-6-carboxylate

A suspension of 2-n-propyl-4-methylbenzimidazol-6- carboxylic acid hydrochloride monohydrate (120 g, 436 mmol) in methanol (750 mL) was charged into a flask equipped in a reflux condenser and a stirrer and cooled to +10⁰C. Thionyl chloride (35 mL, 482 mmol, 1,1 eq) was added dropwise over 1 h, maintaining temperature below +20°C. The reaction mixture was refluxed for 8h, and allowed to cool overnight (12h). Water 200 mL was added, a solution was neutralized, and then pH was adjusted to ~9, by addition of 10% Na₂CO_{3 aq}. (450 mL). Water (200 mL) and ethyl acetate (250 mL) were added. Phases were separated; an aqueous phase was extracted with ethyl acetate (3*200 mL). Combined organic phases were washed with water (1*200 mL) and brine (1*200 mL) and dried over MgSO4, filtered and concentrated to obtain 114 g of product as an dense oil, which crystallized spontaneously in two days. A crude product was crystallized from ethyl acetate /diisopropyl ether (1: 1). Filtrate was concentrated and crystallized from ethyl acetate/ hexanes (1: 1). There was obtained 95,57 g (yield 94,2%) of the title compound as white crystals. M.p. 137-138°C.

¹H NMR (200 MHz, DMSO) δ (ppm): 7,94 (d, IH, J=I, 1, Ar); 7,61 (dd, IH, J=OJ, J=l,5, Ar); 3,86 (s, 3H, -OCH₃); 2,85 (t, 2H, J=7,5, ArCH₂-); 2,54 (s, 3H, Ar-CH₃); 1,83 (sextet, 2H, J=7,5, -CH₂-); 0,97 (t, 3H, J=7,3, -CH₂-CH₃); Example 2 2-n-propyl-4-methyl-6-(2-hydroxyethyl)-lH-benzimidazol

A flask equipped with a mechanical stirrer, a reflux condenser and pressure-equalizing dropping funnel was charged with LiAim (12,0 g). The reactor- set was washed by nitrogen and

THF (500 mL) was added. A suspension of LiAlH4 was cooled to 0-

+2°C, then, while vigorously stirring, a solution of 2-n-propyl-4- methyl- 1 H- benzimidazol-6-carboxylic acid methyl ester (50,0 g) dissolved in THF (320 mL) was added dropwise over 1 h, maintaining the temperature of the reaction below + 10⁰C. Stirring was continued at room temperature not exceeded +20⁰C (3 h). Into the vigorously stirring reaction mixture water (12 mL), IM NaOHaq (12 mL) and more water (12 mL) were added. Stirred for 1 h, then stirring was stopped, and the reaction mixture was kept overnight.

The precipitated residue was filtered off and washed with THF

(2x 100 mL). The filtrate was concentrated to yield 42,7 g (97,3 %) 2- n-propyl-4-methyl-6-(2-hydroxyethyl)-lH-benzimidazol as a white powder (a solidified foam).

M.p. 122- 123°C

¹H NMR (200 MHz, CDCl₃) δ (ppm): 1 1,96 (s, IH, NH); 7, 19 (s, IH, Ar); 6,86 (s, IH, Ar); 5,05 (bt, IH, OH); 4,52 (d, 2H, J=4,8, Ar-CH₂- OH); 2,76 (t, 2H, J=7,5, Ar-CH₂-); 2,45 (s,- 3H, Ar-CH₃); 1,78 (sx, 2H, J=7,3, -CH₂-); 0,93 (t, 3H, J=7,3, -CH₂-CH₃); i³C NMR (50 MHz, DMSO) δ (ppm): 166,9 (C=O); 157,3 (N-C=N); 141,5; 137,9; 123,9; 122,7; 122,6; 1 13,9; 51,8 (O-CH3); 30,5 (Ar- CH2-); 20,9 (-CH2-); 16,7 (Ar-CH3); 13,7 (CH2-CH3); MS EI [M (m/z, rel. %): 204 (21,8), 189 (17.1), 176 (100), 159 (15,6) Example 3 2-n-Propyl-4-methyl-6-(2-formyl)-lH-bβnzimidazol

To the solution of 2-n-propyl-4-methyl-6-(2-hydroxyethyl)- 1-FJ-benzimidazol in THF (44 g, 50 mL) activated manganese(IV) oxide (118 g, 1,36 mol) was added, and the suspension was vigorously stirred for 1-2 h (TLC monitored), keeping the temperature below 35°C. The precipitate was filtered through a Celite® bad, washed with THF (2x25 mL). Both THF filtrates were combined. The solution of crude product in THF may be used in the next step without isolation thereof, or optionally may be concentrated and purified by crystallization.

M.p. 158-159°C

¹H NMR (200 MHz, CDCl₃), δ (ppm): 12,5 (s, IH, NH); 10,01 (s, IH, CHO); 7,94 (s, IH, Ar); 7,63 (s, IH, Ar); 2,99 (t, 2H, J=7,8, Ar-CH₂- ); 2,61 (s, 3H, Ar-CH₃); 1,92 (sx, 2H, J=7,6, -CH₂-); 0,99 (t, 3H, J=7,3, -CH₂-CH₃); MS EI [M (m/z, rel. %): 202 (14,0), 187 (15,6), 174 (100)

Example 4

Methyl 4^>-((6-formyl-4-methyl-2-n-propyl- 1 Jϊ-benzimidazol- 1 - yl)methyl)biphenyl-2-carboxylate

To a solution of 2-n-propyl-4-methyl-6-(2-formyl)-lH- benzimidazol in THF (50 mL), 4'-(bromomethyl)biphenyl-2- carboxylic acid methyl ester (41,7g, 0, 14 mol) and tetrabutylammonium bromide (4,2 g, 0,013 mol) were added and stirred until the solids were completely dissolved. Then, 30% aqueous solution of sodium hydroxide (26,4 g, 0,2 mol) was added and the reaction mixture was stirred at temperature 50⁰C for 2 h. After the reaction mixture was cooled to room temperature water (300 mL) was added, and subsequently pH was adjusted to 5 by addition of IM hydrochloric acid. The obtained solution was extracted with ethyl acetate (3><200 mL). The combined organic phase were washed with brine (200 mL) and dried over magnesium sulfate, filtrated and concentrated to obtain 60 g of the crude product (yield 82%). Crystallization from an ethyl acetate - cyclohexane mixture gave 46, 1 g (yield 65%) of the title compound, purity 99,1% (HPLC). M.p. 115-116°C

¹H NMR (200 MHz, CDCl₃), δ (ppm): 9,98 (s, IH); 7,84 (dd, IH, J=l,3, J=7,5); 7.62 (d, 2H, J=8, l); 7,56-7,36 (m, 2H); 7,33-7,24 (m, 3H); 7,07 (d, 2H, J=8,l), 5,45 (s, 2H); 3,62 (s, 3H); 2,93 (t, 2H, J=7.5); 2,74 (s, 3H); 1,96-1,77 (m, 2H); 1,04 (s, 3H); 1³C NMR (50 MHz, CDCl₃), δ (ppm): 192,2 168,6; 158,6; 147,0; 141,7; 141,3; 135,2; 134,3; 131,4; 131,1; 130,5; 129,9; 129,8; 129,6; 127,4; 125,8; 124,7; 109,2; 51,0; 47, 1; 29,9; 21,9; 16,7, 14,0

Example 5 tert-Butyl 4^>-((6-(hydroxymethyl)-4-methyl-2-n-propyl- IH- benzimidazol- 1 -yl)methyl)biphenylo-2-carboxylate

To a solution of 2-n-propyl-4-methyl-6-(2-hydroxyethyl)-lH- benzimidazol (1,0 eq, 10 mmol, 2,04 g) in acetonitryle (40 mL), under argon, K2CO3 (dried at 120⁰C, 1,5 eq, 15 mmol, 2,07 g) and tetrabutylammonium hydrogen sulfate (0,2 eq, 2 mmol, 0,68 g) were added. 4'-(Bromomethyl)biphenyl-2-carboxylic acid tert-butyl ester (1,0 eq, 10 mmol, 3,47 g) was added. The reaction mixture was stirred at temperature 55°C over 5h, and was left at room temperature overnight. To the reation mixture water (100 mL) and ethyl acetate (5 ml) were added, and the organic solvents were evaporated. The obtained solution was extracted with ethyl acetate (3*40 mL) and the combined organic phases were dried over MgSθ4, filtrated and contrated to give 4,72 g of the product as a white foam.

The product was purified by chromatography on silica gel, using as eluent CHCI3 with gradually added MeOH (0-1%). Fractions containing the product were evaporated to give 3,46 g of the title compound as a white precipitate (yield 73,5%). M.p. 163-164°C

^IH NMR (200 MHz, CDCl₃), δ (ppm): 7,76 (dd, IH, J=l,8, J=7,3); 7.5-7,3 (m, 2H); 7,3-7,2 (m, 3H); 7,1-7,0 (m, 4H); 5,38 (s, 2H); 4,71 (s, 2H); 2,08 (t, 2H, J=8,2); 2,68 (s, 3H); 2,0-1,7 (bs+m, 3H); 1,00 (s, 9H), 1,02 (t, 3H, J=7,3); MS EI [M (m/z, rel. %): 470 (55,7), 442 (35,7), 386 (41,4), 211 (100)

Methyl 4'-((6-(hydroxymethyl)-4-methyl-2-n-propyl- IH- benzimidazol- 1 -yl)methyl)biphenylo-2-carboxylate Methyl ester (3, Ri=CHs) were prepared in an analogous procedure, wherein 3, 10 g of the product was obtained as a white powder (yield 72,4%). M.p. 172-174°C iH NMR (200 MHz, CDCl₃), δ (ppm): 7,81 (dd, IH, J=l,2, J=7,8); 7.54-7,26 (m, 3H); 7,23-7, 19 (m, 2H); 7,06-7,01 (m, 4H); 5,33 (s, 2H); 4,70 (s, 2H); 3,61 (s, 3H); 2,66 (t, 2H); 2,92 (s, 3H); 2,582 (bs, IH); 1,89-1,70 (m, 2H); 1,00 (s, 3H);

^!3C NMR (50 MHz, CDCl₃), δ (ppm): 168,7; 155,0; 1; 141,8; 141,4; 140,9; 135,5; 135,0; 131,4; 130,6; 130,4; 129,9; 129, 1; 128,9; 127,3; 125,8; 121,9; 105,8; 65,6; 51,9; 46,9; 29,7; 21,9; 16,7, 14,0.

Example 6 tert-Butyl 4'-((6-formyl-4-methyl-2-n-propyl-li7-benzimidazol- l-yl)methyl)biphenyl-2-carboxylate

To the suspension of pyridine chlorodichromate (PDC) (2,32 g, 1,5 eq.) in methylene chloride (25 mL) the solution of 4'- ((6-(hydroxymethyl)-4-methyl-2-n-propyl- lH-benzimidazol- 1-yl)- methyl)biphenylo-2-carboxylic acid tert-butyl ester obtained in the previous example (1,45 g, 1,0 mmol) in methylene chloride (25 mL) was added. The reaction mixture was stirred for 24 h at room temperature. To the reaction solution ethyl acetate (20 mL) was added. The solution was filtrated through a Celite® bad, washed with methylene chloride (50 mL) and ethyl acetate (10 mL). The combined solutions were washed with 10% solution of CuSθ4 (2x40 mL), water (40 mL), IM HClaq (40 L) and once again with water (40 mL), dried over MgSθ4, filtrated and concentrated to obtain 1,37 g (yield 94,5%) of the crude aldehyde (5). Crystallization from isopropanol/ water (1:1) gave 1,02 g of the title compound (yield 70,3%).

¹H NMR (200 MHz, CDCl₃), δ (ppm): 9,97 (s, IH); 7,77 (dd, IH,

J=l,8, J=7,3); 7,61 (s, IH); 7.5-7,3 (m, 3H); 7,3-7,2 (m, 3H); 7,1-7,0

(m, 2H); 5,58 (s, 2H); 2,92 (t, 2H, J=8, l); 2,76 (s, 3H); 2, 10 (m, 2H);

1,20 (s, 9H), 1,07 (t, 3H, J=7,2);

MS EI [M (m/z, rel. %): 468 (14,7), 411 (48,9), 384 (36,35), 211

(100)

Methyl 4'-((6-formyl-4-methyl-2-n-propyl- lH-benzimidazol- 1- yl)methyl)biphenyl-2-carboxylate

Methyl ester of compound (5) was obtained in a analogous procedure of yield 58,3%.

Example 7

Telmisartan methyl ester

To the solution of aldehyde (5) (2 g, 4,7 mmol) in N,N- dimethylformamide (DMF) (40 mL) ΛT-methyl-o-nitroaniline (0,89 g, 5,9 mol) was added and stirred over -0,5 h. The reaction mixture was cooled to +10⁰C and IM aqueous solution of sodium dithionite Na2S2U4 (3,5 g, 20,0 mmol, prepared freshly before the use) was added dropwise, keeping the temperature of the mixture below 15°C. When the addition was complete the reaction mixture was heated at temperature 45°C for 5 h, and stirred for 24 h at room temperature. After the completion of the reaction, 5M aqueous ammonia solution (25 mL) and water (25 mL) were added to the reaction mixture. The formed precipitate was filtrated, washed with water (2x25 mL) and dried to give 1,85 g (yield 74,6 %) of the crude product. The product was purified by maceration in ethyl acetate to obtain 1,7 g of the title compound.

¹H NMR (200 MHz, CDCl₃), δ (ppm): 7,02-7,96 (m, 14H, aromatic); 5,39 (s, 2H, N-CH₂-Ph) 3,69 (s, 3H, CH₃-N benzimidazole); 3,54 (s, 3H, OCH₃); 2,86-3,0 (t, 2H, CH₂-CH₂-CH₃); 2,77 (s, 3H, CH₃-Ph benzimidazole); 1,76-2,0 (m, 2H, CH₂-CH₂-CH₃); 0,98-1,12 (t, 3H, CH₂-CH₂-CH₃);

¹³C NMR (135 MHz, CDCl₃), δ (ppm): 168,39; 156,19; 154,37; 142,92; 142,65; 141,44; 140,82; 136,43; 134,76; 134,56; 131,12; 130,42; 130,30; 129,65; 129, 17; 128,72; 127, 13; 125,70; 123,58; 122,20; 122,01; 119, 19; 109,31; 108,65; 51,61; 46,79; 31,50; 29,58; 21,57; 16,55; 13,86.

Example 8

Telmisartan tert-butyl ester

To the solution of tert-butyl 4'-((6-formyl-4-methyl-2-n- propyl- Jff-benzimidazol- 1 -yl) methyl) biphenyl-2-carboxylate ( 150 mg, 0,32 mmol) in ethanol (9 mL), iV-methyl-o-nitroaniline (48 mg, 0,32 mmol) was added and stirred over -0,5 h. IM aqueous solution of sodium dithionite Na2S2θ4 (1 mL, 3,0 eq., prepared freshly before the use) was added. The mixture was stirred at temperature 50⁰C for 2 h and kept overnight (ok. 16 h). An additional amount of N- methyl- o-nitroaniline (20 mg) and IM aqueous solution of sodium dithionite Na2S2U4 (0,5 mL) were added and stirred at temperature 50⁰C for 4 h.

To the cooled reaction mixture IM HCl (5 mL) and water (20 mL) were added. The mixture was extracted with CH2CI2 (4x 10 mL). The combined organic phases were washed with IM HCl (15 mL) and water (15 mL) and dried over MgSO4. The solution was filtered and concentrated to give 223 mg compounds as an intensively yellow film.

The film was purified by chromatography on silica gel, using as eluent CHCI3 with gradually added MeOH (0-3%). There was obtained 117 mg (yield 64,0 %) of telmisartan tert- butyl ester as colorless film.

Example 9 Telmisartan

To telmisartan methyl ester (6,5 g, 12,4 mmol) methanol (180 mL) was added and 3,4M aqueous solution of NaOH (37,0 mL) was added. The mixture was stirred at reflux over 3 h. The reaction progress was controlled by TLC (chloroform/ methanol 10:0,8; telmisartan methyl ester Rf=0,73; telmisartan Rf =0,46). When the substrate disappeared the solution was cooled and methanol was evaporated. Distilled water (ca. 70 mL) was added and pH was adjusted to 4,5-5 by addition of 10% aqueous solution of hydrochloric acid. The formed, light-cream precipitate was filtrated, washed with water and dried to obtain 6.3 g of a crude telmisartan of purity ca. 96% (HPLC).

The crude telmisartan was crystallized twice from N, N- dimethylformamide (DMF), dried first under normal pressure, then in a vacuum drier (50 °C; 0, 1 MPa) to obtain white solid of the purity 99,86 % (HPLC).

¹H NMR (200 MHz, CDCl₃), δ (ppm): 6,94-8,44 (m, 14H, aromatic);

5,39 (s, 2H, N-CH₂-Ph) 3,72 (s, 3H, CH₃-N benzimidazole); 3,02- 3,20 (t, 2H, CH₂-CH₂-CH₃); 2,69 (s, 3H, CH₃-Ph benzimidazole);

1,86-2,20 (m, 2H, CH₂-CH₂-CH₃); 1,06-1,22 (t, 3H, CH₂-CH₂-CH₃);

¹³C NMR (135 MHz, CDCl₃), δ (ppm): 171,11; 156,47; 153,96;

149,49; 142,70; 141,69; 141,03; 135,52; 134,50; 133,89; 133,69;

130,39; 130, 18; 129,30; 128,89; 128,78; 127,37; 127,05; 123,53; 123,09; 121,79; 119,69; 111,201; 109,36; 48,69; 31,74; 29,97;

22,36; 16,92; 14,09

Claims

1. A process for the preparation of telmisartan

comprising: (i) oxidation of a compound of formula (a)

wherein R2 is a hydrogen atom or a substituent of formula (b):

in which R₁ is a protecting group for the carboxyl function, to an aldehyde of formula (c),

in which R2 is as defined in formula (a), and, optionally,

(ii) in case R2 in the compound (c) thus obtained is a hydrogen atom, iV-alkylation of the compound (c) with a biphenyl derivative of formula (b¹),

wherein

X is a leaving group, and R₁ is as defined hereinbefore, to obtain the compound of formula (c), in which R2 is a substituent of formula (b), and R₁ is a protecting group;

(iii) treatment of the compound (c) with iV-methyl-o-nitroaniline

in a reductive cyclocondensation, to obtain a compound of formula (d)

in which R₁ is a protecting group, and finally,

(iv) cleavage of the protecting group R₁.

2. The process according to claim 1, wherein at first the compound (a), in which R2 is a hydrogen atom, is oxidized, and thereafter the obtained compound

is iV-alkylated with a biphenyl derivative of formula (b⁵), wherein X is a leaving group, and R₁ is a protecting group, to form aldehyde of formula (c")

in which R₁ is a protecting group.

The process according to claim 1, wherein the oxidation reaction is carried out with the use of activated manganese(IV) oxide.

The process according to claim 1, wherein at first the compound (a), in which R₁ is a hydrogen atom, is N- alkylated with a biphenyl derivative of formula (b*), wherein X is a leaving group, and Ri is a protecting group, and thereafter the obtained compound

in which Ri is a group of formula (b), is oxidized to obtain the aldehyde of formula (c^*)

in which Ri is a protecting group.

5. The process according to claim 4, wherein the oxidation reaction is carried out with the use of activated manganese(IV) oxide or pyridine chlorodichromate.

6. The process according to any of claims 1-5, wherein an alkylating agent in the iV-alkylation reaction is a biphenyl derivate of formula (b^*)

in which X is a leaving group, and R₁ is C₁-C4-alkyl.

7. The process according to claim 6, wherein an alkylating agent in the iV-alkylation reaction is a biphenyl derivate of formula {b), in which X is a halogen atom or an alkyl-, alkylaryl- or aryl-sulfonyl group, and R₁ is C₁-C4-alkyl.

8. The process according to claim 7, wherein an alkylating agent in the N-alkylation reaction is a biphenyl derivate of formula (b⁵), in which X is a bromine atom, and R₁ is Ci-C4-alkyl.

9. The process according to claim 1, wherein the iV-alkylation reaction in carried out in a biphasic system in the presence of a phase transfer catalyst.

10. The process of claim 8, wherein the phase transfer catalyst is a tertiary ammonium salt.

1 1. The process according to claim 9, wherein the phase transfer catalyst is tetrabutylammonium hydrogen sulfate.

12. The process according to claim 1, wherein the cyclocondensation of aldehyde of formula (c) with JV-methyl- o-nitroaniline is carried out in the presence of sodium dithionite.

13. The process according to claim 12, wherein sodium dithionite is used in proportion of 3 to 5 molar equivalents per molar equivalent of aldehyde of formula (c) .

14. The process according to claim 12, wherein the cyclocondensation reaction of compound (c) is carried out with the use of from 1 to 1,5 molar equivalents of N-methyl- o-nitroaniline per molar equivalent of aldehyde of formula (c).

15. The compound 4'-((6-formyl)-4-methyl-2-propyl-lH- benzimidazol-l-yl)methyl)biphenyl-2-carboxylic acid of formula (c⁵)

wherein R₁ is

16. The compound according to claim 15, wherein R₁ is methyl. 17. The compound according to claim 15, wherein R₁ is terf-butyl.