WO2007048361A1

WO2007048361A1 - A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs

Info

Publication number: WO2007048361A1
Application number: PCT/CZ2006/000073
Authority: WO
Inventors: Stanislav Radl; Jan Stach
Original assignee: Zentiva KS
Current assignee: Zentiva KS
Priority date: 2005-10-27
Filing date: 2006-10-25
Publication date: 2007-05-03
Anticipated expiration: 2008-04-27
Also published as: CZ2005679A3; CZ299902B6

Abstract

A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs of general formula I, wherein R is a metabolically degradable group, B is a heterocyclic moiety with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms, in which the compound of formula I is reacted with water in the presence of a solvent which is partially or completely miscible with water.

Description

A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs

Technical Field

The invention concerns an improved method of removing the triphenyhnethane protecting group from precursors of antihypertensive drugs of general formula I

containing a labile, metabolically degradable group.

The removal of the triphenylmethane protecting group leads to the formation of a precursor of the antihypertensive drug of general formula II

These substances belong to the group of angiotensin II antagonists, which are used therapeutically as cardiovascular system drugs, mainly for the control of high blood pressure. This group includes important drugs, such as losartan (Cozaar^R), irbesartan (Avapro^R), or valsartan (Diovan^R). Unlike these angiotensin receptor antagonists, the substances according to the invention are biologically inactive; the active substance is formed first by the metabolic degradation of group R. These precursors have better bioavailability and are used therapeutically instead of the active substance itself. In the aforementioned general formulae, B represents a heterocyclic unit with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms, and R is a metabolically degradable group.

The method consists in the reaction of the substance of formula I with water in the presence of an organic solvent which is completely, or at least partially, miscible with water, leading to the formation of the substance of formula II.

For R, usually such substituents are selected that contain in their structures acetals of C₂ to C₈ aliphatic or aromatic aldehydes, ketals of C₃ to C₁₀ aliphatic or aromatic ketones, esters of carbonic acid with Ci to Cio aliphatic alcohols, or cyclic 5-, 6-, or 7-membered esters of carbonic acid.

The representatives of such tritylated precursors of antihypertensive drugs include for example 5 -methyl-2-oxo- 1 , 3 -dioxol-4-ylmethyl-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 - [2 ' - (iV-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate (trityl olmesartan medoxomil) of formula III

or l-(cyclohexyloxycarbonyloxy)ethyl-ethoxy-l-[[2'-(N-triphenyhnethyltetrazol-5- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (trityl candesartan cilexetil) of formula IV

(IV)

By removing the trityl protecting group, the corresponding prodrugs olmesartan medoxomil of formula V

and candesartan cilexetil of formula VI

are obtained from these precursors.

These precursors then, in the organism, release the actual active substances olmesartan of formula VII

and candesartan of formula VIII

This approach has the disadvantage that for achieving the desired effect both olmesartan medoxomil and candesartan cilexetil contain the labile ester function which is partially hydrolyzed or reesterified even during the detritylation of the corresponding intermediates trityl olmesartan medoxomil and trityl candesartan cilexetil.

Background Art

The removal of the triphenylmethane protecting group from substituted tetrazoles is usually carried out by the action of a mineral acid in a suitable solvent, for example dioxane (US patent 5,399,578). However, this method is suitable only for substances not containing in their molecules other groups sensitive to acids, which is the case of the above-mentioned compounds. Another method is based on the methano lysis of the triphenylmethane protecting group, where methyltriphenyl ether and free tetrazole are formed during the boil (WO 2005/021535).

Detritylation of trityl olmesartan medoxomil of formula III leading to the formation of olmesartan medoxomil of formula V is described in EP patent 0 503 785, where the substance reacts in the mixture of acetic acid with water.

The method is demanding especially because of time-consuming removing water and acetic acid in the form of an azeotrope with toluene. This results in hydrolysis of the ester function and in formation of olmesartan of formula VII itself, which is, however, in fact, an undesirable impurity. AcOH/water

Detritylation of trityl candesartan cilexetil of formula IV leading to the formation of candesartan cilexetil of formula VI is carried out according to published patents (US patents 5,196,444 and 5,763,619) as follows:

The starting trityl candesartan cilexetil of formula IV, whose synthesis is described in the original patent (US patent 5,196,444) and which is currently already commercially available, is, in methanol using hydrochloric acid, converted into candesartan cilexetil of formula VI. The method described in the original patent (US patent 5,196,444) has a very low yield and the product has to be purified chromato graphically. The Takeda company has improved this key step by using anhydrous hydrogen chloride in methanol (US patent 5,763,619), wherein the amount of decomposition products is lower and the yield is higher. Disadvantages of the aforementioned methods include a high content of impurities associated with the decomposition of the ester function, the use of strongly corrosive acids, and also the need to process the reaction mixture using complicated extractions. Such a production is then not economical.

Application WO 2005/021535 presents a possibility to carry out the detritylation by boiling in methanol. Although the product obtained in this way is purer than when acids are used, methanol also partially decomposes the ester function, leading to the formation of the methyl ester of candesartan. Disclosure of Invention

The subject-matter of the invention consists in an improved method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs having a labile, metabolically degradable group.

The essence of the invention consists in the surprising finding that the removal of the triphenylmethane protecting group from the aforementioned substances can be carried out using only water in a suitable solvent without using acids, which results in a significantly lower decomposition of the ester functions of these substances.

The method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs of general formula I

wherein R is a metabolically degradable group, B is a heterocyclic moiety with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms, according to the invention, comprises reacting the compound of formula I with water in the presence of a solvent which is partially or completely miscible with water.

The reaction is advantageously carried out at a temperature of 30 to 100 °C for 1 to 48 hours, preferably 5 to 20 hours.

In the case of detritylation of trityl olmesartan medoxomil of formula III and trityl candesartan cilexetil of formula IV the reaction can be carried out using water in solvents which are miscible with water. The reaction proceeds faster in dipolar aprotic solvents such as dimethylsulfoxide, dimethylformamide, acetonitrile, or acetone. It proceeds very slowly for example in tetrahydrofuran and dioxane. The reaction is carried out preferably at the boil of the mixture of solvents. The amount of water is usually one to five fold with respect to the weight of the starting substance.

When detritylating trityl olmesartan medoxomil of formula III, the amount of the impurity of formula VII, formed by the hydrolysis of the ester function, is significantly reduced against the method of EP patent 0 503 785 (Table 1).

Table 1:

After the reaction is completed, the resulting trityl alcohol of formula IX

is removed by filtration after the solution is cooled down, or it is removed by subsequent crystallization from a solvent in which olmesartan medoxomil of formula V is insoluble and trityl alcohol of formula IX soluble; the solvent is advantageously selected from a group of polar aprotic solvents or a mixture of polar and nonpolar aprotic solvents.

Polar aprotic solvents are advantageously selected from a group comprising C₃ to C₅ ketones, preferably acetone or ethyl methyl ketone, acetonitrile, and C₁ to C₄ acetates, preferably ethyl or isopropyl acetate.

Nonpolar aprotic solvents that can advantageously be used include C₅ to C₈ aromatic or cyclic compounds, both carbocyclic and heterocyclic, preferably toluene, cyclohexane or tetrahydrofuran. When detritylating trityl candesartan cilexetil of formula IV, the resulting trityl alcohol of formula IX is removed by crystallization from a solvent, or a mixture of solvents, in which candesartan cilexetil of formula IV is insoluble, whereas the trityl alcohol soluble. Alternatively, trityl alcohol of formula IX is removed by stirring with solvents or their mixtures in which candesartan cilexetil of formula IV is insoluble, whereas the trityl alcohol soluble, at a temperature of 5 to 50 ⁰C, preferably at 15 to 30 ⁰C.

Especially suitable mixed solvents are mixtures of solvents in which candesartan cilexetil dissolves easily with solvents in which this substance dissolves only partially. Suitable solvents in which candesartan cilexetil dissolves easily include C₁-C₄ alcohols, preferably methanol, ethanol or 2-propanol, C₁-C₂ halogenated solvents, preferably dichloromethane or chloroform, C₁-C₄ aliphatic ketones, preferably acetone or 2-butanone, dialkyl ethers with Ci- C₄ alkyls, preferably diisopropyl ether and methyl t-butyl ether, and esters OfCi-C₅ carboxylic acids with Ci-C₄ aliphatic alcohols, preferably methyl acetate, ethyl acetate, isopropyl acetate or ethyl propionate. Suitable solvents in which candesartan cilexetil dissolves only partially include cycloalkanes, for example cyclohexane, C₅-C₈ aliphatic hydrocarbons, for example pentane, hexane, heptane or isooctane.

Trityl alcohol of formula IX can advantageously be removed from the crude product by crystallization or stirring out of cyclohexane or toluene.

The invention is further demonstrated in the following examples. The examples, which illustrate the improvement of the method according to the invention, are of an illustrative nature only and do not limit the extent of the invention in any respect.

Examples

Starting trityl olmesartan medoxomil (III) was prepared according to the following Scheme 1. Scheme 1:

Example 1

Ethyl 4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 - { 4- [2-(tetrazol-5-yi)phenyl]phenyl}methyl- imidazole-5-carboxylate (3)

Acetone (200 ml) was added to the weighed ethyl ester of 4-(l -hydroxy- l-methylethyl)-2- propyl-lH-imidazole-5-carboxylic acid (1; 20 g), substance 2 (46.4 g), potash (40 g), and polyethylene glycol 400 (2 g). The resulting mixture was heated to the boil for H h. After filtering off the solids the filtrate was concentrated, ethanol (350 ml) was added to the concentrated filtrate, and the suspension was heated to the boil. After it was cooled to 15 °C (20 minutes), the insoluble portion was sucked off and washed with ethanol (40 ml). After drying (50 ⁰C, in vacuo), 50.7 g of the product (85 %) was obtained. Example 2

Potassium salt of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-{4-[2-(tetrazol-5- yl)phenyl]phenyl}methylimidazole-5-carboxylic acid (4)

Ethyl ester 3 (20 g) was dissolved in THF (80 ml) at 50 ⁰C (60 minutes). After cooling to 25 ⁰C, a 40% solution of KOH (10 ml) was added, and the mixture was stirred vigorously for 24 h. After adding ethyl acetate (10 ml), the solution cleared up (neutralization). After concentrating to ca. 40 ml in vacuo, the mixture was diluted with ethyl acetate (100 ml), and solid NaCl (20 g) was added. After separating the phases, the organic layer was filtered and concentrated to ca. 30 ml in vacuo. Methyl ethyl ketone (50 ml) was added to this solution, the mixture was concentrated to 30 ml in vacuo for the subsequent reaction.

Example 3

Trityl olmesartan medoxomil (III)

A solution of potassium salt 4 in methyl ethyl ketone from the preceding experiment (ca. 20 g of the salt) was diluted with methyl ethyl ketone (290 ml), and, after adding potassium iodide (2 g) and 4-chloromethyl-5-methyl-l,3-dioxol-2-one (7 g), the mixture was stirred at 50 ⁰C for 7.5 h. After the reaction was completed, the mixture was filtered, and the filtrate was washed with methyl ethyl ketone (3 x 50 ml). After concentrating to ca. 160 ml in vacuo, ethanol (250 ml) was added, and the reaction mixture was again concentrated to ca. 300 ml in vacuo.

The concentrated product in ethanol was inoculated and stirred at 50 ⁰C for 0.5 h, and after getting thicker, diluted with ethanol (50 ml) and cooled to 20 °C. The precipitated product was sucked off, washed with ethanol (2 x 20 ml) and dried in a vacuum drier at 50 °C. 14.4 g (86 %) of the product was obtained. Example 4

Olmesartan medoxomil (V)

The starting substance (III; 10 g) was dissolved in acetone (50 ml), and, after adding water (25 g), the mixture was heated to a mild boil for 14 h. After evaporating acetone and adding ethyl acetate (50 ml), water was separated, and the organic layer was again washed with water (10 ml). The extract was concentrated and evaporated with toluene (50 ml) once more, the residue was dissolved in ethyl acetate (20 ml) and toluene (20 ml). The mixture was concentrated to 25 ml and allowed to crystallize under stirring for 30 min; after cooling to 15 °C, the insoluble portion was sucked off and washed with ethyl acetate. 6.5 g of the product was obtained, which, after recrystallization from ethanol, gave 6 g (86 %) of the product with an HPLC purity of 98.7 %.

By further recrystallization from ethyl acetate and cyclohexane, 5.1 g of a sample with an HPLC purity of 99.6 % was obtained. ¹H NMR (250 MHz, CDCl₃) δ: 0.82 (3H, t, J = 7.5 Hz); 1.50 (6H, s); 1.54-1.63 (2H, m); 2.07 (3H, s); 2.48 (2H, t, J = 7.5 Hz); 4.86 (2H, s); 5.32 (2H, s); 6.70 (2H, d, J = 8 Hz); 6.99 (2H, d, J = 8 Hz); 7.3-7.5 (3H, m); 7.72 (IH, dd, J = 1.7 Hz).

Example 5

Olmesartan medoxomil (V)

Water (10 g) was added to a solution of the starting substance (III; 20 g) in acetonitrile (50 ml), and the mixture was heated to a mild boil for 14 h. Acetonitrile was evaporated, and, after dissolving in acetone (150 ml), the mixture was filtered through alumina and concentrated. After crystallization from the mixture tetrahydrofuran / ethyl acetate H g (78 %) of the product with an HPLC purity of 97.0 % was obtained. Recrystallization from methanol and water gave 1O g of the product with an HPLC purity of 99.3 %; m.p. 175- 177 ⁰C. Example 6

Olmesartan medoxomil (V)

Water (10 g) was added to a solution of the starting substance (III; 10 g) in acetonitrile (50 ml), and the mixture was heated to a mild boil for 14 h. Acetonitrile was evaporated, and, after dissolving in acetone (150 ml), the mixture was filtered through silica gel and concentrated. After crystallization from acetonitrile, 4 g (57 %) of the product was obtained. After recrystallization from the mixture methyl tert-butyl ether / ethyl acetate, 3.4 g of the product with an HPLC purity of 99.4 % was obtained; m.p. 175-177 °C.

Example 7

Olmesartan medoxomil (V)

Water (20 g) was added to a solution of the starting substance (III; 20 g) in acetonitrile (100 ml), and the mixture was heated to a mild boil for 14 h. After cooling, the formed trityl alcohol was sucked off, and the mixture was concentrated. After crystallization from isopropyl acetate, 10 g (71 %) of the product with an HPLC purity of 97 % was obtained. The HPLC purity of the product recrystallized from isopropanol was 99.5 %.

Example 8

Olmesartan medoxomil (V)

Water (10 g) was added to a solution of the starting substance (III; 20 g) in acetone (50 ml), and the mixture was heated to a mild boil for 14 h. After the reaction was completed, the mixture was cooled to 0 ⁰C, and the formed trityl alcohol was sucked off. After concentration, a crude product was obtained, which was extracted with ethyl acetate (70 ml). After evaporating the extract and crystallizing from acetone, 10.6 g (76 %) of the product with an HPLC purity of 97.0 % was obtained. Recrystallization from ethyl methyl ketone gave 10.2 g (73 %) of the product with an HPLC purity of 99.3 %; m.p. 175-177 °C. Example 9

Candesartan cilexetil (VI)

A mixture of trityl candesartan cilexetil (IV; 2 g), acetonitrile (20 ml), and water (5 ml) was refluxed for 9 h. Then, 15 ml was distilled off from the reaction mixture over 1 h, the concentration residue was cooled, and toluene (15 ml) was added. The lower layer was separated, the upper organic layer was concentrated by evaporating 12 ml of the solvent, and the mixture was cooled and allowed to stand in a refrigerator overnight. The precipitated portion was sucked off and dried in vacuo at 40 ⁰C. 1.4 g of a white substance with an HPLC purity of 98.2 % was obtained. After crystallization from toluene a product was obtained having the meting point of 160-163 °C (decomp.) and HPLC purity of 99.2 %. ¹H NMR (250 MHz, CDCl₃) δ: 1.13-1.50 (12H, m); 1.64 (2H, m); 1.79 (2H, m); 4.10-4.50 (3H, m); 5.62 (2H, d); 6.65-6.93 (7H, m); 7.27-7.28 (IH, m); 7.46-7.48 (IH, m); 7.56-7.59 (2H, m); 7.98- 8.02 (IH, m).

Example 10

Candesartan cilexetil (VI)

A mixture of trityl candesartan cilexetil (IV; 2 g), acetonitrile (20 ml), and water (5 ml) was refluxed for 9 h. Then, 10 ml was distilled off from the reaction mixture over 1 h, the concentration residue was cooled, and ethyl acetate (10 ml) was added. 25 ml of the solvent was distilled off from the mixture, the same amount of ethyl acetate was added, and the mixture was cooled. The lower layer was separated, the upper organic layer was evaporated, the evaporation residue was dissolved hot in toluene (9 ml), and the solution was cooled and allowed to stand in a refrigerator overnight. The precipitated portion was sucked off and dried in vacuo at 40 ⁰C. 1.5 g of a white substance with an HPLC purity of 98.7 % was obtained. After crystallization from toluene a product was obtained having the meting point of 161- 163 ⁰C (decomp.) and HPLC purity of 99.0 %. Example 11

Candesartan cilexetil (VI)

A mixture of trityl candesartan cilexetil (IV; 2 g), acetonitrile (25 ml), and water (5 ml) was refluxed for 1O h. The reaction mixture was evaporated in vacuo, and the evaporation residue was dissolved hot in toluene (35 ml). The excluded water layer was separated, and the organic layer was concentrated to 15 ml at a normal pressure. The mixture was cooled and allowed to stand in a refrigerator overnight. The precipitated portion was sucked off and dried at 40 ⁰C in vacuo. 1.4 g of a white substance with an HPLC purity of 98.5 % was obtained. After crystallization from cyclohexane a product was obtained having the meting point of 160- 163 °C (decomp.) and HPLC purity of 99.4 %.

Example 12

Candesartan cilexetil (VI)

A mixture of trityl candesartan cilexetil (IV; 2 g), acetonitrile (20 ml), and water (2 ml) was refluxed for 15 h. The reaction mixture was evaporated in vacuo, and the evaporation residue was dissolved hot in toluene (35 ml). The excluded water layer was separated, and the organic layer was concentrated to 15 ml at a normal pressure. The mixture was cooled and allowed to stand in a refrigerator overnight. The precipitated portion was sucked off and dried at 40 °C in vacuo. 1.5 g of a white substance with an HPLC purity of 98.2 % was obtained. After crystallization from the mixture toluene/cyclohexane a product was obtained having the meting point of 160-163 °C (decomp.) and HPLC purity of 99.4 %.

Example 13

Candesartan cilexetil (VI)

A mixture of trityl candesartan cilexetil (IV; 1 g), acetone (35 ml), and water (10 ml) was refluxed for 48 h. The reaction mixture was evaporated in vacuo, the evaporation residue was dissolved hot in toluene (20 ml), and 10 ml of an azeotropic mixture toluene/water was distilled off from the mixture. This process was repeated three times, and, after the last distillation, the resulting concentrated solution was cooled and allowed to stand in a refrigerator overnight. The precipitated portion was sucked off and dried at 40 °C in vacuo. 0.65 g of a white substance with an HPLC purity of 97.2 % was obtained. After crystallization from the mixture toluene/ethanol a product was obtained having the meting point of 160- 163 ⁰C (decomp.) and HPLC purity of 99.6 %.

Example 14

Candesartan cilexetil (VI)

A mixture of trityl candesartan cilexetil (IV; 5 g), acetonitrile (50 ml), and water (12.5 ml) was refluxed for 6 h. Then, 35 ml was distilled off from the reaction mixture over 2.5 h, the concentration residue was cooled, and toluene (35 ml) was added. The lower layer was separated, the upper organic layer was concentrated by evaporating 30 ml of the solvent, and the mixture was cooled and allowed to stand in a refrigerator overnight. The precipitated portion was sucked off and dried at 40 °C in vacuo. 3.1 g of a white substance with an HPLC purity of 98.2 % was obtained. The crystals were boiled with toluene (30 ml) for 30 minutes and then stirred at room temperature overnight. A product was obtained having the meting point of 161-163 ⁰C (decomp.) and HPLC purity of 99.5 %.

Example 15

Candesartan cilexetil (VI)

The crystals obtained by the method described in Example 14 were stirred with acetonitrile (15 ml) at room temperature for 4 hours. A product having HPLC purity of 99.3 % was obtained. Example 16

Candesartan cilexetil (VI)

The crystals obtained by the method described in Example 14 were purified by crystallization from acetonitrile (15 ml) and then by stirring at room temperature for 4 hours. A product having HPLC purity of 99.7 % was obtained.

Example 17

Candesartan cilexetil (VI)

The crystals obtained by the method described in Example 14 were purified by crystallization from the mixture toluene/2-methoxyethane and then by stirring at 10 ⁰C for 6 hours. A product having HPLC purity of 99.4 % was obtained.

Claims

C L A I M S

1. A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs of general formula I

wherein R is a metabolically degradable group, B is a heterocyclic moiety with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms, characterized in reacting the compound of formula I with water in the presence of a solvent which is partially or completely miscible with water.

2. The method according to claim 1, characterized in that the reaction is carried out at a temperature of 30 to 100 ⁰C for 1 to 48 hours.

3. The method according to claim 1 or 2, characterized in that the reaction is carried out at the boiling point of the mixture for 5 to 20 hours.

4. The method according to any of the preceding claims, characterized in that a dipolar aprotic solvent miscible with water is used.

5. The method according to claim 4, characterized in that acetonitrile or acetone is used for the reaction.

6. The method according to any of claims 1 to 5, characterized in that 5-methyl-2-oxo-l,3- dioxol-4-ylmethyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[2'-(iV-triphenylmethyltetrazol-5- yl)biphenyl-4-yl-methyl]imidazole-5-carboxylate of formula III

is used as the compound of formula I, leading to the formation of olmesartan medoxomil of formula V

and trityl alcohol of formula IX

and, after processing, the product is obtained by crystallization from a solvent or a mixture of solvents.

7. The method according to claim 6, characterized in that trityl alcohol of formula IX is removed by crystallization from a solvent in which olmesartan medoxomil of formula V is insoluble, whereas trityl alcohol soluble, the solvent being selected from the group of polar aprotic solvents or mixtures of polar and nonpolar aprotic solvents.

S. The method according to claim 7, characterized in that the polar aprotic solvents are selected from the group comprising C₃ to C₅ ketones, preferably acetone or ethyl methyl ketone, acetonitrile, and Cj to C₄ acetates, preferably ethyl or isopropyl acetate.

9. The method according to claim 7 or 8, characterized in that the nonpolar aprotic solvents are selected from C₅ to C₈ aromatic or cyclic compounds, preferably toluene, cyclohexane or tetrahydrofuran.

10. The method according to claim 6, characterized in that trityl alcohol of formula IX is removed by crystallization from a C₁ to C₅ alcohol, preferably ethanol or isopropanol.

11. The method according to any of claims 1 to 5, characterized in that 1- (cyclohexyloxycarbonyloxy)ethyl-ethoxy-l-[[2'-(iV-triphenylmethyltetrazol-5-yl)biphenyl-4- yl]methyl]benzimidazole-7-carboxylate of formula IV

is used as the compound of formula I, leading to the formation of candesartan cilexetil of formula VI

and trityl alcohol of formula IX

and, after processing, the product is obtained by crystallization from a suitable solvent or a mixture of solvents, or by stirring with a solvent or a mixture of solvents.

12. The method according to claim 9, characterized in that trityl alcohol of formula IX is removed by crystallization from a solvent, or a mixture of solvents, in which candesartan cilexetil of formula IV is insoluble, whereas the trityl alcohol soluble.

13. The method according to claim 11, characterized in that trityl alcohol of formula IX is removed by stirring with solvents or their mixtures in which candesartan cilexetil of formula IV is insoluble, whereas the trityl alcohol soluble, at a temperature of 5 to 50 ⁰C, preferably at 15 to 30 °C.

14. The method according to claim 12 or 13, characterized in that, for the crystallization or stirring, at least one solvent is used from the group comprising: aromatic hydrocarbons, preferably toluene, cyclic aliphatic hydrocarbons, particularly cyclohexane, C₅ to C₈ aliphatic hydrocarbons, for example pentane, hexane, heptane or isooctane, monohydric or polyhydric C₁ to C₄ alcohols, preferably methanol, ethanol, 2-propanol, 2-methoxyethane or ethylene glycol, C₁ to C₂ halogenated solvents, preferably dichloromethane or chloroform, C₁ to C₄ ketones, preferably acetone or ethyl methyl ketone, dialkyl ethers with Ci-C₄ alkyls, preferably diisopropyl ether or methyl t-butyl ether, nitriles of Ci to C₅ carboxylic acids, preferably acetonitrile, and esters of Ci to C₅ carboxylic acids with Ci to C₄ alcohols, preferably methyl acetate, ethyl acetate or isopropyl acetate.