WO2010149360A1

WO2010149360A1 - Process for the preparation of benzimidazoles

Info

Publication number: WO2010149360A1
Application number: PCT/EP2010/003788
Authority: WO
Inventors: Paul Hanselmann; Heilam Wong; Ellen Klegraf; Florencio ZARAGOZA DÖRWALD; Zunliang Ding; Jun Long
Original assignee: Lonza Ltd
Priority date: 2009-06-26
Filing date: 2010-06-24
Publication date: 2010-12-29

Abstract

Substituted benzimidazoles of formula (I), wherein R¹ and R² independently are hydrogen, C_1-6 alkyl or C_3-6 cycloalkyl and R³ is cyano or carboxy, are prepared in a multistep synthesis starting from Ν-acyl-4-halo- anilines of formula (II), wherein R¹ and R² are as defined above and X is chlorine or bromine.

Description

Process for the preparation of benzimidazoles

The invention relates to a process for the production of substituted benzimidazoles of formula

R³ = CN (Ia) R³ = COOH (Ib)

wherein R¹ is hydrogen, C-i-β alkyl or C3-6 cycloalkyl, R² is C1-6 alkyl or C3-6 cycloalkyl and R³ is cyano (Ia) or carboxy (Ib). It further relates to novel intermediates in the pro- cess of the invention.

Herein the term "Ci_-/ralkyl", e.g. "Ci-β-alkyl", represents any linear or branched alkyl group having 1 to n carbon atoms. Ci-6-alkyl represents for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, /e/t-butyl, and the various isomeric pentyls and hexyls. The term "C3-6 cycloalkyl" represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The benzimidazoles of formula I may also exist in the tautomeric form depicted below:

All structural formulae herein are intended to include both tautomeric forms.

Benzimidazoles of formula I are useful as intermediates in the synthesis of pharmaceutically active compounds. In particular, ^methyl^-propylbenzimidazole-θ-carbox- ylic acid (R¹ = methyl, R² = propyl, R³ = carboxy) is a key intermediate in the industrial synthesis of telmisartan, an angiotensin Il receptor antagonist used in the therapy of hypertension.

Several processes for the preparation of benzimidazoles of formula I or related compounds are known in the art. Typically used processes comprise the preparation of nitro-acylaminobenzoates and their ring closure to obtain the corresponding benzimidazoles. From early patents such as US 4 880 804, US 5 591 762 and DE-A 199 17 524 up to more recently published patent applications such as WO-A 2006/044754 the known processes to prepare benzimidazole intermediates for the preparation of telmisartan and derivatives thereof have not been substantially changed. Similar strategies can be found in scientific literature, such as Ries, UJ. et al., J. Med. Chem. 1993, 36, 4040-4051 , or Teramoto, S. et al., J. Med. Chem. 2003, 46, 3033-3044. Although most of their steps are high-yielding, the syntheses known in the art are lengthy and difficult to perform on a large scale. Thus, a shorter synthesis to provide the intermediate of formula I was desired. Furthermore, common syntheses comprise two nitration and two nitro group reduction steps, which are difficult to conduct safely.

It was an object of the instant invention to provide a shorter, cheaper, more efficient and environmentally sound process that is suitable for large scale production of compounds of formula I, for the preparation of telmisartan and derivatives thereof.

According to the invention, substituted benzimidazoles of formula

wherein R¹ is hydrogen, C-ι-6 alkyl or C3-6 cycloalkyl, R² is C1-6 alkyl or C3-6 cycloalkyl, and R³ is cyano or carboxy, are prepared in a process comprising the steps of (i) cyanating an ΛAacyl-yO-haloaniline of formula

wherein R¹ and R² are as defined above and X is chlorine or bromine, to obtain the corresponding cyano compound of formula

wherein R¹ and R² are as defined above,

(ii) nitrating the cyano compound obtained in step (i) to obtain the corresponding nitro compound of formula

wherein R¹ and R² are as defined above,

(iii) reducing and cyclizing the nitro compound obtained in step (ii) to obtain the target compound (Ia) wherein R¹ and R² are as defined above and R³ is cyano, and, optionally, (iv) hydrolyzing the cyano group of compound Ia to obtain the target compound wherein R³ is carboxy (Ib).

In a preferred embodiment, the cyanation in step (i) is effected with potassium hexa- cyanoferrate(ιι) in a polar aprotic solvent and in the presence of a palladium phosphine complex as catalyst. This embodiment is particularly advantageous since potassium hexacyanoferrate(ιι) is much less toxic than the cyanides usually employed in cyanation reactions. Suitable polar aprotic solvents are for example the commonly used amides, ureas or sulfoxides, such as /V.ΛAdimethylformamide, /V./V-dimethylacetamide, /V-methylpyrrolidone, Λ/,/V,Λ/'/V-tetramethylurea or dimethyl sulfoxide.

More preferably, the palladium phosphine complex is tetrakis(triphenylphosphine)- palladium(O).

In another preferred embodiment, the nitration in step (ii) is effected using an alkali metal nitrate in sulfuric acid as nitrating agent. This embodiment is particularly advantageous since the usage of large amounts of nitric acid is avoided.

In still another preferred embodiment, the reduction and cyclization in step (iii) is conducted without isolating an intermediate, using elemental iron in acetic acid as reducing agent.

In another preferred embodiment, the reduction and cyclization in step (iii) is conducted without isolating an intermediate, using an alkali metal dithionite as reducing agent. A particularly preferred is reducing agent is sodium dithionite (Na2S2θ4). The reaction with dithionite is advantageously carried out in an aqueous solvent mixture, such as aqueous ethanol.

If required, the carbonitrile Ia (I, R³ = CN) can be hydrolyzed to yield the corresponding carboxylic acid Ib (I, R³ = COOH). The hydrolysis is preferably carried out using a strong acid, such as hydrochloric acid. The process of the invention is preferably used to prepare compounds (I) wherein R¹ is methyl.

The process of the invention is likewise preferably used to prepare compounds (I) wherein R² is propyl.

Most preferably, R¹ is methyl and R² is propyl.

In a preferred embodiment the ΛAacyl-yO-haloaniline starting material is the bromo com- pound (X = Br).

The compounds of formula

wherein R¹ is Ci-β alkyl or C3-6 cycloalkyl and R² is C1-6 alkyl or C3-6 cycloalkyl, are novel and also an object of the invention.

Preferably, R¹ is methyl, and more preferably R¹ is methyl and R² is propyl.

Another embodiment of the invention are the compounds of formula

wherein R¹ is Ci-e alkyl or C3-6 cycloalkyl and R² is propyl. In an especially preferred compound R¹ is methyl and R² is propyl, i.e., the compound is ΛA(4-cyano-2-methylphenyl)butyramide.

Still another embodiment of the invention are the compounds of formula

wherein R¹ is Ci_6 alkyl or C3-6 cycloalkyl and R² is C1-6 alkyl or C3-6 cycloalkyl.

In an especially preferred compound R¹ is methyl and R² is propyl, i.e., the compound is ΛA(4-cyano-2-methyl-6-nitrophenyl)butyramide.

The following non-limiting examples will further illustrate the invention.

Example 1

ΛA(4-Bromo-2-methylphenyl)butyramide (II, R¹ = CH₃, R² = /J-C₃H₇, X = Br)

Butyryl chloride (36.0 g, 0.338 mol, 1.2 eq.) was added to a solution of 2-methylaniline (30.O g, 0.28 mol, 1.0 eq.) and triethylamine (31.2 g, 0.308 mol, 1.1 eq.) in dichloro- methane (250 ml_) within 35 min at room temperature. The mixture was stirred at room temperature for another 3.5 h and then washed with water and aqueous sodium carbonate solution. The organic layer was dried with anhydrous sodium sulfate and concentrated to give ΛA(2-methylphenyl)butyramide as a white solid (45.27 g, 90%) which was used in the next step without further purification.

¹H NMR (400 MHz, DMSO-αfe): δ 9.23 (s, 1 H), 7.37 (d, J= 7.6 Hz, 1 H), 7.20 (d, J = 7.5 Hz, 1 H), 7.15 (t, J= 7.6 Hz, 1 H), 7.07 (t, J= 6.8 Hz, 1 H), 2.31 (t, J= 7.3 Hz, 2H), 2.20 (s, 3H), 1.63 (m, J= 7.4 Hz, J= 7.3 Hz, 2H), 0.95 (t, J= 7.4 Hz, 3H). The crude ΛA(2-methylphenyl)butyramide (5.01 g, 28 mmol, 1.0 eq.) was dissolved in methanol (5O mL). Aqueous hydrobromic acid (40%, 5.87 g, 29 mmol, 1.0 eq.) was added in one portion. The mixture was cooled (ice-water bath), aqueous hydrogen peroxide (30%, 3.67 g, 29 mmol, 1.0 eq.) was added slowly within 15 min and stirring was continued overnight. After removal of excess methanol, a white solid was obtained by filtration. The wet cake was washed with aqueous sodium carbonate and water and dried under vacuum to give a white solid. Yield: 6.22 g (85%).

¹H NMR (400 MHz, DMSO-αfe): δ 9.26 (s, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J= 8.5 Hz, 1 H), 7.32 (dd, J= 2.0 Hz, J= 8.5 Hz, 1 H), 2.30 (t, J= 7.2 Hz, 2H), 2.18 (s, 3H), 1.61 (m, J= 7.2 Hz, J= 7.4 Hz, 2H), 0.92 (t, J= 7.4 Hz, 3H). 1³C NMR (100 MHz, DMSO-ck): δ 171.6, 136.4, 134.8, 133.1 , 129.1 , 127.3, 117.5, 38.2, 19.2, 18.0, 14.1.

Example 2

/V-(4-Chloro-2-methylphenyl)butyramide (II, R¹ = CH₃, R² = /T-C₃H₇, X = Cl)

/>Butyryl chloride (18.64 g, 0.175 mol, 1.2 eq.) was added to a mixture of 4-chloro- 2-methylaniline (2O g, 0.141 mol, 1.0 eq.) and triethylamine (17.41 g, 0.172 mol, 1.2 eq.) in dichloromethane (250 ml_) within 25 min at room temperature. The reaction mixture was stirred at room temperature for another 18 h. Iced water was then added and the mixture was extracted with dichloromethane. The combined organic layers were washed with aqueous sodium carbonate and water, dried over anhydrous sodium sulfate, and concentrated to give a white solid. Yield: 25 g (80%).

¹H NMR (400 MHz, DMSO-αfe): δ 9.27 (s, 1 H), 7.41 (d, J= 8.5 Hz, 1 H), 7.28 (d, J= 2.3 Hz, 1 H), 7.20 (dd, J= 8.5 Hz, J= 2.3 Hz, 1 H), 2.30 (t, J= 7.4 Hz, 2H), 2.10 (s, 3H), 1.61 (m, J= 7.4 Hz, J= 7.4 Hz, 2H), 0.92 (t, J= 7.4 Hz, 3H). 1³C NMR (100 MHz, DMSO-αfe): δ 171.6, 135.9, 134.4, 130.2, 129.2, 127.0, 126.1 , 38.1 , 19.2, 18.1 , 14.0. Example 3

ΛA(4-Chloro-2-methylphenyl)butyramide (II, R¹ = CH₃, R² = /T-C₃H₇, X = Cl)

A mixture of ΛA(2-methylphenyl)butyramide (1.0 g, 6 mmol, 1.0 eq.), hydrochloric acid (36%, 0.6 ml_, 7 mmol, 1.2 eq.) and aqueous hydrogen peroxide (30%, 0.7 ml_, 7 mmol, 1.2 eq.) in methanol (10 ml_) in an open system equipped with a reflux condenser was heated to 40 ⁰C for 18 h. Preparative TLC isolated ΛA(4-chloro-2-methylphenyl)butyr- amide as a white solid (119 mg, 10%).

Example 4

ΛA(4-Cyano-2-methylphenyl)butyramide (III, R¹ = CH₃, R² = ^C₃H₇)

A mixture of Λ£(4-bromo-2-methylphenyl)butyramide (20.04 g, 78 mmol, 1.0 eq.), po- tassium hexacyanoferrate(ιι) trihydrate (13.17 g, 31 mmol, 0.4 eq.), tetrakis(triphenyl- phosphine)palladium(O) (454 mg, 0.39 mmol, 0.005 eq.), sodium carbonate (9.94 g, 94 mmol, 1.2 eq.) in DMF (200 ml_) was heated to 120 ⁰C for 21 h. The reaction mixture was cooled to room temperature and the precipitated solid was filtrated off. The organic layer was diluted in dichloromethane and washed with water. Volatiles were removed to give the crude product. Ethyl ether was used to dilute the crude product and insoluble solid was filtrated off. The filtrate was concentrated to give a light yellow solid.

Yield: 12.O g (75%).

¹H NMR (400 MHz, DMSO-ofe): δ 9.41 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.69 (d, J= 1.8 Hz, 1 H), 7.62 (dd, J= 8.4 Hz, J= 1.8 Hz, 1 H).

¹³C NMR (100 MHz, DMSO-αfe): δ 172.1 , 141.6, 134.5, 131.2, 130.6, 124.5, 119.4, 106.8, 38.3, 19.1 , 18.0, 14.0. Example 5

ΛA(4-Cyano-2-methylphenyl)butyramide (III, R¹ = CH₃, R² = /J-C₃H₇)

A mixture of ΛA(4-chloro-2-methylphenyl)butyramide (0.504 g, 2.38 mmol, 1.0 eq.), po- tassium hexacyanoferrate(ιι) trihydrate (0.40 g, 0.95 mmol, 0.4 eq.), sodium carbonate

(0.304 g, 2.87 mmol, 1.2 eq.), palladium(ιι) acetate (12.2 mg, 0.05 mmol, 0.02 eq.), tri- phenylphosphine (62.2 mg, 0.24 mmol, 0.1 eq.) in /V,ΛAdimethylacetamide (7 ml_) was heated to 140 ⁰C for 18 h. ΛA(4-Cyano-2-methylphenyl)butyramide was obtained in

40% yield and unreacted starting material was fully recovered. NMR spectra were found identical to those of the product prepared from ΛA(4-bromo-2-methylphenyl)- butyramide.

Example 6 ΛA(4-Cyano-2-methyl-6-nitrophenyl)butyramide (IV, R¹ = CH₃, R² = /T-C₃H₇)

A mixture of sodium nitrate (6.73 g, 79 mmol, 2.0 eq.) and sulfuric acid (98%, 40 ml_) was stirred in an ice-water bath for 15 min. ΛA(4-Cyano-2-methylphenyl)butyramide

(8.00 g, 40 mmol, 1.0 eq.) was then added in portions within 55 min and the mixture was stirred in an ice-water bath for 3 h. The reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium carbonate and water. Volatiles were removed under reduced pressure to give an orange solid.

Yield: 8.01 g (80%). 1H NMR (400 MHz, DMSO-ofe): δ 10.12 (s, 1 H), 8.30 (d, J= 1.7 Hz, 1 H)₁ 8.11 (m, 1 H),

2.34 (s, 3H), 2.33 (t, J= 7.1 Hz, 2H), 1.58 (qd, J= 7.3 Hz, J= 7.1 Hz, 2H), 0.91 (t,

J= 7.3 Hz, 3H).

"C NMR (100 MHz, DMSO-ofe): δ 171.8, 146.4, 138.3, 138.0, 133.5, 126.8, 117.5,

108.8, 37.6, 18.7, 18.1 , 14.0. Example 7

7-Methyl-2-propyl-3/^benzimidazole-5-carbonitrile (I₁ R¹ = CH₃, R² = ^C₃H₇, R³ = CN)

A mixture of ΛA(4-cyano-2-methyl-6-nitrophenyl)butyramide (2.O g, 8 mmol, 1.0 eq.) and iron powder (2.26 g, 41 mmol, 5.0 eq.) in acetic acid (40 mL) was heated to 120 ⁰C for 6 h. HPLC indicated full conversion of reaction. The reaction mixture was then cooled to room temperature and filtrated through a short plug of Celite^®. The filtrate was concentrated using a rotary evaporator, diluted with dichloromethane and washed with sodium carbonate solution. The organic phase was separated and con- centrated to give a off-white solid. Yield: 0.531 g (30%).

¹H NMR (400 MHz, DMSO-ύfe): δ 12.66 (s, 1 H), 7.80 (s, 1 H), 7.73 (m, 1 H), 2.82 (t, J = 7.3 Hz, 2H), 2.50 (s, 3H), 1.73 (qd, J= 7.3 Hz, J= 7.4 Hz, 2H), 0.87 (t, J= 7.4 Hz, 3H). 1³C NMR (100 MHz, DMSO-αfe): δ 158.4, 125.1 , 120.8, 103.4, 30.9, 21.3, 16.9, 14.1.

During this reductive cyclization reaction, ΛA(2-amino-4-cyano-6-methylphenyl)butyr- amide may also be isolated as a major intermediate, especially when conversion was not completed. Spectroscopical data for the intermediate are as follows: 1H NMR (400 MHz, DMSO-ofe): δ 9.01 (s, 1 H), 6.82 (d, J= 1.6 Hz, 1 H), 6.76 (m, 1 H),

2.25 (t, J= 1.2 Hz, 2H), 2.00 (s, 3H), 1.55 (qd, J= 7.4 Hz, J= 7.2 Hz, 2H), 0.86 (t,

J= 7.4 Hz, 3H).

¹³C NMR (100 MHz, DMSO-αfe): δ 171.7, 146.1 , 137.8, 126.7, 121.0, 119.8, 115.8,

109.4, 37.8, 19.1 , 18.3, 14.2.

Example 8

7-Methyl-2-propyl-3Mbenzimidazole-5-carbonitrile (I₁ R¹ = CH₃, R² = /J-C₃H₇, R³ = CN)

A mixture of Λ£(4-cyano-2-methyl-6-nitrophenyl)butyramide (347 mg, 1.42 mmol, 1.0 eq.), sodium dithionite (733 mg, 4.21 mmol, 3.0 eq.) in ethanol (5 mL) and water (10 mL) was heated to 70 ⁰C for 4 h. Dichloromethane and water was added to the mixture. Phase separation and aqueous work-up gave 7-methyl-2-propyl-3A/-benz- imidazole-5-carbonitrile as a off-white solid. Yield: 112 mg (40%).

Example 9

7-Methyl-2-propyl-3A/-benzimidazole-5-carboxylic acid (I₁ R¹ = CH3, R² = /7-C3H7,

R³ = COOH)

The mixture of 7-methyl-2-propyl-3Mbenzoimidazole-5-carbonitrile (250 mg, 1 mmol, 1.0 eq.), aqueous hydrochloric acid (36%, 2.5 ml_, 29 mmol, 2.3 eq.) in 1 ,4-dioxane (2.5 ml_) was heated to 100 ⁰C for 16 h. After removal of volatiles, the concentrate was diluted with methanol, and decolorized with activated carbon to give a white solid. Yield: 85 mg (30%). The spectral data of this product were identical to that of commercial product:

¹H NMR (400 MHz, DMSO-αfe): δ 12.42 (s, 1 H), 7.82 (s, 1 H), 7.56 (s, 1 H), 2.80 (t, J= 7.4 Hz, 2H), 2.50 (s, 3H), 1.79 (qd, J= 7.4 Hz, J = 7.32 Hz, 2H), 0.94 (t, J= 7.32 Hz, 3H). 1³C NMR (100 MHz, DMSO-ofe): δ 168.6, 157.5, 124.1 , 123.3, 31.0, 21.4, 17.1 , 14.2.

Claims

1. A process for the production of substituted benzimidazoles of formula

wherein R¹ is hydrogen, Ci-β alkyl or C3-6 cycloalkyl, R² is C1-6 alkyl or C3-6 cycloalkyl, and R³ is cyano or carboxy, comprising the steps of (i) cyanating an ΛAacyl-yO-haloaniline of formula

wherein R¹ and R² are as defined above, (ii) nitrating the cyano compound obtained in step (i) to obtain the corresponding nitro compound of formula

wherein R¹ and R² are as defined above,

2. The process of claim 1 , wherein the cyanation in step (i) is effected with potassium hexacyanoferrate(ιι) in a polar aprotic solvent and in the presence of a palladium phosphine complex as catalyst.

3. The process of claim 2, wherein the palladium phosphine complex is tetrakis(tri- phenylphosphine)palladium(O).

4. The process of any of claims 1 to 3, wherein the nitration in step (ii) is effected using an alkali metal nitrate in sulfuric acid as nitrating agent.

5. The process of any of claims 1 to 4, wherein the reduction and cyclization in step (iii) is conducted without isolating an intermediate, using elemental iron in acetic acid as reducing agent.

6. The process of any of claims 1 to 4, wherein the reductive cyclization in step (iii) is conducted without isolating an intermediate, using an alkali metal dithionite as reducing agent.

7. The process of any of claims 1 to 6, wherein R¹ is methyl.

8. The process of any of claims 1 to 7, wherein R² is propyl.

9. The process of any of claims 1 to 8, wherein X is bromine.

10. A compound of formula

wherein R¹ is Ci-β alkyl or C3-6 cycloalkyl, and R² is C1-6 alkyl or C3-6 cycloalkyl.

11. The compound of claim 10, wherein R¹ is methyl and R² is propyl.

12. A compound of formula

wherein R¹ is C1-6 alkyl or C3-6 cycloalkyl and R² is propyl.

13. The compound of claim 12, wherein R¹ is methyl and R² is propyl.

14. A compound of formula

wherein R¹ is Ci-6 alkyl or C3-6 cycloalkyl and R² is C1-6 alkyl or C3-6 cycloalkyl.

15. The compound of claim 14, wherein R¹ is methyl and R² is propyl.