WO2010149359A1

WO2010149359A1 - Process and intermediates for the preparation of benzimidazolecarboxylic acids

Info

Publication number: WO2010149359A1
Application number: PCT/EP2010/003787
Authority: WO
Inventors: Paul Hanselmann; Heilam Wong; Ellen Klegraf; Florencio ZARAGOZA DÖRWALD; Zunliang Ding; Wei He (Ryan)
Original assignee: Lonza AG
Current assignee: Lonza AG
Priority date: 2009-06-26
Filing date: 2010-06-24
Publication date: 2010-12-29
Anticipated expiration: 2011-12-26
Also published as: TW201100388A

Abstract

Substituted benzimidazolecarboxylic acids of formula (I), wherein R¹ and R² independently are hydrogen, C_1-6 alkyl or C_3-6 cycloalkyl, are prepared in a four-step synthesis starting from N-acyl-4-haloanilines of formula (II), wherein R¹ is as defined above, R³ is C_1-4 alkyl and X is chlorine or bromine.

Description

Process and intermediates for the preparation of benzimidazolecarboxylic acids

The invention relates to a process for the production of substituted benzimidazole- 6-carboxylic acids of formula

wherein R¹ and R² independently are hydrogen, C1-6 alkyl or C3-6 cycloalkyl. It further relates to novel intermediates in the process 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, te/?-butyl, and the various isomeric pentyls and hexyls. The term "C3-6 cycloalkyl" represents cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Benzimidazoles of formula I are useful as intermediates in the synthesis of pharmaceutically active compounds. In particular, 4-methyl-2-propylbenzimidazole-6-carboxylic acid (R¹ = methyl, R² = propyl) is a key intermediate in the industrial synthesis of telmisartan, an angiotensin Il receptor antagonist used in the therapy of hypertension.

The benzimidazolecarboxylic acids of formula I can exist in two tautomeric forms, namely the 1 H form depicted above and the 3// form (I^') depicted below:

AII compound names and structural formulas used hereinbelow are intended to encompass both tautomeric forms, although, for the sake of simplicity, only the \ H form will be mentioned and/or depicted.

Several processes for the preparation of benzimidazolecarboxylic acids 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, 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 benzimidazolecarboxylic acids of formula

wherein R¹ and R² independently are hydrogen, Ci_β aikyl or C3-6 cycloalkyl, are prepared in a process comprising the steps of (i) cyanating an ΛAacyl-4-haloaniline of formula

wherein R¹ is as defined above, R³ is

alkyl and X is chlorine or bromine, to obtain the corresponding cyano compound of formula

wherein R¹ and R³ are as defined above, nitrating the cyano compound obtained in step (i) to obtain the corresponding nitro compound of formula

wherein R¹ and R³ are as defined above_:

(ii) hydrolyzing the cyano and acylamino groups of the nitro compound obtained in step (i) to obtain the corresponding yo-aminobenzoic acid of formula

wherein R¹ is as defined above, and (iii) reacting said p-aminobenzoic acid in the presence of a reducing agent with an aldehyde of formula

R²-CHO (Vl)

wherein R² is as defined above, to obtain the target compound of formula I.

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 cyana- tion reactions. Suitable polar aprotic solvents are for example the commonly used amides, ureas or sulfoxides, such as /V.ΛAdimethylformamide, /V,Λ/-dimethylacetamide, ΛAmethylpyrrolidone, Λ/,/V,/V^/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 hydrolysis in step (iii) is effected using an aqueous hydrohalic acid such as hydrochloric, hydrobromic or hydriodic acid. Hydrochloric acid is particularly preferred. In still another preferred embodiment, an alkali metal dithionite is used as reducing agent in step (iv), sodium dithionite (Na2S2θ₄) being particularly preferred.

In a preferred embodiment, R¹ in the final product (I), the starting material (II) and the intermediates (III) through (V) is methyl.

In another preferred embodiment, R² in the final product (I) and the aldehyde (Vl) is propyl.

In still another preferred embodiment, R³ in the starting material (II) and the intermediates (III) and (IV) is methyl or propyl.

The compounds of formula

wherein R¹ is Ci-β alkyl or C3-6 cycloalkyl and R³ is propyl, are novel and also an embodiment of the invention.

In a preferred embodiment, R¹ is methyl. The compounds of formula

wherein R¹ is Ci_β alkyl or C3-6 cycloalkyl and R³ is C1-4 alkyl, are likewise novel and an embodiment of the invention.

In a preferred embodiment, R¹ is methyl.

In another preferred embodiment, R³ is methyl or propyl.

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

Example 1

ΛA(4-Bromo-2-methylphenyl)acetamide (II, R¹ = R³ = CH₃, X = Br)

A mixture of 2-methylaniline (5 g, 47 mmol, 1 eq.), acetic anhydride (5 g, 49 mmol, 1.1 eq.) and hexamethylphosphoramide (trace) was stirred at room temperature. The reaction was monitored by TLC or HPLC. After completion of amide formation, aqueous hydrobromic acid (40%, 9.53 g, 47 mmol, 1.0 eq.) was added to the resulting solution of /V-(2-methylphenyl)acetamide and the mixture was cooled to 0 ⁰C. Aqueous hydrogen peroxide (30%, 5.48 g, 47 mmol, 1.0 eq.) was then added slowly within 30 min and stirring was continued overnight. A white precipitate formed and was collected by filtration. The filtrate was concentrated using a rotary evaporator and a second crop of white solid was collected by filtration. The combined white solid was washed with water and aqueous sodium carbonate and dried to give Λ£(4-bromo- 2-methylphenyl)acetamide as a white solid. Yield: 8.50 g (80%).

¹H NMR (400 MHz, DMSO-ύfe): δ 9.32 (s, 1H), 7.41 (d, J= 2.0 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1 H), 7.32 (dd, J = 2.0 Hz, J= 8.8 Hz, 1 H), 2.19 (s, 3H), 2.05 (s, 3H). 1³C NMR (100 MHz, DMSO-αfe): δ 168.8, 136.4, 134.5, 133.1 , 129.1, 127.0, 117.4, 23.8, 18.0.

Example 2

/V-(4-Bromo-2-methylphenyl)butyramide (II, R¹ = CH₃, R³ = /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 carbo- nate 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-ofe): 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)₁ 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-αfc): δ 9.26 (s, 1H), 7.42 (d, J= 2.0 Hz, 1H), 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 Hz₁ 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). "C NMR (100 MHz, DMSO-ofe): δ 171.6, 136.4, 134.8, 133.1 , 129.1 , 127.3, 117.5, 38.2, 19.2, 18.0, 14.1.

Example 3

/V-(4-Chloro-2-methylphenyl)butyramide (II, R¹ = CH₃, R³ = /7-C₃H₇, X = Cl)

/7-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 layer was 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-ofe): 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= IA Hz, 2H), 0.92 (t, J= IA 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 4

ΛA(4-Chloro-2-methylphenyl)butyramide (II, R¹ = CH₃, R³ = /J-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 rnrnσi, 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%). - 10 -

¹³C NMR (100 MHz, DMSO-ofe): 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 7

ΛA(4-Cyano-2-methylphenyl)butyramide (IM₁ R¹ = CH₃, R³ = /J-C₃H₇)

A mixture of ΛA(4-chloro-2-methylphenyl)butyramide (0.504 g, 2.38 mmol, 1.0 eq.), potassium 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.), triphenylphosphine (62.2 mg, 0.24 mmol, 0.1 eq.) in /V,/V-dimethylacetamide (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 8

ΛA(4-Cyano-2-methyl-6-nitrophenyl)acetamide (IV, R¹ = R³ = CH₃)

A mixture of sodium nitrate (4.87 g, 57 mmol, 2 eq) and concentrated sulfuric acid

(98%, 25 mL) was stirred in an ice-water bath for 25 min. ΛA(4-Cyano-2-methyl- phenyl)acetamide (5.00 g, 29 mmol, 1 eq.) was then added in portions slowly. The reaction mixture was stirred in an ice-water bath for 3.5 h before it was poured into ice water to give a yellow precipitate. Ethyl acetate was added. The organic phase was separated and washed with aqueous sodium carbonate. Removal of ethyl acetate by rotary evaporator afforded a yellow solid.

Yield: 5.20 g (80%).

¹H NMR (400 MHz, DMSO-ofe): δ 10.19 (s, 1 H), 8.30 (d, J= 1.68 Hz, 1 H), 8.11 (m, 1 H), 2.34 (s, 3H), 2.07 (s, 3H).

¹³C NMR (100 MHz, DMSO-ύfe): δ 169.1 , 138.4, 137.9, 133.5, 126.9, 117.5, 108.8,

23.2, 18.1. - 9 -

Example 5

ΛA(4-Cyano-2-methylphenyl)acetamide (III, R¹ = R³ = CH3)

A mixture of Λ£(4-bromo-2-methylphenyl)acetamide (20.08 g, 88 mmol, 1.0 eq.) po- tassium hexacyanoferrate(ιι) trihydrate (14.86 g, 35 mmol), tetrakis(triphenylphos- phine)palladium(O) (506.6 mg, 0.44 mmol, 0.5% eq), sodium carbonate (11.23 g, 106 mmol, 1.2 eq) and DMF (200 ml_) was heated to 120 ⁰C for 20 h under nitrogen protection. The reaction mixture was then cooled to room temperature and the precipitated solid was filtrated off. The organic layer was diluted with ethyl acetate, washed with water, and dried with anhydrous sodium sulfate. Volatiles were removed by rotary evaporator to give a white solid. Yield: 10.74 g (72%).

¹H NMR (400 MHz, DMSO-ύfe): δ 9.46 (s, 1 H), 7.84 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.60 (dd, J= 8.4 Hz, J= 2.0 Hz, 1 H), 2.26 (s, 3H), 2.12 (s, 3H). 1³C NMR (100 MHz, DMSO-αfe): δ 169.3, 141.6, 134.4, 131.5, 130.6, 124.2, 119.4, 106.8, 24.1 , 18.0.

Example 6 ΛA(4-Cyano-2-methylphenyl)butyramide (IH₁ R¹ = CH₃, R³ = /J-C₃H₇)

A mixture of ΛA(4-bromo-2-methylphenyl)butyramide (20.04 g, 78 mmol, 1.0 eq.), potassium 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-ck): δ 9.41 (s, 1 H)₁ 7.80 (d, J= 8.4 Hz, 1H), 7.69 (d,

J= 1.8 Hz, 1 H), 7.62 (dd, J= 8.4 Hz, J= 1.8 Hz, 1H). Example 9

ΛA(4-Cyano-2-methyl-6-nitrophenyl)butyramide (IV, R¹ = CH₃, R³ = />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. /V-(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-αfe): δ 10.12 (s, 1 H), 8.30 (d, J = 1.7 Hz, 1 H), 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). 1³C NMR (100 MHz, DMSO-αfe): 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 10 4-Amino-3-methyl-5-nitrobenzoic acid (V, R¹ = CH3)

A mixture of ΛA(4-cyano-2-methyl-6-nitrophenyl)acetamide (1.5 g, 0.07 mol, 1 eq.), concentrated hydrochloric acid (7.5 mL, 88 mmol, 12.8 eq.) and 1 ,4-dioxane (7.5 ml_) was heated to 100 ⁰C for 22 h. The reaction mixture was then cooled to room tempera- ture and water was added. The precipitated solid was collected by filtration and washed with aqueous sodium carbonate and water until the pH of the filtrate reached 7.

The filter cake was dried under vacuum to give a brown solid.

Yield: 0.98 g (73%).

¹H NMR (400 MHz, DMSO-αfe): δ 12.77 (s, 1 H), 8.46 (d, J= 2.0 Hz, 1 H), 7.79, (d, J= 1.0 Hz, 1 H), 7.60, (s, 2H), 2.21 (s, 3H).

¹³C NMR (100 MHz, DMSO-αfe): δ 166.5, 147.5, 135.6, 130.5, 126.9, 126.4, 117.3,

18.4. Example 11

4-Amino-3-methyl-5-nitrobenzoic acid (V, R¹ = CH3)

A mixture of ΛA(4-cyano-2-methyl-6-nitrophenyl)butyramide (315 mg, 1.27 mmol, 1.0 eq.), concentrated hydrochloric acid (1.3 mL, 12.0 M, 15.27 mmol, 12.0 eq.) and

1 ,4-dioxane (1.3 mL) was heated to 100 ⁰C for 24 h. The reaction mixture was then cooled to room temperature and water was added. The precipitated solid was collected by filtration and washed with ethyl acetate and water. The solid was dried under vacuum to give a light brown solid. Yield: 95.5 mg (38%).

¹H NMR (400 MHz, DMSO-αfe): δ 12.77 (s, 1 H), 8.46 (d, J= 2.0 Hz, 1 H), 7.79, (d,

J = 1.0 Hz, 1 H), 7.60, (s, 2H), 2.21 (s, 3H).

¹³C NMR (100 MHz, DMSO-ofe): δ 166.5, 147.5, 135.6, 130.5, 126.9, 126.4, 117.3,

18.4.

Example 12

4-Methyl-2-propyl-1 //-benzimidazole-6-carboxylic acid (I, R¹ = CH3, R² = /M33H7)

A mixture of 4-amino-3-methyl-5-nitrobenzoic acid (0.98 g, 5 mmol, 1 eq.), sodium dithionite (2.47 g, 14 mmol, 2.8 eq.), /7-butyraldehyde (0.38 g, 5 mmol, 1.0 eq.), ethanol (15 mL) and water (15 mL) was heated to 70 ⁰C for 2 h. The reaction mixture was cooled to room temperature and ethanol was removed by rotary evaporator. The solid precipitated was washed with water, collected by filtration and dried under vacuum to give an off-white solid. Yield: 0.41 g (37%).

¹H NMR (400 MHz, DMSO-ofe): δ 12.42 (s. 1 H), 7.82 (s, 1 H), 7,56 (s, I H), 2.80 (t, J= 7 A 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). "C NMR (100 MHz, DMSO-αfc): δ 168.6, 157.5, 124.1 , 123.3, 31.0, 21.4, 17.1 , 14.2.

Claims

A process for the production of substituted benzimidazolecarboxylic acids of formula

wherein R¹ and R² independently are hydrogen, Ci_β alkyl or C3-6 cycloalkyi, comprising the steps of

(i) cyanating an ΛAacyl-4-haloaniline of formula

wherein R¹ is as defined above, R³ is C1-4 alkyl and X is chlorine or bromine, to obtain the corresponding cyano compound of formula

wherein R¹ and R³ are as defined above,

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

wherein R¹ and R³ are as defined above,

(iii) hydrolyzing the cyano and acylamino groups of the nitro compound obtained in step (ii) to obtain the corresponding p-aminobenzoic acid of formula

wherein R¹ is as defined above, and

(iv) reacting said p-aminobenzoic acid in the presence of a reducing agent with an aldehyde of formula

R²-CHO (Vl)

wherein R² is as defined above, to obtained the target compound of formula I.

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 hydrolysis in step (iii) is effected using an aqueous hydrohalic acid.

6. The process of any of claims 1 to 5, wherein in step (iv) an alkali metal dithionite is used 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 R³ is methyl or propyl.

10. A compound of formula

wherein R¹ is Ci-β alkyl or C3-6 cycloalkyl and R³ is propyl.

11. The compound of claim 10 wherein R¹ is methyl.

12. A compound of formula

wherein R¹ is Ci-β alkyl or C3-6 cycloalkyl and R³ is C1-4 alkyl.

13. The compound of claim 12 wherein R¹ is methyl.

14. The compound of claim 12 or 13 wherein R³ is methyl or propyl.