WO1999043650A2

WO1999043650A2 - Process(es) for the preparation of 6-trifluoromethyl-indoline derivatives

Info

Publication number: WO1999043650A2
Application number: PCT/EP1999/001273
Authority: WO
Inventors: Ian Philip Andrews; Erol Ali Faruk; Matthew Gray; Frank Hossner; John Kitteringham; Sandra Jane Paknoham; Martyn Voyle
Original assignee: Smithkline Beecham Plc
Priority date: 1998-02-25
Filing date: 1999-02-22
Publication date: 1999-09-02
Also published as: WO1999043650A3; AU3030899A

Abstract

The present invention relates to a process for the preparation of 5-methyl-6-trifluoromethyl-indoline which is a key intermediate in the preparation of compounds having 5-HT2C receptor antagonist activity. The reaction sequence starts from 1-chloro-2-nitro-4-trifluoromethyl-benzene (VII) via cyano-(2-nitro-trifluoromethylphenyl)acetic acid benzyl ester (VI), 6-trifluoromethyl-indole (V), 6-trifluoromethyl-indoline (IV), 1-benzyl-6-trifluoromethyl-indoline (III), 1-benzyl-5-bromo-6-trifluoromethyl-indoline (II) and 1-benzyl-5-methyl-6-trifluoromethyl-indoline (I). In a further aspect the present invention also relates to the compounds of formulae (I), (II), (III), (IV) and (VI).

Description

PROCESS(ES) FOR THE PREPARATION OF 6-TRIFLUOROMETHYL-INDOLINE

DERIVATIVES

The present invention relates to a new process for preparing 5-methyl-6- trifluoromethyl indoline.

Certain indoles and indolines are useful intermediates for the preparation of compounds which have 5-HT^"2c receptor antagonist activity, such as those described in WO 96/23783 (PCT7EP96/00368) and WO 97/48699 (PCT/EP97/03156). Such a compound is 5-methyl-6-trifluoromethyl indoline which is disclosed in WO 97/48699 (PCT/EP97/03156) as being a key intermediate in the synthesis of 5-methyl-6- trifiuoromethyl-2,3-dihydroindole- 1 -carboxylic acid [6-(2-methylpyridin-3- yloxy)pyridin-3-yl] amide. The disclosed route of synthesis of this intermediate involves many stages, one of which uses the reagent tetramethyltin. Consequently, this methodology is not suitable for use in the large scale production of a pharmaceutical product. It is an object of the present invention, therefore, to provide an improved method of synthesis of 5-methyl-6-trifluoromethylindoline.

The use of alkyl lithium reagents, such as butyl lithium, to effect an aryl lithium/halogen (particularly bromine) exchange reaction is well established within the field of organic chemistry. Such aryl lithium species can be treated with a reagent such as methyl iodide to give the corresponding methylated aryl compound. It is found, however, that such a methodology suffers from the drawback that a competing elimination reaction between the aryl lithium species and butyl halide biproduct can lead to the production of a significant proportion of product where the halogen has been replaced by hydrogen to give the corresponding 'des-methyl' compound as an impurity. There is therefore a requirement for an improved method of synthesis. Shepherd (J.Chem.Soc. Perkin Trans 1, 1988, 961.) describes a process for the preparation of 1,2,4,5 -Tetramethylnaphthalene from l,4-dibromo-2,5-dimethylnapthalene in high yields using methyl lithium in ether, in which the methyl bromide biproduct acts as an alkylating agent. This methodology is not, however, found to be of universal application.

The present invention therefore provides, in a first aspect, a process for the preparation of the compound of formula (I)

(I) which comprises the reaction of the compound of formula (II)

(ID with an organo lithium reagent in an aprotic solvent at a temperature in the range of -60° - +20° C, the said reaction being carried out in the presence of iodomethane or bromomethane.

Preferably the organo lithium reagent is butyl lithium, phenyl lithium or most preferably methyl lithium. Preferably the aprotic solvent is an ethereal solvent but solvents such as hexane and toluene can also be used. Suitable ethereal solvents include TBME (tertiary butyl methyl ether), diethylether or THF. Most preferably the aprotic solvent is TBME. Preferably the reaction is carried out at a temperature in the range of 0 - 15 °C, and most preferably 5-10 °C.

The critical feature of the process for the preparation of a compound of formula (I) is that the resulting aryl lithium species is quenched in-situ with iodomethane or bromomethane already present in the reaction mixture. Such a procedure minimises the amount of the 'des-methyl' impurity, the derivatives of which can otherwise be carried through to the final drug substance when using the compound of formula (I) in an extended synthetic procedure.

Compounds of formula (I) can thereafter be reduced to a desired compound, 5- methyl-6-trifluoromethylindoline, using hydrogen in the presence of a catalyst such as 5- 20% palladium on charcoal. For this reduction to proceed smoothly it is essential to remove the ethereal solvent in which the methyl lithium is supplied. This can be achieved by either isolating the compound of structure (I) as a low melting solid by evaporation of the solvent, or alternatively swapping the ethereal solvent for a suitable high boiling solvent such as n-heptane or isopropanol in a 'put-and-take' distillation. The latter procedure allows for a simplified one-pot process to convert a compound of structure (II) to 5-methyl-6-trifiuoromethylindoline without isolation of the intermediate compound of structure (I).

The compound of structure (II) can be prepared from the compound of structure (III), namely 6-trifluoromethyl-N-benzylindoline

(III) using the controlled addition of N-bromosuccinimide in a dipolar aprotic solvent at a temperature in the range of 15-30°C.

Preferably the aprotic solvent is DMF. Preferably the N-bromosuccinimide will be added stepwise as a molar equivalent over a prolonged period of time such as 30 minutes to 1 hour for small scale reactions but this could be longer for a large scale reaction.

Electrophilic substitution reactions carried out on indolines typically lead to the introduction of a substituent at the 5 and/or 7 position. It has surprisingly been found, utilising the above conditions, that the regioselectivity for the 5 positional isomer is greater than 95%, more typically greater than 98%. Such regioselectivity has been found to be highly reproducible and moreover, is suited to both small scale and larger scale reactions. The level of selectivity eliminates the requirement for an additional purification step when using a compound of formula (II) in an extended synthetic procedure.

The compound of structure (III) can be prepared from the compound of structure (IV), namely 6-trifluoromethylindoline

by N-benzylation using a benzyl halide reagent such as benzyl chloride or benzyl bromide and a suitable base, such as potassium carbonate in an aprotic solvent such as DMF. Typically, a catalytic amount of potassium iodide would also be added to the reaction mixture.

The compound of structure (IV) can be prepared by reduction of the compound of structure (V), namely 6-trifluoromethylindole

(V) using an excess of borane-pyridine complex in an acidic media.

The compound of structure (V) can be prepared by a multi-step procedure described by Tischler and Lanza (Tet. Lett., 1986, 26 , 1653). This procedure is not viable for a large scale manufacture of this compound. Kalir and Pelah (Israel Journal of Chemistry, 1966, 4, pp. 155-159) describes an alternative process for the preparation of 6- trifluoromethylindole which involves a reductive cyclisation of cyano-(2-nitro- trifluoromethylphenyl)acetic acid ethyl ester via the isolated intermediate 2-nitro-4- trifluoromethylbenzyl cyanide. This process does, however suffer from two sigmficant problems which limit its applicability: firstly, the reaction conditions involve using temperatures which are close to the decomposition temperatures; and secondly, the success of such a process is particularly dependent upon the degree of purity of the isolated intermediate as described above. There is therefore a requirement for an improved process that utilises milder experimental conditions and overcomes the problem of intermediate purity. This invention further provides an improved process for preparing 6-trifluoromethylindole (a compound of formula (V)) which comprises reducing the compound of structure (VI)

(VI) using hydrogen in the presence of a noble metal catalyst at a temperature in the range of 20°C to 50°C.

Suitably the noble metal catalyst comprises a metal such as platinum or palladium adsorbed onto an insoluble inert carrier such as charcoal. Preferably the noble metal catalyst is 5-20 % palladium on charcoal. Preferably the reduction is carried out at a temperature between 20°C and 30°C. It will be noted that cyclisation and decarboxylation occur, spontaneously under the preferred reaction conditions, that is to say, there is no requirement to isolate the intermediate 2-nitro-4-trifluromethylbenzyl cyanide.

A compound of structure (VI) can be prepared from a compound of structure (VII) namely, 1 -chloro-2-nitro-4-trifluoromethylbenzene

(VII) by reaction with benzyl cyanoacetate and potassium carbonate in a dipolar aprotic solvent, for example, dimethylformamide at an elevated temperature, for example from 20 to 80°C, preferably between 50 and 70°C.

The above process provides a significantly improved route of synthesis for a compound of formula (V) as a result of the milder experimental conditions utilised. In particular, the lower temperatures used for the synthesis of the compound of formula (VI) avoids the risk of explosive decomposition of such nitro aromatic intermediates.

Compounds of formula (I), (II), (III), (IV) and (VI) are believed to be novel and form a yet further aspect of this invention.

The following Examples serve to illustrate the invention.

Preparation of a compound of formula (VI) - cyano-(2-nitro- trifluoromethylphenyl)acetic acid benzyl ester

Benzyl cyanoacetate (23.58kg, 131.91mol, 98% purity) in DMF is added to a stirred suspension of anhydrous potassium carbonate (37.52kg, 270.11 mol, 99.5%) in DMF at ca 20°C (total volume DMF: 86L) 4-chloro-3-nitrobenzotrifluoride (30.61kg, 131.91 mol, 91.2%) is added maintaining the temperature at 20 to 25 °C and the mixture stirred at this temperature for 30 minutes. The mixture is heated to 50°C over 30 minutes, stirred at this temperature for ca. 20 hours and then cooled to 15°C. Aqueous HC1 (96L 18% HC1) is added maintaining the temperature at 15-20°C, followed by further water (136L) and the mixture is stirred at 15-20°C until homogeneous. The resulting solid is filtered, washed with water to approximately pH 7 and stored as a water wet product. Yield essentially quantitative, ca 20% H2O content.

IH NMR (250MHz, CDCI3): 8.50 (lH,s), 8.03 (IH, dd, J= 1.7, 8.4), 7.97 (IH, d, J=8), 7.43-7.35 (5H, m), 5.82 (IH, s), 5.30 (IH, s), 5.29 (IH, s). MS (APCI-): 363.2 (M-l, 100%).

Preparation of a compound of formula (V) - 6-trifluoromethylindole

A mixture of cyano-(2-nitro-trifluoromethylphenyl)acetic acid benzyl ester (compound of formula (VI))(29.36kg, 63.03 mol, 78.2% purity), IMS (158L), glacial acetic acid (16L) and water (16L) is hydrogenated at 40-50psi (275.8 - 344.8kPa) using 5% Pd/C (5.96 kg, Type 58, 53.4% water wet) as the catalyst, keeping the temperature at 20-30°. At the completion of the hydrogenation the reaction mixture is filtered through Celite

(Diatomaceous Earth) and the filter cake washed with IMS (30L). The combined filtrate is concentrated (to 183L) and diluted with water (365L) to precipitate the product. The product is filtered, washed with water to pH 6-7 and dried in a vacuum oven. Typical yield 71%. IH NMR (250MHz, CDCI3): 8.4 (IH, broad s), 7.75 (IH, d, J=8.7), 7.71 (IH, s), 7.40- 7.37 (2H, m), 6.65 (IH, m) MS (APCI-): 184.0 (M-l, 100%).

Preparation of a compound of formula (IV) - 6-trifluoromethylindoline 5M Hydrochloric acid (630 ml) was added over 1.5 hour to a stirred solution of 6- trifluoromethylindole (compound of formula (V))(45.0g, 0.24 mol) and borane-pyridine complex (112.0g, 1.2 mol) in ethanol (315 ml), maintained at below 10°C. The mixture was then stirred at 0°C for 2 hours. Water (630 ml) was added and the mixture was basified to pH 8.5 with 10M sodium hydroxide solution, whilst maintaining the temperature below 20°C. The mixture was filtered and the title compound, as a white solid, was washed with water (500 ml) and dried. Yield 42.6g, 94%.

Preparation of a compound of formula (III) - 6-trifluoromethyl-N-benzylindoline

A solution of 6-trifluoromethylindoline (compound of formula (IV))(79.7g, 0.426mol) in DMF (0.32L) was added to a 2L flask containing potassium carbonate (66.83g, 0.477 mol) and potassium iodide (6.37g, 0.038mol). Benzyl chloride (58.05g, 53ml, 0.452mol) was added and the resulting mixture was stirred at 80-90° C for 30 minutes. The mixture was then cooled to 5-10°C and treated dropwise with water (80ml) to precipitate the product. Further water (1.52L) was then added and the product filtered off, washed with water and dried at room temperature. Typical yield of title product 116.18g, 98%.

ΪH NMR (200MHz, CDC1₃): 7.34 (5H, m), 7.13 (IH, d), 6.96(1H, d), 6.67 (IH, s), 4.30

(2H, s), 3.40 (2H, t), 3.01 (2H, t).

Preparation of a compound of formula (II) - 5-bromo-6-trifluoromethyl-N-benzyl- indoline

A solution of the 6-trifluoromethyl-N-benzylindoline (compound of formula (III)) in

DMF (2 vols.) was treated slowly with a solution of N-bromosuccinimide (1.05 eq) in DMF (2 vols.) over 45 minutes at room temperature. The mixture was then stirred for an additional 30 minutes before cooling to 10°C and treating dropwise with water (2 vols.) to precipitate the product. Further water (15 vols.) was then added and the product then filtered off, washed with water and dried. Typical weight yield of title product = 94-97%; the isomeric purity was determined by a Gas Chromotagraphy (GC) assay using a CP Sill9CB column and determined as being greater than 98% in all instances, irrespective of scale of reaction.

IH NMR (250MHz, CDCI3): 7.3 (2H, m), 6.7 (IH, s), 4.3 (2H, s), 3.4 (2H, t), 3.00 (2H, t)

Preparation of a compound of formula (I) - 5-methyl-6-trifluoromethyl N-benzyl indoline

To a stirred solution of 5-bromo-6-trifluoromethyl-N-benzylindoline (compound of formula (II))(5g, 14 mmol) and methyl iodide (1.75ml, 28mmol) in TBME (50ml) at 5- 10°C under N₂ was added a 2.5M solution of methyl lithium in diethoxymethane (6.76ml, 16.9 mmol). The reaction was stirred at 5-10°C for 1 hour and quenched with water (25ml). The organic phase was separated and washed with water (25ml). Under atmospheric distillation conditions solvent (40ml) was removed and replaced with 80-100 petrol (40ml). Solvent (25ml) was distilled out and replaced with 80-100 petrol (25ml) This procedure was repeated four times to a constant boiling point of 90°C, and NMR analysis of the residue indicated no remaining diethoxymethane.

Preparation of 5-methyl-6-trifluoromethylindoline

To the above residue was added 80-100 petrol (40ml), the solution cooled to 25°C and 5% Pd/C catalyst (type 58L 0.8g, 50% w/w water) was added. The mixture was treated with hydrogen at 25°C and 50 psi (344.8kPa) for 6 hours. Catalyst was filtered off, washed with 80-100 petrol (20ml x2) and the combined organics cooled to 5-10°C. A 4M solution of hydrogen chloride in 1,4-dioxane (3.5ml, 14mmol) was added and the precipitate stirred at 5-10°C for 1 hour. The white solid was filtered off, washed with 80- 100 petrol (20ml x2) and air dried to give crude 5-methyl-6-trifluoromethylindoline as the hydrochloride salt, 2.95g, 89%> yield and 95% purity.

Crude 5-methyl-6-trifluoromethylindoline (19.4kg) containing 1.54% of the des-methyl product, 6-trifluoromethylindoline was dissolved in isopropanol (116L) and the mixture heated to reflux with stirring, resulting in a clear solution. The solution was cooled to ambient over 1 hour and further cooled to 0°C and stirred at this temperature for 1 hour.

The crystals were filtered off and washed with cold IP A (12L), sucked dry and dried in vacuo at ambient to give product, 16.36kg, 84% yield, contaminated with 0.41% 6- trifluoromethylindoline.

IH NMR (250MHz, CDCI3): 7.0 (IH, s), 6.85 (IH, s), 3.8 (IH, broad s), 3.58 (2H, t),

3.05 (2H, t), 2.35 (3H, s)

MS (APCI+): 202 (M+H)

Claims

A process for the preparation of the compound of formula (I)

(I)

which comprises the reaction of the compound of formula (II)

(II) with an organo lithium reagent in an aprotic solvent at a temperature in the range of -60° - +20° C, the said reaction being carried out in the presence of iodomethane or bromomethane.

2. A process according to claim 1 in which the organo lithium reagent is methyl lithium.

3. A process according to claims 1 or 2 in which the aprotic solvent is TBME

A process according to any of the claims 1 to 3 in which the temperature is

5-10°C.

5. A process according to any of the claims 1 to 4 in which any ethereal solvents are removed by evaporation or distillation with a higher boiling solvent and the product is reduced with hydrogen and a palladium catalyst to give 5-methyl-6- trifluoromethyl indoline.

The compound of structure (I) as claimed in claim 1.

7. The compound of structure (II) as claimed in claim 1.

8. A process according to claim 1 in which the compound of structure (II) is prepared by a process which comprises the bromination of the compound of formula (III)

(III) by the controlled addition of N-bromosuccinimide in a dipolar aprotic solvent at a temperature in the range of 15-30°C.

9. A process according to claim 8 in which the bromination reaction is carried out using N-bromosuccinimide in DMF.

10. A process according to claims 8 and 9 in which the bromination reaction is carried out using a molar equivalence of N-bromosuccinimide in DMF which is added stepwise over a prolonged period of time.

11. The compound of formula (III) as claimed in claim 8.

12. A process according to claim 8 in which the compound of structure (III) is prepared by a process which comprises the reaction of the compound of formula (IV)

(IV) with a benzyl halide reagent and potassium carbonate in DMF in the presence of a catalytic amount of potassium iodide.

13. The compound of formula (IV) as claimed in claim 12.

14. A process according to claim 12 in which the compound of structure (IV) is prepared by a process which comprises the reduction of a compound of formula (V) using an excess of borane-pyridine complex in an acidic media

characterised in that the compound of structure (V) is obtained by the reduction of a compound of formula (VI)

using hydrogen in the presence of a noble metal catalyst at a temperature in the range

20°C to 50°C.

15. A process according to claim 14 in which the noble metal catalyst is 5- 20% palladium on charcoal.

16. The compound of formula (VI) as claimed in claim 14.

17. A process according to claim 14 in which the compound of structure (VI) is prepared by a process which comprises the reaction of a compound of structure (VII)

(VII) with benzyl cyanoacetate and potassium carbonate in a dipolar aprotic solvent at a temperature not exceeding 80°C.

18. A process according to claim 17 in which the dipolar aprotic solvent is dimethylformamide and the reaction temperature used is in the range 50 - 70° C.