Preparation of 13-Cyclohexyl-3-Methoxy-6-[Methyl-(2-(2-[Methyl-(Sulphamoyl)-Amino]-Ethox- y}-Ethyl)-Carbamoyl]-7H-Indolo-{2,1-a]-[2]-Benzazepine-10-Carboxylic Acid

Abstract

The present invention relates to an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-et- hoxy}ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid. The present invention also relates to a new compound, namely tent-butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate, used in this improved method.

Description

[0001] The present invention relates to an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethox- y}-ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid. The present invention also relates to a new compound, namely tent-butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate, used in this improved method.

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[0002] WO 2010 / 003658 describes some macrocyclic indoles that can be used as inhibitors of the hepatitis C virus. The synthesis of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethox- y}-ethyl)-carbamoyl]-7H-indolo-[2,1 -a]-[2]-benzazepine-10-carboxylic acid (Compound `A`) was described there on pages 38 and 39 (see Compound 1e) as a three-step synthesis, giving an overall yield of 62%.

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[0003] The aim of the present invention is to provide an improved method for the synthesis of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethox- y}-ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid (Compound `A`) that is easier to carry out and is more efficient than the method known so far.

[0004] The present invention achieves this aim by providing an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethox- y}-ethyl)-carbamoyl]-7H-indolo-[2, 1 -a]-[2]-benzazepine- 10-carboxylic acid (`Compound A`), characterized in that it comprises the following steps:

[0005] a) 1 0-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo-[2,1 -a]-[2]-benzazepine-6-carboxylic acid (Compound I) is reacted with tent-butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate (`Compound B`) in the presence of a coupling agent in a suitable solvent

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[0006] b) and Compound (II) thus obtained is hydrolysed with an acid to prepare Compound `A`.

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[0007] The coupling agent in Step a) is e.g. carbodiimidazole (CDI), dicyclohexylcarbodiimide (DCC), O-(7-azabenztriazolo-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), bromotri-(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP), a combination of 1-hydroxybenztriazole hydrate (HOBt.H₂O) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI).

[0008] A suitable solvent in Step a) is e.g. dichloromethane, 2-methyltetrahydrofuran, acetonitrile, acetone, 2-butanone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate or toluene.

[0009] The hydrolysis in Step b) can be carried out by using trifluoroacetic acid, methanesulphonic acid, hydrogen chloride, hydrogen bromide, para-toluenesulphonic acid, sulphuric acid or phosphoric acid.

[0010] Steps a) and b) can be carried out as a two-step synthesis, in which Compound (II) is isolated in Step a) before carrying out Step b), or else Steps a) and b) are conducted as a one-vessel synthesis.

[0011] The overall yield obtained in Steps a) and b) is between 86 and 91%, depending on which of the procedures described in Examples 3, 4 and 5 (Experiment B) is used to carry out the new method.

[0012] The present invention also relates to a new compound (Compound `B`) with the following formula, and possible acid-addition salts thereof:

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tert-Butyl-(methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbama- te (Compound `B`)

[0013] The acid-addition salts of Compound `B` include the salts that Compound `B` can form with organic or inorganic acids, such as mineral acids, sulphonic acids, carboxylic acids and phosphorus-containing acids. Examples of salt-forming mineral acids are hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, nitric acid, chloric acid, perchloric acid and phosphoric acid. Salt-forming sulphonic acids are toluenesulphonic acid, benzenesulphonic acid, methanesulphonic acid and trifluormethanesulphonic acid. Salt-forming carboxylic acids are formic acid, acetic acid, propionic acid, butanoic acid and the like. Salt-forming dicarboxylic acids are oxalic acid, malonic acid, succinic acid, glutaric acid and the like. Salt-forming hydroxy-acids are glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and the like. Other salt-forming carboxylic acids are trifluoroacetic acid, benzoic acid, chloroacetic acid, phthalic acid, maleic acid and malonic acid. Phosphorus-containing acids are various phosphono-acids, phosphonic acids and phosphinic acids.

[0014] This new Compound `B` can be synthesized as follows:

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EXPERIMENTAL

[0015] The following abbreviations are used here:

[0016] A/A: active yield

[0017] CDI: carbonyldiimidazole

[0018] CSI: chlorosulphonyl isocyanate

[0019] DBU: 1,8-diaza-bicyclo-[5,4,0]-undecene-7

[0020] DIPE: diisopropyl ether

[0021] DMAP: 4-dimethylaminopyridine

[0022] DME: 1,2-dimethoxyethane

[0023] DMSO-d6: deuterated dimethylsulphoxide

[0024] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride

[0025] F/F: physical yield

[0026] HOBt: 1-hydroxybenzotriazole hydrate

[0027] iPrOAc: isopropyl acetate

[0028] LC: liquid chromatography

[0029] MeCN: acetonitrile

[0030] MEK: methyl ethyl ketone (2-butanone)

[0031] MeTHF: 2-methyltetrahydrofuran

[0032] MeSO3H: methanesulphonic acid

[0033] MIK: methyl isopropyl ketone

[0034] MTBE: methyl tent-butyl ether

[0035] NMR: nuclear magnetic resonance

[0036] tBuOH: tent-butanol

[0037] tBOC: tert-butoxycarbonyl

[0038] THF: tetrahydrofuran

EXAMPLE 1

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[0040] A solution of 8.205 g of chlorosulphonyl isocyanate (58.0 mmol, 1 Eq) in 50 ml of acetonitrile (1 litre/mol) was cooled to -2° C. on an ice/salt bath under nitrogen, using a 500-ml four-neck flask fitted with a thermometer, a magnetic stirrer and a dropping (addition) funnel. A solution of 4.297 g of tent-butanol (58.0 mmol, 1 Eq) in 33 ml of acetonitrile (0.5 l/mol) was added dropwise over 20 minutes, with the temperature remaining below 4° C. Four minutes later (when the temperature had dropped to 1° C.), a solution of DMAP (116.0 mmol, 2 Eq) in 55 ml of acetonitrile (1 litre/mol) was added dropwise over 24 minutes, with the temperature remaining below 5° C.

[0041] The solution was allowed to stand for 65 minutes to ensure the best crystallization, with the temperature remaining below 3° C. The white suspension was filtered on a Buchner funnel filter, giving a non-tacky white powder. The precipitate was dried overnight in a drying cabinet at 40° C. under vacuum, which gave 9.465 g of Intermediate (I).

EXAMPLE 2

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[0043] 109.1 g (0.825 mol) of 1,5-bis-(methylamino)-3-oxapentane and 1.5 litres of acetonitrile were introduced into a reaction vessel with an inert atmosphere. The resulting solution was cooled to 0° C., and 226 g (0.75 mol) of Intermediate (1) was added to it. The mixture thus obtained was stirred first for 6 hours at 10° C., and then for 3 days at 0° C. The precipitate was filtered off and washed with acetonitrile. After drying at 25° C., Compound `B` was obtained in a yield of 95 g (40.6%, corrected for purity) in the form of white crystals.

EXAMPLE 3

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[0045] 0.400 g (0.82 mmol, 1 Eq) of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy- 7H-indolo-[2,1-a]-[2]-benzazepine-6-carboxylic acid (called Compound 1b on page 38 of WO 2010/003658), 0.164 g of HOBt (1.07 mmol, 1.3 Eq) and 0.201 g of EDCI (1.07 mmol, 1.3 Eq) were dissolved in 6.5 ml of MeTHF (8 l/mol) in a closed glass flask. The contents of the flask were stirred for 1 hour at room temperature. 0.469 g of Compound `B` (64.3 wt-%, 0.98 mmol, 1.2 Eq) was then added to the reaction mixture, which was analysed after a reaction time of 18 hours. Analysis by LC indicated that Intermediate (2) had been obtained in a yield of 93.1%.

EXAMPLE 4

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[0047] 12.00 g (24.61 mmol, 1 Eq) of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy- 7H-indolo-[2,1-a]-[2]-benzazepine-6-carboxylic acid, 4.92 g of HOBt (31.99 mmol, 1.3 Eq) and 6.03 g of EDCI (31.99 mmol, 1.3 Eq) were introduced into a 100-ml flask and dissolved in 200 ml of MeTHF (8 l/mol). The contents of the flask were stirred for 1 hour at room temperature. Then 11.663 g of Compound `B` (77.4 wt-%, 29.53 mmol, 1.2 Eq) was added, and the reaction mixture was analysed after a reaction time of 18 hours. Analysis by LC indicated that Intermediate (2) had been obtained in a yield of 98.3%.

[0048] The reaction mixture was then extracted and washed first with two 180-ml portions of H₂O (15 l/mol), and then with two 180-ml portions of an NaHCO₃ solution (15 l/mol). The organic layer was dried with 2.4 g of Na₂SO₄ and filtered, after which the volume of the filtrate obtained was determined. 60 ml of MeTHF was added to make up the volume to 200 ml (8 l/M). Analysis by LC indicated that Intermediate (2) had been obtained in a yield of 93.7%.

EXAMPLE 5

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[0049] Experiment A

[0050] To 13.722 g of Intermediate (2) (16.4 wt-%, 1 Eq, 2.88 mmol) dissolved in MeTHF (8 l/mol) in a 100-ml flask without a nitrogen atmosphere(this solution contained 2.17 wt-% of water), 251 pl of water was added to bring the water content up to 4 wt-%. After the addition of 1.9 ml of MeSO₃H (1 Eq, 28.8 mmol), the reaction mixture was placed on an oil bath heated to 50° C. A sample was taken and analysed after a reaction time of 5 hours. After a reaction time of 22 hours, the reaction mixture was brought to room temperature, and sampled again for analysis. The whole reaction mixture weighed 15.022 g.

Analysis by LC

[0051] After 5 hours: 90.1% of Compound `A`

[0052] After 22 hours: 75.4% of Compound `A`

Experiment B

[0053] 119.6 g of Intermediate (2) (10.27 wt-%, 15.7 mmol, 1 Eq) was dissolved in MeTHF (8 l/mol) in a reaction vessel with a nitrogen atmosphere. The solution contained 2.21 wt-% of water. 2.81 g of water were added to bring the water content up to 4 wt-%. After the addition of 10.31 ml of MeSO₃H (157 mmol, 10 Eq), the reaction mixture was heated to 50° C. After a reaction time of 5 hours, the reaction mixture was cooled to room temperature, and a sample of it was analysed. The whole reaction mixture weighed 119.6 g.

Analysis by LC

[0054] 92.7% of Compound `A`

Claims

1.-7. (canceled)

8. tert-Butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate, and acid-addition salts thereof. ##STR00015##

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