Patent Application
20240109894
The present invention relates to a chemical synthesis route for preparing the RSV inhibiting compound 3-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one, and to new compounds used as intermediate compounds in the multistep process.
Respiratory syncytial virus is a major cause of acute lower respiratory tract infection in young children, immunocompromised adults, and the elderly. Intervention with small-molecule antivirals specific for respiratory syncytial virus presents an important therapeutic opportunity, but no such compound is approved today.
Compound (1), i.e. 3-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one, which can represented by the following structure:
inhibits the replication of the respiratory syncytial virus (RSV) and has been described in WO-2012/080447 as compound P55.
The general pathway for the synthesis of compounds disclosed in WO-2012/080447 involves a Mitsunobu reaction between 2-hydroxymethyl substituted indoles and N-substituted 2-oxo-imidazopyridines. The Mitsunobu reaction, while very useful in small scale laboratory preparations, entails reagents (typically an excess of diisopropyl azodicarboxylate and of triphenylphosphine) that are not preferable in an industrial process. Those reagents generate stoichiometric amounts of diisopropylhydrazodicarboxylate and triphenylphosphine oxide as by-products, or similar by-products if alternative azodicarboxylates and phosphines are used. Removal of those by-products requires elaborate purifications via chromatography or multiple recrystallizations or re-slurries. Those purification operations are not desirable on large scale as they increase the cost of the final product by consuming solvents and purification aids (e.g., silica gel) and also decrease the yield of the desired product. Furthermore, the extended processing time in the plant to remove the reaction by-products, as well as the cost of their disposal, greatly reduce the usefulness of the Mitsunobu reaction at industrial production scale.
The general pathway for the synthesis of compounds disclosed in WO-2012/080447 can be found in Scheme 1 on page 11 and is depicted below:
The coupling reaction as used in WO-2012/080447 to make the compounds of formula (I) of WO-2012/080477 is done according to Mitsunobu reaction conditions using diisopropyl azodicarboxylate and triphenyl phosphine in a suitable solvent such as DMF or THF. Use of the Mitsunobu route results in high levels of impurities that cannot easily be purged from the final compound by crystallization, preventing this process to be considered for commercial manufacturing. The use of the Mitsunobu reaction also results in the isolation of Compound (1) as a grey solid which is not desirable. The discoloration needs to be removed by chromatography, a purification technique that is not preferred for large scale production.
Hence, there is a need for an improved general synthesis route to obtain Compound (1) in high yield and with excellent purity that avoids the use of the Mitsunobu conditions at industrial scale. The process described herein affords highly pure, crystalline intermediates and Compound (1) with purity suitable for manufacturing the drug product. Each chemical step of this novel process is high yielding, uses cheap, safe and commercially available reagents, has a high atom-economy, and allows very efficient purification by crystallization from the reaction mixture.
A novel three-step process for preparing Compound (1) has been found that comprises the steps of amide formation, carbonyl reduction, and cyclization without the need to use Mitsunobu reaction conditions.
In a first embodiment, the present invention relates to a process for preparing Compound (1)
comprising the consecutive steps of
with N4-(2,2,2-trifluoroethyl)pyridine-3,4-diamine of formula (b)
in an appropriate solvent in the presence of a coupling agent and optionally a base; to obtain 5-chloro-1-(3-(methylsulfonyl)propyl)-N-(4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)-1H-indole-2-carboxamide of formula (c);
In a second embodiment the present invention concerns a novel compound of formula (a)
which is 5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indole-2-carboxylic acid.
In a third embodiment the present invention concerns a novel compound of formula (c)
which is 5-chloro-1-(3-(methylsulfonyl)propyl)-N-(4-(2,2,2-trifluoroethyl)amino)pyridin-3-yl)-1H-indole-2-carboxamide.
In a fourth embodiment the present invention concerns a novel compound of formula (d)
which is N3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-N4-(2,2,2-trifluoro-ethyl)pyridine-3,4-diamine.
Step a) is an art-known amide bond formation reaction between a carboxylic acid compound of formula (a) and an amine of formula (b) wherein said amide-bond formation can be performed by mixing the compounds (a) and (b) in an appropriate solvent in the presence of a coupling agent and optionally a base. Appropriate solvents are polar aprotic solvents such as, e.g., N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methylpyrrolidone, N-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile, and butyronitrile. The carboxylic acid compound of formula (a) can be used as such or can first be converted into an activated functional derivative thereof, e.g., acyl isourea, acyl imidazolide, acyl halide, or mixed anhydride. Convenient amide coupling agents are, e.g., EDC (N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride), DIC (N,N′-diisopropylcarbodiimide), DCC (N,N′-dicyclo-hexylcarbodiimide), CDI (1,1′-carbonyldiimidazole), and T3P® (1-propanephosphonic anhydride). Suitable optional bases for use in amide-bond formation reactions are, e.g., trialkyl amines (such as triethylamine, tributylamine, and N,N-diisopropylethylamine), cyclic amines (such as DBU (1,8-diaza-bicyclo[5.4.0]undec-7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene)), pyridine type compounds (such as pyridine, 2- and 4-picoline, and 2,6-lutidine), and DMAP (4-dimethylamino-pyridine). The reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. A highly desirable feature of the above described transformation is the high regioselectivity in the amide-forming step: no coupling is observed between the carboxylic acid of compound (a) and the secondary amine of compound (b), leading to increased yield and purity of compound (c).
Step b) is the conversion of the carbonyl group in the compound of formula (c) to a methylene group by treatment with an appropriate reducing agent. Appropriate reducing agents are, e.g., silicon hydrides (such as Et3SiH and PMHS (poly(methylhydrosiloxane))), aluminium hydrides (such as Dibal-H (diisobutylaluminium hydride) and RedAl (sodium bis(2-methoxy-ethoxy)aluminium hydride)), and boron hydrides (such as LiBH4, NaBH4, and borane complexes BH3.THF, and BH3.Me2S). Borane complexes can conveniently be generated in situ from NaBH4 and a Brønsted acid such as sulfuric acid or a Lewis acid such as boron trihalides (optionally as a complex with an ether solvent), aluminium trichloride, or iodine. Suitable solvents for the amide reduction reaction are ethers, e.g., tetrahydrofuran (THF) and 2-methyl-tetrahydrofuran (2-Me-THF).
In step c) the diamine compound (d) is converted into Compound (1) using a carbonyl transfer reagent such as, e.g., CDI, urea, phosgene, diphosgene, triphosgene, or a chloro-formate such as ethyl or phenyl chloroformate; in a suitable aprotic solvent, e.g., ethyl acetate, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethyl acetamide, N,N-dimethyl formamide, or N-methylpyrrolidone, to provide Compound (1). Optionally, an organic base is added, e.g., triethylamine, tributylamine, N,N-diisopropyl-ethylamine, cyclic amines (such as DBU (1,8-diaza-bicyclo[5.4.0]-undec-7-ene) or DBN (1,5-diazabicyclo[4.3.0]non-5-ene)), imidazoles (such as imidazole or N-methylimidazole), pyridines (such as pyridine, 2- or 4-picoline, or 2,6-lutidine), DMAP (4-dimethylaminopyridine), or an inorganic base such as potassium carbonate.
Compound (1) can optionally be further purified by art-known techniques such as column chromatography or crystallisation.
3-(Methylthio)propan-1-ol (100.00 g) is dissolved under nitrogen atmosphere in dichloromethane (500 mL) and tosyl chloride (188.50 g) is added. The solution is cooled to 0° C.; N,N,N′,N′-tetramethyl-1,6-hexanediamine (4.87 g) and triethylamine (114.40 g) are then added. After completion of the tosylation reaction, water is added and the mixture is stirred at a temperature of 10-15° C. After phase separation, the organic layer is washed with diluted aqueous HCl and subsequently with water. The organic layer is then added dropwise at 25° C. to a vessel containing a solution of potassium peroxymonosulfate (Oxone™) (752.60 g) in water (3000 mL) and stirred until complete oxidation. The organic layer is then washed with water; MTBE (1000 mL) is then added dropwise to the organic layer and, after complete addition, the mixture is cooled to 0° C. The solid is then filtered and dried under reduced pressure to give the product (246.70 g, 90% yield).
1H NMR (600 MHz, CDCl3) δ ppm 2.15-2.28 (m, 2H); 2.45 (s, 3H); 2.91 (s, 3H); 3.05-3.17 (m, 2H); 4.17 (t, J=5.95 Hz, 2H); 7.37 (d, J=8.12 Hz, 2H); 7.78 (d, J=8.31 Hz, 2H) 13C NMR (151 MHz, CDCl3) δ ppm 21.89; 22.45; 41.39; 51.06; 68.06; 128.22; 130.24; 132.72; 145.50
Citric acid monohoydrate (295.00 g) is dissolved in water (370.00 g) and 4-methoxy-3-nitropyridine (179.00 g) is added followed by 2,2,2-trifluoroethylamine (348.00 g). The mixture is stirred at 50° C. until complete conversion. After cooling to room temperature, 2-methyl-tetrahydrofuran (1250 mL) is added and the phases are separated. The aqueous phase is re-extracted with 2-methyltetrahydrofuran (530 mL). The combined organic layers are washed with 7% aqueous NaHCO3 solution (890.00 g) and with water (903.00 g). The organic layer is concentrated to approximately 600 mL. Ethanol (1000 mL) is added, followed by Pd/C (10%, 50% wet, 7.50 g). The mixture is hydrogenated under 45-50 psi (310-345 kPa) hydrogen gas until complete conversion, then cooled to 30-40° C. and filtered over diatomaceous earth (Celite®), and the cake is washed with ethanol. The solvent is switched to pure 2-methyltetrahydrofuran by atmospheric distillation and parallel dosing of 2-methyltetrahydrofuran, reaching a volume of approximately 500 mL. The mixture is cooled to 50-55° C. and toluene (1700 mL) is slowly added. After complete addition, the mixture is cooled to 0-5° C. and the solid is then filtered and dried under reduced pressure to give product (b) (204.00 g, 92% yield).
1H NMR (600 MHz, DMSO-d6) δ ppm 4.03 (qd, J=9.50, 6.80 Hz, 2H); 4.66 (br s, 2H); 5.88 (t, J=6.80 Hz, 1H); 6.60 (d, J=5.29 Hz, 1H); 7.62 (d, J=5.29 Hz, 1H); 7.71 (s, 1H).
13C NMR (151 MHz, DMSO-d6); δ ppm 43.08 (q, J=32.9 Hz); 104.68; 125.61 (q, J=281.0 Hz); 131.02; 135.30; 139.53; 139.94
Ethyl-5-chloro-1H-indole-2-carboxylate (50.00 g), 3-(methylsulfonyl)propyl-4-methylbenzene-sulfonate (71.90 g), potassium carbonate (61.79 g), and tetrabutylammonium hydrogensulfate (3.79 g) are mixed in toluene (500 mL). The mixture is heated to 70° C. until complete conversion, then water (250 mL) is slowly added and the phases are separated at 60° C. The water layer is discarded and water (100 mL) and 50% aqueous NaOH (23.25 g) are added; the mixture is stirred at 60° C. until complete conversion. Water (150 mL) is added and the phases are separated at 60° C. A 80% portion (285.10 g) of the aqueous layer obtained (the other 20% was used for other purposes) is added in portions to a mixture of 34.5% w/w HCl (34.00 g), water (71 mL) and isopropanol (500 mL) at 50° C. Seeding material is added after 25% addition of the aqueous solution. The mixture is stirred for 4 hours at 50° C. and then slowly cooled to 15° C. The product is filtered, washed with a mixture of water (36 mL) and isopropanol (36 mL) and dried under reduced pressure to obtain the product (a) (52.90 g, 93% yield).
1H NMR (600 MHz, DMSO-d6) δ ppm 2.07-2.18 (m, 2H); 2.96 (s, 3H); 3.07-3.14 (m, 2H); 4.67 (t, J=7.18 Hz, 2H); 7.24 (d, J=0.76 Hz, 1H); 7.35 (dd, J=9.06, 2.27 Hz, 1H); 7.70 (d, J=9.06 Hz, 1H); 7.77 (d, J=2.20 Hz, 1H).
13C NMR (151 MHz, DMSO-d6) δ ppm 23.31; 39.99; 42.63; 50.92; 109.67; 112.63; 121.33; 124.83; 125.02; 126.39; 129.22; 137.03; 162.44.
5-Chloro-1-(3-(methylsulfonyl)propyl)-1H-indole-2-carboxylic acid (=compound (a)) (25.00 g) and N4-(2,2,2-trifluoroethyl)pyridine-3,4-diamine (=compound (b)) (15.10 g) are mixed with DMAP (4-dimethyl-aminopyridine) (9.67 g) in acetonitrile (198 mL) at 20° C. under nitrogen atmopshere. EDC (1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride) (30.35 g) is added and after 30 minutes at 20° C. the mixture is gradually heated to 55° C. After additional 2 hours the mixture is gradually heated to 73° C. and water (253 mL) is added over 1 hour. After 30 minutes, seeding material is added. The mixture is gradually cooled to 20° C., after 2 hours filtered and the cake is washed with a mixture of acetonitrile (24 mL) and water (40 mL) and dried under reduced pressure to obtain the product (c) (35.08 g, 91% yield).
1H NMR (600 MHz, DMSO-d6) 1H NMR (600 MHz, DMSO-d6) δ ppm 2.13-2.23 (m, 2H); 2.95 (s, 3H); 3.08-3.19 (m, 2H); 4.00-4.11 (m, 2H) 4.65 (br t, J=7.18 Hz, 2H); 6.66 (br t, J=6.61 Hz, 1H); 6.89 (d, J=6.04 Hz, 1H); 7.34 (dd, J=8.88, 2.08 Hz, 1H); 7.44 (s, 1H); 7.71 (d, J=8.69 Hz, 1H); 7.82 (d, J=1.51 Hz, 1H); 8.10 (s, 1H); 8.13 (d, J=5.67 Hz, 1H); 9.89 (s, 1H).
13C NMR (151 MHz, DMSO-d6) δ ppm 23.29; 39.99; 42.79; 42.88 (q, J=33.2 Hz); 51.01; 105.81; 105.85; 112.33; 119.22; 120.90; 125.50 (q, J=282.1 Hz); 124.11; 124.96; 126.65; 132.42; 136.30; 148.16; 148.43; 149.23; 161.09.
Compound (c) (45.00 g) is suspended in THF (450 mL) and the solvent is distilled with continuous addition of THF until the water content is <0.05% w/w. NaBH4 (10.45 g) is then added followed by slow addition of BF3.THF (51.51 g). Upon complete conversion, methanol (460 mL) is slowly dosed. The solvent is distilled and switched to pure 2-methyltetrahydrofuran (about 700 mL). Water (340 mL) and 50% aqueous NaOH (8.6 mL) are added. The mixture is stirred at 52° C. for 16-24 hours, with continuous addition of 50% aqueous NaOH to keep the pH between 9.5 and 10.5. After phase separation the organic layer is washed at 52° C. with water (368 mL). The organic phase is then azeotropically dried by distillation at atmospheric pressure and concentrated to a volume of about 300 mL. The mixture is gradually cooled to 15° C., after 8 hours filtered, washed with 2-methyltetrahydrofuran and dried under reduced pressure to obtain the product (d) (33.8 g, 77% yield).
1H NMR (600 MHz, DMSO-d6) δ ppm 2.12 (dd, J=7.60 Hz, 2H); 2.94 (s, 3H); 3.17 (t, J=7.81 Hz, 2H); 4.01-4.10 (m, 2H); 4.35 (t, J=7.45 Hz, 2H); 4.51 (d, J=5.27 Hz, 2H); 5.09 (t, J=5.18 Hz, 1H); 6.07 (t, J=6.63 Hz, 1H); 6.50 (s, 1H); 6.67 (d, J=5.27 Hz, 1H); 7.14 (dd, J=8.83, 1.91 Hz, 1H); 7.55 (d, J=8.90 Hz, 1H); 7.57 (d, J=2.00 Hz, 1H); 7.73 (d, J=5.45 Hz, 1H); 7.82 (s, 1H).
13C NMR (151 MHz, DMSO-d6) δ ppm 23.48; 40.35; 40.57; 41.97; 43.65 (q, J=32.7 Hz); 51.38; 101.45; 104.78; 111.68; 119.61; 121.41; 126.10 (q, J=282.3 Hz); 124.45; 128.83; 131.23; 132.55; 135.69; 139.75; 140.82; 141.24.
Compound (d) (38.00 g) and carbonyl diimidazole (26.00 g) are suspended in acetonitrile (480 mL) and the mixture is heated to 75° C. until complete conversion. Acetonitrile (480 mL) is added, the mixture is cooled to 60° C., and seeding material is added followed by water (2.90 g). The mixture is concentrated by reduced pressure distillation at about 10° C. to a final volume of about 350 mL. The slurry is filtered, washed with acetonitrile and dried under reduced pressure to obtain the product Compound (1) (36.00 g, 90% yield).
Compound (1) is further purified by crystallization from a mixture of 2-butanone and water (90; 10 v/v, 10 volumes).
1H NMR (500 MHz, DMSO-d6) δ ppm 1.95 (m, 2H); 2.98 (s, 3H); 3.15 (t, J=7.90 Hz, 2H); 4.38 (t, J=7.90 Hz, 2H); 4.89 (q, J=9.30 Hz, 2H); 5.40 (s, 2H); 6.48 (s, 1H); 7.17 (dd, J=8.70, 2.30 Hz, 1H); 7.44 (d, J=5.30 Hz, 1H); 7.55 (d, J=9.10 Hz, 1H); 7.57 (d, J=1.90 Hz, 1H); 8.31 (d, J=5.30 Hz, 1H); 8.49 (s, 1H).
13C NMR (125 MHz, DMSO-d6) δ ppm 22.95; 37.55; 41.60; 40.20; 42.07 (q, J=34.0 Hz); 50.82; 101.91; 104.59; 111.56; 119.56; 121.70; 124.32 (q, J=279.9 Hz); 124.31; 126.19; 128.04; 129.96; 134.98; 135.28; 135.57; 143.26; 152.44.
Melting point (DSC): 216° C.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/CN2019/114254 | Oct 2019 | WO | international |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/080381 | 10/29/2020 | WO |
