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WO2022184606A1 - Synthesis of rilematovir - Google Patents

Synthesis of rilematovir Download PDF

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Publication number
WO2022184606A1
WO2022184606A1 PCT/EP2022/054915 EP2022054915W WO2022184606A1 WO 2022184606 A1 WO2022184606 A1 WO 2022184606A1 EP 2022054915 W EP2022054915 W EP 2022054915W WO 2022184606 A1 WO2022184606 A1 WO 2022184606A1
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Prior art keywords
formula
alkyl
compound
trifluoroethyl
chloro
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PCT/EP2022/054915
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French (fr)
Inventor
Johan Erwin Edmond Weerts
Marialuisa AUFIERO
Sebastian GAUPP
Florian Damien MEDINA
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Janssen Sciences Ireland Unlimited Company
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Publication of WO2022184606A1 publication Critical patent/WO2022184606A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a multi-step chemical synthesis route for preparing rilematovir, a small molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus (RSV), that is in clinical development for the treatment of infection by RSV.
  • RSV respiratory syncytial virus
  • 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.
  • Rilematovir i.e. 3-( ⁇ 5-chloro-1-[3-(methylsulfonyl)propyl]-1H -indol-2-yl ⁇ methyl)-1 -(2,2,2- trifluoroethyl)-1 ,3-dihydro-2 H-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.
  • RSV respiratory syncytial virus
  • the general pathway for the synthesis of compounds disclosed in WO-2012/080447 involves a Mitsunobu reaction between 2-hydroxymethyl substituted indoles and /V-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 coupling reaction as used in WO-2012/080447 to make the compounds of formula (I) of WO-2012/080447 is done according to Mitsunobu reaction conditions using diisopropyl azodicarboxylate and triphenyl phosphine in a suitable solvent such as DMF or THF.
  • 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 rilematovir 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.
  • a novel multi-step process for preparing rilematovir comprises the steps of /V-alkylation, amide formation, carbonyl reduction, and cyclization without the need to use Mitsunobu reaction conditions.
  • the present invention relates to a process for preparing rilematovir comprising the consecutive steps of a) reacting a compound of formula (a), wherein R 1 is C 1-6 alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C 1-4 alkyl, halo, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, or polyhaloC 1-4 alkyloxy, with a compound of formula (b), wherein W is a leaving group selected from chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, p-methylbenzenesulfonyloxy, and trifluoromethanesulfonyloxy, in a suitable solvent in the presence of a base and optionally in the presence of a phase transfer catalyst to obtain a compound of formula (c), wherein R 1 is C 1-6 alkyl or ary
  • - halo is generic to fluoro, chloro, bromo and iodo
  • - C 1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methyl-propyl and the like;
  • - C 1-6 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methyl-propyl, pentyl, hexyl, and the like; and
  • polyhaloC 1-4 alkyl is defined as polyhalosubstituted C 1-4 alkyl, in particular C 1-4 alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like.
  • Compound (a) is wherein R 1 is C-
  • R 1 is C 1-6 alkyl. More particularly R 1 is ethyl.
  • Compound (b) is wherein W is a leaving group such as, for example, halo, e.g. chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, arylsulfonyloxy such as benzenesulfonyloxy or p-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy and the like reactive leaving groups.
  • W is a sulfonyloxy group. More particularly W is p-methyl- benzenesulfonyloxy.
  • Compound (c) is : wherein R 1 is C-
  • R 1 is C 1-6 alkyl. More particularly R 1 is ethyl.
  • Step a) is an /V-alkylation reaction of a compound of formula (a) with a compound of formula (b) wherein W is an appropriate leaving group such as, for example, halo, e.g. chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, arylsulfonyloxy such as benzenesulfonyloxy or p-methylbenzenesulfonyloxy, trifluoromethane- sulfonyloxy and the like reactive leaving groups.
  • W is an appropriate leaving group such as, for example, halo, e.g. chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, arylsulfonyloxy such as benzenes
  • the reaction can be performed in a suitable solvent such as, for example, acetonitrile, 2-pentanol, isobutanol, dimethyl acetamide, dichloromethane, chloroform, 1,2-dichloroethane, DMF, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, or any mixture thereof, and in the presence of a base such as, for example, sodium carbonate, potassium carbonate, potassium phosphate or triethylamine.
  • a phase transfer catalyst are usually quaternary ammonium salts or phosphonium salts such as e.g.
  • benzyltriethylammonium chloride methyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, or hexadecyltributylphosphonium bromide.
  • the suitable solvent may contain an amount of water. Stirring may enhance the rate of the reaction.
  • the reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. Reaction rate and yield may be enhanced by microwave assisted heating.
  • Step b) is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suitable base.
  • suitable solvents are polar aprotic solvents such as, e.g., / ⁇ /,/ ⁇ /-dimethyl formamide, / ⁇ /,/ ⁇ /-dimethyl acetamide, /V-methylpyrrolidone, /V-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile.
  • Suitable bases are for instance alkoxide bases (e.g. potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert-pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride).
  • the reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
  • Step c) is the conversion of the carbonyl group in the compound of formula (e) to a methylene group by treatment with an appropriate reducing agent.
  • suitable reducing agents are, e.g., silicon hydrides (such as Et3SiH and PMHS (poly(methylhydrosiloxane))), aluminium hydrides (such as DIBAL-H (diisobutylaluminium hydride) and sodium bis(2-methoxy- ethoxy)aluminium hydride (e.g., Red-AI ® ), and boron hydrides (such as LiBH 4 , NaBH 4 , and borane complexes BH 3 .THF, and BH 3 .Me 2 S).
  • silicon hydrides such as Et3SiH and PMHS (poly(methylhydrosiloxane)
  • aluminium hydrides such as DIBAL-H (diisobutylaluminium hydride) and sodium bis(2-meth
  • Borane complexes can conveniently be generated in situ from NaBFU and a Bronsted 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).
  • step d) the diamine compound (f) is converted into rilematovir using a carbonyl transfer reagent such as, e.g., carbonyl diimidazole (CDI), urea, phosgene, diphosgene, triphosgene, or a chloroformate such as ethyl or phenyl chloroformate; in a suitable aprotic solvent, e.g., ethyl acetate, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyl- tetrahydrofuran, / ⁇ /,/ ⁇ /-dimethyl acetamide, / ⁇ /,/ ⁇ /-dimethyl formamide, or /V-methylpyrrolidone, to provide rilematovir.
  • a carbonyl transfer reagent such as, e.g., carbonyl diimidazole (CDI), urea, phosgene, diphos
  • an organic base is added, e.g., triethylamine, tributylamine, / ⁇ /,/ ⁇ /-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 /V-methy- limidazole), pyridines (such as pyridine, 2- or 4-picoline, or 2,6-lutidine), DMAP (4-dimethyl- aminopyridine), L/,L/,L/',L/'-tetramethyl-guanidine (TMG), 1,3,4,6,7,8-hexahydro-2H -pyrimido[1,2- a]pyrimidine (TBD or triazabicyclo-decene), 1,3,4,6,7,7
  • Rilematovir can optionally be further converted into a pharmaceutically acceptable acid addition salt.
  • the pharmaceutically acceptable acid addition salts of rilematovir as mentioned herein are meant to comprise the therapeutically active non-toxic acid salt forms which rilematovir is able to form. These forms can conveniently be obtained by treating rilematovir with an appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxy- butanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluene- sulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • the present invention relates to a process for preparing 5-chloro-1 -(3-(methylsulfonyl)propyl)-/ ⁇ /-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e); comprising the consecutive steps of a) reacting a compound of formula (c), wherein R 1 is C 1-6 alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C 1-4 alkyl, halo, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, or polyhaloC 1-4 alkyloxy; with L/ 4 -(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
  • the above reaction is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suitable base.
  • suitable solvents are polar aprotic solvents such as, e.g., / ⁇ /,/ ⁇ /-dimethyl formamide, / ⁇ /,/ ⁇ /-dimethyl acetamide, /V-methylpyrrolidone, /V-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile.
  • Suitable bases are for instance alkoxide bases (e.g. potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert-pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride).
  • the reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
  • the present invention relates to a process for preparing /V 3 -(( 5- chloro-1-(3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)-/ ⁇ / 4 -(2,2,2-trifluoroethyl)pyridine-3,4- diamine of formula (f); comprising the consecutive steps of a) reacting a compound of formula (c), wherein R 1 is C 1-6 alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C 1-4 alkyl, halo, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, or polyhaloC- ⁇ alkyloxy; with L/ 4 -(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d) in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1
  • Step a) in the third embodiment is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suitable base.
  • suitable solvents are polar aprotic solvents such as, e.g., / ⁇ /,/ ⁇ /-dimethyl formamide, N,N-dimethyl acetamide, /V-methylpyrrolidone, /V-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile.
  • Suitable bases are for instance alkoxide bases (e.g. potassium tert- butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert- pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride).
  • the reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
  • Step b) in the third embodiment is the conversion of the carbonyl group in the compound of formula (e) to a methylene group by treatment with an appropriate reducing agent.
  • suitable reducing agents are, e.g., silicon hydrides (such as EtsSiH and PMHS (poly(methylhydrosiloxane))), aluminium hydrides (such as DIBAL-H (diisobutylaluminium hydride) and sodium bis(2-methoxy-ethoxy)aluminium hydride (e.g., Red-AI ® ), and boron hydrides (such as LiBH 4 , NaBH 4 , and borane complexes BH 3 .THF, and BH 3 .Me 2 S).
  • silicon hydrides such as EtsSiH and PMHS (poly(methylhydrosiloxane)
  • aluminium hydrides such as DIBAL-H (diisobutylaluminium hydride) and sodium bis(
  • Borane complexes can conveniently be generated in situ from NaBH4 and a Br ⁇ nsted 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).
  • the present invention relates to a process for preparing rilematovir comprising the consecutive steps of b) reacting a compound of formula (c), wherein R 1 is C 1-6 alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C 1-4 alkyl, halo, C 1-4 alkyloxy, polyhaloC 1-4 alkyl, or polyhaloC 1-4 alkyloxy; with N 4 -(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
  • Step a) of the fourth embodiment is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suited base.
  • Appropriate solvents are polar aprotic solvents such as, e.g., N,N- dimethyl formamide, L/,/V-dimethyl acetamide, /V-methylpyrrolidone, /V-butyl-pyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile.
  • Suitable bases are for instance alkoxide bases (e.g. potassium tert- butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert- pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride).
  • the reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
  • Step b) of the fourth embodiment is the conversion of the carbonyl group in the compound of formula (e) to a methylene group by treatment with an appropriate reducing agent.
  • suitable reducing agents are, e.g., silicon hydrides (such as Et3SiH and PMHS (poly(methylhydrosiloxane))), aluminium hydrides (such as DIBAL-H (diisobutylaluminium hydride) and sodium bis(2-methoxy-ethoxy)aluminium hydride (e.g., Red-AI ® ), and boron hydrides (such as LiBH 4 , NaBH 4 , and borane complexes BH 3 .THF, and BH 3 .Me 2 S).
  • silicon hydrides such as Et3SiH and PMHS (poly(methylhydrosiloxane)
  • aluminium hydrides such as DIBAL-H (diisobutylaluminium hydride) and sodium bis(
  • Borane complexes can conveniently be generated in situ from NaBH4 and a Br ⁇ nsted 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).
  • step c) of the fourth embodiment the diamine compound (f) is converted into rilematovir 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-methyl- tetrahydrofuran, N,N-dimethyl acetamide, N,/V-dimethyl formamide, or /V-methylpyrrolidone, to provide rilematovir.
  • a carbonyl transfer reagent such as, e.g., CDI, urea, phosgene, diphosgene, triphosgene, or a chloro-formate such as ethy
  • an organic base is added, e.g., triethylamine, tributylamine, L/,/V-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- methyl- imidazole), pyridines (such as pyridine, 2- or 4-picoline, or 2,6-lutidine), DMAP (4-dimethyl- aminopyridine), L/,L/,L/',L/'-tetramethylguanidine (TMG), 1,3,4,6,7,8-hexahydro-2H -pyrimido[1,2- a]pyrimidine (TBD or triazabicyclodecene), 1,3,4,6,7,8-hexahydro-1-methyl,
  • Example 1 synthesis of 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate
  • 3-(Methylthio)propan-1-ol (100.00 g) is dissolved under nitrogen atmosphere in dichloro- methane (500 ml_) and tosyl chloride (188.50 g) is added. The solution is cooled to 0°C; / ⁇ /,/ ⁇ /,/ ⁇ /',/ ⁇ /'-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 HCI and subsequently with water.
  • the organic layer is then added dropwise at 25°C to a vessel containing a solution of potassium peroxymonosulfate (OxoneTM) (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).
  • Example 2 synthesis of / ⁇ / 4 -(2.2.2-trifluoroethyl)pyridine-3,4-diamine compound (d)
  • 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 NaHCCh 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-methyl- tetrahydrofuran 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 (d) (204.00 g, 92% yield).
  • Example 3 synthesis of ethyl 5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indole-2- carboxylate
  • Ethyl-5-chloro-1H -indole-2-carboxylate (10.00 g), 3-(methylsulfonyl)propyl-4-methylbenzene- sulfonate (14.38 g), potassium phosphate (12.34 g), and tetrabutylammonium hydrogen sulfate (0.76 g) are mixed in 2-methyltetrahydrofuran (100.60 mL) and water (0.40 mL). The mixture is heated to 70°C until complete conversion, then water (50.00 mL) is added and the phases are separated at 60°C.
  • the resulting organic layer, containing ethyl 5-chloro-1-(3-(methylsulfonyl)- propyl)-1H-indole-2-carboxylate in solution is used in the next step to convert to 5-chloro-1-(3- (methylsulfonyl)propyl)-/ ⁇ /-(4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)-1H -indole-2-carboxamide.
  • Example 4 synthesis of 5-chloro-1-(3-(methylsulfonyl)propyl)-/ ⁇ /-(4-((2,2.2- trifluoroethvl)amino)pvridin-3-vl)-1H-indole-2-carboxamide - compound (e)
  • Example 5 synthesis of / ⁇ / 3 -((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2- yl)methyl)-/ ⁇ / 4 -(2.2.2-trifluoroethyl)pyridine-3.4-diamine - compound (f)
  • Rilematovir is further purified by crystallization from a mixture of 2-butanone and water (90; 10 v/v, 10 volumes).

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Abstract

The present invention relates to a multi-step chemical synthesis route for preparing rilematovir, a small molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus (RSV), that is in clinical development for the treatment of infection by RSV.

Description

SYNTHESIS OF RILEMATOVIR
[0001] The present invention relates to a multi-step chemical synthesis route for preparing rilematovir, a small molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus (RSV), that is in clinical development for the treatment of infection by RSV.
Background
[0002] 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.
[0003] Rilematovir, i.e. 3-({5-chloro-1-[3-(methylsulfonyl)propyl]-1H -indol-2-yl}methyl)-1 -(2,2,2- trifluoroethyl)-1 ,3-dihydro-2 H-imidazo[4,5-c]pyridin-2-one, which can represented by the following structure :
Figure imgf000002_0001
inhibits the replication of the respiratory syncytial virus (RSV) and has been described in WO-2012/080447 as compound P55.
Prior art
[0004] The general pathway for the synthesis of compounds disclosed in WO-2012/080447 involves a Mitsunobu reaction between 2-hydroxymethyl substituted indoles and /V-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.
[0005] 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 :
Scheme 1 of WO-2012/080447
(II) (III) (I)
[0006] The coupling reaction as used in WO-2012/080447 to make the compounds of formula (I) of WO-2012/080447 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 rilematovir 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.
[0007] Hence, there is a need for an improved general synthesis route to obtain rilematovir 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 rilematovir 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. Description of the invention
[0008] A novel multi-step process for preparing rilematovir has been found that comprises the steps of /V-alkylation, amide formation, carbonyl reduction, and cyclization without the need to use Mitsunobu reaction conditions.
[0009] In a first embodiment, the present invention relates to a process for preparing rilematovir
Figure imgf000004_0002
comprising the consecutive steps of a) reacting a compound of formula (a), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy,
Figure imgf000004_0001
with a compound of formula (b), wherein W is a leaving group selected from chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, p-methylbenzenesulfonyloxy, and trifluoromethanesulfonyloxy,
Figure imgf000004_0003
in a suitable solvent in the presence of a base and optionally in the presence of a phase transfer catalyst to obtain a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy;
Figure imgf000005_0001
b) reacting a compound of formula (c) with N 4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000005_0002
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3-(methylsulfonyl)propyl)-/\/-(4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)- 1H -indole-2-carboxamide of formula (e);
Figure imgf000005_0003
c) reducing the carbonyl group in compound (e) with a reducing agent to obtain N 3-((5-chloro- 1-(3-(methylsulfonyl)propyl)-1 H-indol-2-yl)methyl)-/\/4-(2,2,2-trifluoroethyl)pyridine-3,4- diamine of formula (f);
Figure imgf000005_0004
d) and reacting compound (f) in a suitable aprotic solvent with a carbonyl transfer reagent, optionally in the presence of an organic or inorganic base, to obtain rilematovir which can optionally be further converted into a pharmaceutically acceptable acid addition salt.
[0010] As used in the foregoing definitions :
- halo is generic to fluoro, chloro, bromo and iodo;
- C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methyl-propyl and the like; and
- C1-6alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methyl-propyl, pentyl, hexyl, and the like; and
- polyhaloC1-4alkyl is defined as polyhalosubstituted C1-4alkyl, in particular C1-4alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like.
[0011] Compound (a) is
Figure imgf000006_0001
wherein R1 is C-|-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy. In particular R1 is C1-6alkyl. More particularly R1 is ethyl.
[0012] Compound (b) is
Figure imgf000006_0002
wherein W is a leaving group such as, for example, halo, e.g. chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, arylsulfonyloxy such as benzenesulfonyloxy or p-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy and the like reactive leaving groups. In particular W is a sulfonyloxy group. More particularly W is p-methyl- benzenesulfonyloxy. [0013] Compound (c) is :
Figure imgf000007_0001
wherein R1 is C-|-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC-j^alkyloxy. In particular R1 is C1-6alkyl. More particularly R1 is ethyl.
[0014] Step a) is an /V-alkylation reaction of a compound of formula (a) with a compound of formula (b) wherein W is an appropriate leaving group such as, for example, halo, e.g. chloro, bromo, iodo, or in some instances W may also be a sulfonyloxy group, e.g. methanesulfonyloxy, arylsulfonyloxy such as benzenesulfonyloxy or p-methylbenzenesulfonyloxy, trifluoromethane- sulfonyloxy and the like reactive leaving groups. The reaction can be performed in a suitable solvent such as, for example, acetonitrile, 2-pentanol, isobutanol, dimethyl acetamide, dichloromethane, chloroform, 1,2-dichloroethane, DMF, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, or any mixture thereof, and in the presence of a base such as, for example, sodium carbonate, potassium carbonate, potassium phosphate or triethylamine. The reaction can optionally be performed in the presence of a phase transfer catalyst. Phase transfer catalysts are usually quaternary ammonium salts or phosphonium salts such as e.g. benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, or hexadecyltributylphosphonium bromide. When a phase transfer catalyst is present the suitable solvent may contain an amount of water. Stirring may enhance the rate of the reaction. The reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture. Reaction rate and yield may be enhanced by microwave assisted heating.
[0015] Step b) is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suitable base. Appropriate solvents are polar aprotic solvents such as, e.g., /\/,/\/-dimethyl formamide, /\/,/\/-dimethyl acetamide, /V-methylpyrrolidone, /V-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile. Suitable bases are for instance alkoxide bases (e.g. potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert-pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride). The reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
[0016] Step c) is the conversion of the carbonyl group in the compound of formula (e) 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 sodium bis(2-methoxy- ethoxy)aluminium hydride (e.g., Red-AI®), and boron hydrides (such as LiBH4, NaBH4, and borane complexes BH3.THF, and BH3.Me2S). Borane complexes can conveniently be generated in situ from NaBFU and a Bronsted 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).
[0017] In step d) the diamine compound (f) is converted into rilematovir using a carbonyl transfer reagent such as, e.g., carbonyl diimidazole (CDI), urea, phosgene, diphosgene, triphosgene, or a chloroformate such as ethyl or phenyl chloroformate; in a suitable aprotic solvent, e.g., ethyl acetate, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyl- tetrahydrofuran, /\/,/\/-dimethyl acetamide, /\/,/\/-dimethyl formamide, or /V-methylpyrrolidone, to provide rilematovir. Optionally, an organic base is added, e.g., triethylamine, tributylamine, /\/,/\/-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 /V-methy- limidazole), pyridines (such as pyridine, 2- or 4-picoline, or 2,6-lutidine), DMAP (4-dimethyl- aminopyridine), L/,L/,L/',L/'-tetramethyl-guanidine (TMG), 1,3,4,6,7,8-hexahydro-2H -pyrimido[1,2- a]pyrimidine (TBD or triazabicyclo-decene), 1,3,4,6,7,8-hexahydro-1-methyl-2H -pyrimido[1,2- a]pyrimidine (MeTBD or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) or an inorganic base such as potassium carbonate, potassium phosphate, sodium hydroxide or potassium hydroxide. [0018] Rilematovir can optionally be further purified by techniques such as column chromatography or crystallisation.
[0019] Rilematovir can optionally be further converted into a pharmaceutically acceptable acid addition salt.
[0020] The pharmaceutically acceptable acid addition salts of rilematovir as mentioned herein are meant to comprise the therapeutically active non-toxic acid salt forms which rilematovir is able to form. These forms can conveniently be obtained by treating rilematovir with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxy- butanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluene- sulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
[0021] In a second embodiment, the present invention relates to a process for preparing 5-chloro-1 -(3-(methylsulfonyl)propyl)-/\/-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e);
Figure imgf000009_0001
comprising the consecutive steps of a) reacting a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy; with L/4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000010_0001
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3- (methylsulfonyl)propyl)-/\/-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e).
[0022] The above reaction is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suitable base. Appropriate solvents are polar aprotic solvents such as, e.g., /\/,/\/-dimethyl formamide, /\/,/\/-dimethyl acetamide, /V-methylpyrrolidone, /V-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile. Suitable bases are for instance alkoxide bases (e.g. potassium tert-butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert-pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride). The reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
[0023] In a third embodiment, the present invention relates to a process for preparing /V3-(( 5- chloro-1-(3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)-/\/4-(2,2,2-trifluoroethyl)pyridine-3,4- diamine of formula (f);
Figure imgf000010_0002
comprising the consecutive steps of a) reacting a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC-^alkyloxy; with L/4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000011_0001
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3- (methylsulfonyl)propyl)-/\/-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e);
Figure imgf000011_0002
b) reducing the carbonyl group in compound (e) with a reducing agent to obtain /\/3-((5-chloro-1- (3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)-/\/4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (f).
[0024] Step a) in the third embodiment is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suitable base. Appropriate solvents are polar aprotic solvents such as, e.g., /\/,/\/-dimethyl formamide, N,N-dimethyl acetamide, /V-methylpyrrolidone, /V-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile. Suitable bases are for instance alkoxide bases (e.g. potassium tert- butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert- pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride). The reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
[0025] Step b) in the third embodiment is the conversion of the carbonyl group in the compound of formula (e) to a methylene group by treatment with an appropriate reducing agent. Appropriate reducing agents are, e.g., silicon hydrides (such as EtsSiH and PMHS (poly(methylhydrosiloxane))), aluminium hydrides (such as DIBAL-H (diisobutylaluminium hydride) and sodium bis(2-methoxy-ethoxy)aluminium hydride (e.g., Red-AI®), 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).
[0026] In a fourth embodiment, the present invention relates to a process for preparing rilematovir
Figure imgf000012_0001
comprising the consecutive steps of b) reacting a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy; with N4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000013_0001
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3- (methylsulfonyl)propyl)-/\/-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e);
Figure imgf000013_0002
b) reducing the carbonyl group in compound (e) with a reducing agent to obtain /\/3-((5-chloro- 1-(3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)-/\/4-(2,2,2-trifluoroethyl)pyridine-3,4- diamine of formula (f);
Figure imgf000013_0003
c) and reacting compound (f) in a suitable aprotic solvent with a carbonyl transfer reagent, optionally in the presence of an organic or inorganic base, to obtain rilematovir which can optionally be further converted into a pharmaceutically acceptable acid addition salt.
[0027] Step a) of the fourth embodiment is an amide bond formation reaction between an ester compound of formula (c) and an amine of formula (d) wherein said amide-bond formation can be performed by mixing the compounds (c) and (d) in an appropriate solvent in the presence of a suited base. Appropriate solvents are polar aprotic solvents such as, e.g., N,N- dimethyl formamide, L/,/V-dimethyl acetamide, /V-methylpyrrolidone, /V-butyl-pyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile and butyronitrile. Suitable bases are for instance alkoxide bases (e.g. potassium tert- butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert- pentoxide, lithium ethoxide), inorganic bases (e.g. cesium carbonate), organic bases (e.g. lithium hexamethyldisilazane, lithium amide) or Grignard bases (e.g. methylmagnesium bromide, isopropylmagnesium chloride). The reaction may conveniently be carried out at a temperature ranging between zero degrees centigrade 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 ester compound (c) and the secondary amine of compound (d), leading to increased yield and purity of compound (e).
[0028] Step b) of the fourth embodiment is the conversion of the carbonyl group in the compound of formula (e) 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 sodium bis(2-methoxy-ethoxy)aluminium hydride (e.g., Red-AI®), 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).
[0029] In step c) of the fourth embodiment the diamine compound (f) is converted into rilematovir 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-methyl- tetrahydrofuran, N,N-dimethyl acetamide, N,/V-dimethyl formamide, or /V-methylpyrrolidone, to provide rilematovir. Optionally, an organic base is added, e.g., triethylamine, tributylamine, L/,/V-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- methyl- imidazole), pyridines (such as pyridine, 2- or 4-picoline, or 2,6-lutidine), DMAP (4-dimethyl- aminopyridine), L/,L/,L/',L/'-tetramethylguanidine (TMG), 1,3,4,6,7,8-hexahydro-2H -pyrimido[1,2- a]pyrimidine (TBD or triazabicyclodecene), 1,3,4,6,7,8-hexahydro-1-methyl-2H -pyrimido[1,2- a]pyrimidine (MeTBD or 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) or an inorganic base such as potassium carbonate, potassium phosphate, sodium hydroxide or potassium hydroxide. [0030] The term “seeding” in the working examples refers to the addition of crystalline material to a solution or mixture to initiate crystallisation or recrystallisation. Seeding material can be obtained by spontaneous crystallization.
[0031] Example 1 : synthesis of 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate
Figure imgf000015_0001
3-(Methylthio)propan-1-ol (100.00 g) is dissolved under nitrogen atmosphere in dichloro- methane (500 ml_) and tosyl chloride (188.50 g) is added. The solution is cooled to 0°C; /\/,/\/,/\/',/\/'-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 HCI 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, CDCh) d ppm 2.15 - 2.28 (m, 2 H); 2.45 (s, 3 H); 2.91 (s, 3 H); 3.05 - 3.17 (m, 2 H); 4.17 (t, J= 5.95 Hz, 2 H); 7.37 (d, J=8.12 Hz, 2 H); 7.78 (d, J=8.31 Hz, 2 H)
13C NMR (151 MHz, CDCh) d ppm 21.89; 22.45; 41.39; 51.06; 68.06; 128.22; 130.24; 132.72 ; 145.50
[0032] Example 2 : synthesis of /\/4-(2.2.2-trifluoroethyl)pyridine-3,4-diamine compound (d)
Figure imgf000015_0002
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 NaHCCh 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-methyl- tetrahydrofuran 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 (d) (204.00 g, 92% yield).
1H NMR (600 MHz, DMSO-d6) d ppm 4.03 (qd, J=9.50, 6.80 Hz, 2 H); 4.66 (br s, 2 H); 5.88 (t, J= 6.80 Hz, 1 H); 6.60 (d, J= 5.29 Hz, 1 H); 7.62 (d, J= 5.29 Hz, 1 H); 7.71 (s, 1 H).
13C NMR (151 MHz, DMSO-d6); d 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
[0033] Example 3 : synthesis of ethyl 5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indole-2- carboxylate
Figure imgf000016_0001
Ethyl-5-chloro-1H -indole-2-carboxylate (10.00 g), 3-(methylsulfonyl)propyl-4-methylbenzene- sulfonate (14.38 g), potassium phosphate (12.34 g), and tetrabutylammonium hydrogen sulfate (0.76 g) are mixed in 2-methyltetrahydrofuran (100.60 mL) and water (0.40 mL). The mixture is heated to 70°C until complete conversion, then water (50.00 mL) is added and the phases are separated at 60°C. The resulting organic layer, containing ethyl 5-chloro-1-(3-(methylsulfonyl)- propyl)-1H-indole-2-carboxylate in solution is used in the next step to convert to 5-chloro-1-(3- (methylsulfonyl)propyl)-/\/-(4-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)-1H -indole-2-carboxamide. [0034] Example 4 : synthesis of 5-chloro-1-(3-(methylsulfonyl)propyl)-/\/-(4-((2,2.2- trifluoroethvl)amino)pvridin-3-vl)-1H-indole-2-carboxamide - compound (e)
Figure imgf000017_0001
Ethyl 5-chloro-1-(3-(methylsulfonyl)propyl)-1 H-indole-2-carboxylate in 2-methyltetrahydrofuran solution obtained from example 3 is mixed with N 4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine (9.40 g) and additional 2-methyltetrahydrofuran (56.00 ml_, 156.60 ml_ in total). This mixture is dried via azeotropic distillation. Then, a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran) (94.00 ml_) is added at 20°C over 4 hours. After completion of the reaction, the mixture is quenched with a saturated ammonium chloride solution in water (100.00 ml_) followed by the addition of water (50.00 ml_). The resulting 2-phase mixture is phase separated, discarding the water layer. The resulting organic layer is solvent switched to acetonitrile. After the boiling point of acetonitrile is reached (82°C), the temperature is adjusted to 78°C and water (143.00 ml_) is added. The title product is obtained after a seeded cooling crystallisation and isolation by filtration at 20°C. The product is dried under reduced pressure to give product (e) (17.6g, 71% yield).
1H NMR (600 MHz, DMSO-d6) 1H NMR (600 MHz, DMSO-d6) d ppm 2.13 - 2.23 (m, 2 H); 2.95 (s, 3 H); 3.08 - 3.19 (m, 2 H); 4.00 - 4.11 (m, 2 H) 4.65 (br t, J=7.18 Hz, 2 H); 6.66 (br t, J=6.61 Hz, 1 H); 6.89 (d, J=6.04 Hz, 1 H); 7.34 (dd, J=8.88, 2.08 Hz, 1 H); 7.44 (s, 1 H); 7.71 (d, J=8.69 Hz, 1 H); 7.82 (d, J=1.51 Hz, 1 H); 8.10 (s, 1 H); 8.13 (d, J=5.67 Hz, 1 H); 9.89 (s, 1 H).
13C NMR (151 MHz, DMSO-d6) d 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. [0035] Example 5 : synthesis of /\/3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2- yl)methyl)-/\/4-(2.2.2-trifluoroethyl)pyridine-3.4-diamine - compound (f)
Figure imgf000018_0001
Compound (e) (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 (f) (33.8 g, 77% yield).
1H NMR (600 MHz, DMSO-d6) d ppm 2.12 (dd, J= 7.60 Hz, 2 H); 2.94 (s, 3 H); 3.17 (t, J=7.81 Hz, 2 H); 4.01 - 4.10 (m, 2 H); 4.35 (t, J=7.45 Hz, 2 H); 4.51 (d, J= 5.27 Hz, 2 H); 5.09 (t, J=5.18 Hz, 1 H); 6.07 (t, J= 6.63 Hz, 1 H); 6.50 (s, 1 H); 6.67 (d, J= 5.27 Hz, 1 H); 7.14 (dd, J=8.83, 1.91 Hz, 1 H); 7.55 (d, J=8.90 Hz, 1 H); 7.57 (d, J= 2.00 Hz, 1 H); 7.73 (d, J=5.45 Hz, 1 H); 7.82 (s, 1 H).
13C NMR (151 MHz, DMSO-d6) d 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. [0036] Example 6 : synthesis of rilematovir
Figure imgf000019_0001
Compound (f) (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 rilematovir (36.00 g, 90% yield).
Rilematovir 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) d ppm 1.95 (m, 2 H); 2.98 (s, 3 H); 3.15 (t, J= 7.90 Hz, 2 H); 4.38 (t, J= 7.90 Hz, 2 H); 4.89 (q, J=9.30 Hz, 2 H); 5.40 (s, 2 H); 6.48 (s, 1 H); 7.17 (dd, J= 8.70, 2.30 Hz, 1 H); 7.44 (d, J= 5.30 Hz, 1 H); 7.55 (d, J=9.10 Hz, 1 H); 7.57 (d, J=1.90 Hz, 1 H); 8.31 (d,
J= 5.30 Hz, 1 H); 8.49 (s, 1 H).
13C NMR (125 MHz, DMSO-d6) d 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.

Claims

Claims
A process for preparing rilematovir
Figure imgf000020_0001
comprising the consecutive steps of a) reacting a compound of formula (a), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC-1 -4alkyloxy,
Figure imgf000020_0002
with a compound of formula (b), wherein W is a leaving group selected from chloro, bromo, iodo, methanesulfonyloxy, benzenesulfonyloxy, p-methylbenzenesulfonyloxy, and trifluoromethanesulfonyloxy,
Figure imgf000020_0003
in a suitable solvent in the presence of a base and optionally in the presence of a phase transfer catalyst to obtain a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1 , 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC-1 _4alkyloxy;
Figure imgf000021_0001
b) reacting a compound of formula (c) with N4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000021_0002
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3-(methylsulfonyl)propyl)-/\/-(4-((2,2,2-trifluoroethyl)amino)pyridin-3- yl)-1H -indole-2-carboxamide of formula (e);
Figure imgf000021_0003
c) reducing the carbonyl group in compound (e) with a reducing agent to obtain /V3-(( 5- chloro-1-(3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)-/\/4-(2,2,2-trifluoroethyl)- pyridine-3, 4-diamine of formula (f);
Figure imgf000021_0004
d) and reacting compound (f) in a suitable aprotic solvent with a carbonyl transfer reagent, optionally in the presence of an organic or inorganic base, to obtain rilematovir which can optionally be further converted into a pharmaceutically acceptable acid addition salt.
2. The process as claimed in claim 1 wherein in step a) the solvent is selected from acetonitrile, 2-pentanol, isobutanol, dimethyl acetamide, dichloromethane, chloroform, 1,2-dichloroethane, DMF, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, or any mixture thereof.
3. The process as claimed in claim 1 wherein in step a) the base is selected from sodium carbonate, potassium carbonate, potassium phosphate or triethylamine.
4. The process as claimed in claim 1 wherein in step a) a phase transfer catalyst is present and is selected from quaternary ammonium salts or phosphonium salts.
5. The process as claimed in claim 4 wherein the phase transfer catalyst is selected from benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, or hexadecyltributylphosphonium bromide.
6. The process as claimed in claim 1 wherein in step b) the appropriate solvent is a polar aprotic solvent.
7. The process as claimed in claim 6 wherein the polar aprotic solvent is selected from dimethyl formamide, /\/,/\/-dimethyl acetamide, /V-methylpyrrolidone, /V-butylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, propionitrile, and butyronitrile.
8. The process as claimed in claim 1 wherein in step b) the suitable base is selected from alkoxide bases, inorganic bases, organic bases or Grignard bases.
9. The process as claimed in claim 8 wherein the base is selected from potassium tert- butoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, potassium tert- pentoxide, lithium ethoxide, cesium carbonate, lithium hexamethyldisilazane, lithium amide, methylmagnesium bromide, or isopropylmagnesium chloride.
10. The process as claimed in claim 1 wherein in step c) the reducing agent is a boron or silicon or aluminium hydride or a borane complex.
11. The process as claimed in claim 10 wherein the reducing agent is selected from EtsSiH, poly(methylhydrosiloxane), diisobutylaluminium hydride, sodium bis(2-methoxy- ethoxy)aluminium hydride, LiBH4, NaBH4, BH3.THF, or BH3*Me2S.
12. The process as claimed in claim 1 wherein in step d) the carbonyl transfer reagent is selected from CDI, urea, phosgene, diphosgene, triphosgene, ethyl chloroformate or phenyl chloroform ate.
13. The process as claimed in claim 1 wherein in step d) the suitable aprotic solvent is selected from ethyl acetate, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetra- hydrofuran, /\/,/\/-dimethyl acetamide, N,N-dimethyl formamide, or /V-methylpyrrolidone.
14. The process as claimed in claim 13 wherein the optional organic or inorganic base is selected from triethylamine, tributylamine, /\/,/\/-diisopropylethylamine, DBU (1,8-diaza- bicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), imidazole or /V-methylimidazole pyridine, 2- or 4-picoline or 2,6-lutidine or DMAP (4-dimethylamino- pyridine), L/,L/,L/',L/'-tetramethyl-guanidine, 1 ,3,4,6,7,8-hexahydro-2H -pyrimido[1 ,2-a]- pyrimidine, 1,3,4,6,7,8-hexahydro-1-methyl-2H -pyrimido[1,2-a]pyrimidine, potassium carbonate, potassium phosphate, sodium hydroxide or potassium hydroxide.
15. The process of claim 1 wherein R1 is ethyl and W is p-methylbenzenesulfonyloxy.
16. A process for preparing rilematovir
Figure imgf000023_0001
comprising the consecutive steps of a) reacting a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy; with L/4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000024_0001
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3- (methylsulfonyl)propyl)-/\/-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e);
Figure imgf000024_0002
b) reducing the carbonyl group in compound (e) with a reducing agent to obtain /V3-(( 5- chloro-1-(3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)-/\/4-(2,2,2- trifluoroethyl)pyridine-3, 4-diamine of formula (f);
Figure imgf000024_0003
c) and reacting compound (f) in a suitable aprotic solvent with a carbonyl transfer reagent, optionally in the presence of an organic or inorganic base, to obtain rilematovir which can optionally be further converted into a pharmaceutically acceptable acid addition salt.
17. The process of claim 16 wherein R1 is ethyl.
18. A process for preparing 5-chloro-1-(3-(methylsulfonyl)propyl)-/\/-(4-((2,2,2- trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2-carboxamide of formula (e);
Figure imgf000025_0001
comprising the consecutive steps of a) reacting a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy; with L/4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000025_0003
Figure imgf000025_0002
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3-
(methylsulfonyl)propyl)-/\/-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e).
19. The process of claim 18 wherein R1 is ethyl.
20. A process for preparing /\/3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)- N4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (f);
Figure imgf000026_0001
comprising the consecutive steps of a) reacting a compound of formula (c), wherein R1 is C1-6alkyl or aryl wherein aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from C1-4alkyl, halo, C1-4alkyloxy, polyhaloC1-4alkyl, or polyhaloC1-4alkyloxy; with N4-(2, 2, 2-trifluoroethyl)pyridine-3, 4-diamine of formula (d)
Figure imgf000026_0002
in an appropriate solvent in the presence of a suitable base; to obtain 5-chloro-1-(3- (methylsulfonyl)propyl)-/\/-(4-((2, 2, 2-trifluoroethyl)amino)pyridin-3-yl)-1 H -indole-2- carboxamide of formula (e);
Figure imgf000026_0003
b) reducing the carbonyl group in compound (e) with a reducing agent to obtain /V3-(( 5- chloro-1-(3-(methylsulfonyl)propyl)-1H -indol-2-yl)methyl)-/\/4-(2,2,2-trifluoroethyl)- pyridine-3, 4-diamine of formula (f). 21 The process of claim 20 wherein R1 is ethyl.
PCT/EP2022/054915 2021-03-01 2022-02-28 Synthesis of rilematovir WO2022184606A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001095910A1 (en) * 2000-06-13 2001-12-20 Bristol-Myers Squibb Company Imidazopyridine and imidazopyrimidine antiviral agents
WO2012080447A1 (en) 2010-12-16 2012-06-21 Janssen R&D Ireland Indoles as respiratory syncytial virus antiviral agents
WO2014060411A1 (en) * 2012-10-16 2014-04-24 Janssen R&D Ireland Rsv antiviral compounds
WO2019058271A1 (en) * 2017-09-19 2019-03-28 Lupin Limited Process for the preparation of eluxadoline
WO2021083998A1 (en) * 2019-10-30 2021-05-06 Janssen Sciences Ireland Unlimited Company Synthesis of 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

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001095910A1 (en) * 2000-06-13 2001-12-20 Bristol-Myers Squibb Company Imidazopyridine and imidazopyrimidine antiviral agents
WO2012080447A1 (en) 2010-12-16 2012-06-21 Janssen R&D Ireland Indoles as respiratory syncytial virus antiviral agents
WO2014060411A1 (en) * 2012-10-16 2014-04-24 Janssen R&D Ireland Rsv antiviral compounds
WO2019058271A1 (en) * 2017-09-19 2019-03-28 Lupin Limited Process for the preparation of eluxadoline
WO2021083998A1 (en) * 2019-10-30 2021-05-06 Janssen Sciences Ireland Unlimited Company Synthesis of 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

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