(2R)-2-methyloxirane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-amide (15 mg) was prepared using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid pyrrolidin-3-ylamide dihydrochloride (47 mg), (R)-2-methyl-oxirane (excess) and DIEA (35 uL) in DMF (1 mL). The reaction was stirred at 80° C. overnight. The pure product was isolated through silica gel chromatography using DCM: (10%) methanol in DCM (from 100:0 to 0:100) as eluent system. LC/MS: m/z 534.6. The pure product was isolated through silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: FIG. 5 illustrates the scheme for the synthesis of field-active (2S,7S)2,7-nonanediyl dibutyrate (14): S-propylene oxide (6) (Fluka Chemika-Biochemika, Buchs, Switzerland) was coupled at −20° C. with Grignard reagent 7 in the presence of 0.1 equivalents of a CuI catalyst. Resulting (2S)-8-octen-2-ol (8) was oxidized by m-chloroperoxybenzoic acid (Aldrich Chemical Co.) to the terminal epoxide 9. Hydrolytic kinetic resolution of 9 with Co(II) salen (Jacobsen's) catalyst (R,R)N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminoc (10) (Aldrich Chemical Co.) (24, 25) afforded 2(R),7(S)-1,2-epoxy-7-hydroxyoctane (11), which was separated from unwanted 1,2(S),7(S)-octanetriol (12) by silica flash chromatography [hexane: ether (1:1), then ether as eluents]. Ring opening of 11 with excess of methylmagnesium bromide (Aldrich Chemical Co.) and catalytic amounts of Cul yielded (2S,7S)-2,7-nonanediol (13) which was esterified to (2S,7S)-2,7-nonanediol dibutyrate [14; 77% enantiomeric excess (ee) as determined by chiral GC; 37% overall yield]. GC-MS and NMR data of 14 were consistent with those of 5 (FIG. 4). The remaining 3 stereoisomers of diester 5 were synthesized from (S)- or (R)-propylene oxide (Fluka Chemika-Biochemika) and 5-bromo-pentene (Aldrich Chemical Co.), again by hydrolytic kinetic resolution of terminal epoxide intermediates, with ee of end products ranging between 73-85%.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 2-methylquinolin-7-ol (0.400 g, 2.51 mmol), Cs2CO3 (2.46 g, 7.54 mmol) and DMF (16 mL) was added (R)-2-methyloxirane (0.438 g, 7.54 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1% MeOH in EtOAc) to give (R)-1-(2-methylquinolin-7-yloxy)propan-2-ol (0.471 g, 86%). After cooling the reaction mixture was partitioned between ether and water The aqueous layer was extracted with ether The combined organic layers were washed with water and brine dried concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (1% MeOH in EtOAc)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a room temperature solution of 100 mg (0.23 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-indol-3-yl)ethanol in THF was added 20.0 mg (0.50 mmol) of 60% NaH in mineral oil. After hydrogen evolution ceased, 14.5 mg (0.25 mmol) of (R)-(+)-propylene oxide was added. The reaction was then warmed at 60° C. for 5 hours. The reaction was then cooled to room temperature and diluted with water and extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (20-40% ethyl acetate in hexanes). The major fractions were combined and concentrated to provide 53 mg (46.6%) of the title compound. MS m/z 484.47 (MH+). The reaction was then cooled to room temperature extracted with ether The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude residue was purified by flash chromatography (20-40% ethyl acetate in hexanes) concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a room temperature solution of 100 mg (0.23 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-indol-3-yl)ethanol in THF was added 20.0 mg (0.50 mmol) of 60% NaH in mineral oil. After hydrogen evolution ceased, 14.5 mg (0.25 mmol) of (R)-(+)-propylene oxide was added. The reaction was then warmed at 60° C. for 5 hours. The reaction was then cooled to room temperature and diluted with water and extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (20-40% ethyl acetate in hexanes). The major fractions were combined and concentrated to provide 53 mg (46.6%) of the title compound. MS m/z 484.47 (MH+). The reaction was then cooled to room temperature extracted with ether The combined organic layers were washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude residue was purified by flash chromatography (20-40% ethyl acetate in hexanes) concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 140 mg of (R)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 435 mg of (R)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 403 mg of (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 298 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.1 (M)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alternatively, compound 1 is reacted with (R)-propylene oxide according to the foregoing method to yield (R)-1-(2-hydroxypropyl)-6-benzyloxyindole (R-2). Alternatively, compound 1 is reacted with (S)-propylene oxide according to the foregoing method to yield (S)-1-(2-hydroxypropyl)-6-benzyloxyindole (S-2).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-1-(1H-Pyrrolo[2,3-f]isoquinolin-1-yl)-2-propanol was prepared according to the method described in Example 1 using 1H-pyrrolo[2,3-f]isoquinoline (Farmaco, 1989, 44(12), 1141-55) and (R)-propylene oxide to give 0.77 g (71%) of the product as a white solid. A recrystallised sample [cyclohexane-ethanol (4:1)] gave mp 169-170° C.; Found: C, 74.09; H, 6.28; N, 12.27%. C14H14N2O requires C, 74.31; H, 6.24; N, 12.37%.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of sodium hydride, 60% dispersion in mineral oil, (0.76 g, 18.5 mmol) and THF (30 mL) was cooled to 0° C. under Ar. A mixture of 1H-pyrrolo[2,3-f]quinoline (G. Bartoli, G. Palmieri, M. Bosco and R. Dalpozzo, Tetrahedron Letts., 1989, 30, 2129-2132) (2.5 g, 14.8 mmol) and THF (20 mL) was added and the mixture was left at 0° C. for 1 h. (R)-propylene oxide (2.1 mL, 30 mmol) was added and the mixture was left at room temperature for 48 h. Saturated ammonium chloride solution (100 mL) was added and the mixture was extracted with Et2O (3×100 mL), the extracts were combined, washed with brine (2×100 mL), dried (MgSO4), concentrated in vacuo and purified by column chromatography [SiO2; Et2O] to give the product (0.61 g, 18% yield) as a pale yellow oil: IRνmax(Nujol)/cm−1 3106, 1361, 1117, 826, 805, and 731; NMR δH (400 MHz, CDCl3) 1.35 (3H, d, J 6.5 Hz), 2.76 (1H, br), 4.33 (1H, m), 4.44 (1H, m), 4.56 (I1H, m), 6.64 (1H, d, J 3.0 Hz), 7.20 (1H, d, J 3.0 Hz), 7.30 (1H, dd, J8.5 and 4.5 Hz), 7.71 (1H, d, J 9.0 Hz), 7.87 (1H, d, J 9.0 Hz), 8.52 (1H, d, J 8.5 Hz) and 8.67 (1H, m). was added was added the mixture was extracted with Et2O (3×100 mL) washed with brine (2×100 mL) dried (MgSO4) concentrated in vacuo purified by column chromatography [SiO2; Et2O]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100 mg of (R)-propylene oxide′ was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (R)-methyl 4-(2-hydroxypropylthio)benzoate. 169 mg of (R)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.2 (M)+.