2-(4-Bromobutyl)-1H-isoindole-1,3(2H)-dione

white crystalline powder

Phthalimide 6a (148mg, 1mmol), 124 1, 4-dibromobutane (1.080g, 5mmol), 12 potassium carbonate (276mg, 2mmol) was added to 115 acetone (3mL), and the reaction mixture was refluxed for 2h. After cooling to room temperature, the reaction mixture was purified by column chromatography using 125 PE: acetone (40:1) as eluent to give 126 7a (260mg, 92percent) as a white solid.Phthalimide (3.20 g, 0.05 mmol) was dissolved in acetone (40 mL), potassium carbonate (10.4 g, 0.15 mmol), 1, 4-dibromobutane (9.1 mL, 0.15 mmol), 50 The reaction was carried out at ° C for 12 h, and the reaction was complete by TLC.The reaction mixture was concentrated under reduced vacuo.The organic layer was combined, dried over anhydrous sodium sulfateColumn chromatography (petroleum ether: ethyl acetate = 3:1) gave N-(4-bromobutyl)phthalimide (6.10 g, 86percent).General procedure: To the solution of an imide of general structure B in dry toluene anhydrous KPhthalimide (1.176 g, 7.98 mmol), K2CO3 (3.316 g, 24 mmol) and benzyltriethylammonium chloride (200 mg, 0.88 mmol) were dissolved in acetone (20 mL), A mixture of 1, 4-dibromobutane (2.9 mL, 24 mmol) was added and stirred for 24 h at room temperature. The solvent was evaporated off, the residue was dissolved in water and DCM, the organic phase was separated, the aqueous layer was extracted twice more with DCM, and the organic layers were combined. It was dried over anhydrous sodium sulfate and concentrated by filtration. The residue was purified by column chromatography to give the title compound (1.861 g, yield: 83percent) as a colorless solid.General procedure: Compound 6–9 was prepared according the literature reported by Cheng L etal. [34] and with some modifications. Namely, phthalimide (2.9g, 20mmol) and the appropriate dibromoalkanes (80mmol) were added into MeCN (50mL). After an addition of K0.1 part of 1, 4-dibromobutane, 0.1 part of benzoxazole carboxylate and 0.3 part of potassium carbonatewere mixed into the reacion flask. 20 parts of acetine was added and reacted at room temperature for 10 hours.Filtration and drying were carried out to collect compound 1 in 62.3 percent yield.Into a Sovirel type reactor mechanically stirred, provided with a condenser, an opening for introduction of solids, a system for inerting with nitrogen, and a temperature probe, are loaded 5 mol (1081 g) of 1, 4-dibromobutane and 1 mol (188 g; 98.5percent pure) of potassium phthalimide. The reaction medium is brought under stirring to 115° C. and then kept at this temperature for 15 h. It is verified that the conversion is complete by a measurement of the potassium bromide in the reaction medium. [0048] After cooling of the reaction medium to 80° C., 200 g of water are added. After 15 min of stirring and then decantation, the aqueous phase containing the potassium bromide is removed and then a second washing is carried out (still at 80° C.) with 50 g of water. [0049] The ascending condenser is then replaced by a distillation column and then the excess 1, 4-dibromobutane is distilled under reduced pressure (8-10 mbar) with a bottom temperature from 80 to 120° C. Thus, 815 g of 1, 4-dibromobutane are recovered corresponding to a recovery rate of 1, 4-dibromobutane of 94percent. This latter with a purity greater than 99.8percent may be directly recycled into a later operation. [0050] At the end of the distillation, the reaction medium is left to cool to 75-80° C. and then 325 g of ethanol are added. After homogenization and obtention of a clear organic solution at reflux of ethanol, the reaction medium is left to cool under stirring to room temperature (20° C.). [0051] After crystallization of the N-(4-bromobutyl)phthalimide, the ethanolic suspension of the product is filtered on frit at room temperature. The moist cake is washed with 35 g of ethanol and then dried at 50° C. under reduced pressure (20 mmHg). Thus, 268 g of N-(4-bromobutyl)phthalimide are obtained that correspond to a molar yield of 92percent compared with the potassium phthalimide provided.The phthalimide potassium salt (2.0g, 10 . 7mmol) with 1, 4 - dibromo butane (2.8g, 12 . 9mmol) dissolved in 25 ml dry N, N-dimethylformamide in, for pH 10, room temperature stirring 26h. Dichloromethane is used for extraction three times (100 ml × 3), washed with distilled water, combined with the organic layer, drying by anhydrous magnesium sulphate, concentrated, dichloromethane/distilled water recrystallization, filtering, drying to obtain the white solid, yield of 92.4percent.General procedure: Potassium phthalimide (0.93 g, 5 mmol) was added to a solution of 1, 2-dibromoethane (1.3 mL, 15 mmol) in DMF (8 mL). The mixture was stirred at room temperature overnight and evaporated the solvent in vacuo, the residue dissolved in HPotassium phthalimide (18.62 g, 0.10 mol) and tetrabutylammoniumbromide (TBAB, 5.00 g) were added to a solutionof 1, 4-dibromobutane (35.5 mL, 0.30mol) in N, N-Dimethylformamide (DMF, 240 mL) at room temperature and then the mixture was stirred at 78 °C for 6 h. After the completion of the reaction (monitored by TLC analysis), the mixture was filtered, and washed with DMF (20 mL × 2).The filtrate was evaporated under vacuum to removed DMF, the residual liquid was poured into ice-water bath, immediately a large amount of white solid generated. The white solid was collected by filtration, washed on the filter withwater and dried in vacuum. The crude residue was purifiedby recrystallization from methanol to afford pure N-(4-Bromobutyl) phthalimide 2 (23.60 g, 84percent, m.p. 79-81oC aswhite solid. 1H NMR (CDCl3, 400 MHz), δ: 1.82-1.95 (m, 4H, C13H, C14H), 3.45 (t, J=6.3 Hz, 2H, C15H), 3.73 (t, J=6.6 Hz, 2H, C16H), 7.27-7.74 (m, 2H, C3H, C6H), 7.83-7.86 (m, 2H, C1H, C2H); 13C NMR (CDCl3, 100 MHz), δ:27.3 (C13), 29.9 (C14), 32.8 (C15), 37.0 (C12), 123.3 (C3, C6), 132.1 (C4, C5), 134.0 (C1, C2), 168.4 (C7, C9). KunHu has reported the same compound in 2013 [17], the NMRcharacterization in the literature is described as follows: 1HNMR (CDCl 3, 500 MHz): d 1.84-1.94 (m, 4H), 3.45 (t, 2H, J = 6.0 Hz), 3.73 (t, 2H, J = 6.5 Hz), 7.73 (dd, 2H, J =3.0, 5.5 Hz), 7.85 (dd, 2H, J = 3.0, 5.0 Hz); 13 C NMR(CDCl 3, 125 MHz): d 27.27, 29.89, 32.73, 36.99, 123.27, 132.11, 133.99, 168.36.50 mL DMF, 0.025 mol potassium salt of phthalimide, 0.10 mol 1, 4-dibromobutane and 0.5 g TBAB, 70 reaction 2.0h;Cool to room temperature, Pour ice waterEthyl acetate extraction, Washed, dry, De-soluble, Stand overnight, 5.82 g of N- (4-bromobutyl) phthalimide precipitated as a white solid, m.p. 78-81 ° C, yield 82.5percent.General procedure: A mixture of phthalimide10(6.8 mmol) dissolved in EtOH (20 mL) was gently boiled for about 1h. The hot solution was decanted from any solid into 1.25 mL of a specially prepared solution of KOH (15.25 g KOH dissolved in 15 mL of H50 mL of DMF, 0.025 mol of the potassium salt of phthalimide, 0.10 mol of 1, 4-dibromobutane and 0.5 g of TBAB, reaction at 70° C. for 2.0 h; cooling to room temperature, pouring into ice water, extraction with ethyl acetate, After washing with water, drying and desolvation, the mixture was allowed to stand overnight to precipitate 5.82 g of N-(4-bromobutyl)phthalimide as a white solid, mp 78-81°C, yield 82.5percent.General procedure: The appropriate dibromoalkane derivative 2a-2e (11.9 mmol) was added slowly to a mixture of the starting material phthalimide potassium salt (1) (1g, 5.4 mmol) and anhydrous KGeneral procedure: To a solution of 1.6g (10.0mmol) of (R, S) 4-phenyloxazolin-2-one (13), 3.4g (25.0mmol) of KGeneral procedure: Acetone (150mL) and dibromoalkyl (30mol) were added to a 250mL three-necked round-bottom flask fitted with a mechanical stirrer and reflux condenser. Potassium phthalimide (11.85g, 10 mol) was added slowly over a 15-min period, and then the reaction mixture was heated under reflux for 10h. The reaction mixture was filtered via suction, and the acetone was removed via rotary evaporation. The crude product was purified by flash chromatography on silica gel (EtOAc:petroleum ether=1:14) to afford 2–5 as white solid.To a stirred solution of 1, 4-dibromobutane (2j) (9, 7 mL, 27, 0 mmoi) (100 mL), was added potassIum phthaiate (i—) (5.0 g, 27, 0 mrnol) portion—wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 rnL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 rnL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5.40percent EtOAc / hexanes to afford 3j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 2.3.9(M+1)To a stirred solution of 1, 4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).To a stirred solution of 1, 4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).To a stirred solution of 1, 4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).To a stirred solution of 1, 4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 mm at room temperature. After complete addition, the reaction mixture was stirred at 90 ưC for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).Production Example 25a: Synthesis of (R)-N-(1-(3-(cyclopropylmethoxy)-4- fluorophenyl) ethyl)-4-(2, 4-dioxoimidazolidin-1-yl)butane-1-sulfonamideScheme 11. [0697] Step 1: Synthesis of 2-(4-bromobutyl)isoindoline-1, 3-dione (3-j) To a stirred solution of 1, 4-dibromobutane (2-j) (9.7 mL, 27.0 mmol) in DMF (100 mL), was added potassium phthalate (1-j) (5.0 g, 27.0 mmol) portion-wise over 30 min at room temperature. After complete addition, the reaction mixture was stirred at 90 °C for 18 h, then quenched with water (300 mL) and extracted with diethyl ether (150 mL x 2). The combined organic extracts were washed with water (100 mL x 2), followed by brine (50 mL x 2) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. The crude product was purified by silica gel column chromatography (60- 120 mesh) using 5-10percent EtOAc / hexanes to afford 3-j as an off- white solid (5.5 g, 72.3percent yield). LCMS: 283.9(M+1).General procedure: A mixture of dibromoalkane (23 mmol) and potassium carbonate (12 mmol)was added in acetone (30 mL), and potassium phthalimide (10 mmol) was added slowly over a 15-min period, and then the reaction was heated under reflux for 8-10 h. The reaction mixture was filtered, and the acetone was evaporated in vacuo. The crude product was purified by column chromatography on silica gel using mixtures of petroleum/acetone as eluent) to obtain the white solid compounds 2-4.Syntheses of D, L-Sulforaphane and Erysolin; Compound 9; 2-(4-bromobutyl)isoindoline-l, 3-dione; The following procedure was adapted from that previously reported by Vermeulen, et al (25) 1 , 4-Dibromobutane (4 400 mL, 36 457 mmols) was dissolved in anhydrous DMF (52 mL) and the resulting solution was chilled to 0°C under argon After 15 min, potassium phthahmide (3 459 g, 18 672 mmols) was slowly added to the stirring solution and the reaction was allowed to warm to ambient temperature under argon over 18 h The reaction was concentrated in vacuo and co-stπpped with anhydrous THF several times Products were dissolved in 1 1 HCompound 9: 2-(4-bromobutyl)isoindoline-1, 3-dione. The following procedure was adapted from that previously reported by Vermeulen, et al. (25). 1, 4-Dibromobutane (4.400 mL, 36.457 mmols) was dissolved in anhydrous DMF (52 mL) and the resulting solution was chilled to 0° C. under argon. After 15 min, potassium phthalimide (3.459 g, 18.672 mmols) was slowly added to the stirring solution and the reaction was allowed to warm to ambient temperature under argon over 18 h. The reaction was concentrated in vacuo and co-stripped with anhydrous THF several times. Products were dissolved in 1:1 HInto a Sovirel type reactor mechanically stirred, provided with a condenser, an opening for introduction of solids, a system inerting with nitrogen, and a temperature probe, are loaded 655 g of 1, 4-dibromobutane at 99percent purity (3 mol) and 187 g of potassium phthalimide at 99percent purity (1 mol). The reaction medium is brought under stirring between 115° C. and 120° C. and then kept at this temperature for 12 h. It is verified that the transformation of potassium phthalimide is completed by a measurement of the KBr in the reaction medium and then the excess 1, 4-dibromobutane is evaporated under reduced pressure (10 to 18 mmHg). The recovery rate of the 1, 4-dibromobutane is near 90percent and this latter may be recycled directly into a later operation. [0052] At the end of the distillation, the heterogeneous reaction medium is 120° C.-130° C. Its temperature is lowered to 70° C. and then 320 g of ethanol are introduced. The medium is kept at 70° C. [0053] The contents of the reactor are filtered at 70° C. on a frit kept at this temperature. The moist cake is dried. It essentially contains KBr and diphthalimidobutane. [0054] The ethanolic filtrate is left to cool to 20° C., which causes crystallization of the N-(4-bromobutyl)phthalimide. The ethanolic suspension of the product is filtered on the frit. The moist cake is washed with 2 ethanol fractions and then dried at 50° C. under reduced pressure (20 to 30 mmHg). Thus, 173 g of N-(4-bromobutyl)phthalimide are obtained or an isolated yield of 61percent compared with the potassium phthalimide provided.Potassium phthalimide (65 g, 350 mmol, 1.00 eq.) and tetramethylene dibromide (200 g, 930 mmol, 2.66 eq.) were combined (neat) and heated for 12 hours. The excess tetramethylene dibromide was removed via rotary-evaporation (rotovap). The resulting residue was digested with ethanol and filtered. The material that crystallized on standing was filtered, washed with ethanol, and dried in vacuo. A second crop was obtained by concentration of combined filtrate and washings. The combined mass of crops was 60.5 g (61percent yield).(3)(3)A mixture of 1, 4-dibromobutane (22 mL, 185 mmol) and potassium phthalimide (11.35 g, 61.4 mmol) in 60 mL of DMF was mixed at room temperature for 1 day. Then, the reaction mixture was extracted with hexane (3x150 mL). The hexane fractions were dried over MgS07.8ml (6. 5 X 10General procedure: To a suspension of the appropriate dibromoalkane (33mmol) and potassium carbonate (18mmol) in anhydrous acetone (30mL), and potassium phthalimide (15mmol) was added slowly over a 15min period, and then the reaction mixture was heated under reflux for 8–10h. The reaction mixture was filtered, and the acetone was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (petroleum/acetone as eluent) to obtain 2a-d as white solid.#10;#10;EXAMPLE 81

Molecular Weight:282.13
XLogP3:3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:4
Exact Mass:281.00514
Monoisotopic Mass:281.00514
Topological Polar Surface Area:37.4
Heavy Atom Count:16
Complexity:269
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes