(2R)-3,3-dimethylbutan-2-amine

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

Procedure: 3-Ethoxy-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-1,2-dione (0.4 g, 1.62 mmol) and (R)-2-amino-3,3-dimethylbutane (16 mL of a 0.2M solution in absolute ethanol, 3.20 mmol) in dichloromethane (4 mL) was heated at 80° C. for 4 hours. The reaction mixture was cooled, concentrated under reduced pressure, and the resulting residue was trituated with hexane:ethyl acetate (1:1) to produce a solid, which was filtered and rinsed with hexane:ethyl acetate (1:1). Chromatography with 10% methanol in dichloromethane gave (R)-3-(2-hydroxy-6-methylphenylamino)-4-(2,2,1-trimethylpropyl-amino)-cyclobut-3-ene-1,2-dione, 0.24 g (0.79 mmol, 49%). The reaction mixture was cooled concentrated under reduced pressure to produce a solid, which was filtered rinsed with hexane:ethyl acetate (1:1)

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

Procedure: A mixture of 3-ethoxy-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.250 g, 0.00097 mol) and (R)-2,2,1-trimethylpropylamine (0.2M in ethanol, 9.7 ml, 0.0019 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The reaction is evaporated on a rotary evaporator. The residue is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether with several drops of ethyl acetate to give 3-[(R)-2,2,1-trimethylpropylamino]-4-(2-hydroxy-6-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.230 g (0.00073 mol, 76%) The reaction is evaporated on a rotary evaporator extracted well with 0.25N HCl The organic layer is washed once with distilled water dried (Na2SO4) evaporated to a solid The solid is collected washed with diethyl ether with several drops of ethyl acetate

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

Procedure: A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.395 g, 0.0015 mol) and (R)-2,2,1-trimethylpropylamine (0.2M in ethanol, 23 ml, 0.0046 mol) was stirred at room temperature for two days. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The ethanol is evaporated on a rotary evaporator. The reaction is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-[(R)-2,2,1-trimethylpropylamino]-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.345 g (0.00095 mol, 72%). The ethanol is evaporated on a rotary evaporator extracted well with 0.25N HCl The organic layer is washed once with distilled water dried (Na2SO4) evaporated to a solid The solid is collected washed with diethyl ether

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

Procedure: 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in (R)-1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) gave 131 mg (39%) of the title compound. Mp 164-165° C. 1H NMR (200 MHz, CDCl3): δ=0.9 (s, 9H), 1.0 (d, 3H), 3.0 (m, 1H), 7.37 (s, 2H), 7.50 (d, 2H), 7.68 (s, 1H), 7.80 (d, 2H); Analysis: calc. for C23H22ClF6N3O2S: C, 49.87%; H, 4.00%; N, 7.59%. Found: C, 49.95%; H, 4.15%; N, 7.48%.

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

Procedure: 3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in (R)-1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in Example 17, 2) gave 131 mg (39%) of the title compound. Mp 164-165° C. 1H NMR (200 MHz, CDCl3): δ=0.9 (s, 9H), 1.0 (d, 3H), 3.0 (m, 1H), 7.37 (s, 2H), 7.50 (d, 2H), 7.68 (s, 1H), 7.80 (d, 2H); Analysis: calc. for C23H22ClF6N3O2S: C, 49.87%; H, 4.00%; N, 7.59%. Found: C, 49.95%; H, 4.15%; N, 7.48%.

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

Procedure: 4-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-3-ethylbenzonitrile (1.26 g, 4.66 mmol) and a solution of (R)-1,2,2-trimethylpropylamine (9.3 mmol) in ethanol (58 mL) were stirred at room temperature for 24 hours. The resulting yellow solution was concentrated to a yellow oil, which was dissolved in acetonitrile (20 mL) and stirred at room temperature. The yellow solid which precipitated was filtered off and rinsed with ethyl acetate to yield 0.79 g (52%) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethylbenzonitrile as an off-white solid: mp 235°-237° C.; [α]D25 =+68.20° (DMSO, c 0.0072); 1H NMR (DMSO-d6): δ 8.04 (br s, 1H), 8.04 (d, 1H), 7.69-7.57 (m, 3H), 4.05 (m, 1H), 2.71 (q, 2H), 1.27-1.16 (overlapping doublet and triplet, 6H), 0.91 (s, 9H). IR (KBr): 3278, 2959, 2222, 1793, 1674, 1598, 1576, 1522 cm-1 ; MS (m/z) 325 (M+). The resulting yellow solution was concentrated to a yellow oil, which was dissolved in acetonitrile (20 mL) The yellow solid which precipitated was filtered off rinsed with ethyl acetate

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

Procedure: 4-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-3-ethylbenzonitrile (1.26 g, 4.66 mmol) and a solution of (R)-1,2,2-trimethylpropylamine (9.3 mmol) in ethanol (58 mL) were stirred at room temperature for 24 hours. The resulting yellow solution was concentrated to a yellow oil, which was dissolved in acetonitrile (20 mL) and stirred at room temperature. The yellow solid which precipitated was filtered off and rinsed with ethyl acetate to yield 0.79 g (52%) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethylbenzonitrile as an off-white solid: mp 235°-237° C.; [α]D25 =+68.20° (DMSO, c 0.0072); 1H NMR (DMSO-d6): δ 8.04 (br s, 1H), 8.04 (d, 1H), 7.69-7.57 (m, 3H), 4.05 (m, 1H), 2.71 (q, 2H), 1.27-1.16 (overlapping doublet and triplet, 6H), 0.91 (s, 9H). IR (KBr): 3278, 2959, 2222, 1793, 1674, 1598, 1576, 1522 cm-1 ; MS (m/z) 325 (M+). The resulting yellow solution was concentrated to a yellow oil, which was dissolved in acetonitrile (20 mL) The yellow solid which precipitated was filtered off rinsed with ethyl acetate

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

Procedure: 4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and a solution of (R)-1,2,2-trimethylpropylamine (8.2 mmol) in ethanol (50 mL) were stirred at room temperature for 24 hours. The resulting yellow slurry was filtered and rinsed with ethyl acetate to yield 0.92 g (75%) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-benzonitrile as a yellow solid: spectral data was identical to the product of Example 1, paragraph 2, except with [α]D25 =+12° (DMSO, c 0.009). The resulting yellow slurry was filtered rinsed with ethyl acetate

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

Procedure: 4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and a solution of (R)-1,2,2-trimethylpropylamine (8.2 mmol) in ethanol (50 mL) were stirred at room temperature for 24 hours. The resulting yellow slurry was filtered and rinsed with ethyl acetate to yield 0.92 g (75%) of (+)-(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-benzonitrile as a yellow solid: spectral data was identical to the product of Example 1, paragraph 2, except with [α]D25 =+12° (DMSO, c 0.009). The resulting yellow slurry was filtered rinsed with ethyl acetate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2-(R)-amino-3,3-dimethylbutane (20 mL, 0.148 mol), potassium carbonate (14.3 g, 0.104 mol) and water (50 mL) to a solution of 4-chloro-2-fluoronitrobenzene (13.3 g, 0.076 mol) in THF (450 mL) and stir at 75° C. for 3 h Cool to ambient temperature. Concentrate to ½ volume, dilute with ethyl acetate and wash with 1N HCl (4×100 mL), water, saturated sodium bicarbonate, saturated sodium chloride, dry with magnesium sulfate and concentrate to give the title compound as an orange solid (19.6 g, quant). Cool to ambient temperature Concentrate dilute with ethyl acetate wash with 1N HCl (4×100 mL), water, saturated sodium bicarbonate, saturated sodium chloride dry with magnesium sulfate concentrate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2-(R)-amino-3,3-dimethylbutane (20 mL, 0.148 mol), potassium carbonate (14.3 g, 0.104 mol) and water (50 mL) to a solution of 4-chloro-2-fluoronitrobenzene (13.3 g, 0.076 mol) in THF (450 mL) and stir at 75° C. for 3 h Cool to ambient temperature. Concentrate to ½ volume, dilute with ethyl acetate and wash with 1N HCl (4×100 mL), water, saturated sodium bicarbonate, saturated sodium chloride, dry with magnesium sulfate and concentrate to give the title compound as an orange solid (19.6 g, quant). Cool to ambient temperature Concentrate dilute with ethyl acetate wash with 1N HCl (4×100 mL), water, saturated sodium bicarbonate, saturated sodium chloride dry with magnesium sulfate concentrate

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

Procedure: A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (10 g, 59 mmol) and (R)-2-amino-3,3-dimethylbutane (353 mL of a 0.2M solution in absolute ethanol, 71 mmol) was stirred at room temperature for 24 hours. Another portion of (R)-2-amino-3,3-dimethylbutane (150 mL of a 0.2M solution in absolute ethanol, 30 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The slurry was filtered, and the filtrate concentrated under reduced pressure. The resulting solid was trituated with hexane:ethyl acetate (150:5 mL), then washed with hexane to give 9.78 g (74%) of (R)-3-ethoxy-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione as a white solid: 1H NMR: (DMSO-d6): δ 8.72 and 8.50 (two d, 1H, rotamers), 4.65 (m, 2H), 3.90 and 3.42 (two m, 1H, rotamers), 1.37 and 1.35 (two overlapping t, 3H, rotamers), 1.10 (two overlapping d, 3H, rotamers), 0.85 and 0.84 (two s, 9H, rotamers) ppm. IR (KBr): 3150, 2950, 1800, 1700 cm-1 ; MS (m/z): 225 (M+). The slurry was filtered the filtrate concentrated under reduced pressure ethyl acetate (150:5 mL), then washed with hexane